Active agents for inhibiting recurrence of hematological malignancies in patients having undergone hematopoietic stem cell transplantation

Abstract

The present invention relates to active agents for inhibiting recurrence of hematological malignancies in patients who have undergone hematopoietic stem cell transplantation. A drug for inhibiting recurrence of hematological malignancies and / or a drug for improving survival in a patient who has undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies, the drug having 2-amino-2-[4-(3-benzyloxythiophenyl)-2-chlorphenyl] ethyl-propyl-1, 3-diol or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

[0001] This application is a divisional application of PCT application PCT / JP2019 / 029524, titled "Active Agent for Inhibiting Recurrence of Hematological Malignancies in Patients Who Have Undergone Hematopoietic Stem Cell Transplantation", filed on July 26, 2019. The date when the PCT application entered the Chinese national phase is January 25, 2021, and the application number is 201980050102.5. Technical Field

[0002] The present invention relates to a pharmaceutical preparation for inhibiting recurrence of hematological malignancies and improving survival rate in patients who have undergone hematopoietic stem cell transplantation for treating hematological malignancies. Background Art

[0003] Hematopoietic stem cell transplantation can be performed in patients suffering from hematological malignancies that are difficult to cure with normal chemotherapy for treating hematological malignancies. However, in patients who have undergone hematopoietic stem cell transplantation, recurrence of hematological malignancies may occur, and their survival rate can be further improved.

[0004] 2-Amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol (International Nonproprietary Name: moclavimod) and its salts are equivalent to sphingosine-1-phosphate receptor agonists, and they are known to have immunosuppressive effects (Patent Document 1). It has been reported that the above compounds have been used for treating hepatitis (Patent Document 2), for treating inflammatory bowel disease (Patent Document 3), and for preventing graft-versus-host disease (GvHD) after hematopoietic stem cell transplantation (Patent Document 4), for promoting graft survival after hematopoietic stem cell transplantation (Patent Document 5), etc.

[0005] However, there is no report in which 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol and its salts are used for inhibiting recurrence of hematological malignancies and improving survival rate in patients who have undergone hematopoietic stem cell transplantation for treating hematological malignancies. In addition, it is not known whether S1P receptor agonists or other immunosuppressive agents have such effects.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: PCT International Publication No. WO 03 / 029205

[0009] Patent Document 2: PCT International Publication No. WO 2007 / 043433

[0010] Patent Document 3: PCT International Publication No. WO 2007 / 091501

[0011] Patent Document 4: PCT International Publication No. WO 2014 / 128611

[0012] Patent Document 5: PCT International Publication No. WO 2017 / 153889 Summary of the Invention

[0014] Technical Problem to be Solved by the Invention

[0015] An object of the present invention is to provide a pharmaceutical preparation for inhibiting the recurrence of a hematological malignancy and / or a pharmaceutical preparation for improving the survival rate in a patient who has undergone hematopoietic stem cell transplantation for the treatment of a hematological malignancy.

[0016] Means for Solving the Technical Problem

[0017] The inventors of the present application have found that a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof can achieve the above object. Thus, the present invention has been completed. That is, the present invention includes the following aspects.

[0018] [1] A pharmaceutical preparation for inhibiting the recurrence of a hematological malignancy in a patient who has undergone hematopoietic stem cell transplantation for the treatment of a hematological malignancy, the pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof as an active ingredient.

[0019] [2] A pharmaceutical preparation for improving the survival rate in a patient who has undergone hematopoietic stem cell transplantation for the treatment of a hematological malignancy, the pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] [3] The pharmaceutical preparation according to [1] or [2], which is used in combination with one or more additional immunosuppressants.

[0021] [4] The pharmaceutical preparation according to any one of [1]-[3], wherein the dose of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 1-3 mg / day of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol.

[0022] [5] The pharmaceutical preparation according to any one of [1]-[4], wherein the hematological malignancy is acute myeloid leukemia or acute lymphoblastic leukemia.

