CN101259129A - Combined treatment for acute leukemia and myelodysplastisches syndrom - Google Patents
Combined treatment for acute leukemia and myelodysplastisches syndrom Download PDFInfo
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Abstract
The invention provides a therapeutic method of acute leukaemia such as acute medullary leukaemia and myeloproliferative disorder syndrom and a medicinal composition thereof. Anti-CD33 cytotoxic conjugate and at least one compound selected from anthracycline and pyrimidine or purine nucleoside analogs are adopted by the therapeutic method and the medicinal composition Gemtuzumab ozogamicin, daunomycin and cytosine arabinoside are adopted in a preferential therapeutic method and medicinal composition.
Description
The application be that November 6, application number in 2002 are 02830140.4 the applying date, denomination of invention divides an application for the application for a patent for invention of " combined therapy of acute leukemia and myelodysplastic syndrome ".
Invention field
The Therapeutic Method and the drug regimen of treatment acute leukemia, particularly acute myelogenous leukemia and myelodysplastic syndrome are provided.Therapeutic Method and drug regimen are united to have adopted and are resisted-CD33 peptide-cytotoxic conjugates and at least a chemical compound that is selected from anthracycline and pyrimidine or purine nucleoside analogs, particularly, gemtuzumab Ozogamicin Mylotarg CDP 771 (gemtuzumab ozogamicin), daunorubicin and cytosine arabinoside.
Background of invention
Acute leukemia generally is fast-developing leukemia, and the blast cell that it is characterized by the clone who is derived from the hematopoietic stem cell vicious transformation substitutes normal bone marrow.Two kinds of acute leukemia are arranged at present, i.e. acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML).ALL is a malignant tumor the most general among the child, but adolescence also can fall ill and have second than low peak in the adult.AML also claims acute myeloid leukaemia and acute myeloid leukemia, be more common acute leukemia and increase with its sickness rate of age growth among the adult, but AML also can occur among the child.For two kinds of acute leukemia, the basic goal of treatment is to realize alleviating fully, clinical off-note disappears, and the normal plasma cell that recovers normal plasma cell counting and bone marrow generates, wherein blast cell＜5%, neutrophil cell counting＞1,000-1,500, platelet count＞100,000, and the leukemia clone disappears; Yet the pharmacotherapy of treatment ALL and AML was with in the past different.The?MerckManual，Sec.11，Ch.138(17
th?ed.1997)；Estey，E.，Cancer(2001)92(5)：1059-1073。Initial therapy is intended to inducer remission.Treatment AML is that with the main distinction of treatment ALL AML patient reacts and the relapse rate height medicine generation still less.
The AML patient of alleviating lives more for a long time than the patient of not alleviating fully fully.Have only the patient of alleviating fully to cure potentially, if their alleviation was fully kept 3 years at least.Estey，E.，Cancer(2001)92(5)：1059，1060。AML patient's alleviation inductivity is 50 to 85%, and the patient above 50 years old, especially those surpass 65 years old the then difficult acquisition alleviation of patients.The patient of low percentage ratio (20-40%) understands long-term anosis survival, and described percentage ratio rises to 40-50% in the young patient of bone marrow transplantation treatment.Secondary cases AML patient prognosis mala.The?Merck?Manual，Sec.11，Ch.138(17
th?Ed，1997).
There are a lot of problems in treatment AML, because the normal stem cell precursor is to used reagent sensitivity, and can cause the normal stem cell storehouse by partial destruction at myelogenous leukemia clone's treatment.Usually strong chemotherapy may inducer remission.There are the young patient of person maximum 80% and gerontal patient's (they have constituted AML patient's main body) of about 50% can reach alleviation fully, but the patient bears the misery of serious neutropenia in inducing process, and remission rate is somewhat dependent upon the standard of assisted care.There is patient's the remission rate of unfavorable prognosis factor lower, the secondary AML of described factor such as weak body constitution, myelodysplasia or antitumor agent, numeration of leukocyte height, wide spectrum drug resistance feature and disadvantageous cytogenetics.
B., wait the people, N.Engl..J.Med. (1999) 341:1051-62; Correction. the same; 1484.Still the medical demand of unsatisfied maximum is present among the AML patient more than 70 years old.To these old AML patients, alleviate fully and may compare difficulty, but the quality of life of improving them is purposes that treatment will reach.
Established therapy is based on cytosine arabinoside (a kind of pyrimidine nucleoside analoys) and anthracycline daunorubicin.
B., wait the people, N.Engl..J.Med. (1999) 341:1051-62; Correction. the same; 1484; Burnett, A.K.﹠amp; Eden O.B., Lancet (1997) 349:270-275; Hiddemann, W., Deng the people, J.Clin.Oncol. the initial successful therapy of (1999) 17:3569-76. has also comprised the existing thioguanine that is still used by some medical centre, although the main flow viewpoint thinks that it does not bring extra advantage and thioguanine to be removed from a lot of induction schemes.The substitute of daunorubicin comprises darubicin and mitoxantrone.
B., wait the people, N.Engl..J.Med. (1999) 341:1051-62; Correction. the same; 1484.Etoposide has been added in cytosine arabinoside and the daunorubicin induction scheme, and effect has raising in young patient.
The basic antilepsis of treatment AML comprises continuous 7 days intravenous (IV) infusion cytosine arabinosides, and intravenous is used anthracycline such as daunorubicin or darubicin 3 days during this period, uses at initial 3 days usually.The?Merck?Manual，Sec.11，Ch.138(17
thed.1997)。The therapy of this treatment AML that is widely adopted is called as the 3+7 therapy, and can obtain the complete remission rate of 60-80%.De Nully Brown, P. waits the people, Leukemia (1997) 11:37-41.Treatment causes significant bone marrow depression usually, keeps for a long time before bone marrow recovers usually.The unfavorable result of other of these two kinds of medicines comprises chemical arachnoiditis, myocardial toxicity and neurotoxicity.Antilepsis can repeat, and maximum altogether usually 3 times, to reach alleviation.Before the superinduce therapy, to do a bone marrow analysis behind the fortnight on finishing after antilepsis.If bone marrow is eliminated, that is, reaction is completely arranged, the doctor should wait until after the peripheral blood of patients cell counting recovers and implement another antilepsis more so.If the bone marrow analysis shows disease and still exists promptly, part or minimum reaction are arranged, so can the superinduce therapy and needn't wait the peripheral blood of patients cell counting to recover.So, for a complete reaction person, between two antilepsises the waiting period be 28 to 35 days, be 14 to 21 days for partial reaction and minimal reaction person.For the patient of AML recurrence, the standard inductive treatment of cytosine arabinoside and daunorubicin does not have to produce good response rate, general＜40%, and these patients' poor prognosis.
After the state of an illness is eased, can adopt second therapeutic scheme that uses same medicine or other drug dispelling disease, be called as and consolidate therapy.But the patient of very high percentage ratio is subjected to the torment of disease relapse, even also be like this when consolidating the chemotherapy coupling after alleviation.DeNully Brown, P. waits the people, Leukemia (1997) 11:37-41.
Current trend tends to adopt stronger antilepsis.Someone reports with the cytosine arabinoside of standard dose and compares, and every day is with at most every 12 hours 3g/m in maximum 6 days
2Dosage use the cytosine arabinoside dosage (with daunorubicin and etoposide) of high dose to improve to alleviate the duration for the first time and do not have disease and survive.Bishop, J.F. waits the people, Blood (1996) 87:1710-1717.The arrangement of time of induction duration is no less important perhaps: compare at interval with 14 days of standard or more time, enhanced arrangement of time (wherein second circulate in first circulate carried out in back 10 days) improved anosis survival, although the relevant death of more toxicity occurred.Woods, W.G. waits the people, Blood (1996) 87:4979-4989.
In a single day alleviate and induced, further treatment (alleviating the back treats) is absolutely necessary to preventing recurrence.
