JP7653712B2 - Drugs for high-risk myelodysplastic syndromes - Google Patents

Description

[Related Applications]
This application claims priority based on Japanese Patent Application No. 2019-228026 (filed December 18, 2019), the contents of which are incorporated herein by reference.
[Technical field]
The present invention relates to a novel treatment for myelodysplastic syndrome and the like, characterized by the combined use of azacitidine and thiopurine.

Myelodysplastic syndromes (MDS) are a type of hematopoietic malignancy in which neoplastic hematopoietic cells proliferate in the bone marrow. The disease is most prevalent in the elderly, with the median age of onset being around 70 years. In the bone marrow of MDS patients, hematopoietic cells show morphological abnormalities (dysplasia), and myeloblasts are present in various proportions (5-19%). MDS is classified into several disease types based on the blast ratio and the degree of dysplasia. MDS patients not only present symptoms due to cytopenia (anemia, infection due to neutropenia, bleeding due to thrombocytopenia), but also often progress to a state of acute myeloid leukemia, with the bone marrow and peripheral blood often showing more than 20% myeloblasts. These factors cause severe pathology, making it a disease with a poor prognosis.

An increase in the bone marrow blast ratio indicates the progression of the disease, and is also called advanced MDS. Anti-leukemia chemotherapy drugs such as Cyloside are ineffective against advanced MDS, and azacitidine (trade name: Vidaza) is the only drug that is effective. Azacitidine has a certain degree of effectiveness in about half of the cases with increased bone marrow blasts, and is currently said to be the only drug that can extend the survival time of advanced MDS (References 1 and 2). However, even when azacitidine is effective, the effect often lasts for about a year. Furthermore, when azacitidine is ineffective, the life expectancy is about 4 to 6 months, and there is no known treatment that can improve this (Reference 2).

Mercaptopurine is a type of thiopurine preparation, and is used as a treatment for malignant tumors such as acute and chronic myeloid leukemia and acute lymphocytic leukemia, and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis (References 3-5). The effect of thiopurine preparations on myelodysplastic syndromes is unknown, and the combined use of azacitidine and thiopurine preparations has not been reported.

Fenaux P et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol. 2009, 10(3):223-32. Zeidan AM et al. Blood Cancer Journal 2018, volume 8, Article number: 55. Counseling patients with higher-risk MDS regarding survival with azacitidine therapy: are we using realistic estimates?. "Protocols for Hematology and Oncology: A revised edition" useful in the field. Medical Journal Co., Ltd. 2011. Bradford K, Shih DQ. Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease. World J Gastroenterol. 2011, 17(37):4166-73. Nielsen OH et al. The treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther. 2001, 15(11):1699-708.

The objective of the present invention is to provide a new method for treating MDS, particularly MDS unresponsive to azacitidine monotherapy and high-risk MDS (advanced MDS).

The inventors have discovered that high-risk MDS patients who are unresponsive to azacitidine can be effectively treated by combining the drug with thiopurine preparations such as mercaptopurine, azathioprine, and thioguanine.

That is, the present invention provides the following (1) to (12).
(1) A pharmaceutical for treating myelodysplastic syndrome, comprising administering azacitidine in combination with any one of thiopurine selected from the group consisting of mercaptopurine, azathioprine, and thioguanine.
(2) The pharmaceutical according to (1), wherein azacitidine is administered subcutaneously or intravenously at a dose of 50-100 mg/ ^m2 (body surface area) per day, and thiopurine is administered orally at 0.5-2 mg/kg (body weight) per day as mercaptopurine hydrate, or subcutaneously or intravenously at a dose equivalent to 2-20 mg/ ^m2 (body surface area) per day. Note that "comparable dose" means a dose that gives an equivalent amount of active metabolite (6-TGN) in the body.
(3) The pharmaceutical composition according to (1) or (2), wherein azacitidine and thiopurine are administered daily for at least 5 to 10 days.
(4) The pharmaceutical composition according to (3), which is used in three or more consecutive sets with a drug-free period of at least 14 days between each set.
(5) The pharmaceutical composition according to any one of (1) to (4), wherein azacitidine and thiopurine are formulated separately.
(6) The pharmaceutical according to (5), wherein a pharmaceutical composition containing azacitidine as an active ingredient and a pharmaceutical composition containing thiopurine as an active ingredient are set in one package.
(7) The pharmaceutical according to any one of (1) to (4), which is a fixed-dose combination drug containing azacitidine and thiopurine as active ingredients.
(8) The pharmaceutical according to (6) or (7), which is an injectable preparation containing azacitidine and thiopurine as active ingredients.
(9) The pharmaceutical agent according to any one of (1) to (8), which is administered to a patient with myelodysplastic syndrome who is unresponsive to azacitidine monotherapy.
(10) The medicine according to any one of (1) to (9), wherein the thiopurine is mercaptopurine.
(11) A pharmaceutical for treating myelodysplastic syndrome, comprising azacitidine, and a thiopurine selected from the group consisting of mercaptopurine, azathioprine, and thioguanine, in combination with said pharmaceutical, said pharmaceutical being used in the dosage regimen described in (2) to (4) above.
(12) A pharmaceutical for treating myelodysplastic syndrome, comprising any one of thiopurine selected from the group consisting of mercaptopurine, azathioprine, and thioguanine, in combination with azacitidine, the pharmaceutical being used in the dosage regimen described in (2) to (4) above.

