WO2016071770A2

WO2016071770A2 - Biological markers for identifying ibrutinib resistance in patients having mantle cell lymphoma and methods of using the same

Info

Publication number: WO2016071770A2
Application number: PCT/IB2015/002303
Authority: WO
Inventors: Sriram Balasubramanian; Michael Schaffer; Aleksandra RIZO
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2014-11-05
Filing date: 2015-11-05
Publication date: 2016-05-12
Also published as: WO2016071770A3

Abstract

Disclosed herein are methods of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma and methods of treating a patient having mantle cell lymphoma.

Description

BIOLOGICAL MARKERS FOR IDENTIFYING IBRUTINIB RESISTANCE IN PATIENTS HAVING MANTLE CELL LYMPHOMA AND METHODS OF USING THE SAME

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/075,544, filed November 5, 2014, the disclosure of which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The disclosure relates to biological markers for identifying primary and acquired ibrutinib resistance in patients having mantle cell lymphoma and methods of using the same. In particular, the disclosed methods relate to predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma, and methods of treating a patient having mantle cell lymphoma.

BACKGROUND

[0003] Mantle cell lymphoma (MCL) is a rare and incurable subtype of non-Hodgkin Lymphoma (NHL). It accounts for about 6% of all NHL cases in the Western world. At the molecular level, MCL is uniquely characterized by overexpression of the cell cycle regulator protein cyclin Dl . In association with overexpression of cyclin Dl, other markers such as CD20 and CD5 are also evident in MCL.

[0004] Ibrutinib, a first- in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase, is highly effective in relapsed or refractory mantle cell lymphoma (MCL) patients with an overall response rate (ORR) of 68% (Wang M, et al. N Engl J Med. 2013 369:507-516). Similar efficacy results were observed in a recent phase 2 study in MCL patients who progressed after rituximab containing chemotherapy and bortezomib therapy (SPARK study,

NCT01599949). Despite the promising efficacy data, however, some patients with MCL do not respond to ibrutinib. Thus, although advances in the treatment of MCL have been made, it remains a serious and fatal malignancy for which there is an unmet medical need, particularly for those patients who relapse or become refractory to treatment.

SUMMARY

[0005] Disclosed herein are methods of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma. In some embodiments, the methods can comprise assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are: a) PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF1 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAF l, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCHl, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof; b) ERBB2, MLL2, CARDl 1, JAK3, PLCG2, ITK, NOTCHl, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB 3, AKT1, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSF 11A, TNFRSF13C, TRAF3, KMT2D, MALT1, MYD88, PRDM1, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, IKBKB, JAK2, TAB2, TNFSF 13B, TRAF2, or any combination thereof; or c) any combination of the one or more genes from groups a) and b), wherein the assaying comprises enriching the DNA for the one or more genes and sequencing the DNA, and wherein the patient has a likelihood of responsiveness to treatment with ibrutinib if a mutation in the one or more genes is not detected.

[0006] In some aspects of the disclosed methods of predicting a likelihood of responsiveness to treatment with ibrutinib, the one or more genes can be PIM1 kinase signaling regulators, NF-κΒ signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, PRKCB, or any combination thereof.

[0007] Also disclosed are methods of treating a patient having mantle cell lymphoma comprising administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in one or more genes selected from PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF 11A, NFKBIA, REL, CD79A, MYD88, PLCG2,

CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCHl, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, ERBB2, CARDl 1, BCL6, STAT6, MTTP, RET, TAB3, ATM, BIRC3, STAT3, TEC, TNFRSF 13C, KMT2D, MALT1, PRDM1, TRAF4, RET, EZH2, IKBKB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof.

[0008] In some embodiments of the disclosed methods of treating a patient having mantle cell lymphoma, the one or more genes can be PIM1 kinase signaling regulators, NF-KB signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, PRKCB, or any combination thereof.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0009] It is to be understood that the disclosed methods are not limited to the specific methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.

[0010] It is to be appreciated that certain features of the disclosed methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0011] As used herein, the singular forms "a," "an," and "the" include the plural.

[0012] The following abbreviations are used throughout the specification: MCL (mantle cell lymphoma); PD (progressive disease); TAB2 (TGF-Beta Activated Kinase

1/MAP3K7 Binding Protein 2); WHSCl (Wolf-Hirschhorn Syndrome Candidate 1); MAP3K14 (Mitogen- Activated Protein Kinase Kinase Kinase 14); TRAF3 (TNF Receptor-Associated Factor 3); TNFRSF1 1A (Tumor Necrosis Factor Receptor Superfamily, Member 1 la); MYD88 (Myeloid Differentiation Primary Response 88); NFKBIA (Nuclear Factor Of Kappa Light Polypeptide Gene Enhancer In B-Cells Inhibitor, Alpha); PRKCB (protein kinase C, beta); CREBBP (cAMP -response element binding protein (CREB) binding protein); MLL2 (also known as Lysine (K)-Specific Methyltransferase 2D (KMT2D)); ITK (IL2 -Inducible T-Cell Kinase); MYC (V-Myc Avian Myelocytomatosis Viral Oncogene Homolog); PLCG2

(Phospholipase C, Gamma 2 (Phosphatidylinositol-Specific)); MTOR (Mechanistic Target Of Rapamycin (Serine/Threonine Kinase)); ERBB4 (V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 4); REL (V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog).

[0013] As used herein, "treating" and like terms refer to reducing the severity and/or frequency of MCL symptoms, eliminating MCL symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of MCL symptoms and/or their underlying cause, and improving or remediating damage caused, directly or indirectly, by MCL. [0014] The term "patient" as used herein is intended to mean any animal, in particular, mammals. Thus, the methods are applicable to human and nonhuman animals, although preferably used with mice and humans, and most preferably with humans.

[0015] As used herein, "ibrutinib" (also known as PCI-32765) refers to l-[(3R)-3-[4- amino-3-(4-phenoxyphenyl)-lH-pyrazolo [3, 4 d] pyrimidin-l-yl]-l-piperidinyl]-2-propen-l- one, having a molecular weight of 440.50 g/mole (anhydrous basis), a single chiral center, and being an R-enantiomer.

[0016] As used herein, "refractory mantle cell lymphoma" refers to MCL that is present after treatment.

[0017] As used herein, "relapsed mantle cell lymphoma" refers to MCL that has returned after treatment.

Biological markers for identifying ibrutinib resistance in patients having mantle cell lymphoma

[0018] Disclosed herein are biological markers for identifying ibrutinib resistance in patients having mantle cell lymphoma (MCL). Exemplary biological markers are listed in Table 27 as well as throughout the EXAMPLE section herein. The disclosed biological markers can be used for identifying primary (PR) and/or acquired (AR) ibrutinib resistance.

[0019] Biological markers for identifying ibrutinib resistance in patients having MCL include mutations in one or more genes, wherein the one or more genes are selected from PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF l 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPKl, TRAF5, TRAF6, UGTlAl, NOTCHl, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof; b) ERBB2, MLL2, CARD1 1, JAK3, PLCG2, ITK, NOTCHl, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB3, AKT1, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK,

MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSFl 1A, TNFRSFl 3 C, TRAF3, KMT2D, MALT1, MYD88, PRDM1, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, 1KB KB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof.

[0020] In some embodiments, the biological markers for identifying ibrutinib resistance in patients having MCL include mutations in one or more genes that are indicative of primary ibrutinib resistance. For example, suitable biological markers that are indicative of primary ibrutinib resistance are provided in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in PIM1 kinase, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MTOR, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TAB2, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MAP3K14, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF3, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TNFRSF1 1A, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NFKBIA, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in REL, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CD79A, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MYD88, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in PLCG2, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CREBBP, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MLL2, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in WHSC1, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BCL2, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ERBB4, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MYC, as exemplified in Table 3. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ITK, as exemplified in Table 3.

[0021] Further suitable biological markers that are indicative of primary ibrutinib resistance are provided in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in EGFR, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in WHSC1, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in JAK3, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF3, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in EP300, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BIRC2, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in

TNFRSF1 1A, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TP53, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF1, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in PLCG2, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BLK, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in GRB2, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MAP3K7, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MAPK3, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in RIPK1, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF5, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF6, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in UGT1A1, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NOTCH 1, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in AKT1, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in PRKCB, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BMX, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CD79A, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CHEK2, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NFKBIB, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TAB2, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in VEGFA, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CD40, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NFKB2, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NFKBIA, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NR2C2, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in RELB, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CCND3, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CSK, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MCL1, as exemplified in Table 6. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ERBB2, as exemplified in Table 6.

[0022] Further suitable biological markers that are indicative of primary ibrutinib resistance are provided in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in EGFR, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in WHSC1, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in RELB, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CCND3, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CD40, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CHEK2, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MAP3K7, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TNFAIP3, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF1, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NFKBIA, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CDKN2A, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in EZH2, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in LCK, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CREBBP, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in PLCG2, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BLK, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CYLD, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MYD88, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in STAT6, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BIRC2, as exemplified in Table 21. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MET, as exemplified in Table 21. [0023] In some embodiments, the biological markers for identifying ibrutinib resistance in patients having MCL include mutations in one or more genes that are indicative of acquired ibrutinib resistance. Suitable biological markers that are indicative of acquired ibrutinib resistance are provided in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ERBB2, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MLL2, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CARD 11, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in JAK3, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in PLCG2, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ITK, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NOTCH 1, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TP53, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BCL6, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CREBBP, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MAP3K14, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MET, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in RELB, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in STAT6, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BIRC2, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CCND3, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CD79A, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in EGFR, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in EP300, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MTTP, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NFKBIA, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in RET, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TAB3, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in AKTl, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ATM, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BIRC3, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CD40, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CDKN2A, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CYLD, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in LCK, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MAP3K7, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MAPK3, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MTOR, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MYC, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NR2C2, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in STAT3, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TEC, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TNFRSF1 1A, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TNFRSF 13C, as exemplified in Table 13. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF3, as exemplified in Table 13.

[0024] Further suitable biological markers that are indicative of acquired ibrutinib resistance are provided in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in KMT2D, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ATM, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CREBBP, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MYC, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in PLCG2, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in CARD 1 1, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in EP300, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ERBB2, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ITK, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in LCK, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MALT1, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MYD88, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in PRDMl, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in RELB, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TP53, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF4, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MTOR, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in MTTP, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in RET, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in STAT3, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in STAT6, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in AKT1, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in BIRC2, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in ERBB4, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in EZH2, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in 1KB KB, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in JAK2, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in NOTCH 1, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TAB2, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TNFSF13B, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF2, as exemplified in Table 23. In some aspects, the biological marker for identifying ibrutinib resistance in patients having MCL can include mutations in TRAF3, as exemplified in Table 23. [0025] In some embodiments, the biological markers for identifying ibrutinib resistance in patients having MCL can include mutations in any combination of the above disclosed one or more genes that are indicative of primary ibrutinib resistance and acquired resistance.

[0026] In some aspects, the one or more genes can be PIM1 kinase signaling regulators, NF-KB signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, PRKCB, or any combination thereof. Exemplary PIM1 kinase signaling regulators include, but are not limited to, PIM1 kinase, MTOR, or both.

Exemplary NF-κΒ signaling regulators include, but are not limited to, TAB2, MAP3K14, TRAF3, TNFRSF11A, NFKBIA, REL, or any combination thereof. Exemplary BCR signaling regulators include, but are not limited to, CD79A, MYD88, PLCG2, or any combination thereof. Exemplary epigenetic modulators include, but are not limited to, CREBBP, MLL2, WHSC1, or any combination thereof. Exemplary oncogenes include, but are not limited to, BCL2, ERBB4, MYC, or any combination thereof. Exemplary TEC kinase signaling regulators include ITK. Alternatively, the one or more genes can be a combination of PIM1 kinase signaling regulators, NF-KB signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, and/or PRKCB. "A combination of PIM1 kinase signaling regulators, NF-κΒ signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, and/or PRKCB," is intended to mean that either: 1) the one or more genes are involved in more than one pathway/have more than one function (such as, for example, being an NF-κΒ signaling regulator and BCR signaling regulator); or 2) that a subset of the one or more genes are PIM1 kinase signaling regulators, a subset of the one or more genes are NF-κΒ signaling regulators, a subset of the one or more genes are BCR signaling regulators, a subset of the one or more genes are epigenetic modulators, a subset of the one or more genes are oncogenes, a subset of the one or more genes are TEC kinase signaling regulators, a subset of the one or more genes are CCND3, and/or a subset of the one or more genes are PRKCB.

Methods of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma

[0027] Disclosed herein are methods of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma. In some embodiments, the methods can comprise assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are: a) PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF11A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCLl, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof;

b) ERBB2, MLL2, CARD 1 1, JAK3, PLCG2, ITK, NOTCH 1, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB3, AKT1, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSF1 1A, TNFRSF 13C, TRAF3, KMT2D, MALT1, MYD88, PRDM1, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, IKBKB, JAK2, TAB2, TNFSF 13B, TRAF2, , or any combination thereof; or

c) any combination of the one or more genes from groups a) and b);

wherein the assaying comprises enriching the DNA for the one or more genes and sequencing the DNA, and wherein the patient has a likelihood of responsiveness to treatment with ibrutinib if a mutation in the one or more genes is not detected.

[0028] The disclosed methods can be used to identify primary and/or acquired ibrutinib resistance. To identify patients having primary ibrutinib resistance, the methods can be performed prior to initiation of ibrutinib therapy, following initiation of ibrutinib therapy, or both. For example, the assessing can be performed on the one or more genes from group a) prior to initiation of ibrutinib therapy, following initiation of ibrutinib therapy, or both. Thus, in some embodiments, the methods of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma can comprise, prior to initiation of ibrutinib therapy, assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3,

TNFRSF1 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAF l, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCLl, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof, wherein the assaying comprises enriching the DNA for the one or more genes and sequencing the DNA, and wherein the patient has a likelihood of responsiveness to treatment with ibrutinib if a mutation in the one or more genes is not detected. In some embodiments, the methods of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma can comprise, following initiation of ibrutinib therapy, assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF 11A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPKl, TRAF5, TRAF6, UGTlAl, NOTCHl, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof, wherein the assaying comprises enriching the DNA for the one or more genes and sequencing the DNA, and wherein the patient has a likelihood of responsiveness to treatment with ibrutinib if a mutation in the one or more genes is not detected. In yet other embodiments, the methods of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma can comprise, prior to initiation of ibrutinib therapy and following initiation of ibrutinib therapy, assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF 11A, NFKBIA, REL, CD79A, MYD88, PLCG2,

CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPKl, TRAF5, TRAF6, UGTlAl, NOTCHl, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof, wherein the assaying comprises enriching the DNA for the one or more genes and sequencing the DNA, and wherein the patient has a likelihood of responsiveness to treatment with ibrutinib if a mutation in the one or more genes is not detected.

