JP2020176071A - Novel method and agent for treatment of blood cancer - Google Patents

Abstract

To provide new means that has high effect for the treatment or amelioration of a blood cancer patient, and has reduced side effect.SOLUTION: A combinational medicine is used for the treatment or amelioration of a blood cancer patient and contains 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone or a salt thereof, and venetoclax or a salt thereof.SELECTED DRAWING: None

Description

The present invention relates to 4-amino-1- (2-cyano-2-deoxy-β-D-arabinofuranosyl) -2 (1H) -pyrimidinone for use in the treatment or remission of hematological cancer patients. Regarding combination drugs with Venetoclax.

Hematological cancer is a general term for diseases in which cells in blood have become cancerous, and examples thereof include leukemia, malignant lymphoma, and multiple myeloma. Today, various antitumor agents have been developed, and although blood cancer is no longer an incurable disease, treatment to completely remove cancer cells from the bone marrow of the lesion is available, even for physically fit young people. , Prone to be accompanied by unbearable and serious side effects. Furthermore, although bone marrow transplantation is subsequently required, the amount of bone marrow stored in the bone marrow bank is not sufficient, and it is difficult to find a suitable bone marrow.

4-Amino-1- (2-cyano-2-deoxy-β-D-arabinofuranosyl) -2 (1H) -pyrimidinone (hereinafter referred to as "CNDAC") is a 2'of ribose of deoxycytidine. It has a structure in which the β-position is replaced with a cyano group and is used as an antimetabolite. CNDAC is phosphorylated by intracellular deoxycytidine kinase to form a triphosphory oxide, which is incorporated into the DNA strand, and then in the G2 / M phase of the cell cycle, the sugar site of the nucleobase of CNDAC is β. -It is known to cleave and cleave DNA strands (Patent Document 1, Non-Patent Documents 1 and 2). Therefore, CNDAC is considered to be a clinically effective antitumor agent (Non-Patent Document 3 and Patent Document 2).

Venetoclax has the effect of selectively binding and inhibiting Bcl-2. Overexpression of Bcl-2 has been observed in many cancers, which prevents cancer cells from spontaneous death and the process of self-destruction (apsorption). Venetoclax inhibits this Bcl-2 and has the effect of restoring the process of apoptosis in cancer cells. VENCLEXTA has been approved by the FDA for clinical use as a treatment for chronic lymphocytic leukemia (CLL) for which standard therapy is ineffective. In addition, Venetoclax was approved at the end of 2018 as a therapeutic agent for untreated elderly AML patients in combination therapy with other drugs such as azacitidine, decitabine, and cytarabine, which have the application of acute myeloid leukemia (AML). There is.

Japanese Patent No. 2559917 Japanese Patent No. 5570429

J Med Chem. 1991; 34 (9): 2917-9. J Med Chem. 1993; 36 (26): 4183-9. Mol Pharmacol. 2001; 59 (4): 725-31.

As mentioned above, treatment of blood cancer is still prone to intolerable and serious side effects, and it is not easy to obtain compatible bone marrow that can be transplanted.

Therefore, an object of the present invention is to provide a new means for treating or ameliorating a blood cancer patient, which is highly effective and has few side effects.

As a result of diligent studies to solve the above problems, the present inventors have found that by administering CNDAC or a salt thereof in combination with venetoclax or a salt thereof, a blood cancer patient can be treated or ameliorated by the synergistic effect. I found it.