According to the present invention, it is possible to effectively treat high-risk (advanced stage) MDS, for which there has been no effective treatment until now. The pharmaceutical of the present invention, by combining with medicinal ingredients that have been used in clinical trials and have an established safety record, can treat high-risk (advanced stage) MDS, for which there has been no effective treatment until now.

FIG. 1 shows the changes in white blood cell count (/μL: top graph) and neutrophil count (/μL: bottom graph) after the start of treatment with azacitidine and mercaptopurine. FIG. 2 shows the change in platelet count (10,000/μL) after the start of treatment with azacitidine and mercaptopurine. FIG. 3 shows the change in hemoglobin count (10,000/μL) after the start of treatment with azacitidine and mercaptopurine.

The present invention relates to a pharmaceutical for treating myelodysplastic syndrome, characterized by administering azacitidine and thiopurine in combination. The configuration of the present invention is described below.

1. Myelodysplastic syndromes In the present invention, myelodysplastic syndromes (MDS) are a type of hematopoietic malignant tumor in which tumorigenic hematopoietic cells proliferate in the bone marrow, and are named after the abnormality of blood cell formation (dysplasia) and blood cytopenia. MDS often progresses to acute myeloid leukemia (it has been proposed that acute myeloid leukemia is diagnosed when bone marrow blasts exceed 20%), and is therefore sometimes called a pre-leukemic state.

Depending on the ratio of bone marrow to blasts, etc., MDS can be classified into refractory anemia, sideroblastic refractory anemia, refractory cytopenia with polycytic dysplasia, sideroblastic refractory anemia with polycytic dysplasia, refractory anemia with excessive blasts, 5q- syndrome, and unclassifiable myelodysplastic syndrome. Unless otherwise specified, the term MDS in this invention includes all of these.

As MDS progresses, myeloblasts increase and the risk of progressing to acute myeloid leukemia increases, this high-risk MDS is sometimes called "advanced MDS." The pharmaceutical of the present invention is characterized by its effectiveness against high-risk (advanced) MDS, for which conventional MDS therapies such as chemotherapy are not effective.

2. Azacitidine Azacitidine is a nucleotide analog in which the carbon atom at position 5 of the pyrimidine ring of cytidine is replaced with a nitrogen atom. It inhibits DNA methylation and induces cell differentiation, and is used as a treatment for myelodysplastic syndromes.

According to the dosage and administration method of the azacitidine formulation (trade name: Vidaza (registered trademark) ⁾ approved in Japan, for adults, azacitidine is administered subcutaneously or intravenously over 10 minutes once a day for seven days, followed by a three-week break. This constitutes one cycle, and the standard method of administration of azacitidine is to repeat the administration.

Azacitidine shows some effect in about half of MDS patients with increased bone marrow blasts, but the effect usually lasts for about a year. The drug of the present invention uses azacitidine in combination with thiopurine to effectively treat high-risk (advanced) MDS.

3. Thiopurine (preparation)
Thiopurine or thiopurine preparations are purine metabolic antagonists used in the treatment of leukemia, autoimmune diseases (Crohn's disease, rheumatoid arthritis, etc.), and after organ transplantation. There are three types of thiopurine preparations currently approved: azathioprine, mercaptopurine (6-mercaptopurine), and thioguanine (6-thioguanine) (in Japan, only azacitidine and mercaptopurine are available), all of which exert their effects by being metabolized in the body to 6-thioguanine nucleoside (6-TGN).