[0023] [6] The pharmaceutical preparation as described in any one of [1]-[5] is used for patients 80 days or older.

[0024] [7] The pharmaceutical preparation as described in any one of [1]-[6], wherein the dose of 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 3 mg / day of 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol, and it is used in combination with methotrexate and cyclosporine A.

[0025] [8] 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, which is used to inhibit the recurrence of hematological malignancies in patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies.

[0026] [9] 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, which is used to improve the survival rate of patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies.

[0027]

[10] The compound or a pharmaceutically acceptable salt thereof as described in [8] or [9], which is used in combination with one or more additional immunosuppressants.

[0028]

[11] The compound or a pharmaceutically acceptable salt thereof as described in any one of [8]-

[10] , wherein the dose of 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 1-3 mg / day of 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol.

[0029]

[12] The compound or a pharmaceutically acceptable salt thereof as described in any one of [8]-

[11] , wherein the hematological malignancy is acute myeloid leukemia or acute lymphoblastic leukemia.

[0030]

[13] The compound or a pharmaceutically acceptable salt thereof as described in any one of [8]-

[12] , which is used for patients 80 days or older.

[0031]

[14] The compound or a pharmaceutically acceptable salt thereof as described in any one of [8]-

[13] , wherein the dose of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 3 mg / day of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol, and it is used in combination with methotrexate and cyclosporine A.

[0032]

[15] A method for inhibiting hematological malignancies, the method comprising administering 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof to a patient who has undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies.

[0033]

[16] A method for improving the survival rate of a patient who has undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies, the method comprising administering 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof to the patient.

[0034]

[17] The method as described in

[15] or

[16] , wherein 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional immunosuppressants.

[0035]

[18] The method as described in any one of

[15] -

[17] , wherein the dose of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 1-3 mg / day of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol.

[0036]

[19] The method as described in any one of

[15] -

[18] , wherein the hematological malignancy is acute myeloid leukemia or acute lymphoblastic leukemia.

[0037]

[20] The method as described in any one of

[15] -

[19] , wherein the method is used for a patient for 80 days or more.

[0038]

[21] The method as described in any one of

[15] -

[20] , wherein the dose of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 3 mg / day of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol, and it is used in combination with methotrexate and cyclosporine A.

[0039] Technical effects of the present invention

[0040] According to the present invention, there can be provided a pharmaceutical preparation for inhibiting the recurrence of hematological malignancies in patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies. In addition, there can be provided a pharmaceutical preparation for improving the survival rate of patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies.

[0041] Embodiments of the present invention

[0042] In an embodiment of the present invention, "2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof" can be prepared by the methods disclosed in, for example, WO 03 / 029184 and WO 2006 / 041019.

[0043] In an embodiment of the present invention, as examples of its "pharmaceutically acceptable salts", there may be mentioned, for example, acid addition salts of 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, citrate, tartrate, methanesulfonate, p-toluenesulfonate, etc. Among them, the hydrochloride of 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol is particularly preferred.

[0044] In an embodiment of the present invention, the daily dose of 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof can be appropriately selected according to differences in the patient's body weight, age, health condition, etc. For example, the dose preferably ranges from 0.1 to 30 mg / day, more preferably ranges from 0.5 to 30 mg / day, still more preferably ranges from 1 to 3 mg / day and particularly 3 mg / day of 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol.

[0045] In an embodiment of the present invention, a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof may contain a pharmaceutically acceptable carrier, excipient, binder, diluent, etc.

[0046] In an embodiment of the present invention, based on the common knowledge in the field to which the present invention pertains, a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof can be formulated into dosage forms such as powders, granules, tablets, capsules, solutions, suppositories, and injections. Tablets, capsules, and injections are particularly preferred.