B., wait the people, N.Engl..J.Med. (1999) 341:1051-62; Correction. the same; 1484; Burnett, A.K.﹠amp; Eden O.B., Lancet (1997) 349:270-275; Hiddemann, W. waits the people, J.Clin.Oncol. (1999) 17:3569-76.Viewpoint comprises further chemotherapy, perhaps allos or autologous bone marrow transplantation.According to these viewpoints, when alleviating the first time that is applied to the patient, perhaps about 50% long-term surviving can reach.But, adopt which kind of viewpoint also to have dispute.The most successful chemotherapy regimen uses high dose cytosine arabinoside maximum four courses of treatment, and seems suitable with bone marrow transplantation from the survival aspect.Mayer, people such as R.J., N.Engl.J.Med. (1994) 331:896-903; Cassileth, P.A. waits the people, N.Engl.J.Med. (1998) 339:1649-1656.So the someone supports to strengthen the scheme of alleviating the later stage chemotherapy, and transplanting is left for follow-up recurrence, especially those have favourable cytogenetic patient.Edenfield，W.J?&?Gore，S.D.，Semin.Oncol.(1999)26：21-34。
Another medicine that treatment AML uses be gemtuzumab Ozogamicin Mylotarg CDP 771 (
).In May, 2000, gemtuzumab Ozogamicin Mylotarg CDP 771 was at the U.S. gets permission to treat 60 years old or the above patient that can not consider other cytotoxicity chemotherapy alternatives is recurred first AML.9mg/m
2Gemtuzumab Ozogamicin Mylotarg CDP 771 use in the mode of two hours intravenous infusions.Can behind fortnight, use for second dose.Alleviate though many patients that accept gemtuzumab Ozogamicin Mylotarg CDP 771 have reached fully, yet a considerable amount of patient's platelet recovery postpones or platelet recovery is incomplete.Physician’s?Desk?Reference(56
th?ed.2002)。Hepatic veno-occlusive disease that may be fatal (VOD) has carried out in the middle of the patient of stem cell transplantation after having occurred in the gemtuzumab Ozogamicin Mylotarg CDP 771 treatment.Tack, people such as D.K., Bone MarrowTransplantation (2001) 28 (9): 895-897.Also there is the people to report in July calendar year 2001, accepted patient that gemtuzumab Ozogamicin Mylotarg CDP 771 do not carry out stem cell transplantation develop the danger of remarkable hepatotoxicity and possible sickness rate or mortality rate risen similar 10%, although untested combination or exceeded the gemtuzumab Ozogamicin Mylotarg CDP 771 of the scope of application of indicating before wherein Most patients has been accepted.Giles, F.J. waits the people, and Cancer (2001) 92 (2): 406-413.As the cytosine arabinoside-daunorubicin antilepsis of standard, AML recurrence patient is to response rate possibility＜40% of gemtuzumab Ozogamicin Mylotarg CDP 771 treatment.
The existing people of gemtuzumab Ozogamicin Mylotarg CDP 771 combined therapy attempts and obtains limited success.In a research, by at the 1st day and the 15th day 9mg/m
22 hours intravenous infusions of the gemtuzumab Ozogamicin Mylotarg CDP 771 of dosage are used to the gerontal patient who AML is not treated before this, (between the 28th day and the 35th day behind the last infusion) uses the MICE (mitoxantrone, cytosine arabinoside and etoposide) of one or two course of treatment in 7 days after reaction is estimated to gemtuzumab Ozogamicin Mylotarg CDP 771.The unfavorable result of significant non-blood comprises VOD (6%), arrhythmia (6%) and infection (24%) etc.Whole when inducing EP (end of program), 13 patients are alleviated (38.2%) fully, have realized incomplete alleviate fully (8.8%) of platelet recovery for 3, and the general reaction rate is 47%, and existing relatively AML treatment does not improve.Amadori, S., Deng the people, " Sequential Administrationof Gemtuzumab Ozogamicin (GO) and Intensive Chemotherapy forRemission Induction in Previously Untreated Patients with AMLover the Age of 60:Interim Results of the EORTC Leukemia GroupAML-15A Phase II Trial, " Blood (2001) 98:587a.
In another research, the AML patient of prognosis mala (＞70 years old, toxicity irradiation back myelodysplasia, leukemia are still in development) or according to the scheme treatment of " AML 9503 " by name, the patient accepts twice chemotherapy " pulse " in this scheme, at every turn by 2gm/m
2Cytosine arabinoside (high dose cytosine arabinoside) is used during in time=0 and time=12 hour, and uses 35mg/m immediately after using second dose of cytosine arabinoside
2Mitoxantrone form, use after 96 hours second " pulse ", perhaps according to the scheme treatment of " AML 9798 " by name, the patient accepts twice chemotherapy " pulse " in this scheme, at every turn by 2gm/m
2Cytosine arabinoside is used during in time=0 and time=12 hour, and uses 35mg/m immediately after using second dose of cytosine arabinoside
2Mitoxantrone form, use after 96 hours second " pulse ", use Amifostine then.And AML 9703 complete remission rates are 30%, and AML 9798 is 40%.If it is 9mg/m that chemotherapy makes in preceding 3 days additions of first chemotherapy pulse
2Single agent gemtuzumab Ozogamicin Mylotarg CDP 771, so have two to enter fully and alleviate among the AML patient that four refractory of treatment are healed.Preisler, H .D. waits the people, " Synergistic Antileukemia Effects of Mylotarg andChemotherapy in AML, " Blood (2001) 98:193b.
In a feasibility study,＜60 years old patient accepts H-DAT 3+10 therapy (the 1st, 3,5 day 45mg/m
2Daunorubicin; 1-10 days every days twice (bd) 400mg/m
2Cytosine arabinoside; 1-10 days every days twice 100mg/m
2Thioguanine) and gemtuzumab Ozogamicin Mylotarg CDP 771 (the 1st day 3 or 6mg/m
2Use with 2 hours infusions).Be H-DAT 3+8 second course of treatment, and gemtuzumab Ozogamicin Mylotarg CDP 771 dosage is identical with the course of treatment 1.Though can both tolerate 3mg/m in two therapies
2And 6mg/m
2The gemtuzumab Ozogamicin Mylotarg CDP 771 of dosage, but the gemtuzumab Ozogamicin Mylotarg CDP 771 of using when first course of treatment is 6mg/m
2The Shi Kejian hepatotoxicity raises, and therefore 3mg/m is used in decision since then the 1st and the 2nd course of treatment
2Gemtuzumab Ozogamicin Mylotarg CDP 771.Kell, J.W. waits the people, " Effects of Mylotarg
TM(GemtuzumabOzogamicin, GO) in Combination with Standard InductionChemotherapy in the Treatment of Acute Myeloid Leukaemia (AML): A Feasibility Study, " Blood (2001) 98:123a-124a.
In further research,＜60 years old patient accept H-DAT 3+10 (the 1st, 3,5 day once a day intravenous slowly advance 50mg/m
2Daunorubicin; 1-10 days every days, twice intravenous advanced 200mg/m
2Cytosine arabinoside; 1-10 days every days twice oral 100mg/m
2Thioguanine) or S-DAT 3+10 (the 1st, 3,5 day once a day intravenous slowly advance 50mg/m
2Daunorubicin; 1-10 days every days, twice intravenous advanced 100mg/m
2Cytosine arabinoside; 1-10 days every days twice oral 100mg/m
2Thioguanine) adds 3 or 6mg/m
2Gemtuzumab Ozogamicin Mylotarg CDP 771 as inductive treatment.H-DAT 3+8 (the 1st, 3,5 day once a day intravenous slowly advance 50mg/m
2Daunorubicin; 1-8 days every days, twice intravenous advanced 200mg/m
2Cytosine arabinoside; 1-10 days every days twice oral 100mg/m
2Thioguanine) or S-DAT 3+8 (the 1st, 3,5 day once a day intravenous slowly advance 50mg/m
2Daunorubicin; 1-8 days every days, twice intravenous advanced 100mg/m
2Cytosine arabinoside; 1-10 days every days twice oral 100mg/m
2Thioguanine) have or do not have 3mg/m second course of treatment
2Use during gemtuzumab Ozogamicin Mylotarg CDP 771.After treatment is by MACE (MACE: one hour once a day infusion 100mg/m
2Amsacarine (1-5 days in 5% glucose solution); 1-5 days continuous once a day intravenous infusion 200mg/m
2Cytosine arabinoside, 1-5 days one hour once a day intravenous infusion 100mg/m
2Etoposide) chemotherapy is formed, and wherein has or do not have 3mg/m
2Gemtuzumab Ozogamicin Mylotarg CDP 771.First course of treatment and the patient who accepts gemtuzumab Ozogamicin Mylotarg CDP 771 second course of treatment have the hematology to go up restitution delay and VOD, wherein people's death.6mg/m
2Gemtuzumab Ozogamicin Mylotarg CDP 771 dosage is also relevant with the hepatotoxicity that raises.The conclusion that draws is 3mg/m
2Gemtuzumab Ozogamicin Mylotarg CDP 771 can be used in first course of treatment with H-DAT 3+10, can use in the 3rd course of treatment with MACE, but two gemtuzumab Ozogamicin Mylotarg CDP 771 courses of treatment or gemtuzumab Ozogamicin Mylotarg CDP 771 dosage is increased to 6mg/m in inducing
2Relevant with the toxicity that raises, do not recommend to use.Burnett, A.K. and Kell, J., " TheFeasibility of Combining Immunoconjugate and Chemotherapy inAML, " Hematology J. (June 2002) Vol.3, supp.1, p.156.
