WO2023149443A1 - Pharmaceutical composition for blood cell recovery after cord blood transplant - Google Patents
Pharmaceutical composition for blood cell recovery after cord blood transplant Download PDFInfo
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- WO2023149443A1 WO2023149443A1 PCT/JP2023/003140 JP2023003140W WO2023149443A1 WO 2023149443 A1 WO2023149443 A1 WO 2023149443A1 JP 2023003140 W JP2023003140 W JP 2023003140W WO 2023149443 A1 WO2023149443 A1 WO 2023149443A1
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- romiplostim
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/53—Colony-stimulating factor [CSF]
- C07K14/535—Granulocyte CSF; Granulocyte-macrophage CSF
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
Definitions
- the present invention relates to the use of romiplostim during cord blood transplantation. More particularly, it relates to a pharmaceutical composition for recovering blood cells after cord blood transplantation, containing romiplostim as an active ingredient.
- Hematopoietic stem cell transplantation is performed for diseases such as blood cancer (leukemia, malignant lymphoma, etc.), aplastic anemia, and immunodeficiency, which make it difficult to produce normal blood.
- diseases such as blood cancer (leukemia, malignant lymphoma, etc.), aplastic anemia, and immunodeficiency, which make it difficult to produce normal blood.
- BMT Bone Marrow Transplantation
- PBSCT Peripheral Blood Stem Cell Transplantation
- CBT Cord Blood Transplantation
- Most cases are allogeneic transplants in which stem cells from other people are transplanted, but there are also cases in which autologous transplants are performed in which the patient's bone marrow or peripheral blood stem cells are transplanted.
- engraftment usually, when the recovery of the neutrophil count (neutrophil recovery) is confirmed after hematopoietic stem cell transplantation, it is called engraftment.
- aseptic management and administration of G-CSF preparations and antibiotics are performed to avoid fatal infections until the neutrophil count recovers, deaths due to infections are the largest non-recurrent deaths after stem cell transplantation. is the cause of Also, recovery of platelet count after hematopoietic stem cell transplantation is referred to as “platelet engraftment” or “platelet recovery.”
- platelet engraftment or "platelet recovery.”
- hematopoietic recovery recovery of hematopoietic function including neutrophil recovery and platelet recovery is referred to as "hematopoietic recovery”.
- Cord blood transplantation is known to have a slower hematopoietic recovery, a lower engraftment rate, and a lower survival rate than the other two transplants. Therefore, regarding cord blood transplantation, there is a need for drugs and techniques for assisting engraftment and hastening hematopoietic recovery.
- Treatments to support post-transplantation hematopoietic recovery include prophylactic treatment given before or early after transplantation (prophylactic administration), and therapeutic treatment given post-transplantation if hematopoietic recovery is delayed (therapeutic administration). ).
- prophylactic administration prophylactic treatment given before or early after transplantation
- therapeutic treatment given post-transplantation if hematopoietic recovery is delayed
- SFPR platelet response
- Non-Patent Document 1 the median number of days with a platelet count of ⁇ 50000/ ⁇ L was 43 days in the rhTPO-treated group and 53 days in the control group.
- Pasvolsky et al. reported that although eltrombopag could be administered safely daily from the first day after cord blood transplantation (median 76 days), early platelet recovery could not be confirmed (non-patent literature). 2).
- Romiplostim is a platelet hematopoiesis-stimulating factor preparation that binds to c-Mpl, a receptor for endogenous thrombopoietin (TPO), and enhances platelet production (Patent Document 1).
- Romiplostim was approved in Australia in July 2008 for the treatment of thrombocytopenia in adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP). It is manufactured and sold under trade names such as (registered trademark).
- Romiplostim has also been approved for manufacturing and marketing in Japan, South Korea, and Taiwan for aplastic anemia.
- Non-Patent Document 12 There are reports on the therapeutic administration of romiplostim for platelet engraftment failure and secondary thrombocytopenia after stem cell transplantation. For example, Christakopoulos et al. found that 4-6 doses of romiplostim at 4, 6, 8, or 10 ⁇ g/kg/week resulted in faster platelet recovery than controls in therapeutic administration of engraftment failure after stem cell transplantation. It has been reported that a trend was observed (Non-Patent Document 12).
- Non-Patent Document 15 There are reports on therapeutic administration of romiplostim after allogeneic stem cell transplantation (bone marrow or peripheral blood stem cell transplantation) (Non-Patent Documents 13 and 14) and reports on therapeutic administration of romiplostim for secondary thrombocytopenia after cord blood transplantation. There is (Non-Patent Document 15).
- Non-Patent Documents 16 and 17 a single administration of 250 ⁇ g of romiplostim on the day of transplantation in autologous peripheral blood stem cell transplantation may accelerate platelet recovery compared to the comparison group
- Non-Patent Document 5 administration of romiplostim before and after stem cell transplantation shortened the period of severe platelet decrease
- the object of the present invention is to provide a novel means for promoting blood cell recovery during cord blood transplantation.
- the present invention relates to the following [1] to [13].
- the pharmaceutical composition of [3] wherein the same dose as romiplostim is administered from the start of administration to the fourth time.
- [5] The pharmaceutical composition of [3] or [4], wherein the fifth and subsequent doses of romiplostim are administered at 5 ⁇ g/kg/week or more and up to 20 ⁇ g/kg/week.
- [6] The pharmaceutical composition according to any one of [3] to [5], wherein the range of dose increase/decrease from the fifth time onwards is 5 ⁇ g/kg/week or 10 ⁇ g/kg/week.
- [7] The pharmaceutical composition according to any one of [1] to [6], which is administered subcutaneously or intravenously.
- the pharmaceutical composition of [7] which is administered subcutaneously.
- [9] The pharmaceutical composition according to any one of [1] to [8], which is used in combination with a G-CSF preparation.
- Subjects to whom the pharmaceutical composition is administered are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma who require cord blood transplantation [1] to [ 12], the pharmaceutical composition according to any one of the above.
- the present invention relates to the following [1] to [13].
- [1] A therapeutic method for blood cell recovery in a subject who has undergone cord blood transplantation, characterized in that romiplostim is administered to the subject from the day after the transplantation.
- [2] The method of [1], wherein the blood cells are platelets and/or neutrophils.
- [3] The method of [1] or [2], wherein administration of romiplostim is initiated at 5 or 10 ⁇ g/kg/week, and thereafter administered once a week.
- [4] The method of [3], wherein the same dose of romiplostim is administered from the start of administration to the fourth administration.
- [5] The method of [3] or [4], wherein romiplostim is administered at a dose of 5 ⁇ g/kg/week or more and a maximum of 20 ⁇ g/kg/week from the fifth time onwards.
- [6] The method according to any one of [3] to [5], wherein the amount of romiplostim after the fifth dose is increased or decreased by 5 ⁇ g/kg/week or 10 ⁇ g/kg/week.
- [7] The method of any one of [1] to [6], wherein romiplostim is administered subcutaneously or intravenously.
- Subjects who receive romiplostim are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma who require cord blood transplantation [1]-[12] The method according to any one of
- the present invention relates to the following [1] to [13].
- Romiplostim for use according to any one of [1] to [9] wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
- the present invention relates to the following [1] to [13].
- [1] Use of romiplostim in the manufacture of a pharmaceutical composition containing romiplostim as an active ingredient for recovering blood cells after cord blood transplantation, wherein the pharmaceutical composition is administered from the day after the transplantation. .
- [2] The use according to [1], wherein the blood cells are platelets and/or neutrophils.
- [3] The use according to [1] or [2], wherein the pharmaceutical composition is initially administered at 5 or 10 ⁇ g/kg/week as romiplostim, and thereafter administered once a week.
- [4] The use according to [3], wherein the pharmaceutical composition is administered at the same dose as romiplostim for the fourth time from the start of administration.
- [5] The use according to [3] or [4], wherein the pharmaceutical composition is administered as romiplostim at 5 ⁇ g/kg/week or more and up to 20 ⁇ g/kg/week for the fifth time or later.
- [6] The use according to any one of [3] to [5], characterized in that the range of dose increase/decrease after the 5th dose is 5 ⁇ g/kg/week or 10 ⁇ g/kg/week.
- [7] The use according to any one of [1] to [6], wherein the pharmaceutical composition is administered subcutaneously or intravenously.
- [8] The use of [7], wherein the pharmaceutical composition is administered subcutaneously.
- Subjects to whom the pharmaceutical composition is administered are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma who require cord blood transplantation [1] to [ 12].
- FIG. 1 is a graph showing blood cell recovery after allogeneic cord blood transplantation (listing the results of the 5 ⁇ g/kg administration start group, 10 ⁇ g/kg administration start group, and all cases, the vertical axis is the cumulative recovery rate, and the horizontal axis is days after transplantation).
- FIG. 2 shows case data for each subject in romiplostim administration for platelet recovery after allogeneic cord blood transplantation (Phase I study).
- FIG. 3 shows a comparison of previously reported blood cell recovery data after cord blood transplantation. The median number of days to platelet count ⁇ 50,000/ ⁇ L is 40 to 59 days. Median days to recovery to neutrophil count ⁇ 500/ ⁇ L range from 19 days to 22.5 days. All these figures are calculated from cases that have achieved recovery.
- the present invention relates to a pharmaceutical composition containing romiplostim as an active ingredient for recovering blood cells after cord blood transplantation, characterized by being administered from the day after the transplantation.
- Romiplostim is a recombinant fusion protein with a molecular weight of about 59 kDa, and is a dimer composed of two subunit molecules consisting of 269 amino acid residues (SEQ ID NO: 1). Of the 269 amino acids of the monomer, positions 2-228 are the Fc region of human IgG1, and positions 229-269 consist of a peptide containing the human thrombopoietin receptor (c-Mpl) binding sequence.
- Romiplostim has plateletogenic and/or megakaryopoietic activity.
- Romiplostim binds to the endogenous thrombopoietin (TPO) receptor c-Mpl and enhances platelet production, thereby acting as a platelet hematopoiesis-stimulating agent.
- TPO is a human megakaryocyte and platelet hematopoietic stimulator.
- romiplostim is thought to promote proliferation and differentiation of cells in the process from bone marrow progenitor cells to megakaryocytes, resulting in an increase in platelets (hereinafter also referred to as PLT). It is
- the method for producing romiplostim is not particularly limited as long as it is pharmaceutically acceptable.
- Allogeneic hematopoietic stem cell transplantation is a treatment performed for the purpose of radical cure for intractable hematopoietic diseases. Allogeneic transplantation involves pre-transplant conditioning with large doses of anticancer drugs and total body irradiation to eradicate any remaining tumor cells in the patient and reduce the recipient's immune system because the donor hematopoietic cells are not rejected.
- normal hematopoietic stem cells collected from a donor are transvenously infused, and the hematopoietic stem cells eventually settle in the recipient's bone marrow and reconstruct normal hematopoietic function.
- bone marrow transplantation the case of using bone marrow as a source of hematopoietic stem cells
- peripheral blood stem cell transplantation the case of using stem cells collected from peripheral blood
- umbilical cord blood transplantation the case of using umbilical cord blood transplantation.
- Umbilical cord blood is blood present in the placenta and umbilical cord, and is rich in hematopoietic stem cells. Allogeneic cord blood transplantation places a small burden on the donor, uses cord blood that has been cryopreserved in a cord blood bank in advance, and can be transplanted in a timely manner. Transplantation is possible even without bone marrow transplantation, and there is an advantage that chronic GVHD is less than bone marrow transplantation.
- cord blood transplantation the number of hematopoietic stem cells contained in one unit of cord blood used for transplantation is extremely small compared to the number of hematopoietic stem cells contained in bone marrow or peripheral blood stem cells as grafts. prone to delayed recovery.
- neutrophil recovery in cord blood transplantation has improved in recent years due to advances in pre-transplantation treatment, immunosuppressive methods, and measurement of anti-HLA antibodies, it is still insufficient compared to other transplants.
- allogeneic cord blood transplantation may be simply referred to as cord blood transplantation.
- the pharmaceutical composition of the present invention contains romiplostim as an active ingredient and is used for recovering blood cells after cord blood transplantation.
- blood cell recovery as used herein means neutrophil recovery and/or platelet recovery.
- platelet recovery means an increase in platelet count
- neutrophil recovery means an increase in neutrophil count.
- the subject of administration of the pharmaceutical composition of the present invention is a patient undergoing umbilical cord blood transplantation.
- umbilical cord blood transplantation For example, but not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma patients requiring cord blood transplantation.
- the pharmaceutical composition of the present invention is administered prophylactically to assist engraftment during cord blood transplantation. Specifically, the pharmaceutical composition of the present invention is administered from the day after transplantation, that is, from Day 1 when the day of transplantation is defined as Day 0, to hasten blood cell recovery after cord blood transplantation.
- the pharmaceutical composition of the present invention can be administered intravenously (also referred to as intravenous administration or intravenous injection) or by intravenous infusion (also referred to as intravenous drip or infusion) or subcutaneously (subcutaneous injection) to patients after cord blood transplantation. ) is done.
- intravenously also referred to as intravenous administration or intravenous injection
- intravenous infusion also referred to as intravenous drip or infusion
- subcutaneous injection subcutaneous injection
- the pharmaceutical composition of the present invention is started at 10 ⁇ g/kg/week as romiplostim, and thereafter administered once a week.
- the pharmaceutical composition of the present invention is preferably administered at 10 ⁇ g/kg/week as romiplostim from the start of administration to the 4th dose.
- the fifth and subsequent doses of the pharmaceutical composition of the present invention are preferably more than 5 ⁇ g/kg/week as romiplostim, and preferably 20 ⁇ g/kg/week at most.
- the dosage from the 5th time onwards may be increased or decreased as appropriate while monitoring the patient's condition.
- the range of increase or decrease is preferably 5 ⁇ g/kg/week or 10 ⁇ g/kg/week, more preferably 10 ⁇ g/kg/week.
- the dosage is changed, it is preferable to maintain the modified dosage for 2 to 4 weeks, and more preferably to maintain the modified dosage for 3 weeks.
- the administration period of the pharmaceutical of the present invention can be continued until recovery of hematopoiesis is observed.
- the drug can be discontinued if necessary. For example, if the platelet count is stably over 70,000/ ⁇ L for 2 weeks or over 140,000/ ⁇ L at least once, the dose should be reduced by 1 step (5 ⁇ g/kg) or 2 steps (10 ⁇ g/kg). ).
- the pharmaceutical composition of the present invention is administered at an early stage of cord blood transplantation to promote blood cell recovery.
- Promoting blood cell recovery means promoting neutrophil recovery and/or platelet recovery. It also means promotion of neutrophil count increase and/or platelet count increase promotion. More specifically, the neutrophil count is 500/ ⁇ L or more, the platelet count is 20 ⁇ 10 9 /L (20,000/ ⁇ L) or more, preferably 30 ⁇ 10 9 /L (30,000/ ⁇ L) or more, More preferably, it increases to 50 ⁇ 10 9 /L (50,000/ ⁇ L) or more.
- the pharmaceutical composition of the present invention may be used in conjunction with other treatments or agents that aid engraftment during hematopoietic stem cell transplantation, such as cord blood transplantation.
- the pharmaceutical composition of the present invention is used in combination with G-CSF preparations, GVHD prevention methods (e.g., calcineurin inhibitors such as cyclosporine and tacrolimus, methotrexate, mycophenolate mofetil, etc.), and blood transfusions (platelet transfusion, red blood cell transfusion). be able to.
- the pharmaceutical composition of the present invention can be suitably used for patients for whom G-CSF preparations cannot be expected to sufficiently promote engraftment or increase the platelet count.
- the pharmaceutical composition of the present invention accelerates platelet recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone.
- the pharmaceutical composition of the present invention accelerates neutrophil recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone.
- composition/morphology The pharmaceutical composition of the present invention contains one or more pharmacologically acceptable carriers, additives, pH adjusters and the like.
- Additives include, for example, tonicity agents, buffers, solubilizers, preservatives and the like.
- tonicity agents include, but are not limited to, sodium chloride, calcium chloride, potassium chloride, magnesium chloride, fructose, glucose and D-mannitol.
- buffering agents include compositions containing potassium dihydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, sodium dihydrogen phosphate and disodium hydrogen phosphate, sodium citrate, and sodium citrate hydrate. is mentioned.
- solubilizing agents include ethanol, ethylenediamine, capric acid, L-glutamic acid, L-lysine, calcium oxide, magnesium oxide, sorbitan sesquioleate, D-sorbitol, nicotinamide, propylene glycol, polysorbate 80 and lauromacro Goal (9E.O.) etc.