[0047] In an embodiment of the present invention, as examples of "hematological malignancies", mention may be made, for example, of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), multiple myeloma (MM), B-cell lymphoma (B-lym), myelofibrosis (MF), and the like. In the case of acute myeloid leukemia or acute lymphoblastic leukemia, a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof particularly exhibits a significant effect of improving the survival rate in patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies.

[0048] In an embodiment of the present invention, there is no particular limitation on the patient's age, as long as the age is the target age for normal hematopoietic stem cell transplantation. When a patient undergoes hematopoietic stem cell transplantation, the patient's age is preferably 18 years old or older.

[0049] In an embodiment of the present invention, "inhibiting the recurrence of hematological malignancies" means that, compared with the recurrence rate of hematological malignancies in all patient groups who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies, or compared with the recurrence rate of hematological malignancies in the patient group in the above all patient groups who have not received the pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, the recurrence rate of hematological malignancies in the patient group receiving the pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a salt thereof is reduced. For example, the recurrence rate of hematological malignancies can be calculated from the number of patients with malignancy recurrence relative to the total number of patients who have undergone hematopoietic stem cell transplantation, at the number of days determined after the patient undergoes hematopoietic stem cell transplantation (such as half a year, 1 year, 1.5 years, or 2 years). In addition, the recurrence rate can also be calculated by the Kaplan-Meier method.

[0050] In an embodiment of the present invention, "improving survival rate" means that, compared with the survival rate of all patient groups that have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies, or compared with the survival rate of the patient group in all the above patient groups who have not been administered a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, the survival rate of the patient group administered a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a salt thereof is increased. For example, the survival rate can be calculated based on the number of surviving patients relative to the total number of patients who have undergone hematopoietic stem cell transplantation, at a time determined in days (such as half a year, 1 year, 1.5 years, or 2 years) after the patients have undergone hematopoietic stem cell transplantation. In addition, the recurrence rate can also be calculated by the Kaplan-Meier method.

[0051] In an embodiment of the present invention, a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof can be administered to a patient in combination with other immunosuppressants commonly used in hematopoietic stem cell transplantation. Examples of such immunosuppressants include methotrexate (MTX), cyclosporine A (CyA), tacrolimus (Tac), mycophenolate mofetil, etc. The pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is preferably used in combination with methotrexate and cyclosporine A or tacrolimus. In particular, when used in combination with methotrexate and cyclosporine A, in patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies, the effect of inhibiting the recurrence of hematological malignancies and improving the survival rate is significant. In particular, when the pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is used in combination with methotrexate and cyclosporine A, and the dose of 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol is 3 mg / day, in patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies, the effect of inhibiting the recurrence of hematological malignancies and improving the survival rate is even more significant. The daily doses of these immunosuppressants can be appropriately selected according to the patient's body weight, age, health status, etc. Cyclosporine A can be administered intravenously or orally, with an initial dose of 2.5 mg / kg, for example, every 12 hours for 2 hours. For example, methotrexate can be administered intravenously or orally, with an initial dose of 10 mg / kg.

[0052] Administration of a pharmaceutical preparation comprising 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is initiated before hematopoietic stem cell transplantation and carried out for a certain determined time period after hematopoietic stem cell transplantation. For example, the administration is initiated 11 days before hematopoietic stem cell transplantation and carried out until 100 days after hematopoietic stem cell transplantation. In particular, if the administration period is set to 80 days or more, a significant effect of suppressing the recurrence of hematological malignancies and an effect of improving survival rate are exhibited in patients who have undergone hematopoietic stem cell transplantation.

[0053] In the case of application together with cyclosporine A, for example, on the 8th day (3 days before hematopoietic stem cell transplantation) from the start of administration of a pharmaceutical preparation comprising 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, administration of cyclosporine A is initiated. For example, intravenous administration of cyclosporine A is carried out at an initial dose of 2.5 mg / kg for 2 hours every 12 hours. Dose adjustment is based on toxicity or the concentration of cyclosporine A relative to the target trough concentration (150 - 400 mg / L). If the patient can tolerate oral administration, the administration of cyclosporine A can be changed to oral administration. The initial dose of oral administration can be set to the current dose of intravenous administration. The dose of cyclosporine A is monitored at least once a week and changed to a clinically appropriate dose.