[0029] For patients having acquired ibrutinib resistance, the disclosed methods can be performed following initiation of ibrutinib therapy. For example, the assessing can be performed on the one or more genes from group b) following initiation of ibrutinib therapy. Thus, in some embodiments, the methods of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma can comprise, following initiation of ibrutinib therapy, assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are ERBB2, MLL2, CARD 1 1, JAK3, PLCG2, ITK, NOTCHl, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB3, AKT1, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSFl 1A, TNFRSFl 3 C, TRAF3, KMT2D, MALT1, MYD88, PRDM1, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, 1KB KB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof, wherein the assaying comprises enriching the DNA for the one or more genes and sequencing the DNA, wherein the patient has a likelihood of responsiveness to continued treatment with ibrutinib if a mutation in the one or more genes is not detected.

[0030] The disclosed methods can also be performed to evaluate both primary and acquired ibrutinib resistance in a patient. For example, prior to or following initiation of ibrutinib therapy, a DNA sample from the patient can be assayed to detect a mutation in one or more genes indicative of primary resistance and following initiation of ibrutinib therapy, a DNA sample from the patient can be assayed to detect a mutation in one or more genes indicative of acquired resistance. Thus, the disclosed methods can be performed prior to initiation of ibrutinib therapy and following initiation of ibrutinib therapy. For example, the assessing can be performed on the one or more genes from group c) prior to initiation of ibrutinib therapy and following initiation of ibrutinib therapy. Thus, in some embodiments, the methods of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma can comprise, prior to initiation of ibrutinib therapy and following initiation of ibrutinib therapy, assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSFl 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAF l, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, ERBB2, CARDl l, BCL6, STAT6, MTTP, RET, TAB 3, ATM, BIRC3, STAT3, TEC, TNFRSFl 3 C, KMT2D, MALT1, PRDM1, TRAF4, RET, EZH2, IKBKB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof, wherein the assaying comprises enriching the DNA for the one or more genes and sequencing the DNA, and wherein the patient has a likelihood of responsiveness to treatment, responsiveness to continued treatment, or both, with ibrutinib if a mutation in the one or more genes is not detected.

[0031] The disclosed methods can further comprise treating the patient with ibrutinib if a mutation in the one or more genes is not detected. In the case of patients having, or suspected of having, primary ibrutinib resistance, the treating step can be performed before assaying a DNA sample (in cases where, due to timing concerns, it is recommended to get the patient on treatment before the samples can be analyzed) or following the assaying. Accordingly, in some embodiments, the methods can comprise assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are PIMl kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF1 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAF1, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH 1, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCLl, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof;

wherein the assaying comprises enriching the DNA for the one or more genes and sequencing the DNA,

wherein the patient has a likelihood of responsiveness to treatment with ibrutinib if a mutation in the one or more genes is not detected, and

treating the patient with ibrutinib if a mutation in the one or more genes is not detected.

[0032] In other embodiments, the methods can comprise:

treating the patient with ibrutinib;

assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are PIMl kinase, MTOR, TAB2, MAP3K14, TRAF3,

TNFRSF1 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAF l, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCLl, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof;

continuing to treat the patient with ibrutinib if a mutation in the one or more genes is not detected.

[0033] In the case of patients having, or suspected of having, acquired ibrutinib resistance, the treating step is preferably performed following the assaying. Accordingly, in some embodiments, the methods can comprise assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are ERBB2, MLL2, CARDl 1, JAK3, PLCG2, ITK, NOTCH1, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB3, AKTl, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSFl 1A, TNFRSFl 3 C, TRAF3, KMT2D, MALTl, MYD88, PRDMl, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, IKBKB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof

[0034] In the case of patients having, or suspected of having, both primary and acquired ibrutinib resistance, the treating step can be performed before assaying a DNA sample and following assaying a DNA sample. Accordingly, in some embodiments, the methods can comprise:

treating the patient with ibrutinib;

assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are:

a) PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSFl 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKTl, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof;

b) ERBB2, MLL2, CARDl 1, JAK3, PLCG2, ITK, NOTCH 1, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB3, AKTl, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSFl 1A, TNFRSFl 3 C, TRAF3, KMT2D, MALTl, MYD88, PRDMl, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, IKBKB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof; or c) any combination of the one or more genes from groups a) and b);

[0035] The disclosed methods are equally applicable to patients having newly diagnosed mantle cell lymphoma, relapsed mantle cell lymphoma, or refractory mantle cell lymphoma. In some embodiments, the methods can be used to predict a likelihood of responsiveness to treatment with ibrutinib in a patient having newly diagnosed mantle cell lymphoma. In some embodiments, the methods can be used to predict a likelihood of responsiveness to treatment with ibrutinib in a patient having relapsed mantle cell lymphoma. In other embodiments, the methods can be used to predict a likelihood of responsiveness to treatment with ibrutinib in a patient having refractory mantle cell lymphoma. In yet other embodiments, the methods can be used to predict a likelihood of responsiveness to treatment with ibrutinib in a patient having both relapsed mantle cell lymphoma and refractory mantle cell lymphoma.

[0036] The DNA sample from the patient can be obtained from any source that contains MCL cells, including, but not limited to, blood, bone marrow, lymph fluid, tumor, or any combination thereof. In some embodiments, the DNA sample can be from a tumor biopsy. In other embodiments, the DNA sample can be CD 19-enriched cells from peripheral blood mononucleated cells (PBMCs).

[0037] The DNA sample can be from any suitable stage in the treatment regimen. In some embodiments, for example, the DNA sample can be a pretreatment sample. In some aspects, the pretreatment sample can be a pretreatment tumor sample. In other aspects, the pretreatment sample can be a pretreatment blood sample. In other embodiments, the DNA sample can be a sample obtained after initiation of treatment. In some aspects, for example, the DNA sample can be a tumor sample obtained after initiation of treatment. In other aspects, the DNA sample can be a blood sample obtained after initiation of treatment.

[0038] Any of the biological markers disclosed herein for identifying ibrutinib resistance in patients having MCL can be used in the disclosed methods. For example, suitable biological markers that are indicative of primary ibrutinib resistance are provided in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PIM1 kinase, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MTOR, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TAB2, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K14, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF3, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TNFRSF1 1A, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIA, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in REL, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD79A, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYD88, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CREBBP, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MLL2, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in WHSC1, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BCL2, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB4, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYC, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ITK, as exemplified in Table 3.

[0039] Further suitable biological markers that are indicative of primary ibrutinib resistance are provided in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EGFR, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in WHSC1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in JAK3, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF3, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EP300, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TNFRSF 11A, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TP53, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAFl, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BLK, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in GRB2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K7, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAPK3, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RIPKl, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF5, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF6, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in UGT1A1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in

NOTCH 1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in AKT1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PRKCB, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BMX, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD79A, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CHEK2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIB, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TAB2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in VEGFA, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD40, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKB2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIA, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NR2C2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RELB, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CCND3, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CSK, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MCL1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB2, as exemplified in Table 6.

[0040] Further suitable biological markers that are indicative of primary ibrutinib resistance are provided in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EGFR, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in WHSC1, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RELB, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CCND3, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD40, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CHEK2, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K7, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TNFAIP3, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAFl, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIA, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CDKN2A, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EZH2, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in LCK, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CREBBP, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BLK, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CYLD, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYD88, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in STAT6, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC2, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MET, as exemplified in Table 21.

[0041] Suitable biological markers that are indicative of acquired ibrutinib resistance are provided in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB2, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MLL2, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CARD11, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in JAK3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ITK, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NOTCH 1, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TP53, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BCL6, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CREBBP, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K14, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MET, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RELB, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in STAT6, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC2, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CCND3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD79A, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EGFR, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EP300, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MTTP, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIA, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RET, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TAB3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in AKT1, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ATM, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD40, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in

CDKN2A, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CYLD, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in LCK, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K7, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAPK3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MTOR, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYC, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NR2C2, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in STAT3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TEC, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TNFRSF 11A, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TNFRSF13C, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF3, as exemplified in Table 13.

[0042] Further suitable biological markers that are indicative of acquired ibrutinib resistance are provided in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in KMT2D, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ATM, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CREBBP, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYC, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CARD 1 1, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EP300, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ITK, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in LCK, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MALT1, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYD88, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PRDMl, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RELB, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TP53, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF4, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MTOR, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MTTP, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RET, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in STAT3, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in STAT6, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in AKT1, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB4, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EZH2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in IKBKB, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in JAK2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NOTCH 1, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TAB2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TNFSF 13B, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF3, as exemplified in Table 23. [0043] In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in any combination of the above listed biological markers.

[0044] The disclosed methods can comprise assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are PIM1 kinase signaling regulators, NF-κΒ signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, PRKCB, or any combination thereof, wherein the assaying comprises enriching the DNA for the one or more genes and sequencing the DNA, wherein the patient has a likelihood of responsiveness to treatment with ibrutinib if a mutation in the one or more genes is not detected.

[0045] Suitable PIM1 kinase signaling regulators include, but are not limited to, PIM1 kinase, MTOR, or both. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in PIM1 kinase, as exemplified in Table 3. In other aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in MTOR, as exemplified in Table 3. In yet other aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in PIM1 kinase and MTOR, as exemplified in Table 3.

[0046] Suitable NF-κΒ signaling regulators include, but are not limited to, TAB2, MAP3K14, TRAF3, TNFRSFl 1 A, NFKBIA, REL, or any combination thereof. Thus, in some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in TAB2, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K14, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in TRAF3, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in TNFRSF l 1 A, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIA, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in REL, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in any combination of the above listed genes, as exemplified in Table 3.

[0047] Suitable BCR signaling regulators include, but are not limited to, CD79A, MYD88, PLCG2, or any combination thereof. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in CD79A, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in MYD88, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in any combination of the above listed genes, as exemplified in Table 3.

[0048] Suitable epigenetic modulators include, but are not limited to, CREBBP, MLL2, WHSC1, or any combination thereof. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in CREBBP, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in MLL2, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in WHSC1, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in any combination of the above listed genes, as exemplified in Table 3.

[0049] Suitable oncogenes include, but are not limited to, BCL2, ERBB4, MYC, or any combination thereof. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in BCL2, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in ERBB4, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in MYC, as exemplified in Table 3. In some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in any combination of the above listed genes, as exemplified in Table 3.

[0050] Suitable TEC kinase signaling regulators include ITK. Thus, in some aspects, the method can comprise assaying a DNA sample from the patient to detect a mutation in ITK, as exemplified in Table 3.

[0051] In some embodiments, the method can comprise assaying a DNA sample from the patient to detect a mutation in CCND3, as exemplified in Table 3. In other embodiments, the method can comprise assaying a DNA sample from the patient to detect a mutation in PRKCB, as exemplified in Table 3.

[0052] Alternatively, the one or more genes can be a combination of PIM1 kinase signaling regulators, NF-κΒ signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, and/or PRKCB. "A combination of PIM1 kinase signaling regulators, NF-κΒ signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, and/or PRKCB," is intended to mean that either: 1) the one or more genes are involved in more than one pathway/have more than one function (such as, for example, being an NF-κΒ signaling regulator and BCR signaling regulator); or 2) that a subset of the one or more genes are PIM1 kinase signaling regulators, a subset of the one or more genes are NF-κΒ signaling regulators, a subset of the one or more genes are BCR signaling regulators, a subset of the one or more genes are epigenetic modulators, a subset of the one or more genes are oncogenes, a subset of the one or more genes are TEC kinase signaling regulators, a subset of the one or more genes are CCND3, and/or a subset of the one or more genes are PRKCB.

[0053] Numerous techniques are known in the art for assaying mutations in genes. In some embodiments, for example, the assaying step can comprise enriching the DNA for the one or more genes and sequencing the DNA. Enriching the DNA for the one or more genes can be performed, for example, using the Ovation® Target Enrichment system (NuGEN). Sequencing of the DNA can be performed, for example, by deep sequencing using an Illumina® HiSeq instrument.

[0054] In some embodiments, the patient has progressed after bortezomib therapy. Thus, the methods of predicting a likelihood of responsiveness to treatment with ibrutinib can be performed on a patient having mantle cell lymphoma, wherein the patient is currently receiving, or has in the past received, bortezomib therapy but has progressed while on, or after receiving, bortezomib therapy. In some embodiments, the patient can be resistant to bortezomib.

[0055] In some aspects, the patient has received at least one prior rituximab- chemotherapy regimen.

Methods of treating a patient having mantle cell lymphoma

[0056] Also disclosed herein are methods of treating a patient having mantle cell lymphoma. In some embodiments, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in one or more genes selected from PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF11A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAF 1, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH 1, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, ERBB2, CARD 11, BCL6, STAT6, MTTP, RET, TAB 3, ATM, BIRC3, STAT3, TEC, TNFRSF13C, KMT2D, MALTl, PRDMl, TRAF4, RET, EZH2, IKBKB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof. [0057] The disclosed treatment methods can be used to treat patients having primary and/or acquired ibrutinib resistance, and thus can be performed prior to initiation of ibrutinib therapy, following initiation of single agent ibrutinib therapy, or both. In some embodiments, the disclosed methods can be performed prior to initiation of ibrutinib therapy. In other

embodiments, the disclosed methods can be performed following initiation of ibrutinib therapy. Thus, for example, following initiation of ibrutinib therapy, the disclosed methods can be performed, and if a mutation in the one or more genes is not detected, ibrutinib therapy can be continued. In yet other embodiments, the disclosed methods can be performed prior to initiation of ibrutinib therapy and following initiation of single agent ibrutinib therapy.

[0058] For example, the methods of treating a patient having mantle cell lymphoma can be performed on a patient that does not have a mutation in one or more genes indicative of primary ibrutinib resistance. Thus, in some embodiments, the methods can comprise

administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in one or more genes selected from PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF1 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAF1, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCHl, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof.