- antiseptics examples include phenol, sodium edetate, benzalkonium chloride, chlorocresol, chlorobutanol, sodium salicylate, ethyl parahydroxybenzoate and butyl parahydroxybenzoate.
- pH adjusters examples include hydrochloric acid, dilute hydrochloric acid, glycine, succinic acid, phosphoric acid, phosphates, acetic acid, tartaric acid and meglumine.
- the form of the pharmaceutical composition of the present invention is not particularly limited, and may be a form prepared in advance for subcutaneous administration or a form prepared by dissolving diluted or freeze-dried romiplostim in a solvent for injection such as water at the time of use. good.
- the pharmaceutical composition of the present invention is provided by being filled in a glass container, a plastic container, or the like.
- the shape of the container is not particularly limited, and examples thereof include vials, syringes, bags and bottles.
- a preferred example of the pharmaceutical composition of the present invention is a powdery preparation obtained by freeze-drying romiplostim together with pharmacologically acceptable additives according to a conventional method.
- a specific example of such a pharmaceutical composition is Romiplate (registered trademark).
- Romiplate contains D-mannitol, refined sucrose, L-histidine, polysorbate 20, and dilute hydrochloric acid as additives in a lyophilized product of romiplostim, and is used by appropriately dissolving in water for injection before administration.
- the pharmaceutical composition of the present invention has the above-mentioned usage/dosage and effects, for example, “blood cell recovery after (allogeneic) cord blood transplantation”, “stimulation of increase in platelet count and neutrophil count after (allogeneic) cord blood transplantation” ”, “promoting platelet count increase during (allogeneic) cord blood transplantation”, “blood cell recovery during (allogeneic) hematopoietic stem cell transplantation”, “promoting platelet count increase during (allogeneic) hematopoietic stem cell transplantation”, “hematopoietic stem cell It is commercialized with labels (package inserts and packaging) such as “blood cell recovery during transplantation”, “stimulation of blood cell increase during hematopoietic stem cell transplantation”, and “stimulation of increase in platelet count and neutrophil count during hematopoietic stem cell transplantation”. .
- the invention also provides methods of treatment using the pharmaceutical compositions of the invention. That is, the present invention provides a therapeutic method for blood cell recovery in a subject who has undergone cord blood transplantation, which comprises administering romiplostim to the subject from the day following the transplantation.
- the dosage and administration of romiplostim are as described above.
- Romiplate registered trademark
- romiplostim formulation which is an example of a pharmaceutical composition containing romiplostim as an active ingredient.
- AML acute myeloid leukemia
- ALL acute lymphoblastic leukemia
- MDS myelodysplastic syndrome
- NHL non-Hodgkin lymphoma
- Inclusion Criteria Patients who meet any of (a) to (d) for target disease/disease stage and meet all other registration inclusion criteria.
- AML Cases with less than 5% blasts in the bone marrow in the preliminary examination. However, excluding acute megakaryoblastic leukemia and transition from myeloproliferative disease
- ALL cases with less than 5% blasts in the bone marrow in the preliminary examination
- MDS cases in the bone marrow in the preliminary examination Cases with less than 5% blasts
- NHL Cases in partial remission or complete remission with no bone marrow infiltration in prior examination
- the study drug will be administered subcutaneously once a week from Day 1 to Day 99 (according to the study schedule).
- the starting dose will be 5 ⁇ g/kg (5 ⁇ g/kg group), and the dose from the first dose to just before the fifth dose will be a fixed dose (no increase allowed).
- the starting dose is 5 ⁇ g/kg for the first 3 cases (5 ⁇ g/kg group), and the starting dose for the 4th and subsequent cases is 10 ⁇ g/kg (10 ⁇ g/kg group). Even if the starting dose is 10 ⁇ g/kg, the dose from the first dose to just before the fifth dose should be a fixed dose (dosage increase is not allowed).
- dose reduction/dose interruption should be performed appropriately according to the “dose change regulations in the event of an adverse event”. Regardless of the starting dose, the 5th and subsequent doses will be adjusted according to the dose table below according to the “dose adjustment” criteria.
- the dose should be increased by 2 steps (10 ⁇ g/kg increase), and 20,000/ ⁇ L or more to 50,000/ If the dose is less than ⁇ L, the dose may be increased by one step (5 ⁇ g/kg increase).
- the dose wait at least 2 weeks after the previous dose increase, carefully observe the changes in PLT up to that point, and confirm that there has been no recent rapid increase in PLT. Do not increase the dose before Day28.
- ⁇ Weight loss and drug suspension regulations Regardless of the presence or absence of platelet transfusion, if the PLT consistently exceeds 70,000/ ⁇ L for 2 weeks or exceeds 140,000/ ⁇ L even once, the investigator, etc. will decide to reduce the most recent dose by one step. Reduce the dose (5 ⁇ g/kg dose reduction) or 2-step dose reduction (10 ⁇ g/kg dose reduction) (see dose table in Table 1). In addition, if the PLT exceeds 200,000/ ⁇ L at any dose, the drug should be discontinued immediately. Even if the dose reduction/discontinuation criteria are not met, dose reduction/discontinuation should be performed if there is a concern that the PLT will increase significantly compared to the test value from 1 week ago and significantly exceed 200,000/ ⁇ L.
- ⁇ Dose increase rules after dose reduction/discontinuation If the PLT is less than 70,000/ ⁇ L after dose reduction or withdrawal during the administration period of the study drug, the dose should be increased by one step from the most recent dose according to the dose table in Table 1. After that, the same dose is maintained for 2 weeks, and if no increase in platelets is observed, the dose can be increased by one step. However, before Day28, the dose cannot be increased beyond the starting dose.
- Dose change rules when adverse events occur In the event of an adverse event, dose reduction and drug interruption may be permitted at the discretion of the investigator, etc. If it is necessary to resume administration of this drug after interruption due to the occurrence of an adverse event, administration should be resumed at 5 ⁇ g/kg. After the dose reduction and dose interruption, the dose may be carefully increased at the investigator's discretion. cancel.
- Dose change rules when blasts increased by more than 5% in peripheral blood The presence or absence of recurrence of the primary disease is confirmed, and administration of this drug is suspended until recurrence of the primary disease can be ruled out.
- Either myeloablative or palliative conditioning is selected for transplantation conditioning.
- Umbilical cord blood stored and open to the public in a cord blood bank in Japan is used. Use a single unit with a target of 4/6 or more of HLA-A, -B, and -DR antigens in both GVH and HVG and a total nucleated cell count of 2.0 ⁇ 10 7 /kg per subject body weight.
- the umbilical cord blood is administered intravenously without washing the umbilical cord blood after dissolution.
- G-CSF Granulocyte colony stimulating factor
- Filgrastim or lenograstim will be administered once a day from Day5.
- G-CSF preparations should be administered according to the package insert until the time of neutrophil engraftment. If adverse reactions, etc.
- GVHD prevention For GVHD prevention, calcineurin inhibitors (cyclosporin or tacrolimus) and methotrexate or mycophenolate mofetil are used in combination. In addition, if it is necessary to change the type, dosage, or administration period of the drug due to the onset of GVHD or the side effects of the drug, etc., the change may be made at the discretion of the investigator. 3) blood transfusion a.
- Irradiated red blood cell concentrate (2 units) will be transfused to maintain a target Hb level of 7 g/dL after patient registration. In consideration of clinical symptoms and complications, red blood cell transfusion is permitted at the discretion of the investigator.
- romiplostim included bone pain in 3 patients and injection site reaction in 1 patient.
- Serious adverse events included febrile neutropenia (4 patients), acute GVHD (2 patients), pneumonia (1 patient), HHV6 encephalitis (1 patient), CMV antigenemia (1 patient), and arrhythmia (1 patient). 1) were reported in 5 patients. No recurrence, thrombotic complications, or bone marrow fibrosis were observed. All achieved neutrophil recovery, with a median time to recovery of 14 days (12–32 days). Platelet recovery was achieved in all but one patient who died of pneumonia on day 48. The median number of days to platelets ⁇ 50x10 9 /L was 34 days (range 29–98 days) in patients achieving platelet recovery by Day 100 (83%). Anti-romiplostim antibodies were detected in 1 of 6 patients, but no neutralizing activity was observed.
- Figure 1 shows the results of blood cell recovery after allogeneic cord blood transplantation
- Figure 2 summarizes the case data of each subject.
- the median number of days to platelets ⁇ 50 ⁇ 10 9 /L after cord blood transplantation was 40-59 days, and the median number of days to neutrophils ⁇ 50 ⁇ 10 7 /L. is 19-22.5 days. Note that this number represents the median number of cases that achieved recovery. From the above, it was shown that the patients in this clinical trial recovered not only platelets but also neutrophils at an early stage by administration of romiplostim, and the engraftment achievement rate was favorable.
- platelet recovery and/or neutrophil recovery after cord blood transplantation is accelerated, and safe cord blood transplantation becomes possible.
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Abstract
The present invention relates to a pharmaceutical composition for blood cell recovery after allogeneic cord blood transplant, the pharmaceutical composition containing romiplostim as an active ingredient. The pharmaceutical composition is characterized by being administered starting the day after the transplant. The present invention also relates to a method for treating an allogeneic cord blood transplant recipient using the pharmaceutical composition.
Description
関連出願：
本出願は、日本特許出願２０２２－０１４６５４（２０２２年２月２日出願）に基づく優先権を主張しており、この内容は本明細書に参照として取り込まれる。
技術分野：
本発明は、臍帯血移植時のロミプロスチムの使用に関する。より詳細には、ロミプロスチムを有効成分とする臍帯血移植後の血球回復用の医薬組成物に関する。 Related application:
This application claims priority from Japanese Patent Application No. 2022-014654 (filed February 2, 2022), the contents of which are incorporated herein by reference.
Technical field:
The present invention relates to the use of romiplostim during cord blood transplantation. More particularly, it relates to a pharmaceutical composition for recovering blood cells after cord blood transplantation, containing romiplostim as an active ingredient.
本出願は、日本特許出願２０２２－０１４６５４（２０２２年２月２日出願）に基づく優先権を主張しており、この内容は本明細書に参照として取り込まれる。
技術分野：
本発明は、臍帯血移植時のロミプロスチムの使用に関する。より詳細には、ロミプロスチムを有効成分とする臍帯血移植後の血球回復用の医薬組成物に関する。 Related application:
This application claims priority from Japanese Patent Application No. 2022-014654 (filed February 2, 2022), the contents of which are incorporated herein by reference.
Technical field:
The present invention relates to the use of romiplostim during cord blood transplantation. More particularly, it relates to a pharmaceutical composition for recovering blood cells after cord blood transplantation, containing romiplostim as an active ingredient.
血液がん（白血病、悪性リンパ腫など）、再生不良性貧血や免疫不全症など、正常な血液を作ることが困難な疾患に対しては造血幹細胞移植が行われる。造血幹細胞移植には、骨髄移植（Bone Marrow Transplantation (BMT)）、末梢血幹細胞移植（Peripheral Blood Stem Cell Transplantation (PBSCT)）、臍帯血移植（Cord Blood Transplantation (CBT)）の3種がある。多くは他者の幹細胞を移植する同種他家移植であるが、本人の骨髄や末梢血幹細胞を移植する自家移植である場合もある。
Hematopoietic stem cell transplantation is performed for diseases such as blood cancer (leukemia, malignant lymphoma, etc.), aplastic anemia, and immunodeficiency, which make it difficult to produce normal blood. There are three types of hematopoietic stem cell transplantation: Bone Marrow Transplantation (BMT), Peripheral Blood Stem Cell Transplantation (PBSCT), and Cord Blood Transplantation (CBT). Most cases are allogeneic transplants in which stem cells from other people are transplanted, but there are also cases in which autologous transplants are performed in which the patient's bone marrow or peripheral blood stem cells are transplanted.
通常、造血幹細胞移植後に好中球数の回復（好中球回復）を確認した場合に生着と呼ぶ。好中球数が回復するまでは致死的な感染症を回避するための無菌管理とG-CSF製剤及び抗生物質の投与が行われるものの、感染症による死亡は幹細胞移植後の非再発死亡の最大の原因である。また、造血幹細胞移植後に血小板数が回復することは、「血小板生着」または「血小板回復」という。好中球に遅れて血小板数が回復するが、血小板数が回復するまでは消化管出血や脳出血等の致命的な出血のリスクを回避するため、頻回の血小板輸血が必要とされる。しかし、感染症や抗HLA抗体産生による血小板輸血不応の発現などが報告されており、輸血は最小限にとどめるべきとされている。また、好中球回復と血小板回復を含む造血機能が回復することを「造血回復」という。
Usually, when the recovery of the neutrophil count (neutrophil recovery) is confirmed after hematopoietic stem cell transplantation, it is called engraftment. Although aseptic management and administration of G-CSF preparations and antibiotics are performed to avoid fatal infections until the neutrophil count recovers, deaths due to infections are the largest non-recurrent deaths after stem cell transplantation. is the cause of Also, recovery of platelet count after hematopoietic stem cell transplantation is referred to as "platelet engraftment" or "platelet recovery." Although the platelet count recovers later than that of neutrophils, frequent platelet transfusions are required to avoid the risk of fatal bleeding such as gastrointestinal hemorrhage and cerebral hemorrhage until the platelet count recovers. However, platelet transfusion refractory due to infection and anti-HLA antibody production has been reported, and blood transfusion should be kept to a minimum. In addition, recovery of hematopoietic function including neutrophil recovery and platelet recovery is referred to as "hematopoietic recovery".
臍帯血移植は他の2つの移植に比べて造血回復が遅く、生着割合が低く、生存率が低いことが知られている。そのため、臍帯血移植については生着を補助し、造血回復を早めるための薬剤や技術のニーズがある。
Cord blood transplantation is known to have a slower hematopoietic recovery, a lower engraftment rate, and a lower survival rate than the other two transplants. Therefore, regarding cord blood transplantation, there is a need for drugs and techniques for assisting engraftment and hastening hematopoietic recovery.
移植後の造血回復を補助するための処置には、移植前または移植後早期から行われる予防的処置（予防的投与）、移植後に造血回復が遅延した場合に行われる治療的処置（治療的投与）がある。また、移植後いったん血小板数が増加した後に血小板減少を生じる二次性血小板減少症（SFPR (secondary failure of platelet response)）に対する治療的処置もある。
Treatments to support post-transplantation hematopoietic recovery include prophylactic treatment given before or early after transplantation (prophylactic administration), and therapeutic treatment given post-transplantation if hematopoietic recovery is delayed (therapeutic administration). ). There are also therapeutic treatments for secondary failure of platelet response (SFPR), in which platelet counts increase once after transplantation and then platelets decrease.
Tangらは、臍帯血移植後14日目～28日目までrhTPOを毎日投与することにより、コントロール群と比較して血小板回復が早まることを報告しているが、好中球の回復促進効果は確認されていない（非特許文献１）。具体的には、血小板数が≧50000/μLとなった日数の中央値がrhTPO投与群で43日に対して、コントロール群では53日であった。Pasvolskyらは、臍帯血移植後1日目から毎日（中央値で76日間）エルトロンボパグを安全に投与できたものの、早期の血小板回復は確認できなかったことを報告している（非特許文献２）。ほかにも、臍帯血移植後の血小板回復や好中球回復に関する報告があるが、早期の回復は得られいない（非特許文献３～１１）。
Tang et al. reported that daily administration of rhTPO from day 14 to day 28 after cord blood transplantation accelerated platelet recovery compared with the control group, but the effect of promoting recovery of neutrophils was Not confirmed (Non-Patent Document 1). Specifically, the median number of days with a platelet count of ≧50000/μL was 43 days in the rhTPO-treated group and 53 days in the control group. Pasvolsky et al. reported that although eltrombopag could be administered safely daily from the first day after cord blood transplantation (median 76 days), early platelet recovery could not be confirmed (non-patent literature). 2). In addition, there are reports on platelet recovery and neutrophil recovery after cord blood transplantation, but early recovery has not been obtained (Non-Patent Documents 3 to 11).
ロミプロスチムは、内因性トロンボポエチン（TPO）の受容体であるc-Mplに結合し血小板産生を亢進させる血小板造血刺激因子製剤である（特許文献１）。ロミプロスチムは2008年7月に豪州で「成人慢性免疫性（特発性）血小板減少性紫斑病患者（ITP）における血小板減少症」の治療薬として承認されて以降、60ヵ国以上で承認され、ロミプレート（登録商標）等の販売名で製造販売されている。また、ロミプロスチムは、再生不良性貧血を対象としても日本、韓国、および台湾で製造販売承認を受けている。
Romiplostim is a platelet hematopoiesis-stimulating factor preparation that binds to c-Mpl, a receptor for endogenous thrombopoietin (TPO), and enhances platelet production (Patent Document 1). Romiplostim was approved in Australia in July 2008 for the treatment of thrombocytopenia in adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP). It is manufactured and sold under trade names such as (registered trademark). Romiplostim has also been approved for manufacturing and marketing in Japan, South Korea, and Taiwan for aplastic anemia.
