TW202203942A - Novel therapeutics and novel treating agent for blood cancer having fewer side effects through synergy brought by CNDAC or salt thereof together with venetoclax - Google Patents

Abstract

A purpose of the present invention is to provide a novel means for treating or relieving blood cancer patients. The means brings into a higher effect and has fewer side effects. Moreover, the present invention relates to a combined medicine for a method of treating or relieving blood cancer patients. The combined medicine contains 4-amino-1-(2-cyano-2-deoxy-[beta]-D-arabinofuranosyl)-2(1H)-pyrimidinone or a salt thereof and venetoclax or a salt thereof.

Description

Novel treatment methods and novel therapeutic agents for blood cancer

The present invention relates to a kind of 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone and The combination medicine of Venetoclax.

Blood cancer is a general term for diseases in which cells in the blood become cancerous, and examples thereof include leukemia, malignant lymphoma, and multiple myeloma. Recently, various antitumor agents have been developed, and although blood cancer is not an incurable disease, the treatment for complete removal of cancer cells from the bone marrow of the lesion is likely to be accompanied by severe and unbearable side effects even for young people with physical strength. Furthermore, the current situation is that bone marrow transplantation must be followed up, but the amount of bone marrow preserved in the bone marrow bank is not sufficient, and it is difficult to find suitable bone marrow.

4-Amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone (hereinafter, referred to as "CNDAC") has deoxycytidine The 2'β-position of the ribose is substituted with a cyano group, which is used as an antimetabolite. It is known that CNDAC is phosphorylated by the intracellular deoxycytidine kinase to form a triphosphate, which is introduced into the DNA chain and undergoes β-cleavage at the sugar site of the nucleobase of CNDAC in the G2/M phase of the cell cycle , cutting DNA strands (Patent Document 1, Non-Patent Documents 1, 2). Therefore, CNDAC is regarded as a clinically effective antitumor agent (Non-Patent Document 3, Patent Document 2).

Venetoclax has the effect of selectively binding and inhibiting Bcl-2. Overexpression of Bcl-2 is seen in most cancers, thereby preventing the process of natural or autonomous death (apoptosis) of cancer cells. Venetoclax has the effect of inhibiting the Bcl-2 and restoring the process of apoptosis in cancer cells. Venetoclax is approved by the FDA (Food and Drug Administration, Food and Drug Administration) as a therapeutic agent for chronic lymphocytic leukemia (CLL) ineffective in standard therapy, and is used clinically. In addition, the combination therapy of venetoclax and other agents such as azacitidine, decitabine, cytarabine, etc. for acute myeloid leukemia (AML) was approved in late 2018 for untreated and elderly AML. Therapeutic agent for patients. [Prior Art Literature] [Patent Literature]

Patent Document 1: Japanese Patent No. 2559917 Patent Document 2: Japanese Patent No. 5570429 [Non-patent literature]

Non-patent document 1: J Med Chem. 1991; 34(9): 2917-9. Non-patent document 2: J Med Chem. 1993; 36(26): 4183-9. Non-patent document 3: Mol Pharmacol. 2001; 59(4): 725-31.

[Problems to be Solved by Invention]

As mentioned above, the treatment of blood cancer is still prone to unbearable severe side effects, and it is not easy to obtain suitable bone marrow for transplantation.

Therefore, the object of the present invention is to provide a novel means for the treatment or alleviation of blood cancer patients, which has higher efficacy and less side effects. [Technical means to solve problems]

The inventors of the present invention have conducted intensive studies in order to solve the above-mentioned problems, and as a result, they have found that by administering CNDAC or its salt in combination with venetoclax or its salt, it is possible to treat or relieve blood cancer patients by utilizing their synergistic effect. .