[0059] The methods of treating a patient having mantle cell lymphoma can be performed on a patient that does not have a mutation in one or more genes indicative of acquired ibrutinib resistance. Thus, in some embodiments, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in one or more genes selected from ERBB2, MLL2, CARD 1 1, JAK3, PLCG2, ITK, NOTCHl, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB3, AKT1, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSF1 1A, TNFRSF13C, TRAF3, KMT2D, MALT1, MYD88, PRDM1, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, IKBKB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof.

[0060] Mutations in the one or more genes indicative of primary ibrutinib resistance are exemplified in Table 3, Table 6, and Table 21. Mutations in the one or more genes indicative of acquired ibrutinib resistance are exemplified in Table 13 and 23. Thus, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in one or more genes as disclosed in Tables 3, 6„21, 13, and 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PIM1 kinase, as exemplified in Table 3. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MTOR, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TAB2, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MAP3K14, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF3, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TNFRSF1 1A, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NFKBIA, as exemplified in Table 3. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in REL, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CD79A, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MYD88, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PLCG2, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CREBBP, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MLL2, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in WHSC1, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BCL2, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ERBB4, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MYC, as exemplified in Table 3. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ITK, as exemplified in Table 3.

[0061] In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in EGFR, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in WHSC1, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in JAK3, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF3, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in EP300, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BIRC2, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TNFRSF1 1A, as exemplified in Table 6. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TP53, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAFl, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PLCG2, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BLK, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in GRB2, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MAP3K7, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in

MAPK3, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in RIPK1, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF5, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF6, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in UGT1A1, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NOTCH 1, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in AKT1, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PRKCB, as exemplified in Table 6. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BMX, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CD79A, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CHEK2, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NFKBIB, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TAB2, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in VEGFA, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CD40, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NFKB2, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NFKBIA, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NR2C2, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in RELB, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CCND3, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CSK, as exemplified in Table 6. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MCL1, as exemplified in Table 6. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ERBB2, as exemplified in Table 6.

[0062] In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in EGFR, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in WHSC1, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in RELB, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CCND3, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CD40, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CHEK2, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MAP3K7, as exemplified in Table 21. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TNFAIP3, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF 1 , as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NFKBIA, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CDKN2A, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in EZH2, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in LCK, as exemplified in Table 21. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CREBBP, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PLCG2, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BLK, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CYLD, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MYD88, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in STAT6, as exemplified in Table 21. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BIRC2, as exemplified in Table 21. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MET, as exemplified in Table 21. [0063] In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ERBB2, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MLL2, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CARD11, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in JAK3, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PLCG2, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ITK, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NOTCH 1, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TP53, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BCL6, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CREBBP, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MAP3K14, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MET, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in RELB, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in STAT6, as exemplified in Table 13. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BIRC2, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CCND3, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CD79A, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in EGFR, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in EP300, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MTTP, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NFKBIA, as exemplified in Table 13. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in RET, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TAB3, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in AKT1, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ATM, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BIRC3, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CD40, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in

CDKN2A, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CYLD, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in LCK, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MAP3K7, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MAPK3, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MTOR, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MYC, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NR2C2, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in STAT3, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TEC, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TNFRSF1 1A, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TNFRSF13C, as exemplified in Table 13. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF3, as exemplified in Table 13.

[0064] In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in

KMT2D, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ATM, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CREBBP, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MYC, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PLCG2, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CARD 1 1, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in EP300, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ERBB2, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ITK, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in LCK, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MALT1, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MYD88, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PRDM1, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in RELB, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TP53, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF4, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MTOR, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MTTP, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in RET, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in STAT3, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in STAT6, as exemplified in Table 23. In some aspects, the methods can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in AKT1, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BIRC2, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ERBB4, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in EZH2, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in 1KB KB, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in JAK2, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in

NOTCH 1, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TAB2, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TNFSF13B, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF2, as exemplified in Table 23. In some aspects, the methods can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF3, as exemplified in Table 23.

[0065] The methods of treating a patient having mantle cell lymphoma can further comprise assaying a DNA sample from the patient to detect a mutation in any combination of the above listed biological markers. For example, the assaying can be performed to detect patients having primary ibrutinib resistance, acquired ibrutinib resistance, or both. The assessing can be performed prior to the administering, following the administering, or both. In some

embodiments, the methods can comprise assaying a DNA sample from the patient to detect a mutation in one or more genes, wherein the one or more genes are: a) PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF1 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof;

b) ERBB2, MLL2, CARD 1 1, JAK3, PLCG2, ITK, NOTCH 1, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB3, AKT1, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSF11A, TNFRSF 13C, TRAF3, KMT2D, MALT1, MYD88, PRDM1, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, IKBKB, JAK2, TAB2, TNFSF 13B, TRAF2, or any combination thereof; or

c) any combination of the one or more genes from groups a) and b);

and administering a pharmaceutically effective dose of ibrutinib if the patient does not have a mutation in the one or more genes.

[0066] In some embodiments, the methods can comprise:

administering a pharmaceutically effective dose of ibrutinib to the patient;

a) PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF11A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof;

b) ERBB2, MLL2, CARD 1 1, JAK3, PLCG2, ITK, NOTCH 1, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB 3, AKT1, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSF11A, TNFRSF 13C, TRAF3, KMT2D, MALT1, MYD88, PRDM1, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, IKBKB, JAK2, TAB2, TNFSF 13B, TRAF2, , or any combination thereof; or

c) any combination of the one or more genes from groups a) and b);

and continuing to treat the patient with ibrutinib if a mutation in the one or more genes is not detected.

[0067] As disclosed elsewhere herein, mutations in the one or more genes indicative of primary ibrutinib resistance are exemplified in Table 3, Table 6, and Table 21 and mutations in the one or more genes indicative of acquired ibrutinib resistance are exemplified in Table 13 and 23. Thus, the methods can further comprise assessing a DNA sample from the patient for the presence or absence of a mutation in one or more genes as disclosed in Tables 3, 6, 21, 13, and 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PIM1 kinase, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MTOR, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TAB2, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K14, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF3, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in

TNFRSF1 1A, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIA, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in REL, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD79A, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYD88, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CREBBP, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MLL2, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in WHSC1, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BCL2, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB4, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYC, as exemplified in Table 3. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ITK, as exemplified in Table 3.

[0068] In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EGFR, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in WHSC1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in JAK3, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF3, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EP300, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TNFRSF1 1A, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TP53, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF 1 , as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BLK, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in GRB2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K7, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAPK3, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RIPKl, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF5, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF6, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in UGT1A1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NOTCH 1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in AKT1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PRKCB, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BMX, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD79A, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CHEK2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIB, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TAB2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in VEGFA, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD40, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKB2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIA, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NR2C2, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RELB, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CCND3, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CSK, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MCL1, as exemplified in Table 6. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB2, as exemplified in Table 6.

[0069] In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EGFR, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in WHSC1, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RELB, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CCND3, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD40, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CHEK2, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K7, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TNFAIP3, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF 1 , as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIA, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CDKN2A, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EZH2, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in LCK, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CREBBP, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BLK, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CYLD, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYD88, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in STAT6, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC2, as exemplified in Table 21. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MET, as exemplified in Table 21.

[0070] In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB2, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MLL2, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CARD 11 , as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in JAK3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ITK, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NOTCH 1, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TP53, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BCL6, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CREBBP, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MAP3K14, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MET, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RELB, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in STAT6, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC2, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CCND3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD79A, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EGFR, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EP300, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MTTP, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in NFKBIA, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RET, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TAB3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in AKT1, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ATM, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC3, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CD40, as exemplified in Table 13. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in

[0071] In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in KMT2D, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ATM, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CREBBP, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYC, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PLCG2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in CARDl 1, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EP300, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ITK, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in LCK, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MALTl, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MYD88, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in PRDMl, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RELB, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TP53, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF4, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MTOR, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in MTTP, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in RET, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in STAT3, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in STAT6, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in AKT1, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in BIRC2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in ERBB4, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in EZH2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in 1KB KB, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in JAK2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in

NOTCH 1, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TAB2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TNFSF13B, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF2, as exemplified in Table 23. In some aspects, the methods can comprise assaying a DNA sample from the patient to detect a mutation in TRAF3, as exemplified in Table 23.

[0072] The methods of treating a patient having mantle cell lymphoma can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in one or more genes selected from PIM1 kinase signaling regulators, NF-KB signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, PRKCB, or any combination thereof.

[0073] Suitable PIM1 kinase signaling regulators include, but are not limited to, PIM1 kinase, MTOR, or both. In some aspects, the method can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PIM1 kinase, as exemplified in Table 3. In other aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MTOR, as exemplified in Table 3. In yet other aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PIM1 kinase and MTOR, as exemplified in Table 3.

[0074] Suitable NF-κΒ signaling regulators include, but are not limited to, TAB2, MAP3K14, TRAF3, TNFRSF1 1A, NFKBIA, REL, or any combination thereof. Thus, in some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TAB2, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MAP3K14, as exemplified in Table 3. In some aspects, the method can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TRAF3, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in TNFRSF 11A, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in NFKBIA, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in REL, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in any combination of the above listed genes, as exemplified in Table 3.

[0075] Suitable BCR signaling regulators include, but are not limited to, CD79A, MYD88, PLCG2, or any combination thereof. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CD79A, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MYD88, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PLCG2, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in any combination of the above listed genes, as exemplified in Table 3.

[0076] Suitable epigenetic modulators include, but are not limited to, CREBBP, MLL2, WHSCl, or any combination thereof. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CREBBP, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MLL2, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in WHSCl, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in any combination of the above listed genes, as exemplified in Table 3.

[0077] Suitable oncogenes include, but are not limited to, BCL2, ERBB4, MYC, or any combination thereof. In some aspects, the method can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in BCL2, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ERBB4, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in MYC, as exemplified in Table 3. In some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in any combination of the above listed genes, as exemplified in Table 3.

[0078] Suitable TEC kinase signaling regulators include ITK. Thus, in some aspects, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in ITK, as exemplified in Table 3.

[0079] In some embodiments, the method can comprise administering a

pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in CCND3, as exemplified in Table 3. In other embodiments, the method can comprise administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in PRKCB, as exemplified in Table 3.

[0080] As discussed above, the one or more genes can be a combination of PIM1 kinase signaling regulators, NF-κΒ signaling regulators, BCR signaling regulators, epigenetic modulators, oncogenes, TEC kinase signaling regulators, CCND3, and/or PRKCB.

[0081] The disclosed treatment methods are equally applicable to patients having newly diagnosed MCL, relapsed MCL, or refractory MCL. In some embodiments, the methods can be used to treat a patient having newly diagnosed MCL. In some embodiments, the methods can be used to treat a patient having relapsed MCL. In other embodiments, the methods can be used to treat a patient having refractory MCL. In yet other embodiments, the methods can be used to treat a patient having both relapsed MCL and refractory MCL.

[0082] Numerous techniques are known in the art for detecting mutations in genes. In some embodiments, for example, the detecting step can comprise enriching the DNA for the one or more genes and sequencing the DNA. Enriching the DNA for the one or more genes can be performed, for example, using the Ovation® Target Enrichment system (NuGEN). Sequencing of the DNA can be performed, for example, by deep sequencing using an Illumina® HiSeq instrument.

[0083] In some embodiments, the patient has progressed after bortezomib therapy. Thus, the methods of predicting a likelihood of responsiveness to treatment with ibrutinib can be performed on a patient having mantle cell lymphoma, wherein the patient is currently receiving, or has in the past received, bortezomib therapy but has progressed while on, or after receiving, bortezomib therapy. In some embodiments, the patient can be resistant to bortezomib.

[0084] In some aspects, the patient has received at least one prior rituximab- chemotherapy regimen. EXAMPLES

MCL2001 Study

[0085] Background - The MCL2001 (SPARK) study was a single-arm, multi-center Phase 2 trial of ibrutinib in MCL patients who received at least one prior rituximab-containing chemotherapy regimen and who progressed after bortezomib therapy. The primary endpoint of the study was overall response rate. The key secondary endpoints included overall survival rate, progression-free survival rate, and pharmacokinetic data of ibrutinib. (www.clinitrials.gov: NCT01599949).

[0086] Methods - Patients with MCL received 560 mg/day oral ibrutinib continuously until progressive disease (PD) or unacceptable toxicity occurred. Patients who had PD at the first disease evaluation were considered to have primary resistant disease. DNA was extracted from baseline/pretreatment tumor samples (biopsy or CD 19-enriched cells from peripheral blood mononuclear cells (PBMCs)) and enriched libraries were constructed with probe sets specific for the coding region of 97 genes possibly involved in ibrutinib response and resistance, using the Ovation® Target Enrichment system (NuGEN). Deep sequencing (150 bp, single end reads) was performed on an Illumina® HiSeq™ instrument. Sequences were aligned to the hgl9 reference genome, variants were called using samtools and filters were applied to identify possible somatic mutations (minor allele frequency <1% in dbSNP, >5% and <95% variant allele, >=10 total reads).

Primary ibrutinib resistance

[0087] Results - Twenty five patients (22.7%) of the 120 patients enrolled in this study had Independent Review Committee (IRC)-confirmed disease progression. In these primary treatment resistant patients, the median number of prior lines of systemic therapy was 3 (range 1 - 5 lines); 37% of patients had high risk MIPI score; 64% had bulky disease (longest diameter > 5 cm); 52% had extranodal disease; 32% had bone marrow involvement; and 20% had blastoid subtype. None of these baseline clinical parameters were found to be predictive for primary treatment resistance. Sequence data at baseline was collected from 23 of the 25 patients, with an average of 9 million reads. After data filtering as described above, 27 genes were found with nonsynonymous variants in at least 2 or more patients (see Table 1). The majority of these variants were previously unreported in dbSNP or COSMIC databases. No mutations previously described in CLL patients with acquired resistance to ibrutinib (BTK C481S, PLCg2 R665W) were seen in these patients, although one patient had a different mutation in PLCg2. Genes previously implicated in DLBCL (diffuse large B-cell lymphoma) (Pasqualucci et al. 201 1 Nature Genetics 43:830) such as MLL2 and CREBBP were also found to be mutated in these patients. In addition, mutations in PIM1 and ERBB4 kinase genes were more frequent in patients with progressive disease compared with those patients non-resistant to therapy.

Interestingly, several of the mutations detected affect NF-kB signaling inhibition.

[0088] Biomarkers Objectives - The biomarkers objectives included understanding molecular drivers of primary and acquired ibrutinib resistance. Targeted next generation sequencing panel data was obtained from LabCorp (Anup Madan, <[email protected]>) on July 17, 2014 ('combinedj3anel_17JUL2014.txt'). IRC response groupings were received on July 24, 2014 ('BIOMARKER-LSBGRP.rtf, Kenneth Maahs).