幹細胞移植後の血小板生着不全や二次性血小板減少症に対するロミプロスチムの治療的投与に関する報告がある。例えば、Christakopoulosらは、幹細胞移植後の生着不全に対する治療的投与において、ロミプロスチムを4,6,8,または10μg／kg／週で4～6回投与することで血小板回復がコントロール群よりも早まる傾向が見られたことを報告している（非特許文献１２）。同種幹細胞移植（骨髄又は末梢血幹細胞移植）後のロミプロスチムの治療的投与に関する報告（非特許文献１３及び１４）や、臍帯血移植後の二次性血小板減少症に対するロミプロスチムの治療的投与に関する報告がある（非特許文献１５）。
There are reports on the therapeutic administration of romiplostim for platelet engraftment failure and secondary thrombocytopenia after stem cell transplantation. For example, Christakopoulos et al. found that 4-6 doses of romiplostim at 4, 6, 8, or 10 μg/kg/week resulted in faster platelet recovery than controls in therapeutic administration of engraftment failure after stem cell transplantation. It has been reported that a trend was observed (Non-Patent Document 12). There are reports on therapeutic administration of romiplostim after allogeneic stem cell transplantation (bone marrow or peripheral blood stem cell transplantation) (Non-Patent Documents 13 and 14) and reports on therapeutic administration of romiplostim for secondary thrombocytopenia after cord blood transplantation. There is (Non-Patent Document 15).
予防的投与については、自家末梢血幹細胞移植において、移植当日にロミプロスチム250μgを単回投与することにより、比較群に対して血小板回復が早まる可能性が示唆されたとの報告（非特許文献１６及び１７）や、幹細胞移植前及び移植後のロミプロスチム投与により重度の血小板減少の期間が短縮されたことが推測されるとの報告がある（非特許文献５）。しかし、臍帯血移植や同種骨髄・末梢血幹細胞移植については、これまでロミプロスチムの予防的投与に関する報告はない。
Regarding prophylactic administration, it was suggested that a single administration of 250 μg of romiplostim on the day of transplantation in autologous peripheral blood stem cell transplantation may accelerate platelet recovery compared to the comparison group (Non-Patent Documents 16 and 17 ) and that administration of romiplostim before and after stem cell transplantation shortened the period of severe platelet decrease (Non-Patent Document 5). However, there have been no reports of prophylactic administration of romiplostim for cord blood transplantation or allogeneic bone marrow/peripheral blood stem cell transplantation.
また、これまでにロミプロスチムによる幹細胞移植後の好中球数に対する作用は報告されていない。
In addition, no effect of romiplostim on the number of neutrophils after stem cell transplantation has been reported so far.
本発明の課題は、臍帯血移植時の血球回復を促進するための新規な手段を提供することにある。
The object of the present invention is to provide a novel means for promoting blood cell recovery during cord blood transplantation.
発明者らは、臍帯血移植時におけるロミプロスチムの予防的投与の安全性について検討し、移植直後にロミプロスチムを特定の用法・用量で投与することにより、血球回復が早まることを見出し、本発明を完成した。
The inventors investigated the safety of prophylactic administration of romiplostim during cord blood transplantation, found that administration of romiplostim at a specific dosage and dosage immediately after transplantation accelerated blood cell recovery, and completed the present invention. bottom.
第１の実施態様において、本発明は以下の［１］～［１３］に関する。
［１］ ロミプロスチムを有効成分とする臍帯血移植後の血球回復用の医薬組成物であって、前記移植施行翌日から投与されることを特徴とする、医薬組成物。
［２］ 前記血球が血小板および／または好中球である、［１］に記載の医薬組成物。
［３］ ロミプロスチムとして5または10μg/kg/週で投与開始され、以降週1回投与されることを特徴とする、［１］または［２］に記載の医薬組成物。
［４］ 投与開始から4回目まではロミプロスチムとして同じ用量を投与されることを特徴とする、［３］に記載の医薬組成物。
［５］ 5回目以降はロミプロスチムとして5μg/kg/週以上最大20μg/kg/週で投与されることを特徴とする、［３］または［４］に記載の医薬組成物。
［６］ 5回目以降の増減量幅が5μg/kg/週または10μg/kg/週であることを特徴とする、［３］～［５］のいずれかに記載の医薬組成物。
［７］ 皮下投与または静脈内投与されることを特徴とする、［１］～［６］のいずれかに記載の医薬組成物。
［８］ 皮下投与されることを特徴とする、［７］に記載の医薬組成物。
［９］ G-CSF製剤と併用されることを特徴とする、［１］～［８］のいずれかに記載の医薬組成物。
［１０］ 投与量を変更する場合、3週間は変更後の投与量が維持されることを特徴とする、［１］～［９］のいずれかに記載の医薬組成物。
［１１］ G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める、［１］～［１０］のいずれかに記載の医薬組成物。
［１２］ G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める、［１］～［１１］のいずれかに記載の医薬組成物。
［１３］ 医薬組成物の投与を受ける対象が、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者である、［１］～［１２］のいずれかに記載の医薬組成物。 In a first embodiment, the present invention relates to the following [1] to [13].
[1] A pharmaceutical composition containing romiplostim as an active ingredient for recovering blood cells after cord blood transplantation, which is characterized by being administered from the day after the transplantation.
[2] The pharmaceutical composition of [1], wherein the blood cells are platelets and/or neutrophils.
[3] The pharmaceutical composition according to [1] or [2], which is initially administered at 5 or 10 μg/kg/week as romiplostim, and thereafter administered once a week.
[4] The pharmaceutical composition of [3], wherein the same dose as romiplostim is administered from the start of administration to the fourth time.
[5] The pharmaceutical composition of [3] or [4], wherein the fifth and subsequent doses of romiplostim are administered at 5 μg/kg/week or more and up to 20 μg/kg/week.
[6] The pharmaceutical composition according to any one of [3] to [5], wherein the range of dose increase/decrease from the fifth time onwards is 5 μg/kg/week or 10 μg/kg/week.
[7] The pharmaceutical composition according to any one of [1] to [6], which is administered subcutaneously or intravenously.
[8] The pharmaceutical composition of [7], which is administered subcutaneously.
[9] The pharmaceutical composition according to any one of [1] to [8], which is used in combination with a G-CSF preparation.
[10] The pharmaceutical composition according to any one of [1] to [9], wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
[11] The pharmaceutical composition according to any one of [1] to [10], which accelerates platelet recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone.
[12] The pharmaceutical composition of any one of [1] to [11], which accelerates neutrophil recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone.
[13] Subjects to whom the pharmaceutical composition is administered are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma who require cord blood transplantation [1] to [ 12], the pharmaceutical composition according to any one of the above.
［１］ ロミプロスチムを有効成分とする臍帯血移植後の血球回復用の医薬組成物であって、前記移植施行翌日から投与されることを特徴とする、医薬組成物。
［２］ 前記血球が血小板および／または好中球である、［１］に記載の医薬組成物。
［３］ ロミプロスチムとして5または10μg/kg/週で投与開始され、以降週1回投与されることを特徴とする、［１］または［２］に記載の医薬組成物。
［４］ 投与開始から4回目まではロミプロスチムとして同じ用量を投与されることを特徴とする、［３］に記載の医薬組成物。
［５］ 5回目以降はロミプロスチムとして5μg/kg/週以上最大20μg/kg/週で投与されることを特徴とする、［３］または［４］に記載の医薬組成物。
［６］ 5回目以降の増減量幅が5μg/kg/週または10μg/kg/週であることを特徴とする、［３］～［５］のいずれかに記載の医薬組成物。
［７］ 皮下投与または静脈内投与されることを特徴とする、［１］～［６］のいずれかに記載の医薬組成物。
［８］ 皮下投与されることを特徴とする、［７］に記載の医薬組成物。
［９］ G-CSF製剤と併用されることを特徴とする、［１］～［８］のいずれかに記載の医薬組成物。
［１０］ 投与量を変更する場合、3週間は変更後の投与量が維持されることを特徴とする、［１］～［９］のいずれかに記載の医薬組成物。
［１１］ G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める、［１］～［１０］のいずれかに記載の医薬組成物。
［１２］ G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める、［１］～［１１］のいずれかに記載の医薬組成物。
［１３］ 医薬組成物の投与を受ける対象が、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者である、［１］～［１２］のいずれかに記載の医薬組成物。 In a first embodiment, the present invention relates to the following [1] to [13].
[1] A pharmaceutical composition containing romiplostim as an active ingredient for recovering blood cells after cord blood transplantation, which is characterized by being administered from the day after the transplantation.
[2] The pharmaceutical composition of [1], wherein the blood cells are platelets and/or neutrophils.
[3] The pharmaceutical composition according to [1] or [2], which is initially administered at 5 or 10 μg/kg/week as romiplostim, and thereafter administered once a week.
[4] The pharmaceutical composition of [3], wherein the same dose as romiplostim is administered from the start of administration to the fourth time.
[5] The pharmaceutical composition of [3] or [4], wherein the fifth and subsequent doses of romiplostim are administered at 5 μg/kg/week or more and up to 20 μg/kg/week.
[6] The pharmaceutical composition according to any one of [3] to [5], wherein the range of dose increase/decrease from the fifth time onwards is 5 μg/kg/week or 10 μg/kg/week.
[7] The pharmaceutical composition according to any one of [1] to [6], which is administered subcutaneously or intravenously.
[8] The pharmaceutical composition of [7], which is administered subcutaneously.
[9] The pharmaceutical composition according to any one of [1] to [8], which is used in combination with a G-CSF preparation.
[10] The pharmaceutical composition according to any one of [1] to [9], wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
[11] The pharmaceutical composition according to any one of [1] to [10], which accelerates platelet recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone.
[12] The pharmaceutical composition of any one of [1] to [11], which accelerates neutrophil recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone.
[13] Subjects to whom the pharmaceutical composition is administered are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma who require cord blood transplantation [1] to [ 12], the pharmaceutical composition according to any one of the above.
第２の実施態様において、本発明は以下の［１］～［１３］に関する。
［１］ 臍帯血移植を受けた対象における血球回復のための治療方法であって、前記対象にロミプロスチムを前記移植施行翌日から投与することを特徴とする、方法。
［２］ 前記血球が血小板および／または好中球である、［１］に記載の方法。
［３］ ロミプロスチムとして5または10μg/kg/週で投与開始され、以降週1回投与されることを特徴とする、［１］または［２］に記載の方法。
［４］ 投与開始から4回目まではロミプロスチムを同じ用量で投与することを特徴とする、［３］に記載の方法。
［５］ 5回目以降はロミプロスチムを5μg/kg/週以上最大20μg/kg/週で投与することを特徴とする、［３］または［４］に記載の方法。
［６］ 5回目以降のロミプロスチムの増減量幅が5μg/kg/週または10μg/kg/週であることを特徴とする、［３］～［５］のいずれかに記載の方法。
［７］ ロミプロスチムを皮下投与または静脈投与することを特徴とする、［１］～［６］のいずれかに記載の方法。
［８］ ロミプロスチムを皮下投与することを特徴とする、［７］に記載の方法。
［９］ ロミプロスチムがG-CSF製剤と併用されることを特徴とする、［１］～［８］のいずれかに記載の方法。
［１０］ 投与量を変更する場合、3週間は変更後の投与量が維持されることを特徴とする、［１］～［９］のいずれかに記載の方法。
［１１］ ロミプロスチムがG-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める、［１］～［１０］のいずれかに記載の方法。
［１２］ ロミプロスチムがG-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める、［１］～［１１］のいずれかに記載の方法。
［１３］ ロミプロスチムの投与を受ける対象が、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者である、［１］～［１２］のいずれかに記載の方法。 In a second embodiment, the present invention relates to the following [1] to [13].
[1] A therapeutic method for blood cell recovery in a subject who has undergone cord blood transplantation, characterized in that romiplostim is administered to the subject from the day after the transplantation.
[2] The method of [1], wherein the blood cells are platelets and/or neutrophils.
[3] The method of [1] or [2], wherein administration of romiplostim is initiated at 5 or 10 μg/kg/week, and thereafter administered once a week.
[4] The method of [3], wherein the same dose of romiplostim is administered from the start of administration to the fourth administration.
[5] The method of [3] or [4], wherein romiplostim is administered at a dose of 5 μg/kg/week or more and a maximum of 20 μg/kg/week from the fifth time onwards.
[6] The method according to any one of [3] to [5], wherein the amount of romiplostim after the fifth dose is increased or decreased by 5 μg/kg/week or 10 μg/kg/week.
[7] The method of any one of [1] to [6], wherein romiplostim is administered subcutaneously or intravenously.
[8] The method of [7], which comprises subcutaneously administering romiplostim.
[9] The method of any one of [1] to [8], wherein romiplostim is used in combination with a G-CSF preparation.
[10] The method according to any one of [1] to [9], wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
[11] The method of any one of [1] to [10], wherein when romiplostim is used in combination with a G-CSF preparation, platelet recovery is hastened compared to administration of the G-CSF preparation alone.
[12] The method of any one of [1] to [11], wherein when romiplostim is used in combination with a G-CSF preparation, neutrophil recovery is hastened compared to administration of the G-CSF preparation alone.
[13] Subjects who receive romiplostim are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma who require cord blood transplantation [1]-[12] The method according to any one of
［１］ 臍帯血移植を受けた対象における血球回復のための治療方法であって、前記対象にロミプロスチムを前記移植施行翌日から投与することを特徴とする、方法。
［２］ 前記血球が血小板および／または好中球である、［１］に記載の方法。
［３］ ロミプロスチムとして5または10μg/kg/週で投与開始され、以降週1回投与されることを特徴とする、［１］または［２］に記載の方法。
［４］ 投与開始から4回目まではロミプロスチムを同じ用量で投与することを特徴とする、［３］に記載の方法。
［５］ 5回目以降はロミプロスチムを5μg/kg/週以上最大20μg/kg/週で投与することを特徴とする、［３］または［４］に記載の方法。
［６］ 5回目以降のロミプロスチムの増減量幅が5μg/kg/週または10μg/kg/週であることを特徴とする、［３］～［５］のいずれかに記載の方法。
［７］ ロミプロスチムを皮下投与または静脈投与することを特徴とする、［１］～［６］のいずれかに記載の方法。
［８］ ロミプロスチムを皮下投与することを特徴とする、［７］に記載の方法。
［９］ ロミプロスチムがG-CSF製剤と併用されることを特徴とする、［１］～［８］のいずれかに記載の方法。
［１０］ 投与量を変更する場合、3週間は変更後の投与量が維持されることを特徴とする、［１］～［９］のいずれかに記載の方法。
［１１］ ロミプロスチムがG-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める、［１］～［１０］のいずれかに記載の方法。
［１２］ ロミプロスチムがG-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める、［１］～［１１］のいずれかに記載の方法。
［１３］ ロミプロスチムの投与を受ける対象が、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者である、［１］～［１２］のいずれかに記載の方法。 In a second embodiment, the present invention relates to the following [1] to [13].
[1] A therapeutic method for blood cell recovery in a subject who has undergone cord blood transplantation, characterized in that romiplostim is administered to the subject from the day after the transplantation.
[2] The method of [1], wherein the blood cells are platelets and/or neutrophils.
[3] The method of [1] or [2], wherein administration of romiplostim is initiated at 5 or 10 μg/kg/week, and thereafter administered once a week.
[4] The method of [3], wherein the same dose of romiplostim is administered from the start of administration to the fourth administration.
[5] The method of [3] or [4], wherein romiplostim is administered at a dose of 5 μg/kg/week or more and a maximum of 20 μg/kg/week from the fifth time onwards.
[6] The method according to any one of [3] to [5], wherein the amount of romiplostim after the fifth dose is increased or decreased by 5 μg/kg/week or 10 μg/kg/week.
[7] The method of any one of [1] to [6], wherein romiplostim is administered subcutaneously or intravenously.
[8] The method of [7], which comprises subcutaneously administering romiplostim.
[9] The method of any one of [1] to [8], wherein romiplostim is used in combination with a G-CSF preparation.
[10] The method according to any one of [1] to [9], wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
[11] The method of any one of [1] to [10], wherein when romiplostim is used in combination with a G-CSF preparation, platelet recovery is hastened compared to administration of the G-CSF preparation alone.