In the preliminary study of another assessment safety and effectiveness, with gemtuzumab Ozogamicin Mylotarg CDP 771 with the combined therapy of cytosine arabinoside in be applied to the AML patient of healing greater than 60 years old New Development and recurrence/refractory.By at the 1st to 7 day with 100mg/m
2/ day amount carry out the cytosine arabinoside of continuous infusion, and at the 1st and 15 day with 6mg/m
2The gemtuzumab Ozogamicin Mylotarg CDP 771 of the amount in/sky carries out continuous infusion and comes 6 patients are treated.Although described combination is well tolerated, 4 deaths.In order to reduce the myelosuppressive persistent period after the antilepsis, used gemtuzumab Ozogamicin Mylotarg CDP 771 at the 1st and 8 day, the 1st day consumption is 6mg/m
2, the 8th day consumption is 4mg/m
2In 7 patients that carried out treatment, realized for 3 alleviating completely.Durrant, people such as S., Proc.Amer.Soc.Clin.Oncol. (2002) 21:271a.
In order to evaluate safety and the effectiveness of gemtuzumab Ozogamicin Mylotarg CDP 771, once carried out the I/II phase of making up gemtuzumab Ozogamicin Mylotarg CDP 771, cytosine arabinoside and daunorubicin and studied in the U.S. as the part of AML combined therapy.The I phase part of research is in October, 2000, and the preliminary report electronic edition is published in the 43rd American Society of Hematology AnnualMeeting in November 6 calendar year 2001 and prints November 7 calendar year 2001.DeAngelo, D. waits the people, " Preliminary Report of the Safety and Efficacy of GemtuzumabOzogamicin (
) Given in Combination with Cytarabineand Daunorubicin in Patients with Acute MyeloidLeukemia ", Blood (2001) 98:199 (b).This report has been described the 1st to 7 day continuous infusion 100mg/m
2/ day cytosine arabinoside was used 45mg/m on the the 1st to 3 day
2Daunorubicin and used 6mg/m on the 4th day
2Three patients of gemtuzumab Ozogamicin Mylotarg CDP 771 (dosage group 1) treatment, a New Development (de novo) AML, two AML that recurrence/refractory is healed.This combination can be tolerated well, does not observe dose limitation toxicity (DLT), and two patients reach alleviation.Three recurrence/refractory AML patient of healing joins next dosage group subsequently, and the gemtuzumab Ozogamicin Mylotarg CDP 771 dosage of this group is brought up to 9mg/m
2(dosage group 2), this combination can be by fine tolerances, but three patients all are the nonresponder.6 patients that increase, three New Development AML and AML that three recurrence/refractory by name are healed participates in 9mg/m
2In the dosage level test.Treatment is tolerated again well, and does not see DLT.But relevant ALT/AST rising of two 3 grades of non-medicines and the outbreak of two 4 grades non-medicine related breathing difficulties appear.All three New Development AML patients have reached alleviation and have reset into ANC＞1500/ μ L and platelet＞100,000/ μ L respectively at the 26th, 28 and 36 day.The patient joins next dosage group then, and wherein the dosage of cytosine arabinoside increases to 200mg/m
2/ day (dosage group 3).The combination infusion therapy can be tolerated well, has 4 to observe DLT but enter among 6 patients of this group, the AML patient that refractory is healed after finishing inductive treatment soon just development for liver VOD and in death in the 28th day.Another New Development AML patient is dead and also have reversible 3 grades of ALT to raise because of asystole in the 24th day.According to the inference as a result of front, 6 patients of increase should join dosage group 1 with the expansion data of safety, and if discovery 100mg/m
2/ day cytosine arabinoside, 45mg/m
2Daunorubicin and 6mg/m
2The combination of gemtuzumab Ozogamicin Mylotarg CDP 771 can be by fine tolerance in this expanded set, and the II phase of this research partly starts so, and has about 45 New Development AML patients to add.DeAngelo, D. waits the people, sees above.Can not determine 100mg/m based on the patient who adds I phase study portion limited quantity
2/ day cytosine arabinoside, 45mg/m
2Daunorubicin and 6mg/m
2The effect of the combination of gemtuzumab Ozogamicin Mylotarg CDP 771 can not be determined the effect of this combination with respect to AML standard chemotherapy.
Myelodysplastic syndrome (MDS) is one group of syndrome (preleukemia, refractory anemia, the negative chronic granulocytic leukemia of Ph-, chronic myelomonocytic leukemia, an agnogenic myeloid metaplasia), is common in＞50 years old patient.Its sickness rate is not clear, but is increasing always, may be partly owing to the rising of crowd person in middle and old age population ratio and the leukemic increase of treatment dependency.Contact benzene may be relevant with its development with radiation.At some secondary leukemic early stage (for example, behind contact medicine or the poisonous substance), the visible hypogenetic diagnostic characteristic of cell spinal cord that change or defective.
The?Merck?Manual，Sec.11，Ch.138(17
thed.1997)。
The feature of MDS is the hematopoietic cell clonal expansion, comprise erythrocyte class, bone marrow and the megalokaryocyte form.Normal or the hypercellularity of bone marrow, and invalid hemopoietic causes various kinds of cell to reduce disease, the most normal generation is anemia.The cells produce disorder also with bone marrow and blood in cellular morphology relevant unusually.Extramedullary hemopoiesis may take place, and causes hepatomegaly and splenomegaly.Myelofibrosis appears in the diagnosis once in a while or may develop in mds process.MDS clones unstable and easily develops into AML.FAB classification and any relevant disease are depended in MDS patient's prognosis to a great extent.Refractory anemia patient or unlikely develop into more invasive form with the refractory anemia patient of Sideroblast may die from incoherent reason.
The?Merck?Manual，Sec.11，Ch.138(17th?ed.1997)。
Now also do not set up the Therapeutic Method of MDS.Treatment is carried out RBC blood transfusion, platelet transfusion for supportive to bleeding, antibiotic therapy is carried out in infection.In some patients, (erythropoietin is supported needs, the serious symptomatic granulocytopenia of granulocyte colony-stimulating factor support management at erythrocyte (red blood) center to cytokine therapy, if of course, thrombopoietin support serious symptom thrombocytopenia) can be used as important hemopoietic holder.Right＞patient of 50 years old does not recommend to carry out the allos bone marrow transplantation.Colony stimulating factor (for example, granulocyte colony-stimulating factor, granulocyte-macrophage colony stimutaing factor) has increased the neutrophil cell counting, and the RBC that erythropoietin has increased in 20 to 25% cases generates, but does not demonstrate the survival advantage.If considered age and caryogram, MDS is similar to the reaction and the AML of AML chemotherapy.
The?Merck?Manual，Sec.11，Ch.138(17th?ed.1997)。
Thereby, needing improvement treatment to acute leukemia or myelodysplastic syndrome patient, described treatment will produce higher complete remission rate, thus the survival that increases these patients is wished.Have surprisingly been found that, adopt anti--CD33 peptide-cytotoxic conjugates to compare with the combined therapy of daunorubicin and cytosine arabinoside with the combined therapy of anthracycline and pyrimidine or purine nucleoside analogs, or compare with independent gemtuzumab Ozogamicin Mylotarg CDP 771 significant improvement is arranged on effect, be respectively gemtuzumab Ozogamicin Mylotarg CDP 771, daunorubicin and cytarabine in the described combined therapy particularly.
Summary of the invention
The invention provides a kind of method for the treatment of acute leukemia or MDS, comprise to patient's combined administration of the described treatment of needs is a kind of resisting-CD33 peptide-cytotoxic conjugates and at least a chemical compound that is selected from anthracycline and pyrimidine or purine nucleoside analogs that consumption can effectively improve described acute myelogenous leukemia or described myelodysplastic syndrome.The preferred AML of acute leukemia of treatment.
In preferred embodiments, the cytotoxin in anti--CD33 peptide-cytotoxic conjugates is selected from calicheamicin (calicheamicin) and esperamicin.
In another preferred embodiment, anthracycline is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin (pitarubicin) and valrubicin.
In another preferred embodiment, pyrimidine or purine nucleoside analogs are selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin.