[0054] In the case of application together with tacrolimus, for example, on the 8th day (3 days before hematopoietic stem cell transplantation) from the start of administration of a pharmaceutical preparation comprising 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, administration of tacrolimus is initiated. For example, intravenous administration of tacrolimus is initiated at an initial dose of 0.03 mg / kg. Subsequent doses are determined according to hospital standards and based on blood concentration monitoring. The dose is adjusted to maintain the recommended concentration range of 5 - 15 ng / mL.

[0055] In the case of application together with methotrexate, the dosing schedule and dose of methotrexate will be adapted to hospital standards. For example, 10 mg / kg of methotrexate is administered on the 11th day from the start of administration of a pharmaceutical preparation comprising 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, and 6 mg / kg of methotrexate is administered on the 13th and 16th days respectively.

[0056] When used in combination with mycophenolate, mycophenolate should be administered according to hospital practice. For example, 2 × 100 mg of mycophenolate is administered daily after a small Seattle-type conditioning. The dose is adjusted based on clinical side effects.

[0057] Generally, a conditioning regimen is carried out before hematopoietic stem cell transplantation. The conditioning is performed to suppress the patient's immune cells, reduce the patient's tumor cells, and destroy the patient's hematopoietic function. According to the Reduced-Intensity Conditioning Regimen Workshop of the Center for International Blood and Marlow Transplant Research (CIBMTR), these conditioning regimens are classified as myeloablative conditioning (MAC), reduced-intensity conditioning (RIC), and non-myeloablative conditioning (NMA). The conditioning regimen is an appropriate choice considering the type of hematological malignancy, the patient's general condition, the patient's age, etc. For example, the following can be mentioned.

[0058] (1) Myeloablative conditioning

[0059] High-dose chemotherapy, high-dose total body irradiation (TBI), or a combination thereof is carried out. Examples of chemotherapeutic agents that can be mentioned are cyclophosphamide (CY), cytarabine (CA), etoposide (ETP), busulfan (BU), fludarabine (FLU), melphalan (MEL), methotrexate (MTX), cyclosporine A (CyA), etc. For example, a treatment consisting of the administration of cyclophosphamide followed by total body irradiation, a treatment consisting of the administration of busulfan and cyclophosphamide, etc. can be mentioned. Examples of chemotherapeutic and total body irradiation regimens are, for example:

[0060] 1) Fludarabine (25 mg / m 2 / day × 3 days)

[0061] 2) Busulfan (0.8 mg / kg / 6 hours × 2 - 4 days)

[0062] 3) Cyclophosphamide (60 mg / kg / day × 2 days)

[0063] 4) Total body irradiation (200 cGy × 2 times / day × 3 days)

[0064] (2) Reduced-intensity conditioning

[0065] The reduced-intensity preconditioning is carried out by a combination of chemotherapy with fludarabine and an alkylating agent. Optionally, a low dose of total body irradiation is combined. Examples of alkylating agents in combination with fludarabine can be mentioned busulfan, melphalan, cyclophosphamide, etc. For example, a treatment consisting of the administration of fludarabine and busulfan, etc. can be mentioned.

[0066] (3) Non-myeloablative preconditioning

[0067] The non-myeloablative preconditioning is carried out by chemotherapy, using low-dose total body irradiation or a combination thereof. For example, a mini Seattle-type preconditioning can be mentioned, which consists of the administration of fludarabine or another chemotherapeutic agent (30 mg / m 2 / day × 3 days), followed by total body irradiation (1 × 200 cGy / day × 1 day), etc.

[0068] In an embodiment of the present invention, "hematopoietic stem cell transplantation" may include autologous transplantation and allogeneic transplantation, but preferably allogeneic hematopoietic stem cell transplantation.