(1) Mercaptopurine (6-mercaptopurine)
Mercaptopurine (6-mercaptopurine) is a thiopurine preparation used as a therapeutic agent for malignant tumors such as acute and chronic myeloid leukemia and acute lymphocytic leukemia, and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

According to the dosage and administration instructions for mercaptopurine preparations (trade name: Leukerin (registered trademark)) approved in Japan for the treatment of acute leukemia and chronic myeloid leukemia, the remission-inducing dose is usually 2-3 mg/kg of mercaptopurine hydrate administered orally to adults per day, either alone or in combination with other antitumor drugs. After remission is achieved, a lower dose than the remission-inducing dose is administered orally, either alone or in combination with other antitumor drugs.

On the other hand, in the typical treatment protocol for acute lymphoblastic leukemia, mercaptopurine is administered daily for 2 weeks during consolidation/intensification therapy, for 70 days during intermittent maintenance therapy, and for 12 to 16 months during long-term maintenance therapy (see "Collection of Hematological and Oncological Protocols"). On the other hand, when used for Crohn's disease or ulcerative colitis, it is expected to be effective with daily administration for 12 to 17 weeks, and if an effect is achieved, administration is continued for a longer period (see Nielsen et al., see above).

Currently used mercaptopurine preparations (brand names: Purinethol, Leukerin) are tablets for oral administration, but mercaptopurine can also be administered intravenously (van der Werff Ten Bosch J et al. Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG. Leukemia. 2005, 19(5):721-6.). Therefore, as described below, mercaptopurine can also be formulated as an injection together with azacitidine.

(2) Thioguanine (6-thioguanine)
Thioguanine (6-thioguanine) is a trade name of Tabloid (registered trademark) and is a thiopurine preparation used to maintain remission in acute lymphocytic leukemia and as a second-line treatment for myeloid leukemia, acute myelomonocytic leukemia, and chronic myeloid leukemia. Mercaptopurine exerts its effect by being metabolized to 6-TGN in the body, and thioguanine is its active metabolite, and is expected to have the same effect as mercaptopurine.

Azathioprine, under the trade name Imuran (registered trademark), is a thiopurine preparation used as an immunosuppressant, for induction and maintenance of remission in steroid-dependent Crohn's disease, for treatment-resistant rheumatic diseases, and for autoimmune hepatitis. Azathioprine is a prodrug of mercaptopurine, which is nonenzymatically metabolized in the body to mercaptopurine, which is further metabolized to 6-TGN to exert its effects.

In the pharmaceutical of the present invention, azacitidine is preferably administered subcutaneously or intravenously at a dose of 50-100 mg/ ^m2 (body surface area) per day, more preferably at a dose of 70-80 mg/ ^m2 (body surface area) per day, and most preferably at a dose of 75 mg/ ^m2 (body surface area) per day. The dose may be appropriately reduced depending on the condition of the patient.

Azacitidine is administered once to three times a day, preferably once or twice a day, more preferably once a day on consecutive days. The administration period is 3 to 7 days, preferably 5 to 7 days, more preferably 7 days, with a drug-free period of 7 to 30 days, preferably 14 to 28 days, more preferably 21 days, and administration is repeated for 1 to 3 cycles, preferably 4 to 10 cycles, more preferably as long as the effect is observed. In cases where the drug is effective, discontinuing treatment may cause recurrence of cytopenia, leading to a poor prognosis.

In the pharmaceutical composition of the present invention, thiopurine is administered subcutaneously or intravenously as mercaptopurine hydrate at a dose equivalent to preferably 2-20 mg/ ^m2 (body surface area) per day, more preferably 5-8 mg/ ^m2 (body surface area) per day, and most preferably 6.4 mg/ ^m2 (body surface area) per day, with the dose being appropriately reduced depending on the condition of the patient.

When administered subcutaneously or intravenously, thiopurine is administered once to three times a day, preferably once or twice a day, more preferably once a day for consecutive days. The administration period is 3 to 7 days, preferably 5 to 7 days, more preferably 7 days, with a drug-free period of 7 to 30 days, preferably 14 to 28 days, more preferably 21 days, followed by 1 to 3 cycles, preferably 4 to 10 cycles, more preferably repeated as long as the effect is observed.