[12] The method of any one of [1] to [11], wherein when romiplostim is used in combination with a G-CSF preparation, neutrophil recovery is hastened compared to administration of the G-CSF preparation alone.
[13] Subjects who receive romiplostim are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma who require cord blood transplantation [1]-[12] The method according to any one of
第３の実施態様において、本発明は以下の［１］～［１３］に関する。
［１］ 臍帯血移植を受けた対象における血球回復のための治療方法における使用のためのロミプロスチムであって、前記移植施行翌日からロミプロスチムが投与されることを特徴とする、ロミプロスチム。
［２］ 前記血球が血小板および／または好中球である、［１］に記載のロミプロスチム。
［３］ ロミプロスチムとして5または10μg/kg/週で投与開始され、以降週1回投与されることを特徴とする、［１］または［２］に記載の使用のためのロミプロスチム。
［４］ 投与開始から4回目までは同じ用量で投与されることを特徴とする、［３］に記載の使用のためのロミプロスチム。
［５］ 5回目以降は5μg/kg/週以上最大20μg/kg/週で投与されることを特徴とする、［３］または［４］に記載の使用のためのロミプロスチム。
［６］ 5回目以降の増減量幅が5μg/kg/週または10μg/kg/週であることを特徴とする、［３］～［５］のいずれかに記載の使用のためのロミプロスチム。
［７］ ロミプロスチムが皮下投与または静脈投与されることを特徴とする、［１］～［６］のいずれかに記載の使用のためのロミプロスチム。
［８］ ロミプロスチムが皮下投与されることを特徴とする、［７］に記載の使用のためのロミプロスチム。
［９］ ロミプロスチムがG-CSF製剤と併用されることを特徴とする、［１］～［８］のいずれかに記載の使用のためのロミプロスチム。
［１０］ 投与量を変更する場合、3週間は変更後の投与量が維持されることを特徴とする、［１］～［９］のいずれかに記載の使用のためのロミプロスチム。
［１１］ ロミプロスチムがG-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める、［１］～［１０］のいずれかに記載の使用のためのロミプロスチム。
［１２］ ロミプロスチムがG-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める、［１］～［１１］のいずれかに記載の使用のためのロミプロスチム。
［１３］ ロミプロスチムの投与を受ける対象が、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者である、［１］～［１２］のいずれかに記載の使用のためのロミプロスチム。 In a third embodiment, the present invention relates to the following [1] to [13].
[1] A romiplostim for use in a therapeutic method for blood cell recovery in a subject who has undergone cord blood transplantation, wherein romiplostim is administered from the day following the transplantation.
[2] The romiplostim of [1], wherein the blood cells are platelets and/or neutrophils.
[3] Romiplostim for use according to [1] or [2], characterized in that administration is initiated at 5 or 10 μg/kg/week as romiplostim and thereafter administered once a week.
[4] Romiplostim for use according to [3], characterized in that the same dose is administered from the start to the fourth administration.
[5] Romiplostim for use according to [3] or [4], characterized in that it is administered at a dose of 5 μg/kg/week or more and a maximum of 20 μg/kg/week from the 5th dose onwards.
[6] Romiplostim for use according to any one of [3] to [5], characterized in that the amount increase/decrease range from the 5th time onwards is 5 μg/kg/week or 10 μg/kg/week.
[7] Romiplostim for use according to any one of [1] to [6], wherein the romiplostim is administered subcutaneously or intravenously.
[8] Romiplostim for use according to [7], wherein the romiplostim is administered subcutaneously.
[9] Romiplostim for use according to any one of [1] to [8], characterized in that romiplostim is used in combination with a G-CSF preparation.
[10] Romiplostim for use according to any one of [1] to [9], wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
[11] Romiplostim for use according to any one of [1] to [10], wherein when romiplostim is used in combination with a G-CSF preparation, platelet recovery is hastened compared to administration of the G-CSF preparation alone.
[12] For the use according to any one of [1] to [11], wherein when romiplostim is used in combination with a G-CSF preparation, neutrophil recovery is hastened compared to administration of the G-CSF preparation alone romiplostim.
[13] Subjects who receive romiplostim are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma who require cord blood transplantation [1]-[12] romiplostim for use according to any of
［１］ 臍帯血移植を受けた対象における血球回復のための治療方法における使用のためのロミプロスチムであって、前記移植施行翌日からロミプロスチムが投与されることを特徴とする、ロミプロスチム。
［２］ 前記血球が血小板および／または好中球である、［１］に記載のロミプロスチム。
［３］ ロミプロスチムとして5または10μg/kg/週で投与開始され、以降週1回投与されることを特徴とする、［１］または［２］に記載の使用のためのロミプロスチム。
［４］ 投与開始から4回目までは同じ用量で投与されることを特徴とする、［３］に記載の使用のためのロミプロスチム。
［５］ 5回目以降は5μg/kg/週以上最大20μg/kg/週で投与されることを特徴とする、［３］または［４］に記載の使用のためのロミプロスチム。
［６］ 5回目以降の増減量幅が5μg/kg/週または10μg/kg/週であることを特徴とする、［３］～［５］のいずれかに記載の使用のためのロミプロスチム。
［７］ ロミプロスチムが皮下投与または静脈投与されることを特徴とする、［１］～［６］のいずれかに記載の使用のためのロミプロスチム。
［８］ ロミプロスチムが皮下投与されることを特徴とする、［７］に記載の使用のためのロミプロスチム。
［９］ ロミプロスチムがG-CSF製剤と併用されることを特徴とする、［１］～［８］のいずれかに記載の使用のためのロミプロスチム。
［１０］ 投与量を変更する場合、3週間は変更後の投与量が維持されることを特徴とする、［１］～［９］のいずれかに記載の使用のためのロミプロスチム。
［１１］ ロミプロスチムがG-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める、［１］～［１０］のいずれかに記載の使用のためのロミプロスチム。
［１２］ ロミプロスチムがG-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める、［１］～［１１］のいずれかに記載の使用のためのロミプロスチム。
［１３］ ロミプロスチムの投与を受ける対象が、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者である、［１］～［１２］のいずれかに記載の使用のためのロミプロスチム。 In a third embodiment, the present invention relates to the following [1] to [13].
[1] A romiplostim for use in a therapeutic method for blood cell recovery in a subject who has undergone cord blood transplantation, wherein romiplostim is administered from the day following the transplantation.
[2] The romiplostim of [1], wherein the blood cells are platelets and/or neutrophils.
[3] Romiplostim for use according to [1] or [2], characterized in that administration is initiated at 5 or 10 μg/kg/week as romiplostim and thereafter administered once a week.
[4] Romiplostim for use according to [3], characterized in that the same dose is administered from the start to the fourth administration.
[5] Romiplostim for use according to [3] or [4], characterized in that it is administered at a dose of 5 μg/kg/week or more and a maximum of 20 μg/kg/week from the 5th dose onwards.
[6] Romiplostim for use according to any one of [3] to [5], characterized in that the amount increase/decrease range from the 5th time onwards is 5 μg/kg/week or 10 μg/kg/week.
[7] Romiplostim for use according to any one of [1] to [6], wherein the romiplostim is administered subcutaneously or intravenously.
[8] Romiplostim for use according to [7], wherein the romiplostim is administered subcutaneously.
[9] Romiplostim for use according to any one of [1] to [8], characterized in that romiplostim is used in combination with a G-CSF preparation.
[10] Romiplostim for use according to any one of [1] to [9], wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
[11] Romiplostim for use according to any one of [1] to [10], wherein when romiplostim is used in combination with a G-CSF preparation, platelet recovery is hastened compared to administration of the G-CSF preparation alone.
[12] For the use according to any one of [1] to [11], wherein when romiplostim is used in combination with a G-CSF preparation, neutrophil recovery is hastened compared to administration of the G-CSF preparation alone romiplostim.
[13] Subjects who receive romiplostim are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma who require cord blood transplantation [1]-[12] romiplostim for use according to any of
第４の実施態様において、本発明は以下の［１］～［１３］に関する。
［１］ ロミプロスチムを有効成分とする臍帯血移植後の血球回復用の医薬組成物の製造におけるロミプロスチムの使用であって、医薬組成物が前記移植施行翌日から投与されることを特徴とする、使用。
［２］ 前記血球が血小板および／または好中球である、［１］に記載の使用。
［３］ 医薬組成物が、ロミプロスチムとして5または10μg/kg/週で投与開始され、以降週1回投与されることを特徴とする、［１］または［２］に記載の使用。
［４］ 医薬組成物が、投与開始から4回目まではロミプロスチムとして同じ用量を投与されることを特徴とする、［３］に記載の使用。
［５］ 医薬組成物が、5回目以降はロミプロスチムとして5μg/kg/週以上最大20μg/kg/週で投与されることを特徴とする、［３］または［４］に記載の使用。
［６］ 5回目以降の増減量幅が5μg/kg/週または10μg/kg/週であることを特徴とする、［３］～［５］のいずれかに記載の使用。
［７］ 医薬組成物が、皮下投与または静脈内投与されることを特徴とする、［１］～［６］のいずれかに記載の使用。
［８］ 医薬組成物が、皮下投与されることを特徴とする、［７］に記載の使用。
［９］ 医薬組成物が、G-CSF製剤と併用されることを特徴とする、［１］～［８］のいずれかに記載の使用。
［１０］ 投与量を変更する場合、3週間は変更後の投与量が維持されることを特徴とする、［１］～［９］のいずれかに記載の使用。
［１１］ 医薬組成物が、G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める、［１］～［１０］のいずれかに記載の使用。
［１２］ 医薬組成物が、G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める、［１］～［１１］のいずれかに記載の使用。
［１３］ 医薬組成物の投与を受ける対象が、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者である、［１］～［１２］のいずれかに記載の使用。 In a fourth embodiment, the present invention relates to the following [1] to [13].
[1] Use of romiplostim in the manufacture of a pharmaceutical composition containing romiplostim as an active ingredient for recovering blood cells after cord blood transplantation, wherein the pharmaceutical composition is administered from the day after the transplantation. .
[2] The use according to [1], wherein the blood cells are platelets and/or neutrophils.
[3] The use according to [1] or [2], wherein the pharmaceutical composition is initially administered at 5 or 10 μg/kg/week as romiplostim, and thereafter administered once a week.
[4] The use according to [3], wherein the pharmaceutical composition is administered at the same dose as romiplostim for the fourth time from the start of administration.
[5] The use according to [3] or [4], wherein the pharmaceutical composition is administered as romiplostim at 5 μg/kg/week or more and up to 20 μg/kg/week for the fifth time or later.
[6] The use according to any one of [3] to [5], characterized in that the range of dose increase/decrease after the 5th dose is 5 μg/kg/week or 10 μg/kg/week.
[7] The use according to any one of [1] to [6], wherein the pharmaceutical composition is administered subcutaneously or intravenously.
[8] The use of [7], wherein the pharmaceutical composition is administered subcutaneously.
[9] The use according to any one of [1] to [8], wherein the pharmaceutical composition is used in combination with a G-CSF formulation.
[10] The use according to any one of [1] to [9], wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
[11] The use according to any one of [1] to [10], wherein the pharmaceutical composition accelerates platelet recovery when used in combination with a G-CSF preparation as compared to administration of the G-CSF preparation alone.
[12] The use according to any one of [1] to [11], wherein the pharmaceutical composition accelerates neutrophil recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone. .
[13] Subjects to whom the pharmaceutical composition is administered are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma who require cord blood transplantation [1] to [ 12].
［１］ ロミプロスチムを有効成分とする臍帯血移植後の血球回復用の医薬組成物の製造におけるロミプロスチムの使用であって、医薬組成物が前記移植施行翌日から投与されることを特徴とする、使用。
［２］ 前記血球が血小板および／または好中球である、［１］に記載の使用。
［３］ 医薬組成物が、ロミプロスチムとして5または10μg/kg/週で投与開始され、以降週1回投与されることを特徴とする、［１］または［２］に記載の使用。
［４］ 医薬組成物が、投与開始から4回目まではロミプロスチムとして同じ用量を投与されることを特徴とする、［３］に記載の使用。
［５］ 医薬組成物が、5回目以降はロミプロスチムとして5μg/kg/週以上最大20μg/kg/週で投与されることを特徴とする、［３］または［４］に記載の使用。
［６］ 5回目以降の増減量幅が5μg/kg/週または10μg/kg/週であることを特徴とする、［３］～［５］のいずれかに記載の使用。
［７］ 医薬組成物が、皮下投与または静脈内投与されることを特徴とする、［１］～［６］のいずれかに記載の使用。
［８］ 医薬組成物が、皮下投与されることを特徴とする、［７］に記載の使用。
［９］ 医薬組成物が、G-CSF製剤と併用されることを特徴とする、［１］～［８］のいずれかに記載の使用。
［１０］ 投与量を変更する場合、3週間は変更後の投与量が維持されることを特徴とする、［１］～［９］のいずれかに記載の使用。
［１１］ 医薬組成物が、G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める、［１］～［１０］のいずれかに記載の使用。
［１２］ 医薬組成物が、G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める、［１］～［１１］のいずれかに記載の使用。
［１３］ 医薬組成物の投与を受ける対象が、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者である、［１］～［１２］のいずれかに記載の使用。 In a fourth embodiment, the present invention relates to the following [1] to [13].
[1] Use of romiplostim in the manufacture of a pharmaceutical composition containing romiplostim as an active ingredient for recovering blood cells after cord blood transplantation, wherein the pharmaceutical composition is administered from the day after the transplantation. .
[2] The use according to [1], wherein the blood cells are platelets and/or neutrophils.
[3] The use according to [1] or [2], wherein the pharmaceutical composition is initially administered at 5 or 10 μg/kg/week as romiplostim, and thereafter administered once a week.
[4] The use according to [3], wherein the pharmaceutical composition is administered at the same dose as romiplostim for the fourth time from the start of administration.
[5] The use according to [3] or [4], wherein the pharmaceutical composition is administered as romiplostim at 5 μg/kg/week or more and up to 20 μg/kg/week for the fifth time or later.
[6] The use according to any one of [3] to [5], characterized in that the range of dose increase/decrease after the 5th dose is 5 μg/kg/week or 10 μg/kg/week.
[7] The use according to any one of [1] to [6], wherein the pharmaceutical composition is administered subcutaneously or intravenously.
[8] The use of [7], wherein the pharmaceutical composition is administered subcutaneously.
[9] The use according to any one of [1] to [8], wherein the pharmaceutical composition is used in combination with a G-CSF formulation.
[10] The use according to any one of [1] to [9], wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
[11] The use according to any one of [1] to [10], wherein the pharmaceutical composition accelerates platelet recovery when used in combination with a G-CSF preparation as compared to administration of the G-CSF preparation alone.
[12] The use according to any one of [1] to [11], wherein the pharmaceutical composition accelerates neutrophil recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone. .
[13] Subjects to whom the pharmaceutical composition is administered are patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma who require cord blood transplantation [1] to [ 12].
本発明によれば、臍帯血移植後の血小板数の回復が促進され、安全な臍帯血移植が可能になる。
According to the present invention, recovery of the platelet count after cord blood transplantation is promoted, and safe cord blood transplantation becomes possible.
本発明は、ロミプロスチムを有効成分とする臍帯血移植後の血球回復用の医薬組成物であって、前記移植施行翌日から投与されることを特徴とする、医薬組成物に関する。
The present invention relates to a pharmaceutical composition containing romiplostim as an active ingredient for recovering blood cells after cord blood transplantation, characterized by being administered from the day after the transplantation.
「ロミプロスチム」
ロミプロスチムは、分子量約59 kDaの遺伝子組換え融合タンパク質であり、269個のアミノ酸残基（配列番号１）からなるサブユニット2分子から構成される2量体である。単量体の269個のアミノ酸のうち2～228番目はヒトIgG1のFc領域、また229～269番目はヒトトロンボポエチン受容体（c-Mpl）結合配列を含むペプチドからなる。 "romiplostim"
Romiplostim is a recombinant fusion protein with a molecular weight of about 59 kDa, and is a dimer composed of two subunit molecules consisting of 269 amino acid residues (SEQ ID NO: 1). Of the 269 amino acids of the monomer, positions 2-228 are the Fc region of human IgG1, and positions 229-269 consist of a peptide containing the human thrombopoietin receptor (c-Mpl) binding sequence.
ロミプロスチムは、分子量約59 kDaの遺伝子組換え融合タンパク質であり、269個のアミノ酸残基（配列番号１）からなるサブユニット2分子から構成される2量体である。単量体の269個のアミノ酸のうち2～228番目はヒトIgG1のFc領域、また229～269番目はヒトトロンボポエチン受容体（c-Mpl）結合配列を含むペプチドからなる。 "romiplostim"
Romiplostim is a recombinant fusion protein with a molecular weight of about 59 kDa, and is a dimer composed of two subunit molecules consisting of 269 amino acid residues (SEQ ID NO: 1). Of the 269 amino acids of the monomer, positions 2-228 are the Fc region of human IgG1, and positions 229-269 consist of a peptide containing the human thrombopoietin receptor (c-Mpl) binding sequence.