That is, the present invention includes the following inventions.
[1] A combination drug containing CNDAC or a salt thereof and venetoclax or a salt thereof for use in the treatment or remission of a blood cancer patient.
[2] Blood cancers are acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasm (MPN), and The drug of [1] selected from the group consisting of lymphoma.
[3] The medicament according to [1] or [2], wherein CNDAC or a salt thereof is orally administered.
[4] The drug according to any one of [1] to [3], wherein venetoclax or a salt thereof is orally administered.
[5] The drug according to any one of [1] to [4], wherein the patient is an initial patient and / or an elderly patient.
[6] A pharmaceutical composition containing CNDAC or a salt thereof, which is administered in combination with venetoclax or a salt thereof for use in the treatment or remission of a blood cancer patient.
[7] A pharmaceutical composition containing venetoclax or a salt thereof, which is administered in combination with CNDAC or a salt thereof for use in the treatment or remission of a blood cancer patient.
[8] The pharmaceutical composition of [6] or [7], wherein CNDAC or a salt thereof is orally administered.
[9] The pharmaceutical composition according to any one of [6] to [8], wherein venetoclax or a salt thereof is orally administered.
[10] Blood cancers include acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasm (MPN), and The pharmaceutical composition according to any one of [6] to [9], which is selected from the group consisting of lymphoma.
[11] The pharmaceutical composition according to any one of [6] to [10], wherein the patient is an initial and / or elderly patient.
[12] CNDAC or a salt thereof for use with venetoclax or a salt thereof in a method of treating or relieving a hematological cancer patient.
[13] CNDAC of [12] or a salt thereof, which is orally administered.
[14] CNDAC of [12] or [13] or a salt thereof, to which venetoclax or a salt thereof is orally administered.
[15] Blood cancers include acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasm (MPN), and CNDAC of any of [12] to [14] or a salt thereof selected from the group consisting of lymphoma.
[16] The CNDAC of any of [12] to [15] or a salt thereof, wherein the patient is an initial and / or elderly patient.
[17] Venetoclax or a salt thereof for use with CNDAC or a salt thereof in a method of treatment or remission of a hematological cancer patient.
[18] Venetoclax or a salt thereof, which is orally administered.
[19] Venetoclax or a salt thereof according to [17] or [18] to which CNDAC or a salt thereof is orally administered.
[20] Blood cancers include acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasm (MPN), and Venetoclax or a salt thereof according to any one of [17] to [19] selected from the group consisting of lymphoma.
[21] Venetoclax or a salt thereof according to any one of [17] to [20], wherein the patient is an initial and / or elderly patient.
[22] A method for the treatment or amelioration of blood cancer, which comprises administering to a patient CNDAC or a salt thereof and venetoclax or a salt thereof.
[23] Blood cancers include acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasm (MPN), and The method of [22] selected from the group consisting of lymphoma.
[24] The method of [22] or [23], wherein CNDAC or a salt thereof is orally administered.
[25] The method of any of [22] to [24], wherein venetoclax or a salt thereof is orally administered.
[26] The method of any of [22]-[25], wherein the patient is an initial and / or elderly patient.
[27] CNDAC or a salt thereof in the manufacture of a medicament for use in a method for the treatment or amelioration of blood cancer, which comprises administering CNDAC or a salt thereof and VENCLEXTA or a salt thereof to a blood cancer patient. And / or the use of VENCLEXTA or its salts.
[28] Blood cancers are acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasm (MPN), and Use of [27], selected from the group consisting of lymphoma.
[29] Use of [27] or [28] in which CNDAC or a salt thereof is orally administered in the method for treatment or remission.
[30] The use of any of [27]-[29], wherein in the method for treatment or remission, venetoclax or a salt thereof is orally administered.
[31] Use of any of [27]-[30], wherein the patient is an initial and / or elderly patient.

According to the present invention, it is possible to provide a new means for treating or ameliorating a blood cancer patient, which is highly effective and has few side effects.

The synergistic effect of the combined use of CNDAC or a salt thereof and VENCLEXTA or a salt thereof can provide a high therapeutic or ameliorating effect on blood cancer.

FIG. 1 is a graph showing the results of examining the cell growth inhibitory effect (cell survival rate (%)) of the combined use of DFP-10917 and venetoclax on human-derived acute myeloid leukemia (AML) cells. (A) The results of DFP-10917 alone and the combined use of DFP-10917 and Venetoclax (96.8 pM) are shown. (B) The results of VENCLEXTA alone and VENCLEXTA in combination with DFP-10917 (1.53 μM) are shown. FIG. 2 is a graph showing the results of examining the cell growth inhibitory effect (tumor volume (mm ³ )) of the combined use of DFP-10917 and VENCLEXTA in an animal model transplanted with AML cells. FIG. 3 is a graph showing the results of measuring the body weight (g) after administration of DFP-10917 and / or Venetoclax in an animal model transplanted with AML cells over time.