[0069] The present invention is described by examples. It should be understood that the scope of the present invention is not limited to the examples. Examples

[0070] Clinical trials were conducted as described below.

[0071] 1. Immunosuppressants

[0072] The following four types of immunosuppressants were used in the clinical trials.

[0073] · 2-Amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol hydrochloride (prepared as a capsule containing 0.5, 1, 2, 3, 4 or 5 mg of 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol)

[0074] · Methotrexate

[0075] · Cyclosporine A

[0076] · Tacrolimus

[0077] 2. Patients

[0078] 23 patients participated in the clinical trials. The patients are described as shown in Table 1.

[0079] [Table 1]

[0080]

[0081]

[0082] 3. Schedule

[0083] Clinical tests are conducted according to the following schedule. However, appropriate changes are made according to the patient's condition, etc.

[0084] A: Screening (from day -50 to day -2), Baseline (day -1)

[0085] B: Treatment with 2 - amino - 2 - [4 - (3 - benzyloxybenzenethio)-2 - chlorophenyl]ethyl - propane - 1,3 - diol hydrochloride (from day 1 to day 111)

[0086] B’: Treatment with additional immunosuppressants (according to hospital criteria, etc.)

[0087] C: Conditioning regimen (from day 2 to day 10)

[0088] D: Allogeneic hematopoietic stem cell transplantation (day 11)

[0089] E: Follow - up (from day 12 to day 376), Additional follow - up (starting from day 377)

[0090] 4. Treatment with immunosuppressants

[0091] A predetermined amount of 2 - amino - 2 - [4 - (3 - benzyloxybenzenethio)-2 - chlorophenyl]ethyl - propane - 1,3 - diol hydrochloride is administered to the patient once a day, and additional immunosuppressants are administered to the patient using a dosing schedule and doses according to hospital criteria, etc. The daily dose of 2 - amino - 2 - [4 - (3 - benzyloxybenzenethio)-2 - chlorophenyl]ethyl - propane - 1,3 - diol hydrochloride administered to each patient (the value in terms of 2 - amino - 2 - [4 - (3 - benzyloxybenzenethio)-2 - chlorophenyl]ethyl - propane - 1,3 - diol, the same applies to the following description), the administration time period, and the type of additional immunosuppressants are shown in Table 2 (KRP: 2 - amino - 2 - [4 - (3 - benzyloxybenzenethio)-2 - chlorophenyl]ethyl - propane - 1,3 - diol hydrochloride, MTX: Methotrexate, CyA: Cyclosporine A, and Tac: Tacrolimus).

[0092] [Table 2]

[0093] Patient number Immunosuppressant KRP administration time period 1 KRP 3mg + MTX + CyA 34 days 2 KRP 3mg + MTX + CyA 108 days 3 KRP 3mg + MTX + CyA 107 days 4 KRP 3mg + MTX + CyA 35 days 5 KRP 3mg + MTX + CyA 111 days 6 KRP 3mg + MTX + CyA 107 days 7 KRP 3mg + MTX + CyA 98 days 8 KRP 3mg + MTX + CyA 111 days 9 KRP 3mg + MTX + CyA 86 days 10 KRP 3mg + MTX + CyA 111 days 11 KRP 1mg + MTX + CyA 111 days 12 KRP 3mg + MTX + Tac 79 days 13 KRP 1mg + MTX + CyA 43 days 14 KRP 1mg + MTX + CyA 111 days 15 KRP 3mg + MTX + Tac 111 days 16 KRP 3mg + MTX + Tac 117 days 17 KRP 3mg + MTX + Tac 111 days 18 KRP 3mg + MTX + Tac 111 days 19 KRP 1mg + MTX + CyA 24 days 20 KRP 1mg + MTX + CyA 111 days 21 KRP 3mg + MTX + Tac 62 days 22 KRP 3mg + MTX + Tac 107 days 23 KRP 1mg + MTX + CyA 111 days

[0094] 5. Results

[0095] The conditions of patients who have undergone allogeneic hematopoietic stem cell transplantation are followed up for a certain period of time. The results are shown in Table 3. In this table, the follow - up period, the number of days to recurrence of hematological malignancies, and the number of days to death represent the number of days elapsed since allogeneic hematopoietic stem cell transplantation was performed. The survival rate and recurrence rate are calculated according to the Kaplan - Meier method.