When administered orally, mercaptopurine hydrate is preferably administered at a dose equivalent to 0.5-2 mg/kg (body weight) per day, more preferably 0.75-1.5 mg/kg (body weight) per day, and most preferably 0.8-1.2 mg/kg (body weight) per day. The dose may be reduced as appropriate depending on the patient's condition.

When orally administered, thiopurine is administered once to three times a day, preferably once or twice a day, more preferably once a day for consecutive days. The administration period is 3 to 7 days, preferably 5 to 7 days, more preferably 7 days, with a drug-free period of 7 to 30 days, preferably 14 to 28 days, more preferably 21 days, followed by 1 to 3 cycles, preferably 4 to 10 cycles, more preferably repeated as long as the effect is observed.

The doses described above are those of mercaptopurine hydrate, but in the case of azathioprine and thioguanine, they can be used in a manner and at a dose that will give an equivalent amount of 6-TGN after being metabolized. In other words, "comparable dose" means a dose that will give an equivalent amount of the active metabolite (6-TGN) in the body.

Typically, 75 mg/ ^m2 (body surface area) of azacitidine (approximately 110-160 mg per day for adult males) and 6.4 mg/ ^m2 (body surface area) of mercaptopurine hydrate (approximately 9.6-13.5 mg per day for adult males) are administered intravenously for seven consecutive days followed by a 21-day drug holiday. This constitutes one set, and treatment is continued while symptoms are monitored. Alternatively, 75 mg/ ^m2 (body surface area) of azacitidine (approximately 110-160 mg per day for adult males) is administered intravenously and 40 mg/ ^m2 (body surface area) of mercaptopurine hydrate (approximately 60-85 mg per day for adult males) is administered orally per day for seven consecutive days followed by a 21-day drug holiday. This constitutes one set, and treatment is continued while symptoms are monitored.

5. Form of the pharmaceutical of the present invention The pharmaceutical of the present invention is characterized in that azacitidine and thiopurine are administered in combination. Here, "administering azacitidine and thiopurine in combination" includes simultaneous administration, separate administration consecutively, or administration at a fixed time interval.

In the pharmaceutical composition of the present invention, azacitidine and thiopurine may be separate formulations (pharmaceutical compositions), may be a single formulation (pharmaceutical composition), or may be a kit formulation containing the separate formulations in a single package.

When azacitidine and thiopurine are administered simultaneously, the pharmaceutical of the present invention may be a fixed dose combination drug containing a fixed amount of each of azacitidine and thiopurine mixed in a single formulation or a preparation prepared at the time of use, or separate preparations (pharmaceutical compositions) containing the respective active ingredients may be administered simultaneously.

When azacitidine and thiopurine are in separate formulations, the pharmaceutical composition containing thiopurine as an active ingredient and/or the pharmaceutical composition containing azacitidine as an active ingredient may indicate on their packaging or package insert that they are to be used together, but such indication is not necessarily required.

The pharmaceutical of the present invention is prepared to achieve the desired dosage of the aforementioned active ingredients: azacitidine and thiopurine.

The dosage form of the pharmaceutical of the present invention is not particularly limited, and can be used in a conventional manner such as oral administration or intravenous administration. Although not limited thereto, azacitidine is preferably in the form of an injection (e.g., subcutaneous injection, intravenous injection). Thiopurine is preferably in the form of an injection (e.g., subcutaneous injection, intravenous injection) or an orally administrable dosage form, particularly a solid dosage form (e.g., tablets, powders, granules, capsules, pills, dry syrup, etc.).

A preparation (pharmaceutical composition) containing azacitidine and/or thiopurine may contain, in addition to the active ingredient, a pharma- ceutical acceptable carrier (additive). Examples of such carriers include excipients, disintegrants, binders, lubricants, surfactants, colorants, flavorings, preservatives, stabilizers, buffers, suspending agents, isotonicity agents, flow enhancers, and flavoring agents, but are not limited to these, and other commonly used carriers can be used as appropriate.

Excipients that can be used include sugar, starch, dextrin, white sugar, tragacanth, etc.

Binders include pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.

Lubricants include stearic acid, fatty acid salts such as stearates, talc, silicates, etc.

Solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc.

Disintegrants include low-substituted hydroxypropyl cellulose, chemically modified cellulose and starches.

Solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

Suspending agents or emulsifying agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.

Isotonicity agents include sodium chloride, potassium chloride, glucose, D-sorbitol, D-mannitol, glycerin, urea, etc.