The present invention relates to a method for the treatment or amelioration of blood cancer, which comprises administering CNDAC or a salt thereof and a combination of venetoclax or a salt thereof to a blood cancer patient, and a medicament or combination used in the method. Regarding medicine.

In the present invention, "4-amino-1- (2-cyano-2-deoxy-β-D-arabinofuranosyl) -2 (1H) -pyrimidinone" or "CNDAC" is defined by the following structural formula:

Examples thereof include a compound represented by (1) or a salt thereof. The "salt" may be any pharmaceutically acceptable salt, and examples thereof include acid addition salts and basic addition salts. Examples of the "acid addition salt" include hydrochloride, sulfate, nitrate, phosphate, hydrobromide, carbonate, acetate, trifluoroacetate, p-toluenesulfonate, propionate, and the like. Examples of "basic addition salts" include, but are not limited to, tartrates, fumarates, malates, maleates, citrates, methanesulfonates, and the like. (Sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, etc.), magnesium salt, ammonium salt, etc. (not limited to these). In the present invention, CNDAC hydrochloride or acetate is preferred. More specifically, 4-amino-1- (2-cyano-2-deoxy-β-D-arabinoflanosyl) -2 (1H) -pyrimidinone monohydrochloride is particularly preferred in the present invention. In addition, in this specification, 4-amino-1- (2-cyano-2-deoxy-β-D-arabinoflanosyl) -2 (1H) -pyrimidinone monohydrochloride is described as "DFP-10917". In some cases.

In the present invention, "Venetoclax" is defined as the following structural formula:

Examples thereof include a compound represented by (1) or a salt thereof. The "salt" may be any pharmaceutically acceptable salt, and examples thereof include acid addition salts and basic addition salts. Examples of the "acid addition salt" and the "basic addition salt" include those described above.

CNDAC or a salt thereof, and Venetoclax or a salt thereof may be industrially synthesized according to a conventionally known method, or may be commercially available for pharmaceutical use.

In the present invention, "blood cancer" means cancer originating from a hematopoietic organ. Such blood cancers include acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and myeloid proliferative tumor (MPN). , And lymphoma, but are not limited thereto. Preferably, the blood cancer in the present invention is acute myeloid leukemia (AML).

In the present invention, the "patient" may be a patient with blood cancer and is not particularly limited. The patient may be a first-time patient or a recurrent patient, but is preferably the first-time patient. And / or the age of the patient is not particularly limited, infants (5 years or younger), children (6-14 years), adolescents (15-34 years), middle-aged (35-64 years) or elderly (65 years or older). Patients may be, but preferably elderly patients.

In the present invention, CNDAC or a salt thereof, and venetoclax or a salt thereof are administered in combination to a hematological cancer patient.

In the present invention, "combination administration" means not only when each component is administered simultaneously, but also when each component is sequentially administered at predetermined intervals over a treatment period, before and / or after each component is simultaneously administered. , The case where only one of the components is administered is also included. The administration route and administration means of each component to be administered in combination may be the same or different.

The dose and route of administration of CNDAC or its salt may vary depending on factors such as the type and severity of blood cancer, the age, weight, and condition of the patient, but in combination administration with VENCLEXTA or its salt. Sufficient amounts to treat or ameliorate blood cancer can be administered using any route of administration (oral or parenteral).

For example, the CNDAC or a salt thereof, per day in the amount of CNDAC, relative body surface area 1 m ² of the patient, 1~10mg ^/ m 2 ^/ day, preferably in an amount selected from 4~6mg ^/ m 2 ^/ day Can be administered parenterally. Examples of "parenteral administration" include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, infusion and the like. Particularly preferred is continuous intravenous injection. Continuous intravenous injection means that the above amount is administered by continuous infusion over 168 to 336 hours.