[0089] Targeted Sequencing Variant Filters - A number of variant filters were considered to reduce the likelihood of incorporating sequencing artifacts and germline variants into the association analysis. For the association analysis below, the following filters were applied to the primary variant calls:

- Only Screening/CIDI data

<1% MAF dbSNP

>5% variant allele

<95% variant allele

>10 reads total

[0090] Response Association Analysis - The significance of the variant frequencies was assessed by comparing the response evaluable IRC groups for each gene. For this, "PD" and "Moderate Clinical Benefit" groups were compared to "Intermediate Response" and "Durable Response" groups. Table 1 summarizes the number of subjects in each group with at least one variant along with the Fisher's exact test p-value and odds ratio. P-values have not been corrected for multiple testing.

Table 1

Intermediate

Response + PD + Moderate

GENE Odds Ratio (95 CI) P-value

Durable Clinical Benefit

Response

CREBBP 2/44 (4.5%) 7/42 (16.7%) 0.242 (0.023, 1.380) 0.085

MLL2 1/44 (2.3%) 5/42 (11.9%) 0.175 (0.004, 1.667) 0.106

ITK 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.112

MAP3K14 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.112

MYC 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.112

PLCG2 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.112

TRAF3 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.112

MTOR 2/44 (4.5%) 6/42 (14.3%) 0.290 (0.027, 1.750) 0.152

ERBB4 1/44 (2.3%) 4/42 (9.5%) 0.224 (0.004, 2.397) 0.197

TNFRSF11A 1/44 (2.3%) 4/42 (9.5%) 0.224 (0.004, 2.397) 0.197

REL 0/44 (0.0%) 2/42 (4.8%) 0.000 (0.000, 5.061) 0.236

BMX 3/44 (6.8%) 0/42 (0.0%) Inf (0.400, Inf) 0.242

CYLD 3/44 (6.8%) 0/42 (0.0%) Inf (0.400, Inf) 0.242

PRKCB 1/44 (2.3%) 3/42 (7.1%) 0.306 (0.006, 3.995) 0.355

JAK2 5/44 (11.4%) 2/42 (4.8%) 2.538 (0.387, 28.149) 0.434

BCL2 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

CCND3 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

CD79A 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

MYD88 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

NFKBIA 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

RET 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

TPMT 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

CDKN2A 2/44 (4.5%) 0/42 (0.0%) Inf (0.180, Inf) 0.494

LY 2/44 (4.5%) 0/42 (0.0%) Inf (0.180, Inf) 0.494

CARD 11 1/44 (2.3%) 2/42 (4.8%) 0.469 (0.008, 9.337) 0.612

MAP3K7 1/44 (2.3%) 2/42 (4.8%) 0.469 (0.008, 9.337) 0.612

MAPK3 1/44 (2.3%) 2/42 (4.8%) 0.469 (0.008, 9.337) 0.612

MDM2 1/44 (2.3%) 2/42 (4.8%) 0.469 (0.008, 9.337) 0.612

NR2C2 1/44 (2.3%) 2/42 (4.8%) 0.469 (0.008, 9.337) 0.612

SYK 1/44 (2.3%) 2/42 (4.8%) 0.469 (0.008, 9.337) 0.612

TEC 3/44 (6.8%) 1/42 (2.4%) 2.965 (0.227, 161.121) 0.616

ATM 12/44 (27.3%) 9/42 (21.4%) 1.370 (0.457, 4.235) 0.619

IRS2 10/44 (22.7%) 12/42 (28.6%) 0.738 (0.246, 2.169) 0.624

BIRC3 2/44 (4.5%) 3/42 (7.1%) 0.622 (0.050, 5.736) 0.673

TNFRSF13C 2/44 (4.5%) 3/42 (7.1%) 0.622 (0.050, 5.736) 0.673

TRAF5 4/44 (9.1%) 2/42 (4.8%) 1.984 (0.267, 23.106) 0.677

TXK 4/44 (9.1%) 2/42 (4.8%) 1.984 (0.267, 23.106) 0.677

MALT1 3/44 (6.8%) 4/42 (9.5%) 0.698 (0.096, 4.420) 0.710

MET 5/44 (11.4%) 3/42 (7.1%) 1.657 (0.299, 11.409) 0.714

AKT1 2/44 (4.5%) 2/42 (4.8%) 0.953 (0.066, 13.726) 1.000

JAK3 2/44 (4.5%) 2/42 (4.8%) 0.953 (0.066, 13.726) 1.000

RELB 2/44 (4.5%) 2/42 (4.8%) 0.953 (0.066, 13.726) 1.000

STAT3 2/44 (4.5%) 2/42 (4.8%) 0.953 (0.066, 13.726) 1.000 Intermediate

Response + PD + Moderate

GENE Odds Ratio (95 CI) P-value

Durable Clinical Benefit

Response

TAB3 2/44 (4.5%) 2/42 (4.8%) 0.953 (0.066, 13.726) 1.000

CD40 0/44 (0.0%) 0/42 (0.0%) 0.000 (0.000, Inf) 1.000

PTEN 0/44 (0.0%) 0/42 (0.0%) 0.000 (0.000, Inf) 1.000

TNFAIP3 0/44 (0.0%) 0/42 (0.0%) 0.000 (0.000, Inf) 1.000

TRAF2 0/44 (0.0%) 0/42 (0.0%) 0.000 (0.000, Inf) 1.000

TRAF6 0/44 (0.0%) 0/42 (0.0%) 0.000 (0.000, Inf) 1.000

EP300 5/44 (11.4%) 5/42 (11.9%) 0.949 (0.201, 4.493) 1.000

NOTCH 1 3/44 (6.8%) 3/42 (7.1%) 0.952 (0.120, 7.542) 1.000

BIRC2 1/44 (2.3%) 1/42 (2.4%) 0.954 (0.012, 76.605) 1.000

BLK 1/44 (2.3%) 1/42 (2.4%) 0.954 (0.012, 76.605) 1.000

CHEK2 1/44 (2.3%) 1/42 (2.4%) 0.954 (0.012, 76.605) 1.000

ERBB2 1/44 (2.3%) 1/42 (2.4%) 0.954 (0.012, 76.605) 1.000

MCL1 1/44 (2.3%) 1/42 (2.4%) 0.954 (0.012, 76.605) 1.000

PRDM1 1/44 (2.3%) 1/42 (2.4%) 0.954 (0.012, 76.605) 1.000

TNFRSF13B 1/44 (2.3%) 1/42 (2.4%) 0.954 (0.012, 76.605) 1.000

TRAF1 1/44 (2.3%) 1/42 (2.4%) 0.954 (0.012, 76.605) 1.000

VEGFA 1/44 (2.3%) 1/42 (2.4%) 0.954 (0.012, 76.605) 1.000

MTTP 3/44 (6.8%) 2/42 (4.8%) 1.457 (0.158, 18.304) 1.000

EGFR 2/44 (4.5%) 1/42 (2.4%) 1.938 (0.097, 117.865) 1.000

EZH2 2/44 (4.5%) 1/42 (2.4%) 1.938 (0.097, 117.865) 1.000

NFKB1 2/44 (4.5%) 1/42 (2.4%) 1.938 (0.097, 117.865) 1.000

BCL10 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

BTK 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

CDKN2B 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

GRB2 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

RGS4 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

RIPK1 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

TNF 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

TP53 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

TRAF4 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

UGT1A9 1/44 (2.3%) 0/42 (0.0%) Inf (0.024, Inf) 1.000

[0091] Table 2 summarizes the top 20 genes with an Odds Ratio < 1.

Table 2

Intermediate

Response + PD + Moderate

GENE Odds Ratio (95 CI) P-value

Durable Clinical Benefit

Response

CREBBP 2/44 (4.5%) 7/42 (16.7%) 0.242 (0.023, 1.380) 0.085

MLL2 1/44 (2.3%) 5/42 (1 1.9%) 0.175 (0.004, 1.667) 0.106

ITK 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.1 12

MAP3K14 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.1 12

MYC 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.1 12

PLCG2 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.1 12

TRAF3 0/44 (0.0%) 3/42 (7.1%) 0.000 (0.000, 2.275) 0.1 12

MTOR 2/44 (4.5%) 6/42 (14.3%) 0.290 (0.027, 1.750) 0.152

ERBB4 1/44 (2.3%) 4/42 (9.5%) 0.224 (0.004, 2.397) 0.197

TNFRSF11A 1/44 (2.3%) 4/42 (9.5%) 0.224 (0.004, 2.397) 0.197

REL 0/44 (0.0%) 2/42 (4.8%) 0.000 (0.000, 5.061) 0.236

PRKCB 1/44 (2.3%) 3/42 (7.1%) 0.306 (0.006, 3.995) 0.355

BCL2 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

CCND3 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

CD79A 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

MYD88 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

NFKBIA 0/44 (0.0%) 1/42 (2.4%) 0.000 (0.000, 37.228) 0.488

[0092] Table 3 reflects gene variants from the top 20 genes identified by comparing the "PD" and "Moderate Clinical Benefit" to "Intermediate Response" and "Durable Response" groups. This table is restricted to only those variants observed in the subject samples from the "PD" and "Moderate Clinical Benefit" response groups.

Table 3

AA

Gene Chr. Pos. Ref. Obs. Codon Effect

Change

ITK chr5 156649935 T T A GAT/GAA D186E MISSENSE

ITK chr5 156665140 G G A GTA/ATA V264I MISSENSE

ITK chr5 156671298 A A G CAG/CGG Q420R MISSENSE

MAP3K14 chr 17 43344805 A A G TCC/CCC S765P MISSENSE

MAP3K14 chrl7 43348474 T T|C ACG/GCG T591A MISSENSE

MAP3K14 chr 17 43351859 C C|A GGG/GTG G464V MISSENSE

MAP3K14 chr 17 43364407 T T|C GAT/GGT D181G MISSENSE

MLL2 chr 12 49418721 T T|C AAT/GAT N5265D MISSENSE

MLL2 chr 12 49420580 A A G TGG/CGG W5057R MISSENSE

MLL2 chr 12 49425622 A A G CTC/CCC L4289P MISSENSE

MLL2 chr 12 49426624 A A G CTA/CCA L3955P MISSENSE

MLL2 chr 12 49426630 T T|C CAG/CGG Q3953R MISSENSE

MLL2 chr 12 49433857 A A G TTT/CTT F2566L MISSENSE

MLL2 chr 12 49439745 C C|T GTT/ATT V1567I MISSENSE

MTOR chrl 11167547 A A G TGG/CGG W2549R MISSENSE

MTOR chrl 11174477 A A G TGC/CGC C2400R MISSENSE

MTOR chrl 11189845 G G T TTC/TTA F1888L MISSENSE

MTOR chrl 11189874 T T|C ATG/GTG Ml 879V MISSENSE

MTOR chrl 11288946 T T|C AAC/GAC N937D MISSENSE

MTOR chrl 11300578 T T|C GAC/GGC D523G MISSENSE

MTOR chrl 11316149 T T|C AAA/AGA K202R MISSENSE

MTOR chrl 11319351 T T|C AAA/AGA K39R MISSENSE

MYC chr8 128750680 A A|C ACC/CCC T73P MISSENSE

MYC chr8 128751064 T T|C TCA/CCA S201P MISSENSE

MYC chr8 128752840 A A T TAT/TTT Y334F MISSENSE

MYD88 chr3 38181899 G A A GAT/AAT D175N MISSENSE

NFKBIA chrl4 35873813 A A G ATG/ACG M13T MISSENSE

PIM1 chr6 37138356 T T|C CTC/CCC L2P MISSENSE

PIM1 chr6 37138401 G G A TGC/TAC C17Y MISSENSE

PIM1 chr6 37138627 C C|T TCA/TTA S54L MISSENSE

PIM1 chr6 37138645 A A G GAC/GGC D60G MISSENSE

PIM1 chr6 37138776 A A G GAG/GGG E70G MISSENSE

PIM1 chr6 37141712 T T|C TGT/CGT C263R MISSENSE

PLCG2 chrl 6 81819676 A AT ATG/TTG M28L MISSENSE

PLCG2 chrl 6 81819778 G G A GAG/AAG E62K MISSENSE

PLCG2 chrl 6 81969858 A A G AAG/AGG K976R MISSENSE

PRKCB chrl 6 23847612 T T|C TTC/TCC F39S MISSENSE

PRKCB chrl 6 23847663 T T A TTC/TAC F56Y MISSENSE

PRKCB chrl 6 24185844 A A G TAC/TGC Y446C MISSENSE

REL chr2 61128215 A A G AAT/GAT N131D MISSENSE

REL chr2 61148969 T T|C TAC/CAC Y387H MISSENSE

TAB2 chr6 149699255 T T G ATT/ATG I68M MISSENSE

TAB2 chr6 149700240 G G A GAT/AAT D397N MISSENSE

TAB2 chr6 149700396 A A T ACC/TCC T449S MISSENSE

TAB2 chr6 149720282 A A G AAT/AGT N634S MISSENSE

TAB2 chr6 149720286 T T G ATT/ATG I635M MISSENSE

TNFRSFl lA chrl 8 60028922 T T|C GTT/GCT V209A MISSENSE

TNFRSFl lA chrl 8 60036415 T T|C TTG/TCG L422S MISSENSE

TNFRSFl lA chrl 8 60036669 G G A GCA/ACA A507T MISSENSE

TNFRSFl lA chr 18 60052259 A A G AAG/GAG K615E MISSENSE AA

Gene Chr. Pos. Ref. Obs. Codon Effect

Change

TRAF3 chrl4 103342064 T T A CTG/CAG L134Q MISSENSE

TRAF3 chr 14 103357702 c C|T GCC/GTC A231V MISSENSE

TRAF3 chr 14 103369671 c C|T GCA/GTA A322V MISSENSE

WHSC1 chr4 1940226 A A G ATG/GTG M575V MISSENSE

WHSC1 chr4 1962801 G G A GAG/AAG E1099K MISSENSE

WHSC1 chr4 1976677 A A G ACA/GCA T1 154A MISSENSE

WHSC1 chr4 1977096 A A G AAT/AGT N1197S MISSENSE

Ref = genomic reference allele

Obs = observed variant (which translates to the amino acid change in the same row)

[0093] Conclusion - Sequence analyses were conducted on tumor DNA from the fraction of patients with primary resistance to ibrutinib treatment. These studies revealed a number of novel mutations, including genes involved in NF-kB signaling. Among others, the mutational status of PIMl kinase and ERBB4 kinase genes are of interest with respect to primary resistance to ibrutinib therapy in MCL.