Stabilizers include polyethylene glycol, sodium dextran sulfate, and other amino acids.

Examples of soothing agents include benzyl alcohol.

Examples of buffering agents include buffer solutions such as phosphate, acetate, carbonate, and citrate.

Preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.

Antioxidants include sulfites, ascorbic acid, α-tocopherol, and ethylenediaminetetraacetic acid (EDTA).

Flavoring agents include sweeteners and fragrances commonly used in the pharmaceutical field, and coloring agents include coloring agents commonly used in the pharmaceutical field.

A preferred embodiment of the pharmaceutical of the present invention is an injectable formulation containing azacitidine and thiopurine. The formulation contains a fixed amount of lyophilized azacitidine and a fixed amount of thiopurine in a single vial or in separate vials, together with additives such as D-mannitol and lactose.

The above formulations are suspended or dissolved in water for injection at the time of use, and in the case of intravenous infusion, are further mixed with saline or lactated Ringer's solution. Alternatively, the injectable formulations may be prepared as ready-to-use formulations for filling syringes.

5. Use in the manufacture of a medicament The present invention also provides the use of azacitidine and/or thiopurine in the manufacture of a medicament (composition) for the treatment of MDS.

Specifically, the invention relates to the use of azacitidine in the manufacture of a medicine for treating MDS, characterized by being combined with thiopurine, when the two active ingredients are in separate formulations, and the use of thiopurine in the manufacture of a medicine for treating MDS, characterized by being combined with azacitidine. When the active ingredients are in a combined drug form, the invention relates to the use of azacitidine and thiopurine in the manufacture of a medicine for treating MDS.

6. Combination with known therapies The pharmaceutical agent of the present invention is sufficiently effective against high-risk (advanced) MDS, but depending on the symptoms of the patient, more favorable results can be expected by combining it with existing therapies, such as ESA, androgen, lenalidomide, etc. When bone marrow inflammation is involved in the pathology, it may be combined with an adrenal cortical hormone such as prednisolone.

The present invention will be described in more detail below using examples, but the present invention is not limited to these examples.

Table 1 summarizes the results of representative examples (four cases), and details are provided in Examples 1 to 4. In all cases, the blast ratio increased to 20% or more during Vidaza treatment, and the patient was deemed refractory to Vidaza and initiated on this treatment. The efficacy of the treatment was assessed using the international evaluation criteria (Cheson BD et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 108:419-25.), and all cases were deemed to be in complete remission.

[Example 1]
A 63-year-old male. The diagnosis at the time of starting azacitidine was MDS, EB-2. Six courses of azacitidine treatment (75 mg/m2 per body surface area, subcutaneous injection once a day for 7 days, followed by a 4-week break) were performed, but the patient showed a progression of cytopenia and an increase in myeloblasts in bone marrow tests, and was deemed refractory to Vidaza. The first course of this treatment was started on April 12. In addition to the same amount of Vidaza, the patient was given oral mercaptopurine (60 mg as mercaptopurine hydrate, equivalent to 1 mg/kg of body weight) once a day for 7 days.

result:
The results are shown in Figures 1 to 3. On May 8, the day the second course of this treatment began, pancytopenia improved. This treatment was continued approximately every four weeks, and blood counts gradually returned to normal, which has remained the case to this day. In addition, a bone marrow test before this treatment (April 1, 2019) showed that myeloblasts were 34.2%, but this normalized to 7% on May 7 and 1.8% on June 4. The efficacy of the drug was determined to be complete remission using the International Clinical Evaluation Criteria.

Observations:
In this case, mercaptopurine was taken orally as a powder (corresponding to 40 mg/ ^m2 of body surface area), but if it were administered intravenously, based on the absorption rate of mercaptopurine (16%), it would be possible to administer 6.4 mg/ ^m2 of mercaptopurine hydrate intravenously per body surface area.

Anti-leukemic chemotherapy drugs such as cyclophosphamide are ineffective against advanced MDS, and azacitidine is the only effective treatment. A new treatment method that combines azacitidine and mercaptopurine is used for patients who are unresponsive to azacitidine, and has been effective in many of the cases, making it a groundbreaking treatment.