That is, the present invention includes the following inventions. [1] A combination medicine for use in a method for treating or alleviating blood cancer patients, the combination medicine comprising CNDAC or a salt thereof and venetoclax or a salt thereof. [2] The medicine according to [1], wherein the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Myeloproliferative neoplasms (MPNs) and lymphomas. [3] The medicine of [1] or [2], wherein CNDAC or its salt is administered parenterally. [4] The medicine of any one of [1] to [3], wherein venetoclax or a salt thereof is administered orally. [5] The medicine according to any one of [1] to [4], wherein the patient is a newly diagnosed and/or elderly patient. [6] A pharmaceutical composition for use in a method for treating or relieving blood cancer patients, the pharmaceutical composition comprising CNDAC or a salt thereof administered in combination with venetoclax or a salt thereof. [7] A pharmaceutical composition for use in a method for treating or relieving blood cancer patients, the pharmaceutical composition comprising venetoclax or a salt thereof administered in combination with CNDAC or a salt thereof. [8] The pharmaceutical composition of [6] or [7], wherein CNDAC or its salt is administered parenterally. [9] The pharmaceutical composition according to any one of [6] to [8], wherein venetoclax or a salt thereof is administered orally. [10] The pharmaceutical composition according to any one of [6] to [9], wherein the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL) , chronic lymphocytic leukemia (CLL), myeloproliferative neoplasms (MPN) and lymphoma groups. [11] The pharmaceutical composition according to any one of [6] to [10], wherein the patient is a newly diagnosed and/or elderly patient. [12] A CNDAC or a salt thereof for use with venetoclax or a salt thereof in a method for treating or relieving a patient with blood cancer. [13] The CNDAC of [12] or a salt thereof, which is administered parenterally. [14] CNDAC or a salt thereof according to [12] or [13], wherein venetoclax or a salt thereof is administered orally. [15] The CNDAC or its salt according to any one of [12] to [14], wherein the blood cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL) ), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasms (MPN) and lymphoma. [16] The CNDAC or a salt thereof according to any one of [12] to [15], wherein the patient is a newly diagnosed and/or elderly patient. [17] A venetoclax or a salt thereof for use with CNDAC or a salt thereof in a method for treating or relieving a patient with blood cancer. [18] Venetoclax or a salt thereof according to [17], which is administered orally. [19] Venetoclax or its salt according to [17] or [18], wherein CNDAC or its salt is administered parenterally. [20] The venetoclax or a salt thereof according to any one of [17] to [19], wherein the blood cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia A group consisting of leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative neoplasms (MPN) and lymphoma. [21] The venetoclax or its salt according to any one of [17] to [20], wherein the patient is a newly diagnosed and/or elderly patient. [22] A method for treating or alleviating blood cancer, comprising administering CNDAC or a salt thereof and venetoclax or a salt thereof to a patient. [23] The method of [22], wherein the blood cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Myeloproliferative neoplasms (MPNs) and lymphomas. [24] The method of [22] or [23], wherein CNDAC or a salt thereof is administered parenterally. [25] The method of any one of [22] to [24], wherein venetoclax or a salt thereof is administered orally. [26] The method according to any one of [22] to [25], wherein the patient is a naive and/or elderly patient. [27] Use of CNDAC or a salt thereof and/or venetoclax or a salt thereof for the manufacture of a medicine for a method for treating or alleviating blood cancer, the method for treating or alleviating blood cancer comprising CNDAC or a salt thereof and venetoclax or a salt thereof are administered to a blood cancer patient. [28] The use of [27], wherein the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Myeloproliferative neoplasms (MPNs) and lymphomas. [29] The use of [27] or [28], wherein in the above-mentioned method for treatment or remission, CNDAC or a salt thereof is administered parenterally. [30] The use according to any one of [27] to [29], wherein in the above-mentioned method for treatment or remission, venetoclax or a salt thereof is administered orally. [31] The use according to any one of [27] to [30], wherein the patient is a newly diagnosed and/or elderly patient. [Effect of invention]

According to the present invention, it is possible to provide a novel means for treating or relieving blood cancer patients, which exhibits high efficacy and has fewer side effects.

Through the synergistic effect brought about by the combined use of CNDAC or its salt and venetoclax or its salt, a higher therapeutic or alleviating effect on blood cancer can be obtained.