[0094] The genes involved in primary ibrutinib resistance were further analyzed. A number of variant filters were considered to reduce the likelihood of incorporating sequencing artifacts and germline variants into the association analysis. For the assocation analysis the following filter was applied:

Screening/CID I AND

((FINAL_FOR_WT_BLOCKS > 3 AND FINAL_FOR_MUT_BLOCKS > 3 ) AND (FINAL_REV_WT_BLOCKS > 3 AND FINAL_REV_MUT_BLOCKS > 3 )) AND (minor allele freq < 0.01 OR is.na(minor allele freq)) AND

ALLELE FREQ BLOCK > 10.0 AND

ALLELE FREQ BLOCK < 95.0

[0095] The significance of the variant frequencies was assessed by comparing the response evaluable IRC groups for each gene. For this, "PD" and "Moderate Clinical Benefit" groups were compared to "Intermediate Response" and "Durable Response" groups. Table 4 below summarizes the number of subjects in each group with at least one variant along with the Fisher's exact test p-value and odds ratio. P-values have not been corrected for multiple testing.

Table 4

[0096] Table 5 shows the top genes by mutation recurrence in the primary ibrutinib analysis.

Table 5

Filter 5, Ordered by P-value (0R<1 enriched in Moderate+PD)

[0097] Variants in recurrently mutated genes for preliminary ibrutinib resistance are exemplified in Table 6.

Table 6

Baseline Variant Summary, Variants present in Moderate+PD group (Filter 5)

Exome sequencing - Exome and targeted next generation sequencing data from the Ibrutinib MCL2001 study is shown below. The biomarker objectives for this study include understanding molecular drivers of primary and acquired Ibrutinib resistance. IRC response groupings were received on July 25, 2014 ('biomarker_listing.sas7bdat', Kenneth Maahs). Data was reprocessed by Immuneering and resulting variant calls were merged into multiple files.

[0098] Raw FASTQ next generation sequencing data was obtained for samples in this study from LabCorp and included data for a targeted panel of 97 genes (data not shown) and full exome DNA-seq data. Only tumor samples were profiled as no matching normal samples were available.

[0099] The targeted panel of genes was sequenced using the NuGEN Ovation Target Enrichment System on an Illumina MiSeq sequencer with lOObp single-end reads and coverage target of 100X. The Ovation approach produces sequences with an 8nt barcode for sample identification and an N6 to distinguish independent molecules, whereby true PCR duplicates will have the same Readl/N6 combination. Sequence data was 'paired' in that each lane of read data also included the N6 hexamer barcode as part of the protocol and multiple lanes of sequencing data was available for each sample. The FASTQ data was aligned to the reference genome (human_glk_v37.fasta, lOOOgenomes project:

ftp://ftp.1000genomes.ebi.ac.uk/voll/ftp/technical/reference/) using BWA mem (v0.7.5a-r405, - M flag for subsequent Picard usage). Custom scripts were used to update the resulting SAM files to incorporate N6 read group and sample information, followed by duplicate marking (Picard Tools vl.94), indel realignment, and base recalibration (GATK, v2014.3-3.2.2-7-gf9cba99). Following recalibration, variants were called using MuTect in single-sample mode with a panel of normals data set, dbSNP, and COSMIC annotations

(refseq_exome_10bp_b37_300_lkg_normal_panel.vcf, dbsnp_138.b37.vcf,

b37_CosmicCodingMuts_v70.vcf, and b37_CosmicNonCodingVariants_v70.vcf, respectively). Called variants were merged vcftools and annotated with snpEff.

[0100] Whole exome data was generated for DNA samples using a Nimblegen v3 exome capture kit, KAPA library construction, and Illumina HiSeq2000 sequencer with 100 bp paired-end reads targeting 100 million reads per sample. The FASTQ data was aligned to the reference genome (human_glk_v37.fasta, lOOOgenomes project:

ftp://ftp.1000genomes.ebi.ac.uk/voll/ftp/technical/reference/) using BWA mem (v0.7.5a-r405, - M flag for subsequent Picard usage). Data from samples run across multiple lanes was aggregated, followed by duplicate marking (Picard Tools vl.94), indel realignment and base recalibration (GATK 2014.3-3.2.2-7-gf9cba99). Following recalibration, variants were called using MuTect in single-sample mode with a panel of normals data set, dbSNP, and COSMIC annotations (refseq_exome_10bp_b37_300_lkg_normal_panel.vcf, dbsnp_138.b37.vcf, b37_CosmicCodingMuts_v70.vcf, and b37_CosmicNonCodingVariants_v70.vcf, respectively). Called variants were merged vcftools and annotated with snpEff. To complement the targeted panel data, reported exome variants were restricted to the genomic regions containing the 97 genes represented in the targeted panel described above.

[0101] Variants were filtered based on annotations from the dbSNP and COSMIC databases and the reported mutation effect from snpEff. Variants noted as 'interesting' in the analyses below have one or more effects including:

CODON CHANGE PLUS CODON DELETION,

CODON CHANGE PLUS CODON I SERTION, CODON DELETION,

CODONJNSERTION, FRAME_SHIFT, NON_SY ONYMOUS_CODING,

NON_SY ONYMOUS_START, SPLICE_SITE_ACCEPTOR, SPLICE_SITE_DONOR, START GATNED, START LOST, STOP GAI ED, STOP LOST.

[0102] A summary of the data is shown in Table 7 below.

Table 7

[0103] Subjects with baseline (Screening or C 1D 1) sequencing data by Best Overall Response are shown in Table 8 below.

Table 8

[0104] Subjects with baseline (Screening or C 1D 1) sequencing data by Response Group are shown in Table 9 below.

Table 9

[0105] Table 10 shows the total count of variants detected in Exome and Targeted Panel in the 97 targeted genes. For 13 1 samples with both exome and targeted sequencing data, the table below shows the total number of variants detected in exome alone, targeted panel alone, and in both targeted and exome data.

Table 10

[0106] A number of variant filters were considered to reduce the likelihood of incorporating sequencing artifacts and germline variants into the association analysis. For the assocation analysis below, the following filter was applied:

filter4 (assay. evidence == "Targeted+Exome" & interesting == "interesting"))

[0107] Table 11 below reflects the results from filter 4, which has the highest level of validation since these were found by both methods. The signifiance of the variant frequencies was assessed by comparing the response evaluable IRC groups for each gene. For this, 'PD' and 'Moderate Clinical Benefit' groups were compared to 'Intermediate Response' and 'Durable Response' groups. Table 11 summarizes the number of subjects in each group with at least one variant along with the Fisher's exact test p-value and odds ratio. P-values have not been corrected for multiple testing. Table 11

TNF 0/38 (0.0%) 0/34 (0.0%) 0.000 (0.000, Inf) 1.000

TRAF2 0/38 (0.0%) 0/34 (0.0%) 0.000 (0.000, Inf) 1.000

TRAF4 0/38 (0.0%) 0/34 (0.0%) 0.000 (0.000, Inf) 1.000

NFKB2 2/38 (5.3%) 2/34 (5.9%) 0.890 (0.061, 12.939) 1.000

PLCG2 2/38 (5.3%) 2/34 (5.9%) 0.890 (0.061, 12.939) 1.000

LCK 1/38 (2.6%) 1/34 (2.9%) 0.893 (0.011 , 72.068) 1.000

MET 1/38 (2.6%) 1/34 (2.9%) 0.893 (0.01 1, 72.068) 1.000

NFKBIB 1/38 (2.6%) 1/34 (2.9%) 0.893 (0.011 , 72.068) 1.000

RIPK1 1/38 (2.6%) 1/34 (2.9%) 0.893 (0.011 , 72.068) 1.000

SYK 1/38 (2.6%) 1/34 (2.9%) 0.893 (0.011 , 72.068) 1.000

TRAF6 1/38 (2.6%) 1/34 (2.9%) 0.893 (0.01 1, 72.068) 1.000

WHSC1 1/38 (2.6%) 1/34 (2.9%) 0.893 (0.01 1, 72.068) 1.000

TNFAIP3 5/38 (13.2%) 4/34 (11.8%) 1.134 (0.221 , 6.277) 1.000

BLNK 2/38 (5.3%) 1/34 (2.9%) 1.819 (0.091 , 11 1.313) 1.000

ITK 2/38 (5.3%) 1/34 (2.9%) 1.819 (0.091 , 11 1.313) 1.000

BIRC3 1/38 (2.6%) 0/34 (0.0%) Inf (0.023, Inf) 1.000

BMX 1/38 (2.6%) 0/34 (0.0%) Inf (0.023, Inf) 1.000

CD79A 1/38 (2.6%) 0/34 (0.0%) Inf (0.023, Inf) 1.000

MAP3K7 1/38 (2.6%) 0/34 (0.0%) Inf (0.023, Inf) 1.000

MTTP 1/38 (2.6%) 0/34 (0.0%) Inf (0.023, Inf) 1.000

PIM1 1/38 (2.6%) 0/34 (0.0%) Inf (0.023, Inf) 1.000

SOCS1 1/38 (2.6%) 0/34 (0.0%) Inf (0.023, Inf) 1.000

TNFRSF13C 1/38 (2.6%) 0/34 (0.0%) Inf (0.023, Inf) 1.000

[0108] Table 12 shows the top genes by mutational recurrence from the exome sequencing data using filter 4 above.

Table 12

MAPK3 0.000 (0.000, 34.895) 0.472

MCL1 0.000 (0.000, 34.895) 0.472

MYC 0.000 (0.000, 34.895) 0.472

RET 0.000 (0.000, 34.895) 0.472

TRAF3 0.000 (0.000, 34.895) 0.472

TP53 0.614 (0.154, 2.312) 0.553

EP300 0.437 (0.007, 8.768) 0.599

EZH2 0.711 (0.154, 3.132) 0.746

MLL2 0.877 (0.208, 3.694) 1.000

IRS2 0.000 (0.000, Inf) 1.000

TAB2 0.000 (0.000, Inf) 1.000

TNF 0.000 (0.000, Inf) 1.000

TRAF2 0.000 (0.000, Inf) 1.000

TRAF4 0.000 (0.000, Inf) 1.000

NFKB2 0.890 (0.061, 12.939) 1.000

PLCG2 0.890 (0.061, 12.939) 1.000

LCK 0.893 (0.011, 72.068) 1.000

MET 0.893 (0.011, 72.068) 1.000

NFKBIB 0.893 (0.011, 72.068) 1.000

RIPK1 0.893 (0.011, 72.068) 1.000

SYK 0.893 (0.011, 72.068) 1.000

TRAF6 0.893 (0.011, 72.068) 1.000

WHSC1 0.893 (0.011, 72.068) 1.000

Ibrutinib: Filter 4, Ordered by P-value (01 ¾<1 enriched in IV

Acquired Resistance Analysis

[0109] Table 13 shows the summary of the acquired resistance analysis from the MCL2001 study. Variants found at progression (using Filter 5) that were not detected at ClDl baseline (with no filter applied) are noted.

Table 13

Moderate SD 10000204 CARD 11 chr7 2951887 E1021D NA NA clinical

benefit

PD PD 10001707 CARD 11 chr7 2956925 Q901P NA NA

Moderate SD 33000103 CARD 11 chr7 2956925 Q901R NA NA clinical

benefit

PD PD 10001707 CARD 11 chr7 2956928 L900P NA NA

PD PD 48000101 CARD 11 chr7 2956928 L900P NA NA

Moderate SD 70000401 CARD 11 chr7 2959130 796E NA NA clinical

benefit

PD PD 70000204 CARD 11 chr7 2972189 517R NA NA

Durable PR 10002202 CCND3 chr6 41903798 E172D NA rs3396673 response 4

PD PD 48000101 CCND3 chr6 41908159 I121M NA NA

PD PD 48000101 CCND3 chr6 41909284 E35G NA NA

Moderate SD 33000103 CD40 chr20 44756975 V218G NA NA clinical

benefit

PD PD 48000101 CD79A chrl9 42384940 N154D NA NA

PD PD 70000204 CD79A chrl9 42384940 N154D NA NA

Moderate SD 70000401 CD N2 chr9 21968233 D156N NA NA clinical A

benefit

PD PD 33000501 CREBBP chrl6 3778620 N2105S NA NA

PD PD 33000501 CREBBP chrl6 3778621 N2105 NA NA

D

PD PD 48000101 CREBBP chrl6 3779049 L1962P NA NA

Moderate SD 70000401 CREBBP chrl6 3831230 L513I NA rs6175338 clinical 1 benefit

PD PD 10001707 CYLD chrl6 50825534 V722A NA NA

Moderate PR 10002508 EGFR chr7 55240803 L683M NA rs5566934 clinical 0 benefit

PD PD 48000101 EGFR chr7 55268938 Ml 002 NA NA

V

Intermediate PR 10002502 EP300 chr22 41572894 P1727S NA NA response

Moderate SD 33000103 EP300 chr22 41574509 L2265P NA NA clinical

benefit

Intermediate PR 10002524 ERBB2 chrl7 37864671 F108S NA NA response

Early PR 10007804 ERBB2 chrl7 3₇864674 E109G NA NA censored

response

Intermediate PR 10002524 ERBB2 chrl7 3₇864674 E109A NA NA response PD PD 33000501 ERBB2 chrl7 3₇864674 E109G NA NA