[0096] [Table 3]

[0097]

[0098]

[0099] According to "Hematopoietic cell transplantation in Japan, the 2017 fiscal year, National Survey Report (the Japan Data Center for Hematopoietic Cell Transplantation / the Japan Society for Hematopoietic Cell Transplantation)", the survival rate of patients 1 year after hematopoietic stem cell transplantation is 70.7%. In addition, according to "the 2017 fiscal year, Results of Hematopoietic Stem Cell Transplantation in Japan", (the Japan Data Center for Hematopoietic Cell Transplantation)", the survival rate of patients 1 year after autologous hematopoietic stem cell transplantation is 82.7%, and the survival rate of patients 1 year after allogeneic hematopoietic stem cell transplantation is 54.9 - 73.2%. On the other hand, as is obvious from Table 3, in the case of administering a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, the survival rate of patients 1 year after allogeneic hematopoietic stem cell transplantation is 75%. Therefore, a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof can improve the survival rate of patients undergoing hematopoietic stem cell transplantation.

[0100] It has been reported that the recurrence rate of hematological malignancies after HLA-matched bone marrow ablation transplantation is about 25% to over 60% (Curr Hematol Malig Rep. 2013 June; 8(2): 132 - 140). On the other hand, Table 3 shows that in the case of administering a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, the recurrence rate of hematological malignancies 1 year after allogeneic hematopoietic stem cell transplantation is 40%.

[0101] Table 4 shows the recurrence rate and survival rate of hematological malignancies in patients 1 year after allogeneic hematopoietic stem cell transplantation for each hematological malignancy.

[0102] [Table 4]

[0103] Hematological malignancies Number of patients Relapse rate Survival rate Acute myeloid leukemia 7 patients 43％ 100％ Acute lymphoblastic leukemia 4 patients 25％ 75％ Myelodysplastic syndrome 3 patients 67％ 67％ Chronic myeloid leukemia 4 patients 0％ 100％ Multiple myeloma 1 patient 0％ 100％ B-cell lymphoma 1 patient 0％ 100％ Myelofibrosis 1 patient 100％ 0％ Non-Hodgkin lymphoma / Hodgkin's disease 2 patients 100％ 0％

[0104] According to the above “Results of Hematopoietic Stem Cell Transplantation in Japan in the 2017 Fiscal Year”, the survival rate of patients 1 year after allogeneic hematopoietic stem cell transplantation was 54.9 - 73.2%. On the other hand, Table 4 shows that in the cases where a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof was administered to patients with acute myeloid leukemia and acute lymphoblastic leukemia, the survival rates of patients 1 year after allogeneic hematopoietic stem cell transplantation were 100% and 75% respectively. Therefore, it is obvious that the pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof improved the survival rate of patients with acute myeloid leukemia and acute lymphoblastic leukemia.

[0105] Table 5 shows the recurrence rate and survival rate of hematological malignancies in patients 1 year after allogeneic hematopoietic stem cell transplantation according to each administration period of the pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof.

[0106] [Table 5]

[0107] Administration period Number of patients Relapse rate Survival rate 100 days or more 15 patients 20％ 84％ 80 days or more 17 patients 24％ 86％ 60 days or more 19 patients 32％ 77％

[0108] According to the above "Results of Hematopoietic Stem Cell Transplantation in Japan in the 2017 Fiscal Year", the survival rate of patients 1 year after allogeneic hematopoietic stem cell transplantation was 54.9 - 73.2%. On the other hand, Table 5 shows that in the cases where a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof was administered for 100 days or more, 80 days or more, or 60 days or more, the survival rates of patients 1 year after allogeneic hematopoietic stem cell transplantation were 84%, 86%, and 77% respectively. Therefore, it is obvious that the pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof improved the survival rate of patients undergoing hematopoietic stem cell transplantation.