In addition, the dose and route of administration of VENCLEXTA or its salt may change depending on factors such as the type and severity of blood cancer, the age, weight, and condition of the patient, but in combination with CNDAC or its salt. In administration, an amount sufficient to treat or ameliorate blood cancer can be administered by any route of administration (oral administration or parenteral administration).

For example, venetoclax or a salt thereof may be divided into 1 to 5 times (for example, 2 or 3 times) per day in an amount selected from 20 to 400 mg / day, preferably 200 to 400 mg / day. It can be orally administered daily, every other day, every few days, one day every week, two to three days in January, one day every other week, or one day in January. Alternatively, the amount of intravenous venetoclax or a salt thereof may be administered parenterally at a dose comparable to that when the venetoclax or a salt thereof is orally administered. "Parental administration" can be performed by the method described above.

The combined administration of CNDAC or a salt thereof and venetoclax or a salt thereof may be provided in the form of separate medicines (or pharmaceutical compositions), or may be provided in the form of combination medicines.

When provided as separate medicines (or pharmaceutical compositions), the medicines (or pharmaceutical compositions) are intended to be used in the above-mentioned combined administration, and the "indications / effects" of the attached document thereof. In the column indicating "Dosage and administration", it can be stated that it is used in the above-mentioned combined administration. For example, in the case of a drug (or pharmaceutical composition) containing CNDAC or a salt thereof, the attached document may state that "in combination with VENCLEXTA or a salt thereof" for the treatment or amelioration of blood cancer. If the drug (or pharmaceutical composition) contains VENCLEXTA or a salt thereof, the attached document states "4-amino-1- (2-cyano-2-deoxy-β-D) for the treatment or remission of blood cancer. -Arabinofuranosyl) -2 (1H) -Pyrimidinone or a salt thereof can be used in combination. "

The combination drug may be in the form of a combination drug containing each component in the same composition, or each component is prepared separately and manufactured, packaged and distributed as a single package suitable for combined administration. It may be in the form (that is, the kit preparation).

In the above-mentioned medicine (or pharmaceutical composition) and combination medicine, in addition to the above-mentioned ingredients, excipients, binders, disintegrants, lubricants and the like commonly used in the manufacture of medicines can be included. , Can be produced as a dosage form suitable for the intended administration route.

Examples of excipients include sugars (monosaccharides, disaccharides, polysaccharides such as cyclodextrin and alginic acid), metal salts, kaolin, silicic acid, polyethylene glycol and mixtures thereof.

Examples of the binder include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethyl cellulose, cellac, methyl cellulose, ethyl cellulose, and a mixture thereof.

Examples of the disintegrant include dried starch, sodium alginate, canten powder, laminarin powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and mixtures thereof. Can be mentioned.

Examples of the lubricant include purified talc, stearate, borax, polyethylene glycol and a mixture thereof.

If necessary, further, diluents, stabilizers, isotonic agents, pH adjusters, buffers, solubilizers, suspending agents, colorants, flavoring agents, odorants commonly used in the manufacture of pharmaceuticals. Agents, coating agents, preservatives, preservatives, antioxidants and the like can also be included as appropriate.

For example, examples of dosage forms suitable for oral administration include tablets, rounds, capsules, granules, powders, syrups, suspensions and the like. Those having a solid dosage form can be coated if necessary (for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, etc.).

In addition, examples of dosage forms suitable for parenteral administration include injections and infusions. These dosage forms are provided in a state where they can be freeze-dried and stored, and are used after being dissolved in a buffer solution containing water or a saline solution, etc. to prepare an appropriate concentration before use. You may.