[Example 2]
A 64-year-old male. The diagnosis at the time of starting azacitidine was MDS, EB-2. Azacitidine treatment (75 mg/m2 per body surface area, subcutaneous injection once a day for 7 days, followed by 3 weeks off) was performed for 12 courses, but blood cytopenia and an increase in myeloblasts in bone marrow tests progressed. The patient was determined to be insensitive to Vidaza, and this treatment was started. In addition to the same amount of Vidaza, mercaptopurine was taken orally (60 mg as mercaptopurine hydrate, equivalent to 0.85 mg/kg of body weight) once a day for 7 days. After four courses of this treatment, the patient was judged to be in complete remission according to the International Criteria.

[Example 3]
A 75-year-old male. The diagnosis at the time of starting azacitidine was MDS, EB-2. Three courses of azacitidine treatment (75 mg/m2 per body surface area, subcutaneous injection once a day for 7 days, followed by a 3-week break) were performed, but bone marrow tests showed a progression of an increase in myeloblasts. The patient was determined to be refractory to Vidaza, and this treatment was started. In other words, in addition to the same amount of Vidaza, mercaptopurine was taken orally (60 mg as mercaptopurine hydrate, equivalent to 1 mg/kg of body weight) once a day for 8 days. After five courses of this treatment, the patient was judged to be in complete remission according to the International Clinical Evaluation Criteria. This treatment has been repeated every month since then, and complete remission has been maintained through the 32nd course.

[Example 4]
An 81-year-old male. The diagnosis at the time of starting azacitidine was MDS, RCMD (refractory cytopenia with multilineage dysplasia). Azacitidine treatment was started due to transfusion-dependent anemia (75 mg/ ^m2 per body surface area, subcutaneous injection once a day for 7 days, followed by 3 weeks off). The anemia improved and azacitidine treatment was continued, but after 40 courses of azacitidine treatment, the cytopenia progressed and bone marrow examination showed an increase in myeloblasts. The patient was judged to be refractory to Vidaza and this treatment was started. In other words, in addition to the same amount of Vidaza, mercaptopurine was taken orally (60 mg as mercaptopurine hydrate, equivalent to 1.1 mg/kg of body weight) once a day for 7 days. After four courses of this treatment, the patient was judged to be in complete remission according to the International Criteria.

[Formulation example]
Formulation Example 1 (Injection Formulation)
1) Azacitidine (lyophilized) 100 mg
2) Mercaptopurine hydrate 8.5 mg
3) D-mannitol 100 mg
1), 2) and 3) are mixed and filled into a vial.
The above preparations are suspended or dissolved in water for injection when used, and in the case of intravenous infusion, are further mixed with physiological saline or lactated Ringer's solution. Azacitidine and mercaptopurine may be filled in separate vials together with an additive (D-mannitol).

The pharmaceutical of the present invention is also useful for treating high-risk (advanced) MDS and MDS unresponsive to azacitidine, for which there has previously been no effective treatment.

All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims (9)

A pharmaceutical for treating myelodysplastic syndrome, comprising administering azacitidine and thiopurine in combination ,
The said medicine, wherein the said thiopurine is mercaptopurine . The pharmaceutical composition according to claim 1, characterized in that azacitidine is administered subcutaneously or intravenously at a dose of 50 to 100 mg/ ^m2 (body surface area) per day, and thiopurine is administered orally at a dose of 0.5 to 2 mg/kg (body weight) per day as mercaptopurine hydrate, or subcutaneously or intravenously at a dose equivalent to 2 to 20 mg/ ^m2 (body surface area) per day. The pharmaceutical composition according to claim 1 or 2, characterized in that azacitidine and thiopurine are administered daily for at least 5 to 10 days. The pharmaceutical composition according to claim 3, which is used in three or more consecutive sets with a drug-free period of at least 14 days between each set. The pharmaceutical composition according to any one of claims 1 to 4, wherein azacitidine and thiopurine are formulated separately. The pharmaceutical composition according to claim 5, wherein a pharmaceutical composition containing azacitidine as an active ingredient and a pharmaceutical composition containing thiopurine as an active ingredient are set in one package. The pharmaceutical agent according to any one of claims 1 to 4, which is a fixed-dose combination drug containing azacitidine and thiopurine as active ingredients. The pharmaceutical agent according to claim 6 or 7, which is an injectable preparation containing azacitidine and thiopurine as active ingredients. The pharmaceutical agent according to any one of claims 1 to 8, which is administered to a patient with myelodysplastic syndrome who is unresponsive to azacitidine monotherapy.

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