Early PR 10007804 ERBB2 chrl7 37879585 I624V NA rsl801201 censored

response

PD PD 10001707 ERBB2 chrl7 37884037 P1140T NA NA

Moderate PR 10002508 ERBB2 chrl7 37884037 P1140T NA NA clinical

benefit

PD PD 10002402 ERBB2 chrl7 37884037 P1140A NA NA

Moderate SD 70000401 ERBB2 chrl7 37884037 P1140A NA NA clinical

benefit

Intermediate PR 10002517 ERBB2 chrl7 37884037 P1140A NA NA response

Moderate SD 10002521 ERBB2 chrl7 37884037 P1140A NA NA clinical

benefit

PD PD 70000204 ERBB2 chrl7 37884037 P1140T NA NA

PD PD 10001709 ERBB2 chrl7 37884037 P1140A NA NA

Moderate PDU 33000101 ERBB2 chrl7 37884037 P1140T NA NA clinical

benefit

Moderate PDU 33000101 IT chr5 156638374 K107R NA NA clinical

benefit

PD PD 10001707 IT chr5 156644908 E162D NA NA

PD PD 10001709 ITK chr5 156644908 E162D NA NA

Moderate SD 33000103 ITK chr5 156644908 E162D NA NA clinical

benefit

Durable PR 10002202 JAK3 chrl9 17945696 V722I COSM34 rs3213409 response 213

PD PD 10001707 JAK3 chrl9 17953935 L156P COSMU NA

0717

PD PD 48000101 JAK3 chrl9 17953935 L156H COSMU NA

0717

Intermediate PR 10002502 JAK3 chrl9 17953935 L156P COSMU NA response 0717

PD PD 70000204 JAK3 chrl9 17953935 L156H COSMU NA

0717

Moderate SD 33000103 JAK3 chrl9 17953935 L156P COSMU NA clinical 0717

benefit

PD PD 10001709 LCK chrl 32742250 K276R NA NA

PD PD 33000501 MAP3K chrl7 43364293 -218? NA NA

14

Moderate SD 10002521 MAP3K chrl 7 43364293 -218? NA NA clinical 14

benefit

PD PD 10001709 MAP3K chrl 7 43364293 -218? NA NA 14

Durable PR 10002202 MAP3 chr6 91281421 V76I NA NA response 7

PD PD 70000204 MAP 3 chrl6 30128265 E279 NA rs5585913

3

PD PD 10001707 MET chr7 116340088 L317P NA NA

PD PD 48000101 MET chr7 116340088 L317P NA NA

Moderate SD 70000401 MET chr7 116435969 P1322T NA NA clinical

benefit

PD PD 10002402 MLL2 chrl2 49428694 D3419 NA _rs 1460442

G 82

PD PD 33000501 MLL2 chrl2 49434175 R2460C NA NA

PD PD 70000204 MLL2 chrl2 49437166 E1838G NA NA

Moderate SD 33000103 MLL2 chrl2 49437169 L1837P NA NA clinical

benefit

Moderate SD 10000204 MLL2 chrl2 49440521 C1430Y NA NA clinical

benefit

PD PD 10001707 MLL2 chrl2 49440554 L1419P NA NA

PD PD 48000101 MLL2 chrl2 49440554 L1419P NA NA

PD PD 10001707 MLL2 chrl2 49443634 T1246 COSM94 rsl l29211

0079 15

Moderate SD 33000103 MLL2 chrl2 49443757 V1205 NA NA clinical A

benefit

PD PD 70000204 MTOR chrl 11294202 777E NA NA

PD PD 33000501 MTTP chr4 100504664 I128T COSM11 NA

31316

Intermediate PR 10002502 MTTP chr4 100504664 I128T COSM11 NA response 31316

PD PD 10001707 MYC chr8 128750527 F22L NA rsl465051

92

PD PD 10001707 MYC chr8 128751044 Q194R NA NA

Intermediate PR 10002502 NFKBIA chrl4 35871676 L277P NA NA response

Moderate PDU 33000101 NFKBIA chrl 4 35871676 L277H NA NA clinical

benefit

PD PD 48000101 NOTCH chr9 139396727 L1794H NA NA

1

PD PD 10002402 NOTCH chr9 139401233 R1279H NA rs6175154

1 3

PD PD 48000101 NOTCH chr9 139408968 L734P NA NA

1

Early PR 10007804 NOTCH chr9 139413211 T311P NA NA censored 1

response

PD PD 70000204 NOTCH chr9 139438518 N33S NA NA 1

Moderate PDU 33000101 NR2C2 chr3 15084466 600R NA NA clinical

benefit

PD PD 10002402 PLCG2 chrl6 81819676 M28L NA rs6174904

4

PD PD 70000204 PLCG2 chrl6 81819676 M28L NA rs6174904

4

Moderate SD 10000204 PLCG2 chrl6 81942134 557N NA NA clinical

benefit

PD PD 33000501 PLCG2 chrl6 81969855 L975P NA NA

PD PD 33000501 PLCG2 chrl6 81969858 976R NA NA

PD PD 70000204 PLCG2 chrl6 81969858 976R NA NA

Durable PR 10002202 PLCG2 chrl6 81973601 D1140 NA NA response N

PD PD 10001707 RELB chrl9 45541036 L575P NA NA

PD PD 48000101 RELB chrl9 45541036 L575P NA NA

Moderate SD 70000401 RELB chrl9 45541036 L575P NA NA clinical

benefit

PD PD 48000101 RELB chrl9 45541038 576E NA NA

Moderate SD 70000401 RELB chrl9 45541039 576R NA NA clinical

benefit

Moderate PR 10002508 RET chrlO 43596126 N98S NA NA clinical

benefit

Intermediate PR 97200303 RET chrlO 43609085 E614G NA NA response

Durable PR 10002202 STAT3 chrl7 40469227 L705Q NA NA response

Moderate SD 10000204 STAT6 chrl2 57490429 L714V NA rsl466703 clinical 18 benefit

PD PD 48000101 STAT6 chrl2 57499037 R190G NA NA

Early PR 10007804 STAT6 chrl2 57501389 E85G NA NA censored

response

PD PD 10001707 TAB 3 chrX 30872551 S411P NA NA

PD PD 70000204 TAB 3 chrX 30872551 S411P NA NA

PD PD 48000101 TEC chr4 48140970 E535D NA NA

PD PD 33000501 TNFRSF chrl8 60036594 E482 NA NA

11A

Intermediate PR 97200303 TNFRSF chr22 42321451 H159N NA rs6175676 response 13C 6

Intermediate PR 10002524 TP53 chrl7 7577107 C145W COSM44 NA response 972

Durable PR 10002202 TP53 chrl7 7577120 R141H COSM10 rs2893457 response 660 6 PD PD 70000204 TP53 chrl7 7577123 V140E COSM44 NA

580

Moderate PR 10002508 TP53 chrl7 7577567 C106W COSM45 NA clinical 677 benefit

PD PD 10001707 TRAF3 chrl4 103342767 R159G NA NA

[0110] Table 14 reflects the top genes in acquired ibrutinib resistance from the MCL2001 study by mutation recurrence.

Table 14

TNFRSF1 1A 1

TNFRSF13C 1

TRAF3 1

MCL3001 Study

[0111] Background - The MCL3001 (RAY) study is a Phase 3 study of Imbruvica (ibrutinib) versus temsirolimus in R/R (relapsed/refractory) MCL patients. This trial is a randomized, multi-center, open-label trial of ibrutinib as a monotherapy versus temsirolimus in R R MCL patients who received at least one prior rituximab-containing chemotherapy regimen. The primary endpoint of the study is progression- free-survival when compared to temsirolimus. Approximately 280 eligible patients will be randomly assigned in a 1 : 1 ratio and stratified by the number of prior lines of therapy (1 or 2 versus >=3) and simplified MCL International

Prognostic Index criteria to receive either ibrutinib orally or intravenous temsirolimus infusion.

[0112] Summary - Table 15 shows the best overall response (IRC).

Table 15

I brufmib

[0113] Table 16 shows the biomarker grouping summary.

Table 16

Early Censored Response 0

NED 2

NE 7

Not Grouped 0

Sum 139

Durable Response - Best Overall Response (IRC) of CR or PR with Progression free survival (IRC) >=12 months; Intermediate Response - Best Overall Response (IRC) of CR or PR with uncensored Progression free survival (IRC) >=4 and <12 months; Early Censored Response - Best Overall Response (IRC) of CR or PR with censored Progression free survival (IRC) <12 months; Moderate Clinical Benefit - (Best Overall Response (IRC) of SD ) OR (Best Overall Response (IRC) of PR with uncensored Progression free survival (IRC) <4 months); PD - Best Overall Response (IRC) of PD; NED - Best Overall Response (IRC) of NED; NE - Best Overall Response (IRC) of NE.

[0114] Applied filter - A number of variant filters were considered to reduce the likelihood of incorporating sequencing artifacts and germline variants into the association analysis. The following filter, which reflects the highest level of stringency, was applied to the results:

- filter5 ((FiNAL_FOR_WT_BLOCKS > 3 & FINAL_FOR_MUT_B LOCKS > 3) & (FINAL_REV_WT_B LOCKS > 3 & FINAL_REV_MUT_B LOCKS > 3)) &

(minor allele freq < 0.01 | is.na(minor allele freq)) & ALLELE FREQ BLOCKS >= 10 & ALLELE FREQ BLOCKS < 95)

Primary Resistance Analysis

[0115] The summary of the number of subjects with baseline (Cycle 1 Day 1) targeted sequencing data in each biomarker response group is provided in Table 17 below. Subjects in Biomarker groups: Early Censored Response, NE, NED, and Not Reported were excluded from the analysis.

Table 17

Not Grouped 0

Sum 61

[0116] Primary Resistance Response Association Analysis (Ibrutinib Arm) - Enrichment of variant frequencies by gene was assessed by comparing the response evaluable Biomarker IRC groups for each gene. To determine the significance of enrichment, the "Durable Response + Intermediate Response" group was compared to the "Moderate Clinical Response + PD" group. Table 18 summarizes the number of subjects in each group with at least one variant along with the Fisher's exact test p-value and odds ratio. P-values have not been corrected for multiple testing.

Table 18

MYD88 6/44 (13.6%) 2/13 (15.4%) 0.871 (0.130, 10.007) 1.000

STAT6 6/44 (13.6%) 2/13 (15.4%) 0.871 (0.130, 10.007) 1.000

BIRC2 3/44 (6.8%) 1/13 (7.7%) 0.880 (0.064, 49.890) 1.000

MET 3/44 (6.8%) 1/13 (7.7%) 0.880 (0.064, 49.890) 1.000

ATM 15/44 (34.1%) 4/13 (30.8%) 1.161 (0.266, 6.032) 1.000

TRAF4 9/44 (20.5%) 2/13 (15.4%) 1.406 (0.235, 15.31 1) 1.000

AKT1 2/44 (4.5%) 0/13 (0.0%) Inf (0.054, Inf) 1.000

BCL6 2/44 (4.5%) 0/13 (0.0%) Inf (0.054, Inf) 1.000

BLNK 2/44 (4.5%) 0/13 (0.0%) Inf (0.054, Inf) 1.000

CD79A 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

CD79B 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

ENSG000001 17152 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

ERBB4 2/44 (4.5%) 0/13 (0.0%) Inf (0.054, Inf) 1.000

IRF4 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

IRS2 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

JAK3 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

MALT1 2/44 (4.5%) 0/13 (0.0%) Inf (0.054, Inf) 1.000

MAPK3 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

MCL1 3/44 (6.8%) 0/13 (0.0%) Inf (0.1 19, Inf) 1.000

NFKB 1 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

NFKBIB 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

NR2C2 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

PRKCB 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

RIPK1 2/44 (4.5%) 0/13 (0.0%) Inf (0.054, Inf) 1.000

SOCS1 2/44 (4.5%) 0/13 (0.0%) Inf (0.054, Inf) 1.000

STAT3 2/44 (4.5%) 0/13 (0.0%) Inf (0.054, Inf) 1.000

SYK 2/44 (4.5%) 0/13 (0.0%) Inf (0.054, Inf) 1.000

TAB2 3/44 (6.8%) 0/13 (0.0%) Inf (0.1 19, Inf) 1.000

TNFRSF1 1A 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

TNFRSF13B 3/44 (6.8%) 0/13 (0.0%) Inf (0.1 19, Inf) 1.000

TRAF3 3/44 (6.8%) 0/13 (0.0%) Inf (0.1 19, Inf) 1.000

UGTIAIO 1/44 (2.3%) 0/13 (0.0%) Inf (0.008, Inf) 1.000

TP53 7/44 (15.9%) 2/13 (15.4%) 1.040 (0.163, 1 1.679) 1.000

[0117] The top genes by mutation recurrence in the MCL3001 primary ibrutinib reistance study rrdered by P-value (0R<1 enriched in Moderate+PD) are shown in Table ordered by P-value (0R>=1, enriched in Durable+Intermediate) are shown in Table 20.

Table 19

TRAF1 0.410 (0.041, 5.478) 0.319

NFKBIA 0.287 (0.003, 23.717) 0.407

CDKN2A 0.578 (0.028, 36.492) 0.547

EZH2 0.578 (0.028, 36.492) 0.547

LCK 0.557 (0.069, 6.913) 0.611

CREBBP 0.754 (0.165, 4.026) 0.727

PLCG2 0.751 (0.176, 3.471) 0.742

BLK 0.000 (0.000, Inf) 1.000

CYLD 0.000 (0.000, Inf) 1.000

MYD88 0.871 (0.130, 10.007) 1.000

STAT6 0.871 (0.130, 10.007) 1.000

BIRC2 0.880 (0.064, 49.890) 1.000

MET 0.880 (0.064, 49.890) 1.000

Filter 5, Ordered by P-value (0R<1 enriched in Moderate+PD)

Table 20

NR2C2 Inf (0.008, Inf) 1.000

PRKCB Inf (0.008, Inf) 1.000

RIPK1 Inf (0.054, Inf) 1.000

SOCS1 Inf (0.054, Inf) 1.000

STAT3 Inf (0.054, Inf) 1.000

SYK Inf (0.054, Inf) 1.000

TAB2 Inf (0.119, Inf) 1.000

TNFRSF11A Inf (0.008, Inf) 1.000

TNFRSF13B Inf (0.119, Inf) 1.000

TRAF3 Inf (0.119, Inf) 1.000

UGT1A10 Inf (0.008, Inf) 1.000

TP53 1.040 (0.163, 11.679) 1.000

Filter 5, Ordered by P-value (0R>=1, enriched in Durable+Intermediate)

[0118] Table 21 shows the variants in recurrently mutated genes in the MCL3001 primary ibrutinib resistance study.