The present invention can be used in combination with anticancer agents and radiation therapy used to treat or ameliorate blood cancer. Examples of such anticancer agents include azacitidine, enocitabine, decitabine, cytarabine, cytarabine octofostate, fludarabin, pentostatin, nerarabine, acralubicin, idarubicin, daunorubicin, doxorubicin, cyclophosphamide, 6-mercaptopurine. , Mesotrexate, Busalfan, Naimstin, Lanimustin, Vincristine, Bindesin, Etoposide, Prednisolone, Dexamesazone, Retinoic acid, Tamibarotene, Imatinib, Nirotinib, Dasatinib, Mitozantron, Hydroxyledrea, Asparaginase, Hyacic acid, etc. Not limited to these. Here, "combination administration" is as defined above.

As the anticancer agent, one or a plurality of types can be appropriately selected depending on factors such as the type and severity of blood cancer, the age, weight, and condition of the patient.

The present invention can be used for the purpose of treating or relieving blood cancer. That is, the present invention relates to a method for treating or ameliorating blood cancer, which comprises administering the medicine (or pharmaceutical composition) and combination medicine of the present invention to a blood cancer patient.

In the present invention, "treatment or remission of blood cancer" means not only a state in which the blood cancer has completely disappeared, but also a state in which the blood cancer has decreased or disappeared temporarily or permanently. It also means that the blood cancer has not progressed (exacerbated) and is stable. For example, "treatment or remission of cancer" in the present invention includes a decrease in the number of blood cancer cells in a patient, a decrease in blood cancer marker level, and blood as compared with before administration or ingestion of the composition of the present invention. It includes one or more of improvement of symptoms associated with cancer, overall survival, progression-free survival, extension of scales such as median survival, etc.

According to the present invention, a hematological cancer patient can be treated or ameliorated by administering the above-mentioned medicine (or pharmaceutical composition) and the combination medicine of the present invention. In particular, when the patient is an initial patient and / or an elderly patient, the effect is remarkably observed, and the survival rate (median survival time, etc.) can be greatly increased.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.

Example 1: Combination of 4-amino-1- (2-cyano-2-deoxy-β-D-arabinofuranosyl) -2 (1H) -pyrimidinone monohydrochloride (DFP-10917) and VENCLEXTA in vitro effect

For human-derived acute myeloid leukemia (AML) cell lines KG-1, SKM-1, OCI-AML-2, MV4-11, SKNO-1, DFP-10917 alone, Venetoclax alone, and DFP- 10917 and Benetokurakusu combination allowed to act in each of the various concentrations after 72 hours the number of cells counted by CellTiter-Glo assay in, and the number of cells to calculate an _{IC 50} value is the concentration that reduces by 50%.

As a result, the combined effect of DFP-10917 and VENCLEXTA was observed in 4 types of AML cells (KG-1, OCI-AML-2, MV4-11, SKNO-1).

Example 2: Effect of combined use of DFP-10917 and venetoclax under low protein content In view of the high protein binding rate of venetoclax (> 99.9%), DFP-10917 and venetoclax under low protein content The effect of the combination was investigated.

DFP-10917 alone, Venetoclax alone, and DFP-10917 and Venetoclax combination were allowed to act on the AML cell line MV4-11 at various concentrations, and 48 hours later, the number of cells was measured by MTT assay using Thiazolyl Blue Tetrazolium Bromede. It was counted, and the cell number was calculated and IC ₅₀ value is the concentration that reduces by 50%.

The results are shown in FIG. In the DFP-10917 addition group (FIG. 1 (A)), a slight enhancement of the cell growth inhibitory effect was observed when DFP-10917 and Venetoclax (96.8 pM) were used in combination as compared with DFP-10917 alone. The IC ₅₀ value was 1.53 μM for DFP-10917 alone and 0.51 μM for DFP-10917 in combination with Venetoclax.

On the other hand, in the venetoclax-added group (FIG. 1 (B)), a remarkable enhancement of the cell growth inhibitory effect was observed when Venetoclax and DFP-10917 (1.53 μM) were used in combination as compared with Venetoclax alone. The IC ₅₀ value indicates 96.8pM in Benetokurakusu alone was 9.14pM in combination with Benetokurakusu and DFP-10917. This result shows that the combined use of venetoclax and DFP-10917 enhanced the cell growth inhibitory effect by about 10.6 times as compared with venetoclax alone. Further, the CI (Combination Index) value was calculated from each IC ₅₀ value based on the following formula (F. Bruzzese, et al. Clin. Cancer Res. 2006, 12, 617-625).