[0109] In addition, as described above, it has been reported that the recurrence rate of hematological malignancies after HLA-matched bone marrow ablation transplantation is about 25% to over 60%. On the other hand, Table 5 shows that in the cases where a pharmaceutical preparation containing 2-amino-2-[4-(3-benzyloxybenzenethio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof was administered for 100 days or more or 80 days or more, the recurrence rates of hematological malignancies in patients 1 year after allogeneic hematopoietic stem cell transplantation were 20% and 24% respectively. Therefore, it is also obvious that the above-mentioned pharmaceutical preparation inhibits the recurrence of hematological malignancies in patients undergoing hematopoietic stem cell transplantation.

[0110] Table 6 shows the recurrence rate of hematological malignancies and the survival rate of patients 1 year after allogeneic hematopoietic stem cell transplantation using each immunosuppressant.

[0111] [Table 6]

[0112] Immunosuppressant Number of patients Relapse rate Survival rate KRP 3mg + MTX + CyA 10 patients 20％ 100％ KRP 1mg + MTX + CyA 6 patients 38％ 67％ KRP 3mg + MTX + Tac 7 patients 71％ 36％

[0113] According to the above-mentioned "Results of Hematopoietic Stem Cell Transplantation in Japan in the 2017 Fiscal Year", the 1-year patient survival rate after allogeneic hematopoietic stem cell transplantation was 54.9 - 73.2%. On the other hand, Table 6 shows that in the case of administering a pharmaceutical preparation containing 3 mg of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, methotrexate, and cyclosporine A as immunosuppressants in combination, the 1-year patient survival rate after allogeneic hematopoietic stem cell transplantation was 100%. Therefore, it is obvious that the immunosuppressants improved the survival rate of patients undergoing hematopoietic stem cell transplantation.

[0114] In addition, as described above, it has been reported that the recurrence rate of hematological malignancies after HLA-matched bone marrow ablation transplantation is about 25% to over 60%. On the other hand, Table 6 shows that in the case of administering a combination of a pharmaceutical preparation containing 3 mg of 2-amino-2-[4-(3-benzyloxybenzothio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof, methotrexate, and cyclosporine A as immunosuppressants, the recurrence rate of hematological malignancies in patients 1 year after allogeneic hematopoietic stem cell transplantation was 20%. Therefore, it is also obvious that the above-mentioned immunosuppressants inhibit the recurrence of hematological malignancies in patients undergoing hematopoietic stem cell transplantation.

[0115] Industrial Applicability

[0116] According to the present invention, in patients who have undergone hematopoietic stem cell transplantation for the treatment of hematological malignancies, it is possible to inhibit the recurrence of hematological malignancies and also improve the survival rate. Therefore, new treatment options for the treatment of hematological malignancies can be provided.

Claims

1. Use of a preparation comprising 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating hematological malignancies in a patient in need thereof, wherein the patient has undergone bone marrow ablation and subsequent hematopoietic stem cell transplantation, wherein the 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is administered in combination therapy with tacrolimus, and wherein the treatment is capable of inhibiting the recurrence of hematological malignancies six months, one year, one and a half years or two years after hematopoietic stem cell transplantation.

2. The use according to claim 1, wherein the 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is administered together with tacrolimus and one or more additional immunosuppressants.

3. The use according to claim 1 or 2, wherein the dose of 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol is 1 - 3 mg / day of 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol.

4. The use according to any one of claims 1 - 3, wherein the hematological malignancy is acute myeloid leukemia or acute lymphoblastic leukemia.

5. The use according to any one of claims 1 - 4, wherein the treatment is administered to the patient for 80 days or more.

6. The use according to any one of claims 1 - 5, wherein the dose of 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol is 3 mg / day of 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol and is applied together with tacrolimus.