The present invention further provides a kind of method for the treatment of acute leukemia or MDS patient, comprised to the patient and using: (a) gemtuzumab Ozogamicin Mylotarg CDP 771, consumption are about 3mg/m every day
2To about 9mg/m
2(b) daunorubicin, preferred daunorubicin hydrochloride, consumption is about 45mg/m every day
2To about 60mg/m
2(c) cytosine arabinoside, consumption are about 100mg/m every day
2To about 200mg/m
2
In a preferred embodiment, the gemtuzumab Ozogamicin Mylotarg CDP 771 consumption is about 6mg/m every day
2
In another preferred embodiment, daunorubicin, preferred daunorubicin hydrochloride, consumption is 45mg/m every day
2
In another preferred embodiment, the cytosine arabinoside consumption is 100mg/m every day
2
The present invention further provides a kind of treatment acute leukemia or the syndromic method of MDS, comprised that the patient to needs uses: (a) one day gemtuzumab Ozogamicin Mylotarg CDP 771, consumption are about 3mg/m every day
2To 9mg/m
2(b) three days daunorubicins, consumption are about 45mg/m every day
2To 60mg/m
2(c) at least seven days cytosine arabinosides, consumption are about 100mg/m every day
2To 200mg/m
2
In a preferred embodiment, use daunorubicin in the junior three sky of using cytosine arabinoside, preferred amount of application is 45mg/m every day
2
In another preferred embodiment, cytosine arabinoside was used ten days, more preferably used seven days, and preferable amount is 100mg/m every day
2
In another preferred embodiment, used gemtuzumab Ozogamicin Mylotarg CDP 771 at use cytosine arabinoside to the patient the 4th day to the patient, preferable amount is 6mg/m
2
In another preferred embodiment, use cytosine arabinoside by continuous infusion, pour into fast by intravenous and use daunorubicin, preferred daunorubicin hydrochloride is used gemtuzumab Ozogamicin Mylotarg CDP 771 by 2-hour infusion.
The present invention further provides a kind of inductive drug regimen that strengthens acute leukemia or MDS patient's alleviation, comprise: (a) anti--CD33 peptide-cytotoxic conjugates, wherein the cytotoxin in anti--CD33 peptide-cytotoxic conjugates is selected from calicheamicin and esperamicin; (b) be selected from the anthracycline of the gentle mycin of amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin; And the pyrimidine or the purine nucleoside analogs that (c) are selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin.
The present invention further provides a kind of inductive drug regimen that strengthens acute leukemia or MDS patient's alleviation, comprised gemtuzumab Ozogamicin Mylotarg CDP 771, consumption is about 3mg/m every day
2To about 9mg/m
2, preferred every day 6mg/m
2Daunorubicin, preferred daunorubicin hydrochloride, consumption is about 45mg/m every day
2To about 60mg/m
2, preferred every day 45mg/m
2And cytosine arabinoside, consumption is about 100mg/m every day
2To about 200mg/m
2, preferred every day 100mg/m
2
The present invention further provides a kind of method for the treatment of acute leukemia or MDS, having comprised:
(a) patient who treats to needs uses the treatment of first course of treatment, comprises that (i) uses one day anti--CD33 peptide-cytotoxic conjugates, and wherein the cytotoxin in anti--CD33 peptide-cytotoxic conjugates is selected from calicheamicin and esperamicin; (ii) use the anthracycline that is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin, maximum three days; And (iii) use pyrimidine or the purine nucleoside analogs that is selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin, maximum ten days;
(b) patient who treats to needs uses the treatment of second course of treatment, comprises that (i) uses one day anti--CD33 peptide-cytotoxic conjugates, and wherein the cytotoxin in anti--CD33 peptide-cytotoxic conjugates is selected from calicheamicin and esperamicin; (ii) use a kind of anthracycline that is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin, maximum three days; And (iii) use pyrimidine or the purine nucleoside analogs that is selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin, maximum ten days;
(c) patient who treats to needs uses the treatment of the 3rd course of treatment, comprise that (i) uses the anthracycline that is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin, maximum three days; And (ii) use pyrimidine or the purine nucleoside analogs that is selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin, maximum ten days.
The present invention further provides a kind of method for the treatment of acute leukemia or MDS, having comprised:
(a) patient who treats to needs uses the treatment of first course of treatment, comprises (i) one day gemtuzumab Ozogamicin Mylotarg CDP 771, and consumption is about 3mg/m every day
2To about 9mg/m
2, preferred 6mg/m
2(ii) maximum 3 days daunorubicins, consumption are about 45mg/m every day
2To about 60mg/m
2, preferred 45mg/m
2And (iii) maximum ten days cytosine arabinosides, consumption is about 100mg/m every day
2To about 200mg/m
2, preferred 100mg/m
2
(b) patient who treats to needs uses the treatment of second course of treatment, comprises (i) one day gemtuzumab Ozogamicin Mylotarg CDP 771, and consumption is about 3mg/m every day
2To about 9mg/m
2, preferred 6mg/m
2(ii) maximum 3 days daunorubicins, consumption are about 45mg/m every day
2To about 60mg/m
2, preferred 45mg/m
2And (iii) maximum ten days cytosine arabinosides, consumption is about 100mg/m every day
2To about 200mg/m
2, preferred 100mg/m
2
(c) patient who treats to needs uses the treatment of the 3rd course of treatment, comprises (i) maximum 3 days daunorubicins, and consumption is about 45mg/m every day
2To about 60mg/m
2, preferred 45mg/m
2And (ii) maximum ten days cytosine arabinosides, consumption is about 100mg/m every day
2To about 200mg/m
2, preferred 100mg/m
2
Detailed Description Of The Invention
The invention provides the favourable acute leukemia that is used for the treatment of, such as AML, and the drug regimen and the method for myelodysplastic syndrome (MDS), it adopts anti--CD33 peptide-cytotoxic conjugates, anthracycline and pyrimidine or purine nucleoside analogs.Therapeutic Method described herein and drug regimen provided in this type of patient than the higher complete remission rate of the 3+7 therapy of the daunorubicin of standard and cytosine arabinoside and the quality of life of improvement.It is shocking, adopt a preferred embodiment of gemtuzumab Ozogamicin Mylotarg CDP 771, daunorubicin and cytosine arabinoside to provide than the daunorubicin of standard and the higher complete remission rate of 3+7 therapy of cytosine arabinoside.
Will be that those did not just carry out treatment, and carrying out first (de novo) and treating such as the acute leukemia of AML with the patient of Therapeutic Method that proposes and drug regimen treatment herein, carrying out inductive treatment, carrying out after treatment, once or repeatedly patient that treating and that suffer from MDS after the recurrence.
A kind of compositions of using among the present invention is anti--CD33 peptide-cytotoxic conjugates, wherein anti-CD-33 antibody is puted together a kind of cytotoxic antitumor agents or antibiotic, such as separating the calicheamicin that obtains, perhaps esperamicin the fermented product from a kind of from antibacterial micromonospora echinospora calichensis subspecies (Micromonospora echinosporassp.calichensis).Calicheamicin is in U.S. Patent number 4,970,198; 5,037,651; And describe to some extent in 5,079,233.Esperamicin is in U.S. Patent number 4,675,187; 4,539,203; 4,554,162; And describe to some extent in 4,837,206.The antibody moiety of conjugate can specific bond CD-33 antigen, described antigen is a kind ofly to see the leukemia blast cell and myelomonocyte is the dependent adhesion protein of sialic acid on immature normal cell surface, but on normal hematopoietic stem cell, then do not have, and as targeting unit to these targeted cells delivery of cells toxic agent.This antibody is connected on calicheamicin or the esperamicin.When using N-acetyl group-γ calicheamicin, preferably with a bifunctional linker connection antibody.This type of conjugate and their preparation method are in U.S. Patent number 5,733,001; 5,739,116; 5,767,285; 5,877,296; 5,606,040; 5,712,374; And describe to some extent in 5,714,586, integral body is quoted as a reference herein.