Table 21

G EN E chromosome: location: cosmic.id s.id

EGFR chr7 55242422 p.Trp731Leu COSM53101 NA

EGFR chr7 55242458 p.Ala743Val NA NA

EGFR chr7 55268044 p.Arg962Cys NA rsl7337451

WHSC1 chr4 1936897 p.His528Asn NA rsl39753036

WHSC1 chr4 1962801 p.Ghil099Lys COSM379334 rs772470710

RELB chrl9 45541039 p.Ghi577Asp NA NA

RELB chrl9 45541038 p.Ghi577Gly NA NA

CCND3 chr6 41903798 p.Ghil27* NA rs33966734

CD40 chr20 44756975 p.Va!218Gly NA rs766292495

CHEK2 chr22 29121265 p.Argl80Gln NA rs368570187

MAP3K7 chr6 91233460 p.Thr467Ala NA rs762460576

TNFAIP3 chr6 13819994 p.Gly456Val COSM303677 rs374721883

TRAF1 chr9 12367589 p.Metl39Thr COSM123573 rsl 13495277

5 1

TRAF1 chr9 12367589 p.Prol38Ser NA rs61749212

NFKBIA chrl4 35871673 p.Gln278Arg NA NA

NFKBIA chrl4 35871676 p.Leu277Pro NA NA

CDKN2A chr9 21970904 p.Ser!52Pro NA NA

EZH2 chr7 14852587 p.Glul94Gly NA NA

6

LCK chrl 32742250 p.Lys276Arg NA NA

CREBBP chrl 6 3779049 p.Leu2000Pro NA NA

CREBBP chrl 6 3807895 p.Tyrl l75Cys NA rs28937315

CREBBP chrl 6 3860741 p.Phe280Leu NA NA

CREBBP chrl 6 3900785 p.Glnl04Arg NA NA

PLCG2 chrl 6 81944210 p.Phe607Leu NA NA

PLCG2 chrl 6 81944213 p.Ser608Gly NA NA MYD88 chr3 38182777 p.Ter318Trpext*? NA NA 2

STAT6 chrl2 57493602 p.Ser564Arg NA rs35182390 1

STAT6 chrl2 57499037 p.Arg300Gly NA NA 1

BIRC2 chrl l 10222086 p.Asn92Ser NA NA 1

0

MET chr7 11641199 p.ThrlOlOIle COSM707 rs56391007 1

0

Baseline Variant Summary, Variants present in Moderate+PD group (Filter 5)

Acquired Resistance Analysis

[0119] Subject counts - Summary of subjects with both Screening/CIDI and

Progression/EOT Sequencing data is provided in Table 22. The PFS_EVNTDESC variable represents the Event or Censoring Description for the corresponding PFS by IRC value (PFSIR). The DS-* values represent the LabCorp targeted sequencing data identifiers.

Table 22

Ibrutinib 82000401 PD DS-197648 DS-197580

Ibrutinib 35100202 Study cutoff DS-197667 DS-197771

Ibrutinib 35100205 Study cutoff DS-197578 DS-198103

Ibrutinib 38000703 Study cutoff DS-197841 DS-197798

TRTP Freq

Ibrutinib 20

[0120] Baseline and Progression/EOT Sequence Variants - Variants found at

Progression/EOT (using Filter 6) that were not detected at Screening or ClDl (with no filter applied) are noted in Table 23 below. The PFS_EVNTDESC variable represents the Event or Censoring Description for the corresponding PFS by IRC value. Variants with a dbSNP identifier but no COSMIC identifier were removed from the list.

Table 23

PD 55000103 chr22 415745( 39 EP300 p.Leu2265Pro NA PD 44000605 chr22 41574509 EP300 p.Leu2265Pro NA

PD 44001005 chr22 41574509 EP300 p.Leu2265Pro NA

PD 44000605 chrl7 37864674 ERBB2 p.Glul09Gly NA

PD 44001005 chrl7 37881318 ERBB2 p.Glu837Gly NA

PD 70001101 chr7 148525876 EZH2 p.Glul94Gly NA

PD 49000503 chr8 42174380 IKBKB p.Leu361Phe NA

PD 38000701 chr5 156638374 ITK p.Lysl07Arg NA

PD 44000605 chr5 156644908 ITK p.Glul62Asp NA

PD 44001005 chrl2 49435162 KMT2D p.Thr2131Pro NA

PD 44001005 chrl2 49440551 KMT2D p.Lysl420Arg NA

PD 44001005 chrl2 49440554 KMT2D p.Leul419Pro NA

PD 44001005 chrl2 49445546 KMT2D p.Glu640Asp NA

PD 38000701 chrl2 49445546 KMT2D p.Glu640Asp NA

PD 49000503 chrl2 49445843 KMT2D p.Glu541Asp NA

PD 31000102 chrl2 49445843 KMT2D p.Glu541Asp NA

PD 82000401 chrl2 49446101 KMT2D p.Glu455Asp NA

PD 55000103 chrl 32742250 LCK p.Lys276Arg NA

PD 38000701 chrl 32742250 LCK p.Lys276Arg NA

PD 44000205 chrl 8 56378183 MALT1 p.Glu319Gly NA

PD 44001005 chrl 8 56378183 MALT1 p.Glu319Gly NA

PD 44000605 chrl 8 56378184 MALT1 p.Glu319Asp NA

PD 82000401 chrl 11175454 MTOR p.Glu2363Gly NA

PD 44001005 chrl 11294201 MTOR p.Lys777Arg NA

PD 44001005 chr4 100542385 MTTP p.Phe864Ser NA

PD 31000102 chr8 128750516 MYC p.Leul8Pro NA

PD 44001005 chr8 128752774 MYC p.Leu312Pro NA

PD 49000503 chr8 128752777 MYC p.Lys313Arg NA

PD 70001101 chr3 38182777 MYD88 p.Ter318Trpext NA

*7

PD 44000605 chr3 38182777 MYD88 p.Ter318Trpext NA

*7

PD 44001005 chr3 38182777 MYD88 p.Ter318Trpext NA

*7

PD 82000401 chrl 6 81944210 PLCG2 p.Phe607Leu NA

PD 38000701 chrl 6 81944210 PLCG2 p.Phe607Leu NA

PD 70001101 chrl 6 81944210 PLCG2 p.Phe607Leu NA

PD 44000605 chrl 6 81944211 PLCG2 p.Phe607Ser NA

PD 48000403 chrl 6 81944211 PLCG2 p.Phe607Ser NA

PD 44001005 chr6 106553075 PRDM1 p.Leu347Pro NA

PD 70001101 chr6 106553075 PRDM1 p.Leu347Pro NA

PD 34000402 chrl 9 45541038 RELB p.Glu577Gly NA

PD 46000401 chrl 9 45541039 RELB p.Glu577Asp NA

PD 34000405 chrlO 43596126 RET p.Asn98Ser NA

PD 34000405 chrlO 43606868 RET p.Ser493Pro NA

PD 38000701 chrl 7 40474313 STAT3 p.Glu696Asp NA

PD 48000403 chrl 7 40498591 STAT3 p.Leu90Pro NA

PD 44000605 chrl 2 57490642 STAT6 p.Gln782Arg NA

PD 48000403 chrl 2 57499037 STAT6 p.Arg300Gly NA

PD 82000401 chr6 149700306 TAB2 p.Ser419Pro NA

PD 48000403 chrl 3 108955811 TNFSF13 p.Thr202Ser NA

B

PD 70001101 chrl 7 7577141 TP53 p.Gly266Val COSM99952

Study cutoff 35100202 chrl 7 27075623 TRAF4 p.Lys240Arg NA

[0121] The top genes by mutation recurrence are shown in Table 24.

Table 24

BIRC2 1

ERBB4 1

EZH2 1

IKBKB 1

JAK2 1

NOTCH 1 1

TAB2 1

TNFSF13B 1

TRAF2 1

TRAF3 1

[0122] Biomarker IRC Grouping is shown in Table 25. Table 25

39000202 Ibrutinib PR 20.205 1 Study cutoff Durable Response

82000301 Ibrutinib PR 20.107 1 Study cutoff Durable Response

82000502 Ibrutinib PR 20.107 1 Study cutoff Durable Response

11000401 Ibrutinib PR 20.074 1 Study cutoff Durable Response

88600401 Ibrutinib PR 20.074 1 Study cutoff Durable Response

48001503 Ibrutinib CR 20.041 1 Study cutoff Durable Response

49001001 Ibrutinib CR 20.041 1 Study cutoff Durable Response

38000703 Ibrutinib PR 20.008 1 Study cutoff Durable Response

48000404 Ibrutinib CR 20.008 1 Study cutoff Durable Response

82000302 Ibrutinib PR 19.943 1 Study cutoff Durable Response

82000102 Ibrutinib PR 19.877 1 Study cutoff Durable Response

44000602 Ibrutinib CR 19.844 1 Study cutoff Durable Response

38000801 Ibrutinib CR 19.450 1 Study cutoff Durable Response

48001505 Ibrutinib PR 19.384 1 Study cutoff Durable Response

49000801 Ibrutinib PR 18.661 1 Study cutoff Durable Response

82000203 Ibrutinib PR 18.661 1 Study cutoff Durable Response

32000104 Ibrutinib CR 17.708 1 Study cutoff Durable Response

42002503 Ibrutinib PR 17.018 1 Study cutoff Durable Response

70000803 Ibrutinib CR 16.723 1 Study cutoff Durable Response

49000301 Ibrutinib PR 16.690 1 Study cutoff Durable Response

36000204 Ibrutinib CR 16.624 1 Study cutoff Durable Response

70001801 Ibrutinib PR 16.624 1 Study cutoff Durable Response

57000103 Ibrutinib PR 16.559 1 Study cutoff Durable Response

57000102 Ibrutinib PR 16.164 1 Study cutoff Durable Response

33000403 Ibrutinib CR 15.277 1 Study cutoff Durable Response

32000204 Ibrutinib CR 15.211 1 Study cutoff Durable Response

34000203 Ibrutinib PR 14.982 1 Study cutoff Durable Response

70000105 Ibrutinib PR 14.949 1 Study cutoff Durable Response

49000402 Ibrutinib CR 14.817 1 Study cutoff Durable Response

82000303 Ibrutinib PR 14.620 1 Study cutoff Durable Response

88600102 Ibrutinib PR 14.620 1 Study cutoff Durable Response

31000101 Ibrutinib CR 14.587 1 Study cutoff Durable Response

42002506 Ibrutinib PR 14.587 1 Study cutoff Durable Response

49000401 Ibrutinib PR 14.587 1 Study cutoff Durable Response

55000105 Ibrutinib CR 14.587 1 Study cutoff Durable Response

70000402 Ibrutinib CR 14.587 1 Study cutoff Durable Response

44000208 Ibrutinib PR 14.554 1 Study cutoff Durable Response

70000804 Ibrutinib CR 14.554 1 Study cutoff Durable Response

11000403 Ibrutinib PR 14.522 1 Study cutoff Durable Response

42002504 Ibrutinib PR 14.522 1 Study cutoff Durable Response 82000305 Ibrutinib CR 14.522 1 Study cutoff Durable Response

49001205 Ibrutinib CR 14.390 1 Study cutoff Durable Response

35100205 Ibrutinib PR 14.357 1 Study cutoff Durable Response

33000301 Ibrutinib CR 14.292 1 Study cutoff Durable Response

42002305 Ibrutinib CR 14.094 1 Study cutoff Durable Response

32000702 Ibrutinib PR 12.452 1 Study cutoff Durable Response

36000303 Ibrutinib PR 12.485 1 Withdrew Durable Response consent

38000402 Ibrutinib PR 12.452 1 Withdrew Durable Response consent

48000503 Ibrutinib PR 11.828 0 Death Intermediate Response

36000102 Ibrutinib PR 10.612 0 PD Intermediate Response

70000301 Ibrutinib PR 10.513 0 PD Intermediate Response

33000502 Ibrutinib PR 10.415 0 PD Intermediate Response

70000801 Ibrutinib PR 10.415 0 PD Intermediate Response

82000401 Ibrutinib PR 8.476 0 PD Intermediate Response

34000701 Ibrutinib PR 8.411 0 PD Intermediate Response

46000110 Ibrutinib PR 8.345 0 PD Intermediate Response

70000603 Ibrutinib CR 8.312 0 PD Intermediate Response

32000502 Ibrutinib PR 8.279 0 PD Intermediate Response

11000404 Ibrutinib PR 8.115 0 PD Intermediate Response

44000501 Ibrutinib PR 7.885 0 PD Intermediate Response

31000102 Ibrutinib PR 6.801 0 PD Intermediate Response

55000401 Ibrutinib PR 6.538 0 PD Intermediate Response

46000406 Ibrutinib PR 6.341 0 PD Intermediate Response

82000101 Ibrutinib PR 6.275 0 PD Intermediate Response

33000402 Ibrutinib PR 6.242 0 PD Intermediate Response

39000402 Ibrutinib PR 6.144 0 PD Intermediate Response

46000107 Ibrutinib PR 5.848 0 PD Intermediate Response

70000102 Ibrutinib PR 5.585 0 PD Intermediate Response

34000402 Ibrutinib PR 4.534 0 PD Intermediate Response

44000207 Ibrutinib PR 4.271 0 PD Intermediate Response

48001506 Ibrutinib PR 4.238 0 PD Intermediate Response

48001504 Ibrutinib PR 4.172 0 PD Intermediate Response

55000103 Ibrutinib PR 4.107 0 PD Intermediate Response

46000401 Ibrutinib PR 4.074 0 PD Intermediate Response

49000602 Ibrutinib SD 3.187 0 Death Moderate Clinical

Benefit

88600104 Ibrutinib PR 3.055 0 Death Moderate Clinical

Benefit

46000204 Ibrutinib SD 2.366 0 Death Moderate Clinical

Benefit 38000501 Ibrutinib SD 2.300 0 Death Moderate Clinical

Benefit

49001501 Ibrutinib SD 1.708 0 Death Moderate Clinical

Benefit

34000405 Ibrutinib SD 10.218 0 PD Moderate Clinical

Benefit

44000205 Ibrutinib SD 8.411 0 PD Moderate Clinical

Benefit

55000402 Ibrutinib SD 8.312 0 PD Moderate Clinical

Benefit

38000701 Ibrutinib SD 7.425 0 PD Moderate Clinical

Benefit

11000101 Ibrutinib SD 6.308 0 PD Moderate Clinical

Benefit

39000103 Ibrutinib SD 6.308 0 PD Moderate Clinical

Benefit

42002502 Ibrutinib PR 3.680 0 PD Moderate Clinical

Benefit

11000102 Ibrutinib SD 3.285 0 PD Moderate Clinical

Benefit

57000104 Ibrutinib SD 2.136 0 PD Moderate Clinical

Benefit

70001102 Ibrutinib SD 20.074 1 Study cutoff Moderate Clinical

Benefit

70001803 Ibrutinib SD 14.587 1 Study cutoff Moderate Clinical

Benefit

70001203 Ibrutinib SD 14.522 1 Study cutoff Moderate Clinical

Benefit

36000401 Ibrutinib PD 2.760 0 PD PD

70001101 Ibrutinib PD 2.136 0 PD PD

70001301 Ibrutinib PD 2.136 0 PD PD

32000301 Ibrutinib PD 2.103 0 PD PD

49000101 Ibrutinib PD 2.103 0 PD PD

49000503 Ibrutinib PD 2.103 0 PD PD

49000502 Ibrutinib PD 2.037 0 PD PD

44000605 Ibrutinib PD 1.906 0 PD PD

44000106 Ibrutinib PD 1.774 0 PD PD

11000201 Ibrutinib PD 1.708 0 PD PD

35100401 Ibrutinib PD 1.216 0 PD PD

46000201 Ibrutinib PD 1.051 0 PD PD

48001301 Ibrutinib PD 0.756 0 PD PD

70000103 Ibrutinib PD 0.460 0 PD PD

44000303 Ibrutinib PD 0.361 0 PD PD

44000502 Ibrutinib NED 12.320 0 PD NED 82000402 Ibrutinib NED 20.074 1 Study cutoff NED

48001510 Ibrutinib NE 3.055 0 Death NE

46000106 Ibrutinib NE 2.464 0 Death NE

38000101 Ibrutinib NE 2.004 0 Death NE

35300103 Ibrutinib NE 1.676 0 Death NE

88600501 Ibrutinib NE 0.460 0 Death NE

46000108 Ibrutinib NE 0.230 0 Death NE

39000405 Ibrutinib NE 0.033 1 Withdrew NE consent

[0123] The samples sequenced are shown in Table 26.