The present invention relates to a method for treating or alleviating blood cancer, and a medicine or combination medicine for use in the method, the method comprising administering to a blood cancer patient a combination of CNDAC or a salt thereof and venetoclax or a salt thereof .

In the present invention, "4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone" or "CNDAC" may include the following Structural formula:

所表示之化合物或其鹽。「鹽」只要為藥學上可容許之鹽即可，例如可列舉酸加成鹽或鹼性加成鹽等。作為「酸加成鹽」，例如可列舉：鹽酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、氫溴酸鹽、碳酸鹽、乙酸鹽、三氟乙酸鹽、對甲苯磺酸鹽、丙酸鹽、酒石酸鹽、反丁烯二酸鹽、蘋果酸鹽、順丁烯二酸鹽、檸檬酸鹽、甲磺酸鹽等(並不限定於該等)，作為「鹼性加成鹽」，例如可列舉：鹼金屬鹽(鈉鹽、鉀鹽等)、鹼土金屬鹽(鈣鹽等)、鎂鹽、銨鹽等(並不限定於該等)。於本發明中，較佳為CNDAC之鹽酸鹽或乙酸鹽。更詳細而言，於本發明中，尤佳為4-胺基-1-(2-氰基-2-去氧-β-D-阿拉伯呋喃糖基)-2(1H)-嘧啶酮鹽酸鹽。再者，於本說明書中，有時將4-胺基-1-(2-氰基-2-去氧-β-D-阿拉伯呋喃糖基)-2(1H)-嘧啶酮鹽酸鹽記載為「DFP-10917」。[hua 1]

The represented compound or its salt. The "salt" may be a pharmaceutically acceptable salt, and examples thereof include acid addition salts, basic addition salts, and the like. Examples of the "acid addition salt" include hydrochloride, sulfate, nitrate, phosphate, hydrobromide, carbonate, acetate, trifluoroacetate, p-toluenesulfonate, and propionate , tartrate, fumarate, malate, maleate, citrate, mesylate, etc. (not limited to these), as "basic addition salts", such as Examples include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), magnesium salts, ammonium salts, and the like (not limited to these). In the present invention, it is preferably the hydrochloride or acetate of CNDAC. More specifically, in the present invention, 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone hydrochloride is particularly preferred Salt. In addition, in this specification, 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone hydrochloride is sometimes described It is "DFP-10917".

In the present invention, "Venetoc" can enumerate the following structural formula:

所表示之化合物或其鹽。「鹽」只要為藥學上可容許之鹽即可，例如可列舉酸加成鹽或鹼性加成鹽等。作為「酸加成鹽」或「鹼性加成鹽」，可列舉上述者。[hua 2]

The represented compound or its salt. The "salt" may be a pharmaceutically acceptable salt, and examples thereof include acid addition salts, basic addition salts, and the like. As "acid addition salt" or "basic addition salt", the above-mentioned ones are mentioned.

CNDAC or its salt and venetoclax or its salt can be synthesized industrially according to a previously known method, respectively, or those commercially available as pharmaceuticals can also be used.

In the present invention, "blood cancer" means a cancer arising from the hematopoietic system. Examples of such blood cancers include acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and myeloproliferative neoplasms (MPN). and lymphoma, etc., but not limited to these. In the present invention, it is preferable that the blood cancer is acute myeloid leukemia (AML).

In the present invention, the "patient" is not particularly limited as long as it is a patient of blood cancer. The patient may be a first-episode patient or a relapsed patient, preferably a first-episode patient. And/or the age of the patient is not particularly limited, and can be infants (under 5 years old), children (6-14 years old), youth (15-34 years old), prime (35-64 years old) or senior (65 years old and above) ), preferably elderly patients.

In the present invention, CNDAC or its salt and venetoclax or its salt are administered in combination to blood cancer patients.

In the present invention, "concomitant administration" includes not only the case where each component is administered at the same time, but also the case where each component is administered sequentially at specific intervals during the entire treatment period, before and/or after the simultaneous administration of each component. In the case of administering only one ingredient. The route of administration or the means of administration of each component administered in combination may be the same or different.