ロミプロスチムは、血小板生成活性および／または巨核球生成活性を有する。ロミプロスチムは、内因性トロンボポエチン（TPO）の受容体であるc-Mplに結合し血小板産生を亢進させることで、血小板造血刺激因子製剤として作用する。TPOは、ヒトの巨核球・血小板造血刺激因子である。ロミプロスチムは、c-Mpl に結合し活性化させることで、骨髄前駆細胞から巨核球に至る過程における細胞の増殖及び分化を促進し、結果として血小板（以下、PLTとも表記する）を増加させると考えられている。
Romiplostim has plateletogenic and/or megakaryopoietic activity. Romiplostim binds to the endogenous thrombopoietin (TPO) receptor c-Mpl and enhances platelet production, thereby acting as a platelet hematopoiesis-stimulating agent. TPO is a human megakaryocyte and platelet hematopoietic stimulator. By binding to and activating c-Mpl, romiplostim is thought to promote proliferation and differentiation of cells in the process from bone marrow progenitor cells to megakaryocytes, resulting in an increase in platelets (hereinafter also referred to as PLT). It is
本発明において、ロミプロスチムの製造方法は、医薬として許容される限り、特に限定されない。
In the present invention, the method for producing romiplostim is not particularly limited as long as it is pharmaceutically acceptable.
「同種造血幹細胞移植」
同種造血幹細胞移植（以下、同種移植）は、難治性造血器疾患に対し、根治を目的として行われる治療である。同種移植では、大量の抗がん剤や全身放射線照射を用いた移植前処置を行うことによって、患者体内に残存している腫瘍細胞を根絶し、ドナー造血細胞が拒絶されないためにレシピエントの免疫を抑制する。移植前処置に引き続いて、ドナーから採取した正常な造血幹細胞を経静脈的に輸注することで、造血幹細胞がやがてレシピエントの骨髄に定着し、正常な造血機能を再構築する。造血幹細胞の供給源として骨髄を用いる場合を骨髄移植、末梢血から採取された幹細胞を用いる場合を末梢血幹細胞移植、臍帯血を用いる場合を臍帯血移植という。 “Allogeneic hematopoietic stem cell transplantation”
Allogeneic hematopoietic stem cell transplantation (hereinafter referred to as allogeneic transplantation) is a treatment performed for the purpose of radical cure for intractable hematopoietic diseases. Allogeneic transplantation involves pre-transplant conditioning with large doses of anticancer drugs and total body irradiation to eradicate any remaining tumor cells in the patient and reduce the recipient's immune system because the donor hematopoietic cells are not rejected. suppress Following pretreatment for transplantation, normal hematopoietic stem cells collected from a donor are transvenously infused, and the hematopoietic stem cells eventually settle in the recipient's bone marrow and reconstruct normal hematopoietic function. The case of using bone marrow as a source of hematopoietic stem cells is called bone marrow transplantation, the case of using stem cells collected from peripheral blood is called peripheral blood stem cell transplantation, and the case of using umbilical cord blood is called umbilical cord blood transplantation.
同種造血幹細胞移植（以下、同種移植）は、難治性造血器疾患に対し、根治を目的として行われる治療である。同種移植では、大量の抗がん剤や全身放射線照射を用いた移植前処置を行うことによって、患者体内に残存している腫瘍細胞を根絶し、ドナー造血細胞が拒絶されないためにレシピエントの免疫を抑制する。移植前処置に引き続いて、ドナーから採取した正常な造血幹細胞を経静脈的に輸注することで、造血幹細胞がやがてレシピエントの骨髄に定着し、正常な造血機能を再構築する。造血幹細胞の供給源として骨髄を用いる場合を骨髄移植、末梢血から採取された幹細胞を用いる場合を末梢血幹細胞移植、臍帯血を用いる場合を臍帯血移植という。 “Allogeneic hematopoietic stem cell transplantation”
Allogeneic hematopoietic stem cell transplantation (hereinafter referred to as allogeneic transplantation) is a treatment performed for the purpose of radical cure for intractable hematopoietic diseases. Allogeneic transplantation involves pre-transplant conditioning with large doses of anticancer drugs and total body irradiation to eradicate any remaining tumor cells in the patient and reduce the recipient's immune system because the donor hematopoietic cells are not rejected. suppress Following pretreatment for transplantation, normal hematopoietic stem cells collected from a donor are transvenously infused, and the hematopoietic stem cells eventually settle in the recipient's bone marrow and reconstruct normal hematopoietic function. The case of using bone marrow as a source of hematopoietic stem cells is called bone marrow transplantation, the case of using stem cells collected from peripheral blood is called peripheral blood stem cell transplantation, and the case of using umbilical cord blood is called umbilical cord blood transplantation.
「同種臍帯血移植」
臍帯血は胎盤や臍帯に存在する血液であり、造血幹細胞が豊富に含まれている。同種臍帯血移植は、ドナーの負担が小さく、あらかじめ臍帯血バンクに凍結保存されている臍帯血を使用するため時期を逸さずに移植ができ、また臍帯血のHLAがレシピエントと完全に適合しなくても移植が可能であり、慢性GVHDが骨髄移植と比較して少ないという利点がある。 "Allogeneic Cord Blood Transplantation"
Umbilical cord blood is blood present in the placenta and umbilical cord, and is rich in hematopoietic stem cells. Allogeneic cord blood transplantation places a small burden on the donor, uses cord blood that has been cryopreserved in a cord blood bank in advance, and can be transplanted in a timely manner. Transplantation is possible even without bone marrow transplantation, and there is an advantage that chronic GVHD is less than bone marrow transplantation.
臍帯血は胎盤や臍帯に存在する血液であり、造血幹細胞が豊富に含まれている。同種臍帯血移植は、ドナーの負担が小さく、あらかじめ臍帯血バンクに凍結保存されている臍帯血を使用するため時期を逸さずに移植ができ、また臍帯血のHLAがレシピエントと完全に適合しなくても移植が可能であり、慢性GVHDが骨髄移植と比較して少ないという利点がある。 "Allogeneic Cord Blood Transplantation"
Umbilical cord blood is blood present in the placenta and umbilical cord, and is rich in hematopoietic stem cells. Allogeneic cord blood transplantation places a small burden on the donor, uses cord blood that has been cryopreserved in a cord blood bank in advance, and can be transplanted in a timely manner. Transplantation is possible even without bone marrow transplantation, and there is an advantage that chronic GVHD is less than bone marrow transplantation.
一方、移植に用いられる臍帯血1ユニットに含まれる造血幹細胞数は、移植片としての骨髄や末梢血幹細胞に含まれる造血幹細胞と比較して極めて少ないため、臍帯血移植後には血球回復不全、血球回復遅延が生じやすい。移植前処置や免疫抑制法の進歩や、抗HLA抗体の測定等により、近年臍帯血移植における好中球回復は改善しているが、他の移植片と比較して依然として不十分である。本明細書においては、同種臍帯血移植を単に臍帯血移植と記載することもある。
On the other hand, the number of hematopoietic stem cells contained in one unit of cord blood used for transplantation is extremely small compared to the number of hematopoietic stem cells contained in bone marrow or peripheral blood stem cells as grafts. prone to delayed recovery. Although neutrophil recovery in cord blood transplantation has improved in recent years due to advances in pre-transplantation treatment, immunosuppressive methods, and measurement of anti-HLA antibodies, it is still insufficient compared to other transplants. In the present specification, allogeneic cord blood transplantation may be simply referred to as cord blood transplantation.
「本発明の医薬組成物」
本発明の医薬組成物は、ロミプロスチムを有効成分とし、臍帯血移植後の血球回復用の医薬組成物である。後述するように、本明細書において、「血球回復」とは好中球回復および／または血小板回復を意味する。また、「血小板回復」とは血小板数が増加することを、「好中球回復」とは好中球数が増加することを意味する。 "Pharmaceutical composition of the present invention"
The pharmaceutical composition of the present invention contains romiplostim as an active ingredient and is used for recovering blood cells after cord blood transplantation. As described below, "blood cell recovery" as used herein means neutrophil recovery and/or platelet recovery. Further, "platelet recovery" means an increase in platelet count, and "neutrophil recovery" means an increase in neutrophil count.
本発明の医薬組成物は、ロミプロスチムを有効成分とし、臍帯血移植後の血球回復用の医薬組成物である。後述するように、本明細書において、「血球回復」とは好中球回復および／または血小板回復を意味する。また、「血小板回復」とは血小板数が増加することを、「好中球回復」とは好中球数が増加することを意味する。 "Pharmaceutical composition of the present invention"
The pharmaceutical composition of the present invention contains romiplostim as an active ingredient and is used for recovering blood cells after cord blood transplantation. As described below, "blood cell recovery" as used herein means neutrophil recovery and/or platelet recovery. Further, "platelet recovery" means an increase in platelet count, and "neutrophil recovery" means an increase in neutrophil count.
投与対象：
本発明の医薬組成物の投与対象は、臍帯血移植を受ける患者である。例えば、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者であるが、これらに限定されない。 Administered to:
The subject of administration of the pharmaceutical composition of the present invention is a patient undergoing umbilical cord blood transplantation. For example, but not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma patients requiring cord blood transplantation.
本発明の医薬組成物の投与対象は、臍帯血移植を受ける患者である。例えば、急性骨髄性白血病、急性リンパ性白血病、骨髄異形成症候群、非ホジキンリンパ腫患者で、臍帯血移植を必要とする患者であるが、これらに限定されない。 Administered to:
The subject of administration of the pharmaceutical composition of the present invention is a patient undergoing umbilical cord blood transplantation. For example, but not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma patients requiring cord blood transplantation.
用法・用量：
本発明の医薬組成物は、臍帯血移植時の生着を補助するために予防的投与される。具体的に言えば、本発明の医薬組成物は、移植施行翌日、すなわち移植日をDay 0とした場合にDay 1から投与され、臍帯血移植後の血球回復を早める。 Usage and dosage:
The pharmaceutical composition of the present invention is administered prophylactically to assist engraftment during cord blood transplantation. Specifically, the pharmaceutical composition of the present invention is administered from the day after transplantation, that is, from Day 1 when the day of transplantation is defined asDay 0, to hasten blood cell recovery after cord blood transplantation.
本発明の医薬組成物は、臍帯血移植時の生着を補助するために予防的投与される。具体的に言えば、本発明の医薬組成物は、移植施行翌日、すなわち移植日をDay 0とした場合にDay 1から投与され、臍帯血移植後の血球回復を早める。 Usage and dosage:
The pharmaceutical composition of the present invention is administered prophylactically to assist engraftment during cord blood transplantation. Specifically, the pharmaceutical composition of the present invention is administered from the day after transplantation, that is, from Day 1 when the day of transplantation is defined as
本発明の医薬組成物は、臍帯血移植後の患者に静注（経静脈投与または静脈注射とも称する）または点滴静注（点滴静脈注射または点滴とも称する）により静脈内投与又は皮下投与（皮下注射）される。
The pharmaceutical composition of the present invention can be administered intravenously (also referred to as intravenous administration or intravenous injection) or by intravenous infusion (also referred to as intravenous drip or infusion) or subcutaneously (subcutaneous injection) to patients after cord blood transplantation. ) is done.
例えば、本発明の医薬組成物はロミプロスチムとして10μg/kg/週で投与開始され、以降週1回投与される。
For example, the pharmaceutical composition of the present invention is started at 10 μg/kg/week as romiplostim, and thereafter administered once a week.
本発明の医薬組成物は、投与開始から4回目までは、ロミプロスチムとして10μg/kg/週で投与されることが好ましい。
The pharmaceutical composition of the present invention is preferably administered at 10 μg/kg/week as romiplostim from the start of administration to the 4th dose.
本発明の医薬組成物の5回目以降の投与量は、ロミプロスチムとして5μg/kg/週よりも多いことが好ましく、また最大でも20μg/kg/週とすることが好ましい。
The fifth and subsequent doses of the pharmaceutical composition of the present invention are preferably more than 5 μg/kg/week as romiplostim, and preferably 20 μg/kg/week at most.
5回目以降の投与量は患者の状態をみながら適宜増減してもよい。5回目以降に投与量を増減する場合、その増減量幅は、5μg/kg/週または10μg/kg/週とすることが好ましく、10μg/kg/週とすることがより好ましい。投与量を変更する場合、2～4週間は変更後の投与量を維持することが好ましく、その中でも3週間は変更後の投与量を維持することがより好ましい。
The dosage from the 5th time onwards may be increased or decreased as appropriate while monitoring the patient's condition. When the dosage is increased or decreased from the fifth time onward, the range of increase or decrease is preferably 5 μg/kg/week or 10 μg/kg/week, more preferably 10 μg/kg/week. When the dosage is changed, it is preferable to maintain the modified dosage for 2 to 4 weeks, and more preferably to maintain the modified dosage for 3 weeks.
本発明の医薬の投与期間は造血回復が認められるまで継続することができる。また、必要に応じて休薬することもできる。例えば、血小板が2週にわたって安定して7万/μLを超えるか、1回でも14万/μLを超えた場合、用量を1段階減量（5μg/kg減量）若しくは2段階減量（10μg/kg減量）してもよい。
The administration period of the pharmaceutical of the present invention can be continued until recovery of hematopoiesis is observed. In addition, the drug can be discontinued if necessary. For example, if the platelet count is stably over 70,000/μL for 2 weeks or over 140,000/μL at least once, the dose should be reduced by 1 step (5 μg/kg) or 2 steps (10 μg/kg). ).
効果：
本発明の医薬組成物は、臍帯血移植の早期段階で投与され、血球回復を促進させる。血球回復の促進とは、好中球回復および／または血小板回復の促進を意味する。また、好中球数の増加促進、および／または血小板数の増加促進を意味する。より具体的には、好中球数は500/μL以上に、血小板数は20×109/L（2万/μL）以上、好ましくは30×109/L（3万/μL）以上、より好ましくは50×109/L（5万/μL）以上に増加することが好ましい。 effect:
The pharmaceutical composition of the present invention is administered at an early stage of cord blood transplantation to promote blood cell recovery. Promoting blood cell recovery means promoting neutrophil recovery and/or platelet recovery. It also means promotion of neutrophil count increase and/or platelet count increase promotion. More specifically, the neutrophil count is 500/μL or more, the platelet count is 20×10 9 /L (20,000/μL) or more, preferably 30×10 9 /L (30,000/μL) or more, More preferably, it increases to 50×10 9 /L (50,000/μL) or more.
本発明の医薬組成物は、臍帯血移植の早期段階で投与され、血球回復を促進させる。血球回復の促進とは、好中球回復および／または血小板回復の促進を意味する。また、好中球数の増加促進、および／または血小板数の増加促進を意味する。より具体的には、好中球数は500/μL以上に、血小板数は20×109/L（2万/μL）以上、好ましくは30×109/L（3万/μL）以上、より好ましくは50×109/L（5万/μL）以上に増加することが好ましい。 effect:
The pharmaceutical composition of the present invention is administered at an early stage of cord blood transplantation to promote blood cell recovery. Promoting blood cell recovery means promoting neutrophil recovery and/or platelet recovery. It also means promotion of neutrophil count increase and/or platelet count increase promotion. More specifically, the neutrophil count is 500/μL or more, the platelet count is 20×10 9 /L (20,000/μL) or more, preferably 30×10 9 /L (30,000/μL) or more, More preferably, it increases to 50×10 9 /L (50,000/μL) or more.
他の処置・薬剤との併用：
本発明の医薬組成物は、臍帯血移植などの造血幹細胞移植時の生着を補助する他の処置や薬剤とともに使用されてもよい。例えば、本発明の医薬組成物は、G-CSF製剤、GVHD予防法（例えば、シクロスポリン、タクロリムスなどのカルシニューリン阻害剤、メトトレキサート、ミコフェノール酸モフェチルなど）、輸血（血小板輸血、赤血球輸血）と併用することができる。 Concomitant use with other treatments/drugs:
The pharmaceutical composition of the present invention may be used in conjunction with other treatments or agents that aid engraftment during hematopoietic stem cell transplantation, such as cord blood transplantation. For example, the pharmaceutical composition of the present invention is used in combination with G-CSF preparations, GVHD prevention methods (e.g., calcineurin inhibitors such as cyclosporine and tacrolimus, methotrexate, mycophenolate mofetil, etc.), and blood transfusions (platelet transfusion, red blood cell transfusion). be able to.