Table 26

Ibrutinib 38000703 Screening Screening DS-197841

Ibrutinib 38000703 Progression/EOT EOT DS-197798

Ibrutinib 39000101 C1D1 C1D1 DS-197649

Ibrutinib 39000102 Screening Screening DS-197783

Ibrutinib 39000103 Progression/EOT Progression DS-197627

Ibrutinib 39000202 C2D1 C2D1 DS-198095

Ibrutinib 39000402 Progression/EOT Progression DS-197832

Ibrutinib 42002401 Screening Screening DS-197813

Ibrutinib 42002501 Screening Screening DS-199385

Ibrutinib 42002502 C1D1 C1D1 DS-199371

Ibrutinib 42002502 Progression/EOT EOT DS-197586

Ibrutinib 42002503 Screening Screening DS-197850

Ibrutinib 42002504 Screening Screening DS-197613

Ibrutinib 42002506 C1D1 C1D1 DS-197741

Ibrutinib 44000205 Screening Screening DS-197642

Ibrutinib 44000205 Progression/EOT Progression DS-197668

Ibrutinib 44000207 C1D1 C1D1 DS-197797

Ibrutinib 44000208 Screening Screening DS-197660

Ibrutinib 44000501 Screening Screening DS-197724

Ibrutinib 44000605 Screening Screening-?? DS-197633

Ibrutinib 44000605 Progression/EOT EOT DS-197609

Ibrutinib 44001005 Screening Screening DS-197870

Ibrutinib 44001005 Progression/EOT EOT DS-197824

Ibrutinib 46000106 C1D1 C1D1 DS-197823

Ibrutinib 46000107 C1D1 C1D1 DS-197808

Ibrutinib 46000108 C1D1 C1D1 DS-199448

Ibrutinib 46000204 Screening Screening DS-197594

Ibrutinib 46000204 Progression/EOT EOT DS-197763

Ibrutinib 46000401 Screening Screening DS-197807

Ibrutinib 46000401 C1D1 C1D1 DS-197646

Ibrutinib 46000401 Progression/EOT EOT DS-197704

Ibrutinib 46000405 Screening Screening DS-199378

Ibrutinib 46000406 Screening Screening DS-197710

Ibrutinib 48000403 Screening Screening DS-197748

Ibrutinib 48000403 Progression/EOT Progression/EOT DS-197777

Ibrutinib 48000503 C1D1 C1D1 DS-197861

Ibrutinib 48000503 Progression/EOT EOT DS-197784

Ibrutinib 48001301 Screening Screening DS-197811

Ibrutinib 48001505 Screening Screening DS-199392

Ibrutinib 48001510 Screening Screening DS-197607 Ibrutinib 48001510 C1D1 C1D1 DS-197610

Ibrutinib 49000101 Progression/EOT EOT DS-197796

Ibrutinib 49000301 Screening Screening DS-197801

Ibrutinib 49000401 Screening Screening DS-197624

Ibrutinib 49000402 C2D1 C2D1 DS-197665

Ibrutinib 49000503 Screening Screening DS-197579

Ibrutinib 49000503 C1D1 C1D1 DS-197617

Ibrutinib 49000503 Progression/EOT Progression DS-197806

Ibrutinib 49000602 Screening Screening DS-199422

Ibrutinib 49000602 C1D1 C1D1 DS-199393

Ibrutinib 49000801 Screening Screening DS-197595

Ibrutinib 49001001 C2D1 C2D1 DS-197804

Ibrutinib 49001202 Screening Screening DS-199396

Ibrutinib 49001205 Screening Screening DS-197776

Ibrutinib 49001501 C2D1 C2D1 DS-198121

Ibrutinib 49001501 Progression/EOT EOT DS-197767

Ibrutinib 55000103 Screening Screening DS-199386

Ibrutinib 55000103 Progression/EOT EOT DS-197576

Ibrutinib 55000106 Screening Screening DS-197761

Ibrutinib 55000401 Progression/EOT Progression DS-197662

Ibrutinib 57000103 Screening Screening DS-197632

Ibrutinib 57000104 Progression/EOT Progression-(BM) DS-197816

Ibrutinib 70000601 Progression/EOT EOT DS-198102

Ibrutinib 70000701 C2D1 C2D1 DS-197677

Ibrutinib 70000801 Screening Screening DS-197643

Ibrutinib 70001101 Screening Screening DS-197818

Ibrutinib 70001101 Progression/EOT Progression DS-197684

Ibrutinib 70001801 C2D1 C2D1 DS-197757

Ibrutinib 82000101 Screening Screening DS-197758

Ibrutinib 82000102 C3D1 C3D1 DS-197626

Ibrutinib 82000203 C2D1 C2D1 DS-197726

Ibrutinib 82000303 Screening Screening DS-197770

Ibrutinib 82000305 Screening Screening DS-197715

Ibrutinib 82000401 C1D1 C1D1 DS-197648

Ibrutinib 82000401 Progression/EOT EOT DS-197580

Ibrutinib 82000501 C3D1 C3D1 DS-197846

Ibrutinib 82000502 Screening Screening DS-197831

Ibrutinib 88600102 Screening Screening DS-197751

Ibrutinib 88600104 Screening Screening DS-197618

Ibrutinib 88600401 Screening Screening DS-199375 Summary of MCL2001 and MCL3001 studies

[0124] Genes with mutations in MCL from primary resistance (PR) and acquired resistance (AR) analyses are summarized in Table 27 below.

Table 27

RELB MAPK3 TRAF3

CCND3 MTOR

CSK MYC

MCL1 NR2C2

ERBB2 STAT3

TEC

TNFRSF 11A

TNFRSF 13C

TRAF3

* Genes ranked by p-value for Ibrutinib arm only where odds ratio < 1 (mutation enrichment in PD+intermediate response group)

** Genes with mutations in the acquired resistance analysis ranked from most mutations to fewest

Source Filter

MCL2001 PR LabCorp, Filter 5 (31MAR2015 data)

MCL3001 PR LabCorp, Filter 5

MCL2001 AR LabCorp, Filter 5 (31MAR2015 data)

MCL3001 AR LabCorp, Filter 5

[0125] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

[0126] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

EMBODIMENTS

The following list of embodiments is intended to complement, rather than displace or supersede, the previous descriptions.

Embodiment 1. A method of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma, comprising:

b) ERBB2, MLL2, CARD 1 1, JAK3, PLCG2, ITK, NOTCH 1, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB 3, AKT1, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSF11A, TNFRSF 13C, TRAF3, KMT2D, MALT1, MYD88, PRDM1, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, IKBKB, JAK2, TAB2, TNFSF 13B, TRAF2, or any combination thereof; or

c) any combination of the one or more genes from groups a) and b);

wherein the assaying comprises:

enriching the DNA for the one or more genes; and

sequencing the DNA,

wherein the patient has a likelihood of responsiveness to treatment with ibrutinib if a mutation in the one or more genes is not detected.

Embodiment 2. The method of embodiment 1, wherein the assessing is performed on the one or more genes from group a) prior to initiation of ibrutinib therapy, following initiation of ibrutinib therapy, or both.

Embodiment 3. The method of embodiment 1, wherein the assessing is performed on the one or more genes from group b) following initiation of ibrutinib therapy. Embodiment 4. The method of embodiment 1, wherein the assessing is performed on the one or more genes from group c) prior to initiation of ibrutinib therapy and following initiation of ibrutinib therapy.

Embodiment 5. The method of any one of the previous embodiments, further comprising treating the patient with ibrutinib if a mutation in the one or more genes is not detected. Embodiment 6. The method of any one of the previous embodiments, wherein the mantle cell lymphoma is relapsed mantle cell lymphoma, refractory mantle cell lymphoma, or both.

Embodiment 7. The method of any one of the previous embodiments, wherein the patient has progressed after bortezomib therapy.

Embodiment 8. The method of any one of the previous embodiments, wherein the patient has received at least one prior rituximab-chemotherapy regimen.

Embodiment 9. A method of treating a patient having mantle cell lymphoma comprising: administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in one or more genes selected from PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF 11A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSCl, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKTl, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, ERBB2, CARD 1 1, BCL6, STAT6, MTTP, RET, TAB3, ATM, BIRC3, STAT3, TEC, TNFRSF 13C, KMT2D, MALTl, PRDMl, TRAF4, RET, EZH2, IKBKB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof.

Embodiment 10. The method of embodiment 9, further comprising assessing a DNA

sample from the patient for the presence or absence of a mutation in the one or more genes.

Embodiment 11. The method embodiment 10, wherein the assessing is performed prior to the administering, following the administering, or both.

Embodiment 12. The method of any one of embodiments 9-1 1, wherein the mantle cell lymphoma is relapsed mantle cell lymphoma, refractory mantle cell lymphoma, or both. Embodiment 13. The method of any one of embodiments 9-12, wherein the patient has progressed after bortezomib therapy. Embodiment 14. The method of any one of embodiments 9-13, wherein the patient has received at least one prior rituximab-chemotherapy regimen.

Claims

What is Claimed:

1. A method of predicting a likelihood of responsiveness to treatment with ibrutinib in a patient having mantle cell lymphoma, comprising:

d) PIMl kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSFl 1A, NFKBIA, REL, CD79A, MYD88, PLCG2, CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKT1, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, or any combination thereof;

e) ERBB2, MLL2, CARD 11, JAK3, PLCG2, ITK, NOTCH 1, TP53, BCL6, CREBBP, MAP3K14, MET, RELB, STAT6, BIRC2, CCND3, CD79A, EGFR, EP300, MTTP, NFKBIA, RET, TAB 3, AKT1, ATM, BIRC3, CD40, CDKN2A, CYLD, LCK, MAP3K7, MAPK3, MTOR, MYC, NR2C2, STAT3, TEC, TNFRSFl 1A, TNFRSFl 3 C, TRAF3, KMT2D, MALT1, MYD88, PRDM1, RELB, TRAF4, MTOR, RET, STAT6, ERBB4, EZH2, IKBKB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof; or

f) any combination of the one or more genes from groups a) and b);

wherein the assaying comprises:

enriching the DNA for the one or more genes; and

sequencing the DNA,

2. The method of claim 1, wherein the assessing is performed on the one or more genes from group a) prior to initiation of ibrutinib therapy, following initiation of ibrutinib therapy, or both.

3. The method of claim 1, wherein the assessing is performed on the one or more genes from group b) following initiation of ibrutinib therapy.

4. The method of claim 1, wherein the assessing is performed on the one or more genes from group c) prior to initiation of ibrutinib therapy and following initiation of ibrutinib therapy.

5. The method of any one of the previous claims, further comprising treating the patient with ibrutinib if a mutation in the one or more genes is not detected.

6. The method of any one of the previous claims, wherein the mantle cell lymphoma is relapsed mantle cell lymphoma, refractory mantle cell lymphoma, or both.

7. The method of any one of the previous claims, wherein the patient has progressed after bortezomib therapy.

8. The method of any one of the previous claims, wherein the patient has received at least one prior rituximab-chemotherapy regimen.

9. A method of treating a patient having mantle cell lymphoma comprising:

administering a pharmaceutically effective dose of ibrutinib to the patient, wherein the patient does not have a mutation in one or more genes selected from PIM1 kinase, MTOR, TAB2, MAP3K14, TRAF3, TNFRSF 11A, NFKBIA, REL, CD79A, MYD88, PLCG2,

CREBBP, MLL2, WHSC1, BCL2, ERBB4, MYC, ITK, EGFR, JAK3, EP300, BIRC2, TP53, TRAFl, BLK, GRB2, MAP3K7, MAPK3, RIPK1, TRAF5, TRAF6, UGT1A1, NOTCH1, AKTl, PRKCB, BMX, CHEK2, NFKBIB, VEGFA, CD40, NFKB2, NR2C2, RELB, CCND3, CSK, MCL1, ERBB2, TNFAIP3, CDKN2A, EZH2, LCK, CYLD, STAT6, MET, ERBB2, CARD 1 1, BCL6, STAT6, MTTP, RET, TAB3, ATM, BIRC3, STAT3, TEC, TNFRSF 13C, KMT2D, MALTl, PRDMl, TRAF4, RET, EZH2, IKBKB, JAK2, TAB2, TNFSF13B, TRAF2, or any combination thereof.

10. The method of claim 9, further comprising assessing a DNA sample from the patient for the presence or absence of a mutation in the one or more genes.

11. The method claim 10, wherein the assessing is performed prior to the administering, following the administering, or both.

12. The method of any one of claims 9-1 1, wherein the mantle cell lymphoma is relapsed mantle cell lymphoma, refractory mantle cell lymphoma, or both.

13. The method of any one of claims 9-12, wherein the patient has progressed after bortezomib therapy.

14. The method of any one of claims 9-13, wherein the patient has received at least one prior rituximab-chemotherapy regimen.