The dosage and route of administration of CNDAC or its salts may vary depending on factors such as the type or severity of the blood cancer, and the patient's age, body weight, and state. Any route of administration (oral or parenteral) administers an amount sufficient to treat or alleviate blood cancer.

For example, CNDAC or a salt thereof can be administered parenterally in an amount selected from 1 to 10 mg/m ² /day, preferably 4, per day relative to 1 m ² of the patient's body surface area in terms of CNDAC Amounts of ~6 mg/m ² /day. Examples of "parenteral administration" include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and drip. Especially preferred is continuous intravenous injection. Continuous intravenous injection means continuous drip administration of the above amounts over a period of 168 to 336 hours. The administration interval is not particularly limited.

In addition, the dosage and route of administration of venetoclax or its salts may vary depending on factors such as the type or severity of the blood cancer, the patient's age, body weight, and state. An amount sufficient to treat or ameliorate the blood cancer can be administered using any route of administration (oral or parenteral).

For example, it can be selected from the amount of 20-400 mg/day, preferably 200-400 mg/day, 1 to 5 times a day (for example, 2 times or 3 times), every day, every other day, every few days, every Venetoclax or a salt thereof is orally administered on 1 day a week, 2 to 3 days a month, 1 day every other week, or 1 day a month. Alternatively, venetoclax or a salt thereof may be administered parenterally in an amount comparable to that described above for oral administration in an amount of intravenous venetoclax or a salt thereof. "Non-oral administration" can be carried out by the above-mentioned method.

CNDAC or its salt and venetoclax or its salt to be administered in combination can be provided in the form of respective pharmaceuticals (or pharmaceutical compositions), respectively, or can be provided in the form of combined pharmaceuticals.

When provided in the form of their respective medicines (or pharmaceutical compositions), the medicines (or pharmaceutical compositions) are intended to be administered by the above-mentioned concomitant administration. Alternatively, in the column indicating "Usage and Dosage", the above-mentioned combined administration can be described for use. For example, in the case of a medicine (or pharmaceutical composition) containing CNDAC or its salt, the purpose of "use with venetoclax or its salt" for the purpose of treating or alleviating blood cancer may be stated in its appendix. The medicine (or pharmaceutical composition) of gram or its salt can be described in its appendix "with 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)- 2(1H)-Pyrimidone or its salt in combination" for the purpose of treating or relieving blood cancer.

Combination medicines may be in the form of formulations containing the ingredients in the same composition, or may be in the form of a formulation (ie, a kit) in which the ingredients are prepared separately and delivered in a single package suitable for concomitant administration Manufacturing, packaging, distribution.

In the above-mentioned medicine (or pharmaceutical composition) and combination medicine, in addition to the above-mentioned components, excipients, binding agents, disintegrating agents, lubricants, etc. commonly used in the manufacture of medicines may be further included, which can be manufactured into suitable formulations. Dosage form for the desired route of administration.

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

Examples of the binding agent include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethyl acetate Cellulose, and mixtures thereof, etc.

Examples of disintegrating agents include dry starch, sodium alginate, agar powder, kelp sugar powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride Esters, starches, lactose and mixtures of these, etc.

As a lubricant, a refined talc, a stearate, a borax, a polyethylene glycol, a mixture of these, etc. are mentioned, for example.

If necessary, diluents, stabilizers, isotonic agents, pH adjusters, buffers, solubilizers, suspending agents, colorants, flavoring agents, flavoring agents, and packaging agents commonly used in the manufacture of pharmaceuticals may also be appropriately included. Coating agents, preservatives, preservatives, antioxidants, etc.

For example, as dosage forms suitable for oral administration, lozenges, pills, capsules, granules, powders, syrups, suspensions and the like can be mentioned. Those with solid dosage forms may optionally apply a coating (eg, dragee-coated pills, gelatin-coated lozenges, enteric-coated lozenges, etc.).