本発明の医薬組成物は、臍帯血移植などの造血幹細胞移植時の生着を補助する他の処置や薬剤とともに使用されてもよい。例えば、本発明の医薬組成物は、G-CSF製剤、GVHD予防法（例えば、シクロスポリン、タクロリムスなどのカルシニューリン阻害剤、メトトレキサート、ミコフェノール酸モフェチルなど）、輸血（血小板輸血、赤血球輸血）と併用することができる。 Concomitant use with other treatments/drugs:
The pharmaceutical composition of the present invention may be used in conjunction with other treatments or agents that aid engraftment during hematopoietic stem cell transplantation, such as cord blood transplantation. For example, the pharmaceutical composition of the present invention is used in combination with G-CSF preparations, GVHD prevention methods (e.g., calcineurin inhibitors such as cyclosporine and tacrolimus, methotrexate, mycophenolate mofetil, etc.), and blood transfusions (platelet transfusion, red blood cell transfusion). be able to.
本発明の医薬組成物は、G-CSF製剤では十分な生着促進、血小板数の増加が期待できない患者に好適に使用することができる。本発明の医薬組成物は、G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める。また、本発明の医薬組成物は、G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める。
The pharmaceutical composition of the present invention can be suitably used for patients for whom G-CSF preparations cannot be expected to sufficiently promote engraftment or increase the platelet count. The pharmaceutical composition of the present invention accelerates platelet recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone. In addition, the pharmaceutical composition of the present invention accelerates neutrophil recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone.
組成・形態：
本発明の医薬組成物は、薬理学的に許容される一つまたはそれ以上の担体、添加剤若しくはpH調整剤等を含む。添加剤としては、例えば、等張化剤、緩衝剤、溶解補助剤および防腐剤等が挙げられる。 Composition/morphology:
The pharmaceutical composition of the present invention contains one or more pharmacologically acceptable carriers, additives, pH adjusters and the like. Additives include, for example, tonicity agents, buffers, solubilizers, preservatives and the like.
本発明の医薬組成物は、薬理学的に許容される一つまたはそれ以上の担体、添加剤若しくはpH調整剤等を含む。添加剤としては、例えば、等張化剤、緩衝剤、溶解補助剤および防腐剤等が挙げられる。 Composition/morphology:
The pharmaceutical composition of the present invention contains one or more pharmacologically acceptable carriers, additives, pH adjusters and the like. Additives include, for example, tonicity agents, buffers, solubilizers, preservatives and the like.
等張化剤としては、特に限定されないが、例えば、塩化ナトリウム、塩化カルシウム、塩化カリウム、塩化マグネシウム、果糖、グルコースおよびD-マンニトールが挙げられる。
Examples of tonicity agents include, but are not limited to, sodium chloride, calcium chloride, potassium chloride, magnesium chloride, fructose, glucose and D-mannitol.
緩衝剤としては、例えば、リン酸二水素カリウム、リン酸水素二カリウム、リン酸三ナトリウム、リン酸二水素ナトリウムおよびリン酸水素二ナトリウム、クエン酸ナトリウム、クエン酸ナトリウム水和物を含む組成物が挙げられる。
Examples of buffering agents include compositions containing potassium dihydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, sodium dihydrogen phosphate and disodium hydrogen phosphate, sodium citrate, and sodium citrate hydrate. is mentioned.
溶解補助剤としては、例えば、エタノール、エチレンジアミン、カプリン酸、L-グルタミン酸、L-リジン、酸化カルシウム、酸化マグネシウム、セスキオレイン酸ソルビタン、D-ソルビトール、ニコチン酸アミド、プロピレングリコール、ポリソルベート80およびラウロマクロゴール(9E.O.)等が挙げられる。
Examples of solubilizing agents include ethanol, ethylenediamine, capric acid, L-glutamic acid, L-lysine, calcium oxide, magnesium oxide, sorbitan sesquioleate, D-sorbitol, nicotinamide, propylene glycol, polysorbate 80 and lauromacro Goal (9E.O.) etc.
防腐剤としては、例えば、フェノール、エデト酸ナトリウム、塩化ベンザルコニウム、クロロクレゾール、クロロブタノール、サリチル酸ナトリウム、パラオキシ安息香酸エチルおよびパラオキシ安息香酸ブチル等が挙げられる。
Examples of antiseptics include phenol, sodium edetate, benzalkonium chloride, chlorocresol, chlorobutanol, sodium salicylate, ethyl parahydroxybenzoate and butyl parahydroxybenzoate.
pH調整剤としては、例えば、塩酸、希塩酸、グリシン、コハク酸、リン酸、リン酸塩、酢酸、酒石酸およびメグルミン等が挙げられる。
Examples of pH adjusters include hydrochloric acid, dilute hydrochloric acid, glycine, succinic acid, phosphoric acid, phosphates, acetic acid, tartaric acid and meglumine.
本発明の医薬組成物の形態は、特に限定されず、皮下投与用にあらかじめ調製された形態でも、使用時に希釈あるいは凍結乾燥したロミプロスチムを水等の注射用溶媒に溶解して調製される形態でもよい。
The form of the pharmaceutical composition of the present invention is not particularly limited, and may be a form prepared in advance for subcutaneous administration or a form prepared by dissolving diluted or freeze-dried romiplostim in a solvent for injection such as water at the time of use. good.
本発明の医薬組成物は、ガラス容器およびプラスチック容器等に充填して提供される。容器の形状は、特に限定されず、例えば、バイアル、シリンジ、バッグおよびボトル等が挙げられる。
The pharmaceutical composition of the present invention is provided by being filled in a glass container, a plastic container, or the like. The shape of the container is not particularly limited, and examples thereof include vials, syringes, bags and bottles.
本発明の医薬組成物の好ましい一例として、ロミプロスチムを薬理学的に許容し得る添加物とともに常法に従って凍結乾燥することによって得られる粉末状の製剤を挙げることができる。そのような医薬組成物の具体例として、ロミプレート（登録商標）を挙げることができる。ロミプレート（登録商標）は、ロミプロスチムの凍結乾燥物に、添加物としてD-マンニトール、精製白糖、L-ヒスチジン、ポリソルベート20、希塩酸を含み、投与前に注射用水に適宜溶解して使用される。
A preferred example of the pharmaceutical composition of the present invention is a powdery preparation obtained by freeze-drying romiplostim together with pharmacologically acceptable additives according to a conventional method. A specific example of such a pharmaceutical composition is Romiplate (registered trademark). Romiplate (registered trademark) contains D-mannitol, refined sucrose, L-histidine, polysorbate 20, and dilute hydrochloric acid as additives in a lyophilized product of romiplostim, and is used by appropriately dissolving in water for injection before administration.
本発明の医薬組成物は、上述した用法・用量や効果、例えば、「（同種）臍帯血移植後の血球回復」、「（同種）臍帯血移植時の血小板数及び好中球数の増加促進」、「（同種）臍帯血移植時の血小板数の増加促進」、「（同種）造血幹細胞移植時の血球回復」、「（同種）造血幹細胞移植時の血小板数の増加促進」、「造血幹細胞移植時の血球回復」、「造血幹細胞移植時の血球の増加促進」、「造血幹細胞移植時の血小板数及び好中球数の増加促進」などの表示（添付文書やパッケージ）とともに製品化される。
The pharmaceutical composition of the present invention has the above-mentioned usage/dosage and effects, for example, "blood cell recovery after (allogeneic) cord blood transplantation", "stimulation of increase in platelet count and neutrophil count after (allogeneic) cord blood transplantation" ”, “promoting platelet count increase during (allogeneic) cord blood transplantation”, “blood cell recovery during (allogeneic) hematopoietic stem cell transplantation”, “promoting platelet count increase during (allogeneic) hematopoietic stem cell transplantation”, “hematopoietic stem cell It is commercialized with labels (package inserts and packaging) such as "blood cell recovery during transplantation", "stimulation of blood cell increase during hematopoietic stem cell transplantation", and "stimulation of increase in platelet count and neutrophil count during hematopoietic stem cell transplantation". .
治療方法
本発明は本発明の医薬組成物を用いた治療方法も提供する。すなわち、臍帯血移植を受けた対象における血球回復のための治療方法であって、前記対象にロミプロスチムを前記移植施行翌日から投与することを特徴とする方法を提供する。ロミプロスチムの用法用用量は上記したとおりである。 Methods of Treatment The invention also provides methods of treatment using the pharmaceutical compositions of the invention. That is, the present invention provides a therapeutic method for blood cell recovery in a subject who has undergone cord blood transplantation, which comprises administering romiplostim to the subject from the day following the transplantation. The dosage and administration of romiplostim are as described above.
本発明は本発明の医薬組成物を用いた治療方法も提供する。すなわち、臍帯血移植を受けた対象における血球回復のための治療方法であって、前記対象にロミプロスチムを前記移植施行翌日から投与することを特徴とする方法を提供する。ロミプロスチムの用法用用量は上記したとおりである。 Methods of Treatment The invention also provides methods of treatment using the pharmaceutical compositions of the invention. That is, the present invention provides a therapeutic method for blood cell recovery in a subject who has undergone cord blood transplantation, which comprises administering romiplostim to the subject from the day following the transplantation. The dosage and administration of romiplostim are as described above.
以下の実施例により、本発明を具体的に説明するが、実施例は本発明の単なる例示に過ぎず、本発明の範囲を限定するものではない。以下の実施例ではロミプロスチム製剤としてロミプレート（登録商標）を使用したが、これはロミプロスチムを有効成分として含む医薬組成物の１例である。
Although the present invention will be specifically described by the following examples, the examples are merely illustrations of the present invention and do not limit the scope of the present invention. In the following examples, Romiplate (registered trademark) was used as a romiplostim formulation, which is an example of a pharmaceutical composition containing romiplostim as an active ingredient.
I. 試験
同種臍帯血移植後の血小板回復に対するロミプロスチム投与（第I相試験）
II. 治験デザイン
単施設非盲検非対照試験 I. Trials Romiplostim Administration for Platelet Recovery After Allogeneic Cord Blood Transplantation (Phase I Trial)
II. Study design Single-center, open-label, uncontrolled study
同種臍帯血移植後の血小板回復に対するロミプロスチム投与（第I相試験）
II. 治験デザイン
単施設非盲検非対照試験 I. Trials Romiplostim Administration for Platelet Recovery After Allogeneic Cord Blood Transplantation (Phase I Trial)
II. Study design Single-center, open-label, uncontrolled study
III. 対象
急性骨髄性白血病（AML）、急性リンパ性白血病（ALL）、骨髄異形成症候群（MDS）、非ホジキンリンパ腫（NHL）患者で同種臍帯血移植を行う患者 III. Target Patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) who undergo allogeneic cord blood transplantation
急性骨髄性白血病（AML）、急性リンパ性白血病（ALL）、骨髄異形成症候群（MDS）、非ホジキンリンパ腫（NHL）患者で同種臍帯血移植を行う患者 III. Target Patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL) who undergo allogeneic cord blood transplantation
IV. 選択基準
対象疾患・病期が(a)～(d)のいずれかを満たし、さらにその他の登録選択基準を全て満たす患者。
（a）AML：事前検査において骨髄中の芽球が 5％未満の症例とする。但し、急性巨核芽球性白血病及び骨髄増殖性疾患からの移行を除く
（b）ALL：事前検査において骨髄中の芽球が5％未満の症例とする
（c）MDS：事前検査において骨髄中の芽球が5％未満の症例とする
（d）NHL：部分寛解期あるいは完全寛解期にあって、事前検査において骨髄浸潤のない症例とする IV. Inclusion Criteria Patients who meet any of (a) to (d) for target disease/disease stage and meet all other registration inclusion criteria.
(a) AML: Cases with less than 5% blasts in the bone marrow in the preliminary examination. However, excluding acute megakaryoblastic leukemia and transition from myeloproliferative disease (b) ALL: cases with less than 5% blasts in the bone marrow in the preliminary examination (c) MDS: cases in the bone marrow in the preliminary examination Cases with less than 5% blasts (d) NHL: Cases in partial remission or complete remission with no bone marrow infiltration in prior examination
対象疾患・病期が(a)～(d)のいずれかを満たし、さらにその他の登録選択基準を全て満たす患者。
（a）AML：事前検査において骨髄中の芽球が 5％未満の症例とする。但し、急性巨核芽球性白血病及び骨髄増殖性疾患からの移行を除く
（b）ALL：事前検査において骨髄中の芽球が5％未満の症例とする
（c）MDS：事前検査において骨髄中の芽球が5％未満の症例とする
（d）NHL：部分寛解期あるいは完全寛解期にあって、事前検査において骨髄浸潤のない症例とする IV. Inclusion Criteria Patients who meet any of (a) to (d) for target disease/disease stage and meet all other registration inclusion criteria.
(a) AML: Cases with less than 5% blasts in the bone marrow in the preliminary examination. However, excluding acute megakaryoblastic leukemia and transition from myeloproliferative disease (b) ALL: cases with less than 5% blasts in the bone marrow in the preliminary examination (c) MDS: cases in the bone marrow in the preliminary examination Cases with less than 5% blasts (d) NHL: Cases in partial remission or complete remission with no bone marrow infiltration in prior examination
V. 評価項目
[主要評価項目]
ロミプロスチム投与との関連を否定できない（治験薬との関連あり）全ての有害事象の発生 V. Evaluation items
[Primary endpoint]
All adverse events that cannot be ruled out related to romiplostim administration (related to study drug)
[主要評価項目]
ロミプロスチム投与との関連を否定できない（治験薬との関連あり）全ての有害事象の発生 V. Evaluation items
[Primary endpoint]
All adverse events that cannot be ruled out related to romiplostim administration (related to study drug)
[副次的評価項目]
□Day57のPLT5万/μL以上の累積達成率
□好中球生着日
□PLT2万/μL達成日
□PLT5万/μL達成日
□血小板輸血単位数
□出血イベント
□血栓イベント
□骨髄の線維化
□原疾患の再発
□非再発死亡 [Secondary endpoints]
□ Cumulative achievement rate of PLT 50,000/μL or more onDay 57 □ Date of neutrophil engraftment □ Date of achievement of PLT 20,000/μL □ Date of achievement of PLT 50,000/μL Recurrence of primary disease Non-recurrence death
□Day57のPLT5万/μL以上の累積達成率
□好中球生着日
□PLT2万/μL達成日
□PLT5万/μL達成日
□血小板輸血単位数
□出血イベント
□血栓イベント
□骨髄の線維化
□原疾患の再発
□非再発死亡 [Secondary endpoints]
□ Cumulative achievement rate of PLT 50,000/μL or more on
VI. 治験計画
[投与方法]
治験薬はDay1よりDay99まで、週1回（治験スケジュールに従うこと）、皮下投与する。開始用量は、5μg/kg（5μg/kg群）とし、初回投与から5回目投与直前までの投与量は固定用量（増量は認めない）とする。最初の3例は開始用量を5μg/kgとし（5μg/kg群）、4例目以降は開始用量を10μg/kg（10μg/kg群）とする。10μg/kgを開始用量とした場合も、初回投与から5回目投与直前までの投与量は固定用量（増量は認めない）とする。なお、当該期間に「減量・休薬規定」に該当した、又は、有害事象が発現した場合には「有害事象発生時の用量変更規定」、それぞれの基準に従い適切に減量・休薬する。開始用量がいずれの場合も5回目及びそれ以降の投与量は、「用量調整」の基準に則り、下記用量表に従って調節する。 VI. Study Plan
[Administration method]
The study drug will be administered subcutaneously once a week from Day 1 to Day 99 (according to the study schedule). The starting dose will be 5 μg/kg (5 μg/kg group), and the dose from the first dose to just before the fifth dose will be a fixed dose (no increase allowed). The starting dose is 5 μg/kg for the first 3 cases (5 μg/kg group), and the starting dose for the 4th and subsequent cases is 10 μg/kg (10 μg/kg group). Even if the starting dose is 10 μg/kg, the dose from the first dose to just before the fifth dose should be a fixed dose (dosage increase is not allowed). In addition, if the “dose reduction/dose interruption regulations” apply during the relevant period, or if an adverse event occurs, dose reduction/dose interruption should be performed appropriately according to the “dose change regulations in the event of an adverse event”. Regardless of the starting dose, the 5th and subsequent doses will be adjusted according to the dose table below according to the “dose adjustment” criteria.