7. The use according to any one of claims 1 - 6, wherein the dose of 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol is 3 mg / day of 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol and is applied together with tacrolimus and methotrexate.

8. Use of a preparation comprising 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a patient at risk of recurrence of hematological malignancies after the patient has undergone bone marrow ablation and subsequent hematopoietic stem cell transplantation, wherein the 2-amino-2-[4-(3-benzyloxybenzenesulfanyl)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is administered in combination therapy with tacrolimus, and wherein the treatment is capable of inhibiting the recurrence of hematological malignancies six months, one year, one and a half years or two years after hematopoietic stem cell transplantation.

9. The use according to claim 8, wherein 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is administered together with tacrolimus and one or more additional immunosuppressants.

10. The use according to claim 8 or 9, wherein the dose of 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 1-3 mg / day of 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol.

11. The use according to any one of claims 8-10, wherein the hematological malignancy is acute myeloid leukemia or acute lymphoblastic leukemia.

12. The use according to any one of claims 8-11, wherein the treatment is administered to the patient for 80 days or more.

13. The use according to claim 10, wherein the dose of 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 3 mg / day of 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol, and it is applied together with tacrolimus.

14. The use according to any one of claims 10-13, wherein the dose of 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 3 mg / day of 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol, and it is applied together with tacrolimus and methotrexate.

15. The use of a combination of 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof and tacrolimus in the manufacture of a medicament for treating hematological malignancies in a patient in need thereof, wherein the patient has undergone bone marrow ablation and subsequent hematopoietic stem cell transplantation, and wherein the treatment is capable of inhibiting the recurrence of hematological malignancies six months, one year, one and a half years or two years after hematopoietic stem cell transplantation.

16. The use according to claim 15, wherein 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is administered together with one or more additional immunosuppressants.

17. The use according to claim 15 or 16, wherein the dose of 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol or a pharmaceutically acceptable salt thereof is 1-3 mg / day of 2-amino-2-[4-(3-benzyloxy phenylthio)-2-chlorophenyl]ethyl-propane-1,3-diol.

18. The use according to any one of claims 15-17, wherein the hematological malignancy is acute myeloid leukemia or acute lymphoblastic leukemia.

19. The use according to any one of claims 15 - 18, wherein the treatment is administered to the patient for 80 days or more.

20. Use of a combination of 2 - amino - 2 - [4-(3 - benzyloxybenzenethio)-2 - chlorophenyl]ethyl - propane - 1,3 - diol or a pharmaceutically acceptable salt thereof and tacrolimus in the manufacture of a medicament for treating a patient at risk of relapse of a hematological malignancy after the patient has undergone myeloablation and subsequent hematopoietic stem cell transplantation, wherein the treatment is capable of inhibiting the relapse of the hematological malignancy six months, one year, one and a half years or two years after the hematopoietic stem cell transplantation.

21. The use according to claim 20, wherein 2 - amino - 2 - [4-(3 - benzyloxybenzenethio)-2 - chlorophenyl]ethyl - propane - 1,3 - diol or a pharmaceutically acceptable salt thereof is administered together with one or more additional immunosuppressants.

22. The use according to claim 20 or 21, wherein the dose of 2 - amino - 2 - [4-(3 - benzyloxybenzenethio)-2 - chlorophenyl]ethyl - propane - 1,3 - diol is 1 - 3 mg / day of 2 - amino - 2 - [4-(3 - benzyloxybenzenethio)-2 - chlorophenyl]ethyl - propane - 1,3 - diol.

23. The use according to any one of claims 20 - 22, wherein the hematological malignancy is acute myeloid leukemia or acute lymphoblastic leukemia.

24. The use according to any one of claims 20 - 23, wherein the treatment is administered to the patient for 80 days or more.

25. The use according to claim 1 or 8 or 15, wherein the survival of the patient is improved one year after the hematopoietic stem cell transplantation.

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