Moreover, as a dosage form suitable for parenteral administration, an injection, a drip, etc. are mentioned. These dosage forms can be provided in a state that can be freeze-dried and stored, and when used, they are dissolved in a buffer containing water or physiological saline to adjust to an appropriate concentration before use.

The present invention can be used in combination with anticancer agents or radiation therapy for the treatment or alleviation of blood cancers. Examples of such anticancer agents include azacitidine, enoxacitabine, decitabine, cytarabine, cytarabine octadecyl phosphate, fludarabine, and pentostat Butin, Nelarabine, Aclarithromycin, Idamycin, Daunorubicin, Doxorubicin, Cyclophosphamide, 6-Mercaptopurine, Methotrexate, Busulfan, Nimustine, Ramustine, vincristine, vindesine, etoposide, prednisolone, dexamethasone, retinoic acid, tamibarotene, imatinib, nilotinib, dasatinib, Mitoxantrone, hydroxyurea, aspartase, arsenite, interferon, lenalidomide, etc., but not limited to these. Here, "concomitant administration" is as defined above.

One or more of the anticancer agents can be appropriately selected depending on factors such as the type or severity of the blood cancer, the age, weight, and state of the patient.

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

In the present invention, "treatment or remission of blood cancer" means not only a state in which blood cancer completely disappears, but also a state in which blood cancer is temporarily or permanently reduced or disappeared, or a state in which blood cancer does not develop (advance) and is stabilized. condition. For example, "treating or relieving cancer" in the present invention includes one or more of the following states: the number of blood cancer cells in the patient is reduced compared to before administration or ingestion of the composition of the present invention; the level of blood cancer markers is reduced; accompanied by Improvement of symptoms of blood cancer; prolongation of overall survival, progression-free survival, median survival and other indicators.

According to the present invention, blood cancer patients can be treated or alleviated by administering the above-mentioned medicines (or pharmaceutical compositions) and combination medicines of the present invention. Especially when the patients are newly diagnosed and/or elderly patients, the effect is obvious, and the survival rate (median survival period, etc.) can be greatly improved.

Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these. [Example]

Example 1: 4-Amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone hydrochloride in vitro (DFP-10917) Combined effect with Venetoc

DFP-10917 alone, venetoclax alone, and DFP-10917 and venetoclax in combination were applied to KG-1 and SKM-1, which are human-derived acute myeloid leukemia (AML) cell lines, at various concentrations, respectively. , OCI-AML-2, MV4-11, SKNO-1, after 72 hours, the number of cells was counted by CellTiter-Glo assay, and the IC ₅₀ value was calculated at the concentration that reduced the number of cells by 50%.

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

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

DFP-10917 alone, venetoclax alone, and DFP-10917 and venetoclax in combination were acted on MV4-11 as an AML cell line at various concentrations, respectively, after 48 hours by using thiazole blue tetrazolium bromide ( The MTT assay of Thiazolyl Blue Tetrazolium Bromide) counts the number of cells, and calculates the concentration that reduces the number of cells by 50%, the _IC50 value.

The results are shown in FIG. 1 . In the DFP-10917-added group (FIG. 1(A)), the cell proliferation inhibitory effect was slightly enhanced in the combined use of DFP-10917 and venetoclax (96.8 pM) compared with DFP-10917 alone. Regarding _IC50 values, DFP-10917 alone showed 1.53 μM, and when DFP-10917 was used in combination with venetoclax, it was 0.51 μM.

On the other hand, in the venetoclax-added group ( FIG. 1(B )), the combined use of venetoclax and DFP-10917 (1.53 μM) showed a cell proliferation inhibitory effect compared with venetoclax alone significantly enhanced. Regarding _IC50 values, venetoclax showed 96.8 pM alone and 9.14 pM when venetoclax was used in combination with DFP-10917. This result showed that by using venetoclax in combination with DFP-10917, the cell proliferation inhibitory effect was enhanced about 10.6-fold compared with venetoclax alone. Moreover, from each _IC50 value, the CI (Combination Index) value was calculated based on the following formula (F. Bruzzese, et al. Clin. Cancer Res. 2006, 12, 617-625).

