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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
  • A61K38/13—Cyclosporins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

• the present invention relates to an agent for suppressing the recurrence of a hematological malignancy and improving the survival rate in a patient who has undergone hematopoietic stem cell transplantation for the treatment of a hematological malignancy.
• Hematopoietic stem cell transplantation may be used to treat patients with hematological malignancies that are difficult to cure with normal chemotherapy. However, in patients who have undergone hematopoietic stem cell transplantation, hematologic malignancies may recur and there is still room for improvement in their survival rates.
• 2-Amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol (international generic name: moclavimod) and salts thereof are sphingosine-1-phosphate-receptive. It is a body agonist and is known to have an immunosuppressive effect (Patent Document 1).
• the compound has been used for the treatment of hepatitis (Patent Document 2), the treatment of inflammatory bowel disease (Patent Document 3), and the prevention of graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation (Patent Document 2).
• Literature 4 the use of promoting graft survival after hematopoietic stem cell transplantation (Patent Literature 5) are reported.
• a drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof solves the above problems. And found that the present invention was completed. That is, the present invention includes the following.
• the dose of 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 2- Any of [1] to [3], which is 1 to 3 mg / day in terms of amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol.
• the drug according to any one of the above.
• the agent according to any one of [1] to [4], wherein the hematological malignancy is acute myeloid leukemia or acute lymphocytic leukemia.
• [6] The agent according to any one of [1] to [5], which is used for a patient for 80 days or more.
• the dose of 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 2- It is 3 mg / day in terms of amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol and is used together with methotrexate and cyclosporin A, [1 ] The drug according to any one of [6] to [6].
• the dose of 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 2- Any of [8] to [10], which is 1 to 3 mg / day in terms of amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol. Or a pharmaceutically acceptable salt thereof.
• the dose of 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 2- It is 3 mg / day in terms of amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol and is used together with methotrexate and cyclosporin A [8 ] The compound according to any one of [13] or a pharmaceutically acceptable salt thereof.
• the dose of 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 2- Any of [15] to [17], which is 1 to 3 mg / day in terms of amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol.
• the present invention it is possible to provide a drug for suppressing the recurrence of a hematological malignancy in a patient who has undergone hematopoietic stem cell transplantation for the treatment of a hematological malignancy. Further, the present invention can provide a drug for improving the survival rate of a patient who has undergone hematopoietic stem cell transplantation for treatment of a hematological malignancy.
• “2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof” includes, for example, , WO 03/029184 and WO 2006/041019.
• examples of the “pharmaceutically acceptable salt” include, for example, 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol Acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, citrate, tartrate, methanesulfonate, p-toluenesulfonate and the like.
• 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol hydrochloride is particularly preferred.
• the daily administration of 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof The amount can be appropriately selected depending on the patient's weight, age, health condition and the like. For example, it is preferably 0.1 to 30 mg / day in terms of 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol, and 0.5 to 30 mg / day. -5 mg / day is more preferable, 1-3 mg / day is further preferable, and 3 mg / day is particularly preferable.
• the drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is , Pharmaceutically acceptable carriers, excipients, binders, diluents and the like.
• the drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is Based on ordinary knowledge in the field to which the present invention pertains, dosage forms such as powders, granules, tablets, capsules, solutions, suppositories, and injections can be made. Tablets, capsules and injections are particularly preferred.
• the “hematological malignancy” includes, for example, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplasia Syndrome (MDS), multiple myeloma (MM), B-cell lymphoma (B-lym), myelofibrosis (MF) and the like.
• Drugs containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof are particularly useful in acute bone marrow.
• myeloid leukemia or acute lymphocytic leukemia the effect of improving the survival rate in patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies is significant.
• the age of the patient is not particularly limited as long as it is a target age for normal hematopoietic stem cell transplantation, but preferably, the age at the time of receiving the hematopoietic stem cell transplantation is 18 years or older.
• the “suppression of recurrence of hematological malignancies” is compared with the recurrence rate of hematologic malignancies in all patient groups who have received hematopoietic stem cell transplantation for the treatment of hematologic malignancies, or Of patients who do not receive a drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or pharmaceutically acceptable compared to the recurrence rate of hematological malignancies in the group Mean that the rate of recurrence of hematological malignancies is low in the group of patients administered the drug containing the salt thereof.
• the recurrence rate of hematologic malignancies can be determined, for example, by determining the number of days after the patient received hematopoietic stem cell transplantation (eg, half a year, one year, 1.5 years, or two years). It can be calculated from the number of relapsed malignant tumors relative to the total number of patients who have received stem cell transplantation. It can also be calculated by the Kaplan-Meier method.