The preferred form of the anti--CD33 peptide-cytotoxic conjugates that uses among the present invention is gemtuzumab Ozogamicin Mylotarg CDP 771, and a kind of chemotherapy agents of being made up of recombinant humanized IgG4, described humanization IgG4 are the κ antibody of puting together with calicheamicin.Can buy gemtuzumab Ozogamicin Mylotarg CDP 771
(WyethPharmaceuticals, Philadelphia, PA).The antibody moiety specific bond CD-33 antigen of gemtuzumab Ozogamicin Mylotarg CDP 771.The aminoacid sequence that gemtuzumab Ozogamicin Mylotarg CDP 771 contains about 98.3% is the people source.It is to come from deriving in conjunction with the murine antibody (p67.7) of CD33 that but constant region and framework region contain human sequence's complementary determining region.This antibody is connected to N-acetyl group-γ calicheamicin by a bifunctional linker.The antibody load 4-6 mole calicheamicin/mole antibody of gemtuzumab Ozogamicin Mylotarg CDP 771 nearly 50%.Remaining 50% antibody does not have Connection Card miramycin derivant.The gemtuzumab Ozogamicin Mylotarg CDP 771 molecular weight is 151 to 153kDa.Gemtuzumab Ozogamicin Mylotarg CDP 771 and preparation method thereof is in U.S. Patent number 5,733,001; 5,739,116; 5,767,285; 5,877,296; 5,606,040; 5,712,374; And describe to some extent in 5,714,586, integral body is quoted as a reference herein.When the single agents therapy of AML was treated in conduct, the gemtuzumab Ozogamicin Mylotarg CDP 771 recommended dose was 9mg/m
2, use with two hours intravenous infusions.Single recommendation treatment with gemtuzumab Ozogamicin Mylotarg CDP 771 is two doses altogether the course of treatment, every dose of interval 14 days.In combined therapy of the present invention, the gemtuzumab Ozogamicin Mylotarg CDP 771 amount of application is about 3mg/m every day
2To 9mg/m
2
U.S. Patent number 5,773, described among the capable and embodiment 112 of 001 the 62nd hurdle 37-46 with based on mg/m
2The clinical dosage of body surface is described and is compared, based on calicheamicin equivalent (that is 10 μ g calicheamicin/m,
2Protein) calicheamicin conjugate comprises the dosage of gemtuzumab Ozogamicin Mylotarg CDP 771.When calicheamicin is added on the antibody, be approximately 27 μ g calicheamicin/mg protein.Potion 9mg/m
2Gemtuzumab Ozogamicin Mylotarg CDP 771 be equivalent to 243 μ g calicheamicin/m
2Protein.Potion 6mg/m
2Gemtuzumab Ozogamicin Mylotarg CDP 771 be equivalent to 162 μ g calicheamicin/m
2Protein.Potion 3mg/m
2Gemtuzumab Ozogamicin Mylotarg CDP 771 be equivalent to 81 μ g calicheamicin/m
2Protein.
Another compositions of using among the present invention is anthracycline, and promptly a kind of anticarcinogen is made up of 3 parts: a pigmented aglycone, an amino sugar and a side chain.Anthracycline comprises amycin, daunorubicin, complies with this than star, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin.Referring to
Merck Index(13
ThEd.2001).
The preferred anthracycline that uses among the present invention is daunorubicin.Daunorubicin is also spoken approvingly of the promise mycin, is a kind of anthracycline cytotoxic antibiotics in the rhodomycin group, derives from ripple match streptomycete (Streptomyces peucetius), and it is used to treat acute leukemia.
Stedman’s?Medical?Dictionary(27
th?ed。2002)。Daunorubicin has 4-ring anthracycline part, is connected in a kind of amino sugar daunosamine by a glycosidic bond.Also can from sky blue little red strepto-(Streptomyces coeruleorubidus), separate daunorubicin and have following chemical name: hydrochloric acid (8S-is suitable)-8-acetyl group-10-[(3-amino-2; 3; 6-three deoxidations-(α)-L-lysol-own pyrans glycosyl) oxygen] 7; 8; 9,10-tetrahydrochysene-6,8; 11-trihydroxy-1-methoxyl group-5,12-aphthacene diketone.Daunorubicin is used hydrochloride form always, but dosage is represented with alkali.
The preferred form of the daunorubicin that uses among the present invention is a daunorubicin hydrochloride, i.e. the hydrochlorate of daunorubicin.Daunorubicin hydrochloride can with
Be purchased (BedfordLaboratories, Bedford Ohio).Also can use chemical name hydrochloric acid (1S, 3S)-3-acetyl group-1,2,3,4,6,11-six hydrogen-3,5,12-three hydrogen base-10-methoxyl group-6,11-dioxy aphthacene 3-amino-2,3,6-three deoxidations-(α)-lysol pyranoside is described it.Its molecular formula is C
27H
29NO
10HCl, molecular weight 563.99.At treatment adult acute nonlymphocytic leukemia, in AML and ALL, daunorubicin hydrochloride uses as single agents, has obtained 40 to 50% complete remission rate, and obtains 53 to 65% complete remission rate with the cytosine arabinoside coupling.
Physician’s?Desk?Reference(56
th?ed.2002)。Usually, use 30-45mg/m once a day in two to three days mode of intravenous infusion
2Daunorubicin continue three days.In the high dose therapy, use 50mg/m once a day
2Daunorubicin continue three days.
Daunorubicin also can have been bought with the form of daunorubicin citrate lipidosome injection, as
(Gilead Sciences, Inc., Foster City, CA).
The citrate aqueous solution that contains daunorubicin is loaded in lipid carrier (liposome) capsule of the about 45nm of average diameter that is made up of distearoyl phosphatidylcholine and cholesterol (2: 1 mol ratios) lipid bilayer.Lipid is 18.7: 1 (TLs: daunorubicin alkali), be equivalent to the distearoyl phosphatidylcholine of 10: 5: 1 mol ratios: cholesterol: daunorubicin to the weight ratio of medicine.Every bottle
Contain the daunorubicin citrate that is equivalent to 50mg daunorubicin alkali, be loaded in the liposome methods of forming by 704mg distearoyl phosphatidylcholine and 168mg cholesterol.The liposome of parcel daunorubicin is dispersed in and contains 2,125mg sucrose, 94mg glycine and 7mg calcium chloride dihydrate contain in the water quality cumulative volume 25ml/ bottle.The pH of dispersion is 4.9 to 6.0.
Use by intravenous, surpass 60 minutes, dosage is 40mg/m
2, carry out dosage per two weeks and repeat.
The 3rd compositions of using among the present invention is pyrimidine nucleoside analoys or purine nucleoside analogs.The representative of these nucleoside analogs is cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin.Referring to
Merck Index(13
ThEd.2001).
The preferred cytosine arabinoside of the pyrimidine nucleoside analoys that uses among the present invention, be also referred to as cytosine arabinoside (arabinosylcytosine) (aC, araC), cytosine arabinoside (arabinocytidine), perhaps arabinofuranosyl cytidine (arabinofuranosylcytosine).Chemically, cytosine arabinoside is 4-amino-1-(β)-D-arabinofuranosyl base-2 (1H)-pyrimidone, is also referred to as cytarabin (C
9H
13N
3O
5, molecular weight 243.22).Cytosine arabinoside is the phase specificity antineoplastic agent of cell cycle, only exerts an influence at cell division S phase pair cell.It is the chemical compound of a kind of arabinose and cytosine, suppresses the biosynthesis of DNA and because of its antiviral with suppress the tumor growth characteristic and be used as chemotherapeutics.Usually, use 100-200mg/m once a day in the mode of intravenous constant current infusion
2Cytosine arabinoside, continue five to ten days, general seven days.Also can be with the mode administered twice every day 100mg/m of quick intravenous injection
2The cytosine arabinoside of body surface.But cytosine arabinoside can be with maximum 3g/m once a day
2Amount use.In the high dose therapy, used maximum 3g/m in the mode of intravenous infusion in per 12 hours
2Cytosine arabinoside, continue maximum 6 days.
Cytosine arabinoside also can with the cytosine arabinoside lipidosome injection as
(form CA) has been bought for ChironCorporation, Emeryville.
Be the sterile injectable suspension of antimetabolite cytosine arabinoside, be loaded in many bubble lipid base granule capsules.Every bottle contains the 50mg cytosine arabinoside.Active component cytosine arabinoside concentration is 10mg/ml, is loaded in the granule capsule.Non-active ingredient and about separately concentration are cholesterol, 4.1mg/ml; Glycerol trioleate, 1.2mg/ml; Dioleoyl phospholipid phatidylcholine (DOPC), 5.7mg/ml; And two palmityl phosphatidyl glycerols (DPPG), 1.0mg/ml.The pH of product is between 5.5 to 8.5.
Be to use in the sheath.
The invention provides the method for several treatment acute leukemia or MDS.In a kind of method, resist-CD33 peptide-cytotoxic conjugates and at least a chemical compound that is selected from anthracycline and pyrimidine or purine nucleoside analogs to patient's combined administration, dose can effectively improve the symptom of acute leukemia such as AML or MDS.Preferably, the cytotoxin in anti--CD33 peptide-cytotoxic conjugates is calicheamicin or esperamicin.Anthracycline is preferably selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin.Pyrimidine or purine nucleoside analogs are preferably selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and isoniazid (tubercid).Cytotoxin in anti--CD33 conjugate most preferably is a calicheamicin, and anthracycline most preferably is daunorubicin or daunorubicin hydrochloride, and pyrimidine nucleoside analoys most preferably is cytosine arabinoside.