CI value = when used with _{IC 50} values of DFP-10917 (0.51μM) / DFP -10917 alone _{IC 50} values (1.53μM) + when used with _{IC 50} values of Benetokurakusu (9.14pM) / Benetokurakusu alone the IC ₅₀ values (96.8pM) + [DFP-10917 alone _{IC 50} values (1.53μM) × Benetokurakusu alone _{IC 50} values (96.8pM)] / _{[IC 50} value of DFP-10917 during combination (0 .51μM) + _{IC 50} values of Benetokurakusu at the time of combination (9.14pM)]
The CI value is based on 1, and when the CI value = 1, the additive effect is shown, and when the CI value <1, the synergistic effect is shown.

Since the CI value is about 0.43 from the above formula, it was confirmed that the effect obtained by the combined use of DFP-10917 and Venetoclax is a synergistic effect.

Example 3: Effect of combined use of DFP-10917 and Venetoclax in an animal model OCI-AML-2, which is an AML cell line, was subcutaneously transplanted into NOD SCID mice (5 × 10 ⁶ cells / mouse) to prepare a cancer-bearing model mouse. did.

DFP-10917 was implanted in mice with Alzet® osmotic mini-pump and administered continuously at a dose of 3 mg / kg / day for 7 days.
VENCLEXTA was orally administered at a dose of 100 mg / kg / day for 14 days.
Only the vehicle was administered as a control.
Administration was started 7 days after transplantation.

The results are shown in FIG.
It was confirmed that when DFP-10917 and Venetoclax were administered in combination, tumor growth was further suppressed as compared with the case where each was administered alone. On the other hand, no significant change in body weight was observed in each mouse during the test period, and no side effects (toxicity) due to the combined use of DFP-10917 and venetoclax were confirmed (Fig. 3).

Claims (11)

4-Amino-1- (2-cyano-2-deoxy-β-D-arabinofuranosyl) -2 (1H) -pyrimidinone or a salt thereof and venetoclax for use in the treatment or remission of patients with hematological malignancies Or a combination drug containing a salt thereof. Hematological cancers consist of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasm (MPN), and lymphoma. The medicament according to claim 1, which is selected from the group. The medicament according to claim 1 or 2, wherein 4-amino-1- (2-cyano-2-deoxy-β-D-arabinofuranosyl) -2 (1H) -pyrimidinone or a salt thereof is orally administered. .. The medicament according to any one of claims 1 to 3, wherein VENCLEXTA or a salt thereof is orally administered. The medicament according to any one of claims 1 to 4, wherein the patient is an initial patient and / or an elderly patient. 4-Amino-1- (2-cyano-2-deoxy-β-D-arabinoflanosyl) -2 administered in combination with VENCLEXTA or a salt thereof for use in the treatment or remission of patients with hematological malignancies (1H) -A pharmaceutical composition containing pyrimidinone or a salt thereof. In combination with 4-amino-1- (2-cyano-2-deoxy-β-D-arabinofuranosyl) -2 (1H) -pyrimidinone or a salt thereof for use in the treatment or remission of patients with hematological malignancies. A pharmaceutical composition comprising venetoclax or a salt thereof to be administered. The medicament according to claim 6 or 7, wherein 4-amino-1- (2-cyano-2-deoxy-β-D-arabinofuranosyl) -2 (1H) -pyrimidinone or a salt thereof is orally administered. Composition. The pharmaceutical composition according to any one of claims 6 to 8, wherein venetoclax or a salt thereof is orally administered. Hematological cancers consist of acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasm (MPN), and lymphoma. The pharmaceutical composition according to any one of claims 6 to 9, selected from the group. The pharmaceutical composition according to any one of claims 6 to 10, wherein the patient is an initial and / or elderly patient.