• the “improvement of survival rate” is compared with the survival rate of all patient groups who have received hematopoietic stem cell transplantation for the treatment of hematological malignancies, or 2-amino-2 of all the patient groups. Compared with the survival rate in a group of patients not receiving-[4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a drug containing a pharmaceutically acceptable salt thereof.
• the survival rate of the group is high.
• the survival rate is determined by, for example, the number of days after the patient received the hematopoietic stem cell transplant (eg, half a year, one year, 1.5 years, or two years) after the hematopoietic stem cell transplant. From the total number of patients. It can also be calculated by the Kaplan-Meier method.
• the drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is It can be administered to patients in combination with other immunosuppressants commonly used in hematopoietic stem cell transplantation.
• immunosuppressant include methotrexate (MTX), cyclosporin A (CyA), tacrolimus (Tac), mycophenolate and the like.
• Drugs containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof are methotrexate and cyclosporin A Alternatively, it is preferably used together with tacrolimus. In particular, when used together with methotrexate and cyclosporin A, the effect of suppressing the recurrence of hematologic malignancy and improving the survival rate in patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies are remarkable.
• drugs containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof are treated with methotrexate and cyclosporin A together with A-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof
• the dose is 3 mg / day in terms of 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol
• the effects of suppressing the recurrence of hematological malignancies and improving the survival rate are even more remarkable.
• the daily dose of these immunosuppressants can be appropriately selected depending on the patient's body weight, age, health condition, and the like.
• Cyclosporin A can be administered intravenously or orally, for example, at an initial dose of 2.5 mg / kg every 12 hours for 2 hours.
• Methotrexate can be administered, for example, intravenously or orally at an initial dose of 10 mg / kg.
• Administration of a drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof can be performed by administering a hematopoietic stem cell. It begins prior to transplantation and is administered for a period of time after hematopoietic stem cell transplantation. For example, administration is started 11 days before hematopoietic stem cell transplantation and administered until 100 days after hematopoietic stem cell transplantation.
• the administration period is set to 80 days or more, the effect of suppressing the recurrence of hematologic malignancies and improving the survival rate in patients who have undergone hematopoietic stem cell transplantation for the treatment of hematologic malignancies are remarkable. .
• cyclosporin A When cyclosporin A is used together, for example, 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof
• administration of cyclosporin A is started.
• cyclosporin A initiates intravenous administration at an initial dose of 2.5 mg / kg every 2 hours for 2 hours. Dose adjustments are made based on toxicity and the concentration of cyclosporin A relative to the target trough concentration (150-400 mg / L). Cyclosporin A is changed to oral administration if the patient can tolerate oral administration.
• the initial dose for oral administration will be that of the current intravenous dose.
• the dose of cyclosporin A is monitored at least weekly and changed to clinically relevant.
• tacrolimus When tacrolimus is used together, for example, 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is used.
• administration of tacrolimus On day 8 (3 days prior to hematopoietic stem cell transplantation) from the start of administration of the contained drug, administration of tacrolimus is started. For example, tacrolimus begins intravenous administration at an initial dose of 0.03 mg / kg. Subsequent doses are determined by hospital standards and based on blood concentration monitoring. The dose is adjusted to maintain a recommended concentration of 5-15 ng / mL.
• methotrexate is used together, the dosing schedule and dose of methotrexate will be adapted to hospital standards. For example, from the start of administration of a drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof. Administer 10 mg / kg on day 11 and 6 mg / kg methotrexate on days 13 and 16.
• mycophenolate is administered according to hospital practice. For example, 2 ⁇ 100 mg mycophenolate per day after mini Seattle pretreatment. Adjust doses based on clinical side effects.
• transplantation pretreatment is performed prior to hematopoietic stem cell transplantation.
• Transplant pretreatment is performed to suppress the patient's immune cells, reduce the patient's tumor cells, and destroy the patient's hematopoietic function.
• Pre-transplant treatments were reduced-intensity pre-treatment (MAC), non-destructive (MAC) and non-destructive (MAC) with reduced-intensity-conditioning-Regimen-Workshop by Center for International, Blood and Marlow, Transplant, Research (CIBMTR). ).
• the pretreatment for transplantation is appropriately selected in consideration of the type of hematological malignancy, the general condition of the patient, the age of the patient, and the like. For example, the following are mentioned.