In another Therapeutic Method, use gemtuzumab Ozogamicin Mylotarg CDP 771 to acute leukemia or MDS patient, consumption is about 3mg/m every day
2To about 9mg/m
2Daunorubicin, preferred daunorubicin hydrochloride, consumption is about 45mg/m every day
2To about 60mg/m
2Cytosine arabinoside, consumption are about 100mg/m every day
2To about 200mg/m
2Preferably, the gemtuzumab Ozogamicin Mylotarg CDP 771 amount of application is about 6mg/m every day
2Daunorubicin, preferred daunorubicin hydrochloride, preferred amount of application is 45mg/m every day
2The preferred amount of application of cytosine arabinoside is 100mg/m every day
2
In another Therapeutic Method, use one day gemtuzumab Ozogamicin Mylotarg CDP 771 to acute leukemia or MDS patient, consumption is about 3mg/m
2To 9mg/m
2Three days daunorubicins, consumption are about 45mg/m every day
2To 60mg/m
2At least seven days cytosine arabinosides, consumption are about 100mg/m every day
2To 200mg/m
2Preferably, use daunorubicin in the junior three sky of using cytosine arabinoside, preferred amount of application is 45mg/m every day
2Cytosine arabinoside was preferably used ten days, more preferably used seven days, and preferable amount is 100mg/m every day
2Preferably used gemtuzumab Ozogamicin Mylotarg CDP 771 at use cytosine arabinoside to the patient the 4th day, preferable amount is 6mg/m
2In a preferred embodiment, use cytosine arabinoside in the mode of continuous infusion, pour into fast with intravenous and use daunorubicin, preferred daunorubicin hydrochloride is used gemtuzumab Ozogamicin Mylotarg CDP 771 in the mode of 2 hours infusions.
The present invention also provides and has been used to strengthen acute leukemia or MDS patient is alleviated inductive pharmaceutical composition.A kind ofly be used to strengthen acute leukemia or MDS patient and alleviate inductive pharmaceutical composition and comprise anti--CD33 peptide-cytotoxic conjugates, anthracycline and pyrimidine or purine nucleoside analogs.Cytotoxin in anti--CD33 peptide-cytotoxic conjugates can be selected from calicheamicin and esperamicin.Anthracycline can be selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin.Pyrimidine or purine nucleoside analogs can be selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin.
Another pharmaceutical composition comprises gemtuzumab Ozogamicin Mylotarg CDP 771, and consumption is about 3mg/m every day
2To about 9mg/m
2, preferred every day 6mg/m
2, daunorubicin, preferred daunorubicin hydrochloride, consumption is about 45mg/m every day
2To about 60mg/m
2, preferred every day 45mg/m
2, and cytosine arabinoside, consumption is about 100mg/m every day
2To about 200mg/m
2, preferred every day 100mg/m
2
The characteristic of acute leukemia and myelodysplastic syndrome need be used intense prior chemotherapy to induce patient's alleviation of suffering from these diseases.In one embodiment of the invention, comprise anti--CD33 peptide-cytotoxic conjugates the single course of treatment of combined therapy to patient's administering therapeutic effective dose, together with one or more chemotherapeutics, such as anthracycline, pyrimidine or purine nucleoside analogs.The present invention also provides Therapeutic Method, wherein uses many courses of treatment of combined therapy, comprises anti--CD33 peptide-cytotoxic conjugates and other chemotherapeutics.These therapies can be used two to five courses of treatment at least, and this depends on the medicine of using, the order of severity of disease and patient's situation.
In another Therapeutic Method of the present invention, use three treatment courses of treatment to acute leukemia or MDS patient.First was treated in the course of treatment, used the anti-CD 33 peptide-cytotoxic conjugates one day to the patient; Maximum three days of anthracycline; Pyrimidine or purine nucleoside analogs maximum ten days.Cytotoxin in anti--CD33 peptide-cytotoxic conjugates can be selected from calicheamicin and esperamicin.Anthracycline can be selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin.Pyrimidine or purine nucleoside analogs can be selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin.Repeat first treatment course of treatment as second treatment course of treatment, wherein use anti--CD33 peptide-cytotoxic conjugates one day to the patient; Maximum three days of anthracycline; Pyrimidine or purine nucleoside analogs maximum ten days.Can use the 3rd course of treatment to the patient, it comprises to the patient uses a kind of amycin that is selected from, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, maximum three days of the anthracycline of pirarubicin and valrubicin, a kind of cytosine arabinoside that is selected from, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, the pyrimidine of thiazole furan quinoline and tubercidin or purine nucleoside analogs maximum ten days.
In another these class methods of treatment acute leukemia or MDS patient, use first course of treatment to the patient, comprise one day gemtuzumab Ozogamicin Mylotarg CDP 771, consumption is about 3mg/m every day
2To about 9mg/m
2, preferred every day 6mg/m
2Maximum three days daunorubicins, consumption are about 45mg/m every day
2To about 60mg/m
2, preferred every day 45mg/m
2Maximum ten days cytosine arabinoside, consumption are about 100mg/m every day
2To about 200mg/m
2, preferred every day 100mg/m
2Use second course of treatment to the patient, comprise one day gemtuzumab Ozogamicin Mylotarg CDP 771, consumption about 3mg/m every day
2To about 9mg/m
2, preferred every day 6mg/m
2Maximum three days daunorubicins, consumption are about 45mg/m every day
2To about 60mg/m
2, preferred every day 45mg/m
2Maximum ten days cytosine arabinoside, consumption are about 100mg/m every day
2To about 200mg/m
2, preferred every day 100mg/m
2Can use the 3rd course of treatment to the patient, comprise maximum three days daunorubicins, consumption is about 45mg/m every day
2To about 60mg/m
2, preferred every day 45mg/m
2Maximum ten days cytosine arabinoside, consumption are about 100mg/m every day
2To about 200mg/m
2, preferred every day 100mg/m
2
Astonishing and unpredictable consequence disclosed herein is anti--CD33 peptide-cytotoxic conjugates, anthracycline and pyrimidine or the purine nucleoside analogs synergistic ability in the multiple symptom relevant with acute leukemia or MDS of treatment." work in coordination with " with being meant that herein benefit that these anti-tumor compositions of combined administration bring surpasses a kind of situation of the algebraical sum of using the effect that combination partner produces separately.As what show in the following examples, anti--the CD33 peptide-cytotoxic conjugates, anthracycline and pyrimidine or purine nucleoside analogs combined therapy are worked in coordination with aspect the effectiveness of alleviating measurement fully in treatment acute leukemia and raising.Anti--CD33 peptide-cytotoxic conjugates that this combined therapy has with low dosage more obtains the advantage of equifinality, thereby has reduced the toxic and side effects that conjugate brings, and improves patient's quality of life, improves patient's chance of surviving.
When using other chemotherapeutics, patient individual can be subjected to treating the supervision of doctor under the mode that sees fit.Combined therapy agent described herein may be thought essential immunosuppressant with the treatment doctor, synergist and alleviate the side effect agent and use together.
In the treatment practice, the dosage of the reagent that adopts according to the present invention may be because of reagent, the patient's age of receiving treatment, body weight and clinical condition and clinician or practitioner's the experience and the factor and the variation to some extent of judgement and other influence selection dosage of implementing treatment.Generally, dosage should enough produce previously defined alleviation fully.The effective dose of pharmaceutical agent provides the dosage of the objectively appraisable improvement that clinicist or other titular observers notice.In order to use convenient and the dosage unification, the compositions for preparing these antitumoral compounds dosage unit forms has superiority especially." dosage unit form " used herein is meant the physics discrete unit of the single dose that is used for being treated the patient, per unit contains the antitumoral compounds of scheduled volume, this amount is through calculating, so that it produces the desired therapeutic effect with required pharmaceutical carrier." pharmaceutically acceptable carrier " used herein comprises any solvent, disperse medium, and coating, antibacterial agent and antifungal, isotonic agent and postpone absorbent or the like, other composition of they and active component and method of application and preparation is compatible and harmless to the receiver.
The preparation that the pharmaceutical composition that sees combination among the present invention depends on expection may also comprise, carrier that pharmacy is acceptable, nontoxic or diluent, and they are defined as often being used to preparing the carrier of the pharmaceutical composition of using to animal or people.Select diluent otherwise the biological activity of influence combination.The example of this type of diluent is distilled water, normal saline, Ringer's solution, glucose solution and Hank ' s solution.In addition, pharmaceutical composition or preparation also may comprise other carrier, adjuvant or non-toxicity, non-therapeutic, non-immunogenic stabilizing agent or the like.The effective dose of this type of diluent or carrier should be the amount that can effectively obtain the acceptable preparation of pharmacy aspect the dissolubility of composition or biological activity or the like.