[投与方法]
治験薬はDay1よりDay99まで、週1回（治験スケジュールに従うこと）、皮下投与する。開始用量は、5μg/kg（5μg/kg群）とし、初回投与から5回目投与直前までの投与量は固定用量（増量は認めない）とする。最初の3例は開始用量を5μg/kgとし（5μg/kg群）、4例目以降は開始用量を10μg/kg（10μg/kg群）とする。10μg/kgを開始用量とした場合も、初回投与から5回目投与直前までの投与量は固定用量（増量は認めない）とする。なお、当該期間に「減量・休薬規定」に該当した、又は、有害事象が発現した場合には「有害事象発生時の用量変更規定」、それぞれの基準に従い適切に減量・休薬する。開始用量がいずれの場合も5回目及びそれ以降の投与量は、「用量調整」の基準に則り、下記用量表に従って調節する。 VI. Study Plan
[Administration method]
The study drug will be administered subcutaneously once a week from Day 1 to Day 99 (according to the study schedule). The starting dose will be 5 μg/kg (5 μg/kg group), and the dose from the first dose to just before the fifth dose will be a fixed dose (no increase allowed). The starting dose is 5 μg/kg for the first 3 cases (5 μg/kg group), and the starting dose for the 4th and subsequent cases is 10 μg/kg (10 μg/kg group). Even if the starting dose is 10 μg/kg, the dose from the first dose to just before the fifth dose should be a fixed dose (dosage increase is not allowed). In addition, if the “dose reduction/dose interruption regulations” apply during the relevant period, or if an adverse event occurs, dose reduction/dose interruption should be performed appropriately according to the “dose change regulations in the event of an adverse event”. Regardless of the starting dose, the 5th and subsequent doses will be adjusted according to the dose table below according to the “dose adjustment” criteria.
[用量調整]
◆増量規定：
Day29以降、輸血後の一時的血小板上昇を除きPLTが2万/μL未満の場合は、安全性も考慮した上で2段階増量（10μg/kg増量）、また、2万/μL以上5万/μL未満の場合は、1段階増量（5μg/kg増量）することを可とする。増量する際には、前回増量から少なくとも2週以上の間隔を空け、それまでのPLT推移を十分観察し、直近でPLTの急増がないことを確認の上で実施することとする。Day28以前の増量は不可とする。 [Dose adjustment]
◆Increase regulations:
AfterDay 29, if the PLT is less than 20,000/μL, excluding a temporary increase in platelets after transfusion, the dose should be increased by 2 steps (10μg/kg increase), and 20,000/μL or more to 50,000/ If the dose is less than μL, the dose may be increased by one step (5 μg/kg increase). When increasing the dose, wait at least 2 weeks after the previous dose increase, carefully observe the changes in PLT up to that point, and confirm that there has been no recent rapid increase in PLT. Do not increase the dose before Day28.
◆増量規定：
Day29以降、輸血後の一時的血小板上昇を除きPLTが2万/μL未満の場合は、安全性も考慮した上で2段階増量（10μg/kg増量）、また、2万/μL以上5万/μL未満の場合は、1段階増量（5μg/kg増量）することを可とする。増量する際には、前回増量から少なくとも2週以上の間隔を空け、それまでのPLT推移を十分観察し、直近でPLTの急増がないことを確認の上で実施することとする。Day28以前の増量は不可とする。 [Dose adjustment]
◆Increase regulations:
After
◆減量・休薬規定：
血小板輸血の有無に関わらず、PLTが2週にわたって安定して7万/μLを超えるか、1回でも14万/μLを超えた場合、治験責任医師等の判断により、直近の用量を1段階減量（5μg/kg減量）若しくは2段階減量（10μg/kg減量）する（表１の用量表参照）。また、いかなる投与量においてもPLTが20万/μLを超えた場合には速やかに休薬する。減量・休薬基準に該当しない場合においても、1週前の検査値と比較しPLTが急増し、20万/μLを大きく超えることが懸念される場合には、減量・休薬する。 ◆ Weight loss and drug suspension regulations:
Regardless of the presence or absence of platelet transfusion, if the PLT consistently exceeds 70,000/μL for 2 weeks or exceeds 140,000/μL even once, the investigator, etc. will decide to reduce the most recent dose by one step. Reduce the dose (5 μg/kg dose reduction) or 2-step dose reduction (10 μg/kg dose reduction) (see dose table in Table 1). In addition, if the PLT exceeds 200,000/μL at any dose, the drug should be discontinued immediately. Even if the dose reduction/discontinuation criteria are not met, dose reduction/discontinuation should be performed if there is a concern that the PLT will increase significantly compared to the test value from 1 week ago and significantly exceed 200,000/μL.
血小板輸血の有無に関わらず、PLTが2週にわたって安定して7万/μLを超えるか、1回でも14万/μLを超えた場合、治験責任医師等の判断により、直近の用量を1段階減量（5μg/kg減量）若しくは2段階減量（10μg/kg減量）する（表１の用量表参照）。また、いかなる投与量においてもPLTが20万/μLを超えた場合には速やかに休薬する。減量・休薬基準に該当しない場合においても、1週前の検査値と比較しPLTが急増し、20万/μLを大きく超えることが懸念される場合には、減量・休薬する。 ◆ Weight loss and drug suspension regulations:
Regardless of the presence or absence of platelet transfusion, if the PLT consistently exceeds 70,000/μL for 2 weeks or exceeds 140,000/μL even once, the investigator, etc. will decide to reduce the most recent dose by one step. Reduce the dose (5 μg/kg dose reduction) or 2-step dose reduction (10 μg/kg dose reduction) (see dose table in Table 1). In addition, if the PLT exceeds 200,000/μL at any dose, the drug should be discontinued immediately. Even if the dose reduction/discontinuation criteria are not met, dose reduction/discontinuation should be performed if there is a concern that the PLT will increase significantly compared to the test value from 1 week ago and significantly exceed 200,000/μL.
◆減量後・休薬後の増量規定：
治験薬の投与期間中に本剤の減量若しくは休薬後にPLTが7万/μL未満となった場合には、表１の用量表に従って直近の用量より1段階増量する。その後2週間同じ用量を維持し、血小板の増加が認められない場合は、更に1段階増量することを可とする。但し、Day28以前は開始用量を超える増量は不可とする。 ◆Dose increase rules after dose reduction/discontinuation:
If the PLT is less than 70,000/μL after dose reduction or withdrawal during the administration period of the study drug, the dose should be increased by one step from the most recent dose according to the dose table in Table 1. After that, the same dose is maintained for 2 weeks, and if no increase in platelets is observed, the dose can be increased by one step. However, before Day28, the dose cannot be increased beyond the starting dose.
治験薬の投与期間中に本剤の減量若しくは休薬後にPLTが7万/μL未満となった場合には、表１の用量表に従って直近の用量より1段階増量する。その後2週間同じ用量を維持し、血小板の増加が認められない場合は、更に1段階増量することを可とする。但し、Day28以前は開始用量を超える増量は不可とする。 ◆Dose increase rules after dose reduction/discontinuation:
If the PLT is less than 70,000/μL after dose reduction or withdrawal during the administration period of the study drug, the dose should be increased by one step from the most recent dose according to the dose table in Table 1. After that, the same dose is maintained for 2 weeks, and if no increase in platelets is observed, the dose can be increased by one step. However, before Day28, the dose cannot be increased beyond the starting dose.
◆有害事象発生時の用量変更規定：
有害事象発現の場合は、治験責任医師等の判断にて減量及び休薬を可とする。なお、有害事象発現による休薬後に本剤投与を再開する必要がある場合には、5μg/kgにて投与を再開する。なお、当該減量及び休薬後に、治験責任医師等の判断にて慎重に増量することを可とするが、再開時／増量時に当該有害事象が悪化する傾向が認められた際には速やかに投与を中止する。 ◆ Dose change rules when adverse events occur:
In the event of an adverse event, dose reduction and drug interruption may be permitted at the discretion of the investigator, etc. If it is necessary to resume administration of this drug after interruption due to the occurrence of an adverse event, administration should be resumed at 5 μg/kg. After the dose reduction and dose interruption, the dose may be carefully increased at the investigator's discretion. cancel.
有害事象発現の場合は、治験責任医師等の判断にて減量及び休薬を可とする。なお、有害事象発現による休薬後に本剤投与を再開する必要がある場合には、5μg/kgにて投与を再開する。なお、当該減量及び休薬後に、治験責任医師等の判断にて慎重に増量することを可とするが、再開時／増量時に当該有害事象が悪化する傾向が認められた際には速やかに投与を中止する。 ◆ Dose change rules when adverse events occur:
In the event of an adverse event, dose reduction and drug interruption may be permitted at the discretion of the investigator, etc. If it is necessary to resume administration of this drug after interruption due to the occurrence of an adverse event, administration should be resumed at 5 μg/kg. After the dose reduction and dose interruption, the dose may be carefully increased at the investigator's discretion. cancel.
◆末梢血液中に5％を超える芽球の増加が認められた場合の用量変更規定：
原疾患の再発の有無を確認し、原疾患の再発が否定できるまで本剤の投与を休薬する。 ◆ Dose change rules when blasts increased by more than 5% in peripheral blood:
The presence or absence of recurrence of the primary disease is confirmed, and administration of this drug is suspended until recurrence of the primary disease can be ruled out.
原疾患の再発の有無を確認し、原疾患の再発が否定できるまで本剤の投与を休薬する。 ◆ Dose change rules when blasts increased by more than 5% in peripheral blood:
The presence or absence of recurrence of the primary disease is confirmed, and administration of this drug is suspended until recurrence of the primary disease can be ruled out.
[投与期間]
99日間 [Administration period]
99 days
99日間 [Administration period]
99 days
[移植前処置]
移植前処置は、骨髄破壊的前処置又は緩和的前処置のいずれかを選択する。 [Transplant pretreatment]
Either myeloablative or palliative conditioning is selected for transplantation conditioning.
移植前処置は、骨髄破壊的前処置又は緩和的前処置のいずれかを選択する。 [Transplant pretreatment]
Either myeloablative or palliative conditioning is selected for transplantation conditioning.
[臍帯血移植]
日本のさい帯血バンクに保存且つ公開されている臍帯血を用いる。GVH、HVG双方向にHLA-A、-B、-DR抗原4/6以上適合且つ被験者体重あたり全有核細胞数は2.0×107/kgを目安に単一ユニットを用いる。なお、溶解後の臍帯血洗浄は行わず、臍帯血を経静脈的に投与する。 [Cord blood transplantation]
Umbilical cord blood stored and open to the public in a cord blood bank in Japan is used. Use a single unit with a target of 4/6 or more of HLA-A, -B, and -DR antigens in both GVH and HVG and a total nucleated cell count of 2.0×10 7 /kg per subject body weight. The umbilical cord blood is administered intravenously without washing the umbilical cord blood after dissolution.
日本のさい帯血バンクに保存且つ公開されている臍帯血を用いる。GVH、HVG双方向にHLA-A、-B、-DR抗原4/6以上適合且つ被験者体重あたり全有核細胞数は2.0×107/kgを目安に単一ユニットを用いる。なお、溶解後の臍帯血洗浄は行わず、臍帯血を経静脈的に投与する。 [Cord blood transplantation]
Umbilical cord blood stored and open to the public in a cord blood bank in Japan is used. Use a single unit with a target of 4/6 or more of HLA-A, -B, and -DR antigens in both GVH and HVG and a total nucleated cell count of 2.0×10 7 /kg per subject body weight. The umbilical cord blood is administered intravenously without washing the umbilical cord blood after dissolution.
[併用薬及び併用療法]
治験薬投与前から投与され治療期においても継続して投与されている薬剤、治験薬投与開始日から後観察終了時検査までに治験薬以外に投与された薬剤又は治療法を併用薬、併用療法とする。以下の1）から3）は各投与基準を目安として治験薬と併用する。
1）顆粒球コロニー刺激因子（G-CSF）
Day5からフィルグラスチム又はレノグラスチムを1日1回点滴投与する。G-CSF製剤は好中球生着時までを目安に添付文書に従って投与する。なお、G-CSF製剤投与による副作用等がみられた場合には必要に応じてG-CSF製剤の投与を中止し、速やかに適切な処置を実施する。
2）GVHD予防
GVHD予防法はカルシニューリン阻害剤（シクロスポリンあるいはタクロリムス）に加えて、メトトレキサートあるいはミコフェノール酸モフェチルの2剤併用とする。なお、GVHD発症時や当該薬剤等の副作用等により、薬剤の種類、投与量、投与期間を変更する必要がある場合は治験責任医師等の判断にて、その変更を可とする。
3）輸血
a. 血小板輸血
患者登録後から骨髄機能が回復するまでの期間は、PLTが1～2万/μL以上を維持するように放射線照射済み濃厚血小板製剤10単位を輸血する。なお、重篤な出血傾向出現時や観血的処置前等には、治験責任医師等の判断で血小板輸血を可とする。
b. 赤血球輸血
患者登録後からHb値の目安として7g/dLを維持するように、放射線照射済み赤血球濃厚液（2単位）を輸血する。なお、臨床症状や合併症を考慮し、治験責任医師等の判断で赤血球輸血を可とする。 [Concomitant drugs and concomitant therapy]
Drugs that have been administered before administration of the study drug and continue to be administered during the treatment period, drugs or treatments other than the study drug that have been administered from the start of administration of the study drug to the examination at the end of follow-up, concomitant drugs, concomitant therapy and The following 1) to 3) should be used concomitantly with the investigational drug, using each dosing standard as a guideline.
1) Granulocyte colony stimulating factor (G-CSF)
Filgrastim or lenograstim will be administered once a day from Day5. G-CSF preparations should be administered according to the package insert until the time of neutrophil engraftment. If adverse reactions, etc. due to administration of G-CSF preparations are observed, the administration of G-CSF preparations should be discontinued as necessary, and appropriate measures should be promptly taken.
2) GVHD prevention For GVHD prevention, calcineurin inhibitors (cyclosporin or tacrolimus) and methotrexate or mycophenolate mofetil are used in combination. In addition, if it is necessary to change the type, dosage, or administration period of the drug due to the onset of GVHD or the side effects of the drug, etc., the change may be made at the discretion of the investigator.
3) blood transfusion
a. During the period from registration of platelet transfusion patients to recovery of bone marrow function, 10 units of irradiated platelet concentrates should be transfused to maintain a PLT of 10,000 to 20,000/μL or higher. Platelet transfusion is permissible at the discretion of the investigator, etc., when a serious bleeding tendency appears or before invasive procedures.
b. Irradiated red blood cell concentrate (2 units) will be transfused to maintain a target Hb level of 7 g/dL after patient registration. In consideration of clinical symptoms and complications, red blood cell transfusion is permitted at the discretion of the investigator.
治験薬投与前から投与され治療期においても継続して投与されている薬剤、治験薬投与開始日から後観察終了時検査までに治験薬以外に投与された薬剤又は治療法を併用薬、併用療法とする。以下の1）から3）は各投与基準を目安として治験薬と併用する。
1）顆粒球コロニー刺激因子（G-CSF）
Day5からフィルグラスチム又はレノグラスチムを1日1回点滴投与する。G-CSF製剤は好中球生着時までを目安に添付文書に従って投与する。なお、G-CSF製剤投与による副作用等がみられた場合には必要に応じてG-CSF製剤の投与を中止し、速やかに適切な処置を実施する。
2）GVHD予防
GVHD予防法はカルシニューリン阻害剤（シクロスポリンあるいはタクロリムス）に加えて、メトトレキサートあるいはミコフェノール酸モフェチルの2剤併用とする。なお、GVHD発症時や当該薬剤等の副作用等により、薬剤の種類、投与量、投与期間を変更する必要がある場合は治験責任医師等の判断にて、その変更を可とする。
3）輸血
a. 血小板輸血
患者登録後から骨髄機能が回復するまでの期間は、PLTが1～2万/μL以上を維持するように放射線照射済み濃厚血小板製剤10単位を輸血する。なお、重篤な出血傾向出現時や観血的処置前等には、治験責任医師等の判断で血小板輸血を可とする。
b. 赤血球輸血
患者登録後からHb値の目安として7g/dLを維持するように、放射線照射済み赤血球濃厚液（2単位）を輸血する。なお、臨床症状や合併症を考慮し、治験責任医師等の判断で赤血球輸血を可とする。 [Concomitant drugs and concomitant therapy]
Drugs that have been administered before administration of the study drug and continue to be administered during the treatment period, drugs or treatments other than the study drug that have been administered from the start of administration of the study drug to the examination at the end of follow-up, concomitant drugs, concomitant therapy and The following 1) to 3) should be used concomitantly with the investigational drug, using each dosing standard as a guideline.