• Chemotherapeutic agents include cyclophosphamide (CY), cytarabine (CA), etoposide (ETP), busulfan (BU), fludarabine (FLU), melphalan (MEL), methotrexate (MTX), and cyclosporin A (CyA) And the like.
• CY cyclophosphamide
• CA cytarabine
• ETP etoposide
• BU busulfan
• FLU fludarabine
• MEL melphalan
• MTX methotrexate
• CyA cyclosporin A
• a treatment consisting of administration of cyclophosphamide followed by whole-body irradiation a treatment consisting of administration of busulfan and cyclophosphamide and the like can be mentioned.
• Chemotherapy and whole body radiation regimens include, for example: 1) Fludarabine (25 mg / m 2 / day x 3 days) 2) Busulfan (0.8 mg / kg / 6 hours x 2-4 days) 3) Cyclophosphamide (60 mg / kg / day x 2 days) 4) Irradiation of whole body (200 cGy x 2 times / day x 3 days)
• Pretreatment for reduced intensity The treatment is performed by chemotherapy combining fludarabine and an alkylating agent.
• Alkylating agents combined with fludarabine include busulfan, melphalan, cyclophosphamide and the like.
• treatment including administration of fludarabine and busulfan and the like can be mentioned.
• Non-myeloablative pretreatment Chemotherapy, low-dose whole-body irradiation, or a combination thereof.
• mini Seattle pretreatment consisting of administration of fludarabine or other chemotherapeutic agent (30 mg / m 2 / day ⁇ 3 days) followed by whole body irradiation (1 ⁇ 200 cGy / day ⁇ 1 day) and the like.
• hematopoietic stem cell transplant may include both autologous transplantation and allogeneic transplantation, but is preferably allogeneic hematopoietic stem cell transplantation.
• Immunosuppressants The following four immunosuppressants were used in clinical trials. ⁇ 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol hydrochloride (2-amino-2- [4- (3-benzyloxyphenyl) (Prepared as capsules containing 0.5, 1, 2, 3, 4, or 5 mg in terms of thio) -2-chlorophenyl] ethyl-propane-1,3-diol) ⁇ Methotrexate ⁇ Cyclosporin A ⁇ Tacrolimus
• Results The condition of patients who received allogeneic hematopoietic stem cell transplantation was observed for a certain period. Table 3 shows the results. In the table, the observation period, the number of days of recurrence and death of hematological malignancies represent the number of days from the day of allogeneic hematopoietic stem cell transplantation. The survival rate and the recurrence rate were calculated by the Kaplan-Meier method.
• Table 3 shows that a drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is used.
• the survival rate of the patient one year after allogeneic hematopoietic stem cell transplantation is 75%, so that 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane
• Drugs containing -1,3-diol or a pharmaceutically acceptable salt thereof have been shown to improve the survival of patients undergoing hematopoietic stem cell transplantation.
• Table 4 shows the recurrence rate of hematological malignancies and the survival rate of patients one year after allogeneic hematopoietic stem cell transplantation by hematological malignancy.
• the survival rate of patients one year after allogeneic hematopoietic stem cell transplantation is 54.9 to 73.2%.
• Table 4 shows that a drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof Is administered, the survival rates of patients in one year after allogeneic hematopoietic stem cell transplantation are 100% and 75% in acute myeloid leukemia and acute lymphoblastic leukemia, respectively.
• 2-amino-2- [4- ( Drugs containing 3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof are useful for the survival of patients with acute myeloid leukemia and acute lymphocytic leukemia. It has become clear that it improves.
• Table 5 shows the recurrence rate of hematological malignancies and the patient's survival rate one year after allogeneic hematopoietic stem cell transplantation.
• the survival rate of patients one year after allogeneic hematopoietic stem cell transplantation is 54.9 to 73.2%.
• Table 5 shows that a drug containing 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is used.
• the survival rates of patients one year after allogeneic hematopoietic stem cell transplantation are 84%, 86%, and 77%, respectively. Was found to improve the survival rate.
• Table 6 shows the recurrence rate of hematological malignancies and survival rate of patients one year after allogeneic hematopoietic stem cell transplantation by immunosuppressant.
• the recurrence rate of hematological malignancies after HLA-matched myeloablative transplantation has been reported to be about 25% to over 60%.
• Table 6 shows that 3 mg of 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol or a pharmaceutically acceptable drug was used as an immunosuppressant.
• a combination of a drug containing its salt, methotrexate and cyclosporin A is administered together, the recurrence rate of hematologic malignancy one year after allogeneic hematopoietic stem cell transplantation is 20%. It was also found to suppress tumor recurrence.

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