Treatment is used for parenteral, and each antitumoral compounds all can be integrated with sterile injectable solution.Sterile injectable solution can be incorporated in a kind of suitable pharmaceutical acceptable carrier by antitumoral compounds and the various other components with aequum, then filtration sterilization and making.As for dispersion, each all can prepare by extra antitumoral compounds is incorporated in the sterile carrier, and described carrier contains basic disperse medium and other is selected from the essential composition of the listed composition of enumerating herein.As for sterile injectable liquid, each can by extra antitumoral compounds powder and, appoint and select ground, component in the solution of the front filtration sterilization of any extra expectation is integrated and is prepared, and wherein this powder prepares (for example vacuum drying and lyophilization) with any suitable technology.Use this type of medium and reagent be known in the art (referring to as, Remington ' s Pharmaceutical Sciences, 18thed. (1990), Mack Publishing Co., Easton, PA 18042, pages1435-1712, its disclosure is incorporated in this as a reference).Supplementary active ingredients also can be integrated in the said composition.The given dose of antitumoral compounds calculates according to patient general body weight or body surface area.The factor of other decision suitable dose can comprise the stadium of acute myelogenous leukemia or myelodysplastic syndrome (New Development or recurrence), the order of severity, route of administration and patient's age, sex and the medical condition of disease.Determine to relate to the necessary further optimization of the suitable therapeutic dose of each preparation that reaches mentioned herein, carry out with conventional means by those skilled in the art to calculating.Also can determine dosage in conjunction with correct dose-response data with the known mensuration that is used for definite dosage.So, for example, change in order to reach the desired therapeutic effect be used for the treatment of acute myelogenous leukemia or myelodysplastic syndrome among the present invention antitumoral compounds dosage within the scope of the invention.
If oral medication is used as a kind of selection, then antitumoral compounds and excipient can be integrated and adopted the tablet that to ingest, buccal tablet, lozenge, capsule, elixir, suspension, syrup, thin slice (wafer) or the like form, perhaps also can directly be added to it in the food of diet.Tablet, lozenge, pill, capsule etc. can also contain following material: a kind of binding agent such as tragacanth gum, Radix Acaciae senegalis, corn starch or gelatin; Excipient is such as dicalcium phosphate; Disintegrating agent such as corn starch, alginic acid or the like; Lubricant is such as magnesium stearate; Sweetener such as sucrose, lactose or glucide; Fumet such as Mentha arvensis L. syn.M.haplocalyxBrig, wintergreen oil or Fructus Pruni pseudocerasi or mandarin orange flavoring agent.When unit dosage form was capsule, except material type described herein, it can contain liquid-carrier.Multiple other materials can be used as coating or is used to modify the physical form of dosage unit.For example, tablet, pill or capsule can apply with Lac, sugar or the two.Certainly, it all should be medicinal pure and nontoxic substantially in use amount preparing the used any material of any dosage unit form.In addition, antitumoral compounds can also be incorporated in the prepared product or preparation that continues to discharge.The amount of antitumoral compounds should make and can obtain suitable dose in this type of compositions that is used for the treatment of.
The embodiment that should be understood that the detailed description of front and back just is used for illustrating of the present invention, can not be used as limitation of the scope of the invention.Can make variations and modifications to disclosed embodiment, these are apparent for a person skilled in the art, can not break away from spirit of the present invention and scope.And all patents, patent application and publication cited herein all are hereby incorporated by.
Embodiment
Embodiment 1
Be safety and the effectiveness of assessment gemtuzumab Ozogamicin Mylotarg CDP 771, carried out the research of 1/2 phase that gemtuzumab Ozogamicin Mylotarg CDP 771 and cytosine arabinoside and daunorubicin are combined in the U.S. as the part of the combination treatment of treatment AML.From November in October, 2000 to calendar year 2001, recurrence, refractory are healed or New Development AML patient entered for 1 phase.The maximum tolerated dose of determining is confirmed as cytosine arabinoside 100mg/m
2/ day, use by the 1st to 7 day continuous infusion; Daunorubicin 45mg/m
2The the 1st to 3 day, use by the quick perfusion of intravenous; Gemtuzumab Ozogamicin Mylotarg CDP 771 6mg/m
2, by using at the 4th day 2 hours infusions.This is studied 2 phases parts and begins to recruit in November calendar year 2001, and 45 patients are recruited in plan, have found 42 at present.
The detailed assessment of safety and effectiveness is carried out on one's body 19 patients that treat with this combination antilepsis at first, follows up a case by regular visits to subsequently at least 28 days.Recruit 16 men and three woman altogether, median age is 46 years old (scope, 20 to 60).One, ten and three patients be included into respectively height (favorable)-, medium-and low-dangerous cytogenetics group.Five patients' CYTOGENETIC ANALYSIS OF ONE does not obtain.17 patients have found out baseline myeloid leukemia blast cell, and the number percentage rate is 60% in the blast cell.Combined therapy has all been finished the inductive treatment of planning by fine tolerance and 19 patients.
Three patients (16%) had reported NCI 3 grades on the same day of infusion gemtuzumab Ozogamicin Mylotarg CDP 771 and have had a fever/catch cold.The incidence rate of 3 grades of AST/ALT risings is 16%; Do not report 3 grades or 4 grades of hyperbilirubinemia.There is not hepatic veno-occlusive disease/hole shape to block the syndrome case.3 grades or 4 grades of infection rates are 32%.Early treatment's mortality rate is 0%.Induce again with cytosine arabinoside and daunorubicin AML greatly remnants about the 15th day four needs of patients.A central patient left this research at the 15th day, induce with containing height-dosage cytosine arabinoside (HDAC) therapy again, and its effectiveness can't be estimated.
There are 15 (83%) to reach among 18 patients and alleviate (CR) fully, be characterized as the AML blast cell from peripheral blood disappear, haematogonium≤5% bone marrow of AML outside the no marrow, cellularity 〉=20% and external count and return to neutrophil cell absolute counting (ANC) 〉=1500/ μ L and platelet recovery to 〉=100,000/ μ L.Do not alleviate and patient's report of platelet incomplete recovery (CRp) fully.Among the patient that three do not alleviate, two diseases increase the weight of, and one reaches acute leukemic remission but need carry out radiotherapy to the chloroma of remnants.Among the CR patient, the time median that returns to ANC 〉=1500/ μ L is 38 days, and the time median of platelet 〉=100,000/ μ L is 30 days.The patient is followed up a case by regular visits to too short time (following up a case by regular visits to median 193 days) that can not determine that alleviation continues of time.
100mg/m
2/ day cytosine arabinoside, 45mg/m
2Daunorubicin and 6mg/m
2The combination of gemtuzumab Ozogamicin Mylotarg CDP 771 is tolerated well, and the low hepatotoxicity of tool also leads CR and brings up to 83%.The historical control data of Southwest Oncology Group (SWOG) show seven days 100mg/m
2/ day cytosine arabinoside and three days 45mg/m
2It is 60% that the CR of the standard care of daunorubicin leads.100mg/m
2/ day cytosine arabinoside, 45mg/m
2Daunorubicin and 6mg/m
2The combination of gemtuzumab Ozogamicin Mylotarg CDP 771 has significantly improved CR than standard care and has led.
Embodiment 2
Before the AML15 clinical trial of Medical Research Center starts, in 67 patients of a safety research of Britain, combination gemtuzumab Ozogamicin Mylotarg CDP 771 and intense prior chemotherapy induced and/or the feasibility consolidated is assessed.Purpose is the chemotherapy of combination gemtuzumab Ozogamicin Mylotarg CDP 771 and clinical trial plan, (DAT; Daunorubicin, AraC, thioguanine or DA; Daunorubicin, AraC; Perhaps FLAG-IDA; Fludarabine, AraC, G-CSF, darubicin) as the 1st course of treatment.First day use 3mg/m of 55 patient's chemotherapy
2Gemtuzumab Ozogamicin Mylotarg CDP 771 is used the 1st course of treatment.33 patients accept gemtuzumab Ozogamicin Mylotarg CDP 771 and DAT.8 patients accept gemtuzumab Ozogamicin Mylotarg CDP 771 and DA.14 patients accept gemtuzumab Ozogamicin Mylotarg CDP 771 and FLAG-Ida.Among 55 patients of treatment, 41 (85%) people enter fully to be alleviated, and first classification course of treatment (break down) is as follows: (1) DAT=26/32; (2) DA=7/8; (3) FLAG-Ida=8/8.In the clinical trial of another one MRC AML12 by name, 720 patients are single with the H-DAT treatment in first course of treatment before this, and those patients' 64% have reached fully to be alleviated.In this research, ANV recovers (1 * 10
9/ l) time median is 27 days (mobility scale 9-54), platelet 〉=100 * 10
9/ l is 30 days (mobility scale 21-48), and this numerical value is in the scope of list with average+ISD of 720 patients of H-DAT treatment of MRC AML 12 clinical trials.Non-hemopoietic toxicity is limited to liver.Whole maximum toxicity are 1 grade=5 patients, 2 grades=22 patients, 3 grades=13 patients and 4 grades=10 patients.In 3 grades and the 4 grades of toxicity, determine that 7 people are relevant with the gemtuzumab Ozogamicin Mylotarg CDP 771 treatment.A possible influencing factor is to contain thioguanine.And have only 1 to have hepatotoxicity to compare among the receiver of no thioguanine in 16 treatment plans, contain in the treatment plan among 39 patients of thioguanine, 3 grades or 4 grades of hepatotoxicities take place in 22 people.