CI value = _IC50 value of DFP-10917 when used in combination (0.51 μM)/ _IC50 value of DFP-10917 alone (1.53 μM) + _IC50 value of venetoclax when used in combination (9.14 pM)/venetoclax IC ₅₀ value alone (96.8 pM) + [IC ₅₀ value of DFP-10917 alone (1.53 μM) × IC ₅₀ value of venetoclax alone (96.8 pM)]/[IC ₅₀ value of DFP-10917 when used in combination (0.51 μM) + the IC ₅₀ value of venetoclax when used in combination (9.14 pM)] The CI value is based on 1, when the CI value = 1, it means an additive effect, and when the CI value is less than 1, it means synergy effect.

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

Example 3: Combined effect of DFP-10917 and venetoclax in animal model OCI-AML-2, an AML cell line, was subcutaneously transplanted into NOD SCID mice (5×10 ⁶ cells/mouse) to create a tumor-bearing model mice.

DFP-10917 is an Alzet (registered trademark) micro-osmotic pump embedded in mice, and administered continuously for 7 days at a dose of 3 mg/kg/day. Venetoclax was administered orally at 100 mg/kg/day for 14 days. Vehicles alone were administered to controls. Dosing begins on day 7 post-transplantation.

The results are shown in FIG. 2 . When DFP-10917 was administered in combination with venetoclax, it was confirmed that tumor growth was further inhibited than when each was administered alone. On the other hand, no significant body weight change was observed in each mouse during the entire test period, and side effects (toxicity) caused by the combined use of DFP-10917 and venetoclax were not recognized ( FIG. 3 ).

Fig. 1 is a graph showing the results obtained by investigating the cell proliferation inhibitory effect (cell survival rate (%)) of DFP-10917 and venetoclax in combination with human-derived acute myeloid leukemia (AML) cells. (A) shows the results of DFP-10917 alone and DFP-10917 in combination with venetoclax (96.8 pM). (B) shows the results of venetoclax alone and the combination of venetoclax and DFP-10917 (1.53 μM). Fig. 2 is a graph showing the results obtained by investigating the cell proliferation inhibitory effect (tumor volume (mm ³ )) of the combined use of DFP-10917 and venetoclax in an AML cell-transplanted animal model. Figure 3 is a graph showing the results obtained over time to determine body weight (g) following administration of DFP-10917 and/or venetoclax in a cellular animal model of transplanted AML.

Claims (11)

A combination medicine for use in a method for treating or relieving blood cancer patients, the combination medicine comprising 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)- 2(1H)-pyrimidinone or a salt thereof and venetoclax or a salt thereof. The medicine of claim 1, wherein the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), myeloproliferative Tumor (MPN) and lymphoma group. The medicine 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 a non- Administered orally. The medicament of any one of claims 1 to 3, wherein venetoclax or a salt thereof is administered orally. The medicine according to any one of claims 1 to 4, wherein the patient is a newly diagnosed and/or elderly patient. A pharmaceutical composition for use in a method for treating or relieving blood cancer patients, the pharmaceutical composition comprising 4-amino-1-(2-cyano-2 administered in combination with venetoclax or a salt thereof -Deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone or a salt thereof. A pharmaceutical composition for use in a method for treating or relieving blood cancer patients, the pharmaceutical composition comprising and 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranose yl)-2(1H)-pyrimidinone or a salt thereof and venetoclax or a salt thereof administered. The pharmaceutical composition of claim 6 or 7, wherein 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone or a salt thereof It is administered non-orally. The pharmaceutical composition of any one of claims 6 to 8, wherein venetoclax or a salt thereof is administered orally. The pharmaceutical composition of any one of claims 6 to 9, wherein the blood cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia A group consisting of leukemia (CLL), myeloproliferative neoplasm (MPN) and lymphoma. The pharmaceutical composition according to any one of claims 6 to 10, wherein the patient is a naive and/or elderly patient.

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