1) Granulocyte colony stimulating factor (G-CSF)
Filgrastim or lenograstim will be administered once a day from Day5. G-CSF preparations should be administered according to the package insert until the time of neutrophil engraftment. If adverse reactions, etc. due to administration of G-CSF preparations are observed, the administration of G-CSF preparations should be discontinued as necessary, and appropriate measures should be promptly taken.
2) GVHD prevention For GVHD prevention, calcineurin inhibitors (cyclosporin or tacrolimus) and methotrexate or mycophenolate mofetil are used in combination. In addition, if it is necessary to change the type, dosage, or administration period of the drug due to the onset of GVHD or the side effects of the drug, etc., the change may be made at the discretion of the investigator.
3) blood transfusion
a. During the period from registration of platelet transfusion patients to recovery of bone marrow function, 10 units of irradiated platelet concentrates should be transfused to maintain a PLT of 10,000 to 20,000/μL or higher. Platelet transfusion is permissible at the discretion of the investigator, etc., when a serious bleeding tendency appears or before invasive procedures.
b. Irradiated red blood cell concentrate (2 units) will be transfused to maintain a target Hb level of 7 g/dL after patient registration. In consideration of clinical symptoms and complications, red blood cell transfusion is permitted at the discretion of the investigator.
[血球回復時期]
それぞれ以下のように規定する。
(1)好中球生着日
治験薬投与後で、WBC×好中球（Seg＋Band）割合から算出された好中球数が、3以上の連続した検査日において500/μLを上回った場合の最初の日付（G-CSF製剤投与下の有無を問わない）。
(2)PLT2万/μL達成日
治験薬投与後で、7日間以内に血小板輸血を実施しておらず、3以上の連続した検査日においてPLTが2万/μLを上回った場合の最初の日付。
(3)PLT5万/μL達成日
治験薬投与後で、7日間以内に血小板輸血を実施しておらず、3以上の連続した検査日においてPLTが5万/μLを上回った場合の最初の日付。 [Blood cell recovery time]
Each is specified as follows.
(1) Neutrophil engraftment day After administration of the study drug, if the neutrophil count calculated from WBC × neutrophil (Seg + Band) ratio exceeds 500 / μL on 3 or more consecutive test days First date (with or without G-CSF preparation).
(2) Day of achieving PLT 20,000/μL The first date when PLT exceeds 20,000/μL on 3 or more consecutive test days without platelet transfusion within 7 days after administration of the study drug. .
(3) Day of achieving PLT 50,000/μL The first date when PLT exceeds 50,000/μL on 3 or more consecutive test days without platelet transfusion within 7 days after administration of the study drug. .
それぞれ以下のように規定する。
(1)好中球生着日
治験薬投与後で、WBC×好中球（Seg＋Band）割合から算出された好中球数が、3以上の連続した検査日において500/μLを上回った場合の最初の日付（G-CSF製剤投与下の有無を問わない）。
(2)PLT2万/μL達成日
治験薬投与後で、7日間以内に血小板輸血を実施しておらず、3以上の連続した検査日においてPLTが2万/μLを上回った場合の最初の日付。
(3)PLT5万/μL達成日
治験薬投与後で、7日間以内に血小板輸血を実施しておらず、3以上の連続した検査日においてPLTが5万/μLを上回った場合の最初の日付。 [Blood cell recovery time]
Each is specified as follows.
(1) Neutrophil engraftment day After administration of the study drug, if the neutrophil count calculated from WBC × neutrophil (Seg + Band) ratio exceeds 500 / μL on 3 or more consecutive test days First date (with or without G-CSF preparation).
(2) Day of achieving PLT 20,000/μL The first date when PLT exceeds 20,000/μL on 3 or more consecutive test days without platelet transfusion within 7 days after administration of the study drug. .
(3) Day of achieving PLT 50,000/μL The first date when PLT exceeds 50,000/μL on 3 or more consecutive test days without platelet transfusion within 7 days after administration of the study drug. .
［結果］
7名の患者が登録され、除外基準に当てはまった患者を除いた6名にロミプロスチムが投与された。評価可能な6名の患者のうち、3例が5μg/kg投与開始、3例が10μg/kg投与開始であり、年齢中央値は40歳（範囲、19～57歳）であった。診断名は、AML（2名）、ALL（3名）、MDS（1名）であった。移植前処置として、4名の患者には骨髄破壊的前処置を、2名の患者には強度を下げた緩和的前処置を実施した。GHVDの予防として、タクロリムスとミコフェノール酸モフェチルを投与した。ロミプロスチムの投与回数の中央値は5.5回（3～15回）、最大投与量は20μg/kgだった。ロミプロスチムに関連すると思われる事象は、骨痛が3名、注射部位反応が1名だった。重篤な有害事象は、発熱性好中球減少症（4名）、急性GVHD（2名）、肺炎（1名）、HHV6脳炎（1名）、CMV抗原血症（1名）、不整脈（1名）の計10件が5名の患者で報告された。再発、血栓性合併症、骨髄の線維化は認められなかった。全員が好中球回復を達成し、回復までの日数の中央値は14日（12～32日）だった。血小板回復は、48日目に肺炎で死亡した1名を除くすべての患者で達成された。血小板≧50x109/Lになるまでの日数の中央値は、Day100までに血小板回復を達成した症例（83％）において34日（29～98日）であった。6名の患者のうち1名に抗ロミプロスチム抗体が検出されたが、中和活性は認められなかった。 [result]
Seven patients were enrolled and six, excluding those who met the exclusion criteria, received romiplostim. Of the 6 evaluable patients, 3 were 5 μg/kg initiation and 3 were 10 μg/kg initiation, with a median age of 40 years (range, 19–57 years). The diagnoses were AML (2), ALL (3), and MDS (1). Four patients received myeloablative conditioning and two patients received palliative conditioning at reduced intensity as transplant conditioning. Tacrolimus and mycophenolate mofetil were administered as prophylaxis for GHVD. The median number of romiplostim doses was 5.5 (ranging from 3 to 15), with a maximum dose of 20 μg/kg. Events considered to be related to romiplostim included bone pain in 3 patients and injection site reaction in 1 patient. Serious adverse events included febrile neutropenia (4 patients), acute GVHD (2 patients), pneumonia (1 patient), HHV6 encephalitis (1 patient), CMV antigenemia (1 patient), and arrhythmia (1 patient). 1) were reported in 5 patients. No recurrence, thrombotic complications, or bone marrow fibrosis were observed. All achieved neutrophil recovery, with a median time to recovery of 14 days (12–32 days). Platelet recovery was achieved in all but one patient who died of pneumonia onday 48. The median number of days to platelets ≥50x10 9 /L was 34 days (range 29–98 days) in patients achieving platelet recovery by Day 100 (83%). Anti-romiplostim antibodies were detected in 1 of 6 patients, but no neutralizing activity was observed.
7名の患者が登録され、除外基準に当てはまった患者を除いた6名にロミプロスチムが投与された。評価可能な6名の患者のうち、3例が5μg/kg投与開始、3例が10μg/kg投与開始であり、年齢中央値は40歳（範囲、19～57歳）であった。診断名は、AML（2名）、ALL（3名）、MDS（1名）であった。移植前処置として、4名の患者には骨髄破壊的前処置を、2名の患者には強度を下げた緩和的前処置を実施した。GHVDの予防として、タクロリムスとミコフェノール酸モフェチルを投与した。ロミプロスチムの投与回数の中央値は5.5回（3～15回）、最大投与量は20μg/kgだった。ロミプロスチムに関連すると思われる事象は、骨痛が3名、注射部位反応が1名だった。重篤な有害事象は、発熱性好中球減少症（4名）、急性GVHD（2名）、肺炎（1名）、HHV6脳炎（1名）、CMV抗原血症（1名）、不整脈（1名）の計10件が5名の患者で報告された。再発、血栓性合併症、骨髄の線維化は認められなかった。全員が好中球回復を達成し、回復までの日数の中央値は14日（12～32日）だった。血小板回復は、48日目に肺炎で死亡した1名を除くすべての患者で達成された。血小板≧50x109/Lになるまでの日数の中央値は、Day100までに血小板回復を達成した症例（83％）において34日（29～98日）であった。6名の患者のうち1名に抗ロミプロスチム抗体が検出されたが、中和活性は認められなかった。 [result]
Seven patients were enrolled and six, excluding those who met the exclusion criteria, received romiplostim. Of the 6 evaluable patients, 3 were 5 μg/kg initiation and 3 were 10 μg/kg initiation, with a median age of 40 years (range, 19–57 years). The diagnoses were AML (2), ALL (3), and MDS (1). Four patients received myeloablative conditioning and two patients received palliative conditioning at reduced intensity as transplant conditioning. Tacrolimus and mycophenolate mofetil were administered as prophylaxis for GHVD. The median number of romiplostim doses was 5.5 (ranging from 3 to 15), with a maximum dose of 20 μg/kg. Events considered to be related to romiplostim included bone pain in 3 patients and injection site reaction in 1 patient. Serious adverse events included febrile neutropenia (4 patients), acute GVHD (2 patients), pneumonia (1 patient), HHV6 encephalitis (1 patient), CMV antigenemia (1 patient), and arrhythmia (1 patient). 1) were reported in 5 patients. No recurrence, thrombotic complications, or bone marrow fibrosis were observed. All achieved neutrophil recovery, with a median time to recovery of 14 days (12–32 days). Platelet recovery was achieved in all but one patient who died of pneumonia on
図１に同種臍帯血移植後の血球回復結果を、図２に各被験者の症例データをまとめて示す。
Figure 1 shows the results of blood cell recovery after allogeneic cord blood transplantation, and Figure 2 summarizes the case data of each subject.
また、臍帯血移植後の血小板回復と好中球回復までの日数に関するこれまでの報告を図３に示す（各データは、上から順に、Koknuma 2021, Yoshimi 2008, Ooi 2008, Ooi 2009, Sato 2011, Takahashi 2004, Nishida 2021, Ooi 2006, 及びTang 2020に基づく。）。
In addition, previous reports on the number of days until platelet recovery and neutrophil recovery after cord blood transplantation are shown in Fig. 3 , Takahashi 2004, Nishida 2021, Ooi 2006, and Tang 2020.).
図３に示されるように、臍帯血移植後に血小板≧50x109/Lになるまでの日数の中央値は40～59日であり、好中球≧50x107/Lになるまでの日数の中央値は19～22.5日である。なお、この数値は回復を達成した症例の中央値を示している。以上より、本治験の患者は、ロミプロスチム投与により血小板だけでなく好中球も早期に回復し、生着達成率も良好であることが示された。
As shown in FIG. 3, the median number of days to platelets ≧50×10 9 /L after cord blood transplantation was 40-59 days, and the median number of days to neutrophils ≧50×10 7 /L. is 19-22.5 days. Note that this number represents the median number of cases that achieved recovery. From the above, it was shown that the patients in this clinical trial recovered not only platelets but also neutrophils at an early stage by administration of romiplostim, and the engraftment achievement rate was favorable.
［結論］
本治験により、臍帯血移植の初期段階でロミプロスチムは安全に投与することができ、またロミプロスチムの投与により早期の血球回復が可能になることが確認された。 [Conclusion]
This trial confirmed that romiplostim can be safely administered in the early stages of cord blood transplantation and that administration of romiplostim enables early blood cell recovery.
本治験により、臍帯血移植の初期段階でロミプロスチムは安全に投与することができ、またロミプロスチムの投与により早期の血球回復が可能になることが確認された。 [Conclusion]
This trial confirmed that romiplostim can be safely administered in the early stages of cord blood transplantation and that administration of romiplostim enables early blood cell recovery.
本発明によれば、臍帯血移植後の血小板回復および／または好中球回復を早め、安全な臍帯血移植が可能になる。
According to the present invention, platelet recovery and/or neutrophil recovery after cord blood transplantation is accelerated, and safe cord blood transplantation becomes possible.
本明細書中で引用した全ての刊行物、特許及び特許出願をそのまま参考として本明細書中にとり入れるものとする。
All publications, patents and patent applications cited in this specification shall be incorporated herein by reference.
Claims (12)
- ロミプロスチムを有効成分とする臍帯血移植後の血球回復用の医薬組成物であって、前記移植施行翌日から投与されることを特徴とする、医薬組成物。 A pharmaceutical composition containing romiplostim as an active ingredient for recovering blood cells after cord blood transplantation, characterized by being administered from the day after the transplantation.
- 前記血球が血小板および／または好中球である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the blood cells are platelets and/or neutrophils.
- ロミプロスチムとして5または10μg/kg/週で投与開始され、以降週1回投与されることを特徴とする、請求項１または２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, characterized in that administration of romiplostim is initiated at 5 or 10 μg/kg/week and thereafter administered once a week.
- 投与開始から4回目まではロミプロスチムとして同じ用量を投与されることを特徴とする、請求項３に記載の医薬組成物。 The pharmaceutical composition according to claim 3, characterized in that the same dose as romiplostim is administered from the start of administration to the fourth time.
- 5回目以降はロミプロスチムとして5μg/kg/週以上最大20μg/kg/週で投与されることを特徴とする、請求項３または４に記載の医薬組成物。 The pharmaceutical composition according to claim 3 or 4, characterized in that the fifth and subsequent doses of romiplostim are administered at a dose of 5 μg/kg/week or more and a maximum of 20 μg/kg/week.
- 5回目以降の増減量幅が5μg/kg/週または10μg/kg/週であることを特徴とする、請求項３～５のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 3 to 5, wherein the range of increase and decrease after the fifth dose is 5 µg/kg/week or 10 µg/kg/week.
- 皮下投与または静脈内投与されることを特徴とする、請求項１～６のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, which is administered subcutaneously or intravenously.
- 皮下投与されることを特徴とする、請求項７に記載の医薬組成物。 The pharmaceutical composition according to claim 7, which is administered subcutaneously.
- G-CSF製剤と併用されることを特徴とする、請求項１～８のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 8, which is used in combination with a G-CSF preparation.
- 投与量を変更する場合、3週間は変更後の投与量が維持されることを特徴とする、請求項１～９のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, wherein when the dosage is changed, the dosage after the change is maintained for 3 weeks.
- G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して血小板回復を早める、請求項１～１０のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 10, which accelerates platelet recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone.
- G-CSF製剤と併用された場合に、G-CSF製剤単独投与と比較して好中球回復を早める、請求項１～１１のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 11, which accelerates neutrophil recovery when used in combination with a G-CSF preparation compared to administration of the G-CSF preparation alone.
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| US20130259825A1 (en) * | 2012-04-02 | 2013-10-03 | William Tse | Method for Enhancing Umbilical Cord Blood Engraftment |
| WO2020085467A1 (en) * | 2018-10-26 | 2020-04-30 | 協和キリン株式会社 | Pharmaceutical composition for treating aplastic anemia |
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| US20130259825A1 (en) * | 2012-04-02 | 2013-10-03 | William Tse | Method for Enhancing Umbilical Cord Blood Engraftment |
| WO2020085467A1 (en) * | 2018-10-26 | 2020-04-30 | 協和キリン株式会社 | Pharmaceutical composition for treating aplastic anemia |
Non-Patent Citations (3)
| Title |
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| CHRISTAKOPOULOS GEORGIOS E.; DEFOR TODD E.; HAGE STEFANIE; WAGNER JOHN E.; LINDEN MICHAEL A.; BRUNSTEIN CLAUDIO; BEJANYAN NELLI; V: "Phase I Dose-Finding, Safety, and Tolerability Trial of Romiplostim to Improve Platelet Recovery After UCB Transplantation", TRANSPLANTATION AND CELLULAR THERAPY, ELSEVIER, AMSTERDAM, NL, vol. 27, no. 6, 2 March 2021 (2021-03-02), AMSTERDAM, NL , XP086635942, ISSN: 2666-6367, DOI: 10.1016/j.jtct.2021.02.033 * |
| KURITA N., Y. MARUYAMA, Y. SUEHARA, K. HATTORI, T. SAKAMOTO, T. KATO, Y. YOKOYAMA, N. OBARA, K. MARUO, K. HASHIMOTO, M. SAKATA-Y: "P453. Safety proof of romiplostim immediately after cord-blood transplantation: Results of a phase 1 trial", BONE MARROW TRANSPLANTATION, NATURE PUBLISHING GROUP, GB, vol. 57, no. S1, 1 November 2022 (2022-11-01), GB , pages 346, XP093083302, ISSN: 0268-3369, DOI: 10.1038/s41409-022-01798-0 * |
| TATSUTOSHI NAKAHATA: "Clinical applications of cytokines for hematopoietic stem cell transplantation", EXPERIMENTAL MEDICINE, YODOSHA CO., LTD., JP, vol. 18, no. 15, 1 January 2000 (2000-01-01), JP , pages 211 (2189) - 217 (2195), XP009548433, ISSN: 0288-5514 * |
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