Other nine patients have accepted H-DAT and 6mg/m
2Gemtuzumab Ozogamicin Mylotarg CDP 771, eight patients reached fully in first course of treatment to be alleviated.Hemopoietic recovers not prolong, but 3 grades or 4 grades of hepatotoxicities have taken place 3 patients, and wherein VOD sample syndrome takes place 2 people, and two people are rehabilitation from this disease.6mg/m
2The gemtuzumab Ozogamicin Mylotarg CDP 771 of dosage is considered to infeasible.
15 patients have accepted 3mg/m in first and second courses of treatment
2Dosage gemtuzumab Ozogamicin Mylotarg CDP 771 (DAT3+10 and DAT 3+8).5 patient ANC recover to postpone, and 11 human blood platelets recover to postpone, and the two postpones 5 people.3 grades and 4 grades of hepatotoxicities are found 3 examples, and wherein VOD sample syndrome takes place 2 people.
17 patients have accepted 3mg/m in the 3rd course of treatment
2Dosage gemtuzumab Ozogamicin Mylotarg CDP 771 and MACE (MACE:Amsacarine, AraC, etoposide or high dose AraC) chemotherapy.Have only patient's development to surpass 2 grades hepatotoxicity.12 patients accept 3mg/m in first course of treatment
2The dosage gemtuzumab Ozogamicin Mylotarg CDP 771 is induced, and accepts 3mg/m in the 3rd course of treatment
2The dosage gemtuzumab Ozogamicin Mylotarg CDP 771 is induced.This appears to feasible, but the further research of this therapy is still being carried out.
All accept 3mg/m in first course of treatment
2The patient's of dosage gemtuzumab Ozogamicin Mylotarg CDP 771 overall survival rate was 73% at 6th month, was 68% at 12nd month.Accept 3mg/m
2Dosage gemtuzumab Ozogamicin Mylotarg CDP 771 and do not have the inductive patient of thioguanine, the 6th month survival rate is 91%.
Claims (5)
1. anti--the CD33 peptide-cytotoxic conjugates, anthracycline and pyrimidine or purine nucleoside analogs are used for the treatment of application aspect the anxious medicine of giving birth to leukemia or MDS in preparation, wherein said anti--the CD33 peptide-cytotoxic conjugates is selected from calicheamicin and esperamicin; Described anthracycline is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin; Described pyrimidine or purine nucleoside analogs are selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin; And described treatment comprises and using at least two courses of treatment, comprising:
(a) use one day anti--CD33 peptide-cytotoxic conjugates, wherein the cytotoxin in anti--CD33 peptide-cytotoxic conjugates is selected from calicheamicin and esperamicin;
(b) use the anthracycline that is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin, maximum three days;
(c) use pyrimidine or the purine nucleoside analogs that is selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin, maximum ten days; And
(d) repeat (a) to (c).
2. according to the application of claim 1, wherein comprise last course of treatment:
(a) use the anthracycline that is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin, maximum three days; And
(b) use pyrimidine or the purine nucleoside analogs that is selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin, maximum ten days.
3. anti--the CD33 peptide-cytotoxic conjugates, anthracycline and pyrimidine or purine nucleoside analogs are used for the treatment of the application aspect the medicine of acute leukemia or MDS in preparation, wherein said anti--cytotoxin in the CD33 peptide-cytotoxic conjugates is selected from calicheamicin and esperamicin; Described anthracycline is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin; Described pyrimidine or purine nucleoside analogs are selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin; And described treatment comprises:
(a) as first course of treatment, use and comprise: (i) use one day anti--CD33 peptide-cytotoxic conjugates, wherein the cytotoxin in anti--CD33 peptide-cytotoxic conjugates is selected from calicheamicin and esperamicin; (ii) use the anthracycline that is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin, maximum three days; And (iii) use pyrimidine or the purine nucleoside analogs that is selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin, maximum ten days;
(b), use and comprise as second course of treatment: (i) use one day anti--CD33 peptide-cytotoxic conjugates, wherein said anti--cytotoxin in CD33 cell disposition conjugate is selected from calicheamicin and esperamicin; (ii) use the anthracycline that is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin, maximum three days; And (iii) use pyrimidine or the purine nucleoside analogs that is selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin, maximum ten days; And
C) as the 3rd course of treatment, use and comprise: (i) use the anthracycline that is selected from amycin, daunorubicin, darubicin, aklavine, zorubicin, mitoxantrone, the gentle mycin of table, carminomycin, nogalamycin, Mei Luogerui, pirarubicin and valrubicin, maximum three days; And (ii) use pyrimidine or the purine nucleoside analogs that is selected from cytosine arabinoside, gemcitabine, trifluridine, ancitabine, BH-AC, azacytidine, doxifluridine, pentostatin, broxuridine, capecitabine, cladribine, decitabing, floxuridine, fludarabine, gougerotin, puromycin, tegafur, thiazole furan quinoline and tubercidin, maximum ten days.
4. gemtuzumab Ozogamicin Mylotarg CDP 771, daunorubicin and cytosine arabinoside are used for the treatment of the application aspect the medicine of acute myelogenous leukemia or myelodysplastic syndrome in preparation, comprising:
(a), use and comprise as first course of treatment:
(i) one day gemtuzumab Ozogamicin Mylotarg CDP 771, consumption are about 3mg/m every day
2To about 9mg/m
2
(ii) maximum three days daunorubicins, consumption are about 45mg/m every day
2To about 60mg/m
2And
(iii) maximum ten days cytosine arabinosides, consumption is about 100mg/m every day
2To about 200mg/m
2(b), use and comprise as second course of treatment:
(i) one day gemtuzumab Ozogamicin Mylotarg CDP 771, consumption are about 3mg/m every day
2To about 9mg/m
2
(ii) maximum three days daunorubicins, consumption are about 45mg/m every day
2To about 60mg/m
2And
(iii) maximum ten days cytosine arabinosides, consumption is about 100mg/m every day
2To about 200mg/m
2
(c), use and comprise as the 3rd course of treatment:
(i) maximum three days daunorubicins, consumption is about 45mg/m every day
2To about 60mg/m
2And
(ii) maximum ten days cytosine arabinosides, consumption is about 100mg/m every day
2To about 200mg/m
2
5. gemtuzumab Ozogamicin Mylotarg CDP 771, daunorubicin and cytosine arabinoside are used for the treatment of the application aspect the medicine of acute myelogenous leukemia or myelodysplastic syndrome in preparation, and described treatment comprises:
(a), use and comprise as first course of treatment:
(i) one day gemtuzumab Ozogamicin Mylotarg CDP 771, consumption are 6mg/m every day
2
(ii) maximum three days daunorubicins, consumption are 45mg/m every day
2And
(iii) maximum ten days cytosine arabinosides, consumption is 100mg/m every day
2200mg/m
2
(b), use and comprise as second course of treatment:
(i) one day gemtuzumab Ozogamicin Mylotarg CDP 771, consumption are 6mg/m every day
2
(ii) maximum three days daunorubicins, consumption are 45mg/m every day
2And
(iii) maximum ten days cytosine arabinosides, consumption is 100mg/m every day
2
(c), use and comprise as the 3rd course of treatment:
(i) maximum three days daunorubicins, consumption is 45mg/m every day
2And
(ii) maximum ten days cytosine arabinosides, consumption is 100mg/m every day
2
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102327599A (en) * | 2010-06-07 | 2012-01-25 | 泰立克公司 | Be used to treat the compositions and the method for myelodysplastic syndrome |
| WO2018133835A1 (en) * | 2017-01-20 | 2018-07-26 | National Institute Of Biological Sciences, Beijing | Nucleoside analogue regulating mammalian circadian rhythm |
-
2002
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102327599A (en) * | 2010-06-07 | 2012-01-25 | 泰立克公司 | Be used to treat the compositions and the method for myelodysplastic syndrome |
| WO2018133835A1 (en) * | 2017-01-20 | 2018-07-26 | National Institute Of Biological Sciences, Beijing | Nucleoside analogue regulating mammalian circadian rhythm |
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