WO2021125261A1 - Agent thérapeutique pour le syndrome myélodysplasique à haut risque - Google Patents

Agent thérapeutique pour le syndrome myélodysplasique à haut risque Download PDF

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WO2021125261A1
WO2021125261A1 PCT/JP2020/047149 JP2020047149W WO2021125261A1 WO 2021125261 A1 WO2021125261 A1 WO 2021125261A1 JP 2020047149 W JP2020047149 W JP 2020047149W WO 2021125261 A1 WO2021125261 A1 WO 2021125261A1
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azacitidine
thiopurine
mercaptopurine
drug
administered
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PCT/JP2020/047149
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English (en)
Japanese (ja)
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清行 緒方
由美 山元
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一般社団法人 東京血液疾患研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel treatment for myelodysplastic syndrome and the like, which is characterized by the combined use of azacitidine and thiopurine.
  • MDS Myelodysplastic syndromes
  • MDS presents with cytopenia symptoms (anemia, neutropenia infection, thrombocytopenia bleeding), and often over 20% of myeloblasts in the bone marrow and peripheral blood during the course, a condition of acute myeloid leukemia. Move to. And it is a disease with a poor prognosis that causes a serious pathological condition by these.
  • An increase in the myeloblast ratio indicates the progression of the disease and is also called advanced stage MDS.
  • Anti-leukemia chemotherapeutic agents such as Kiroside have no effect on advanced-stage MDS, and azacitidine (trade name: Vidaza) is the only effective.
  • Azacitidine has a certain effect on about half of the cases with increased myeloblasts, and is currently said to be the only drug capable of prolonging survival in advanced MDS (References 1 and 2).
  • the effect often lasts for about a year.
  • the life expectancy when azacitidine becomes ineffective is about 4 to 6 months, and no treatment to improve this is known (Reference 2).
  • Mercaptopurine is a type of thiopurine preparation and is used as a therapeutic agent for malignant tumors such as acute and chronic myelogenous leukemia and acute lymphocytic leukemia, and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis (cited). Document 3-5). The effect of the thiopurine preparation on myelodysplastic syndrome is unknown, and the combined use of azacitidine and the thiopurine preparation has not been reported.
  • An object of the present invention is to provide a new treatment method for MDS, which is effective for MDS, particularly MDS that is unresponsive to azacitidine monotherapy and high-risk MDS (advanced MDS).
  • thiopurine preparations such as mercaptopurine, azathioprine, and thioguanine for MDS patients who have become unresponsive to azacitidine.
  • the present invention provides the following (1) to (12).
  • a therapeutic agent for myelodysplastic syndrome which comprises administering azacitidine in combination with any thiopurine selected from the group consisting of mercaptopurine, azathioprine, and thioguanine.
  • Azacitidine is administered subcutaneously or intravenously at a dose of 50 to 100 mg / m 2 (body surface area) per day, and thiopurine is 0.5 to 2 mg / kg (body weight) per day as mercaptopurine hydrate.
  • the “comparable dose” means a dose that gives an equivalent amount of the active metabolite (6-TGN) in the body.
  • (3) The medicament according to (1) or (2), wherein azacitidine and thiopurine are administered daily for at least 5 to 10 days.
  • (4) The drug according to (3), which is characterized in that three or more sets are continuously used with a drug holiday of at least 14 days.
  • (5) The drug according to any one of (1) to (4), wherein azacitidine and thiopurine are separately formulated.
  • (6) The drug according to (5), wherein the pharmaceutical composition containing azacitidine as an active ingredient and the pharmaceutical composition containing thiopurine as an active ingredient are set in one package.
  • the drug according to any one of (1) to (4) which is a fixed-dose combination drug containing azacitidine and thiopurine as active ingredients.
  • the pharmaceutical product according to (6) or (7) which is an injectable preparation containing azacitidine and thiopurine as active ingredients.
  • the medicament according to any one of (1) to (8) which is administered to a patient with myelodysplastic syndrome who does not respond to azacitidine monotherapy.
  • a therapeutic agent for myelodysplastic syndrome containing azacitidine which is used in combination with any thiopurine selected from the group consisting of mercaptopurine, azathioprine, and thioguanine. This medicine is used in the dosages (2) to (4) above.
  • a therapeutic agent for myelodysplastic syndrome which comprises any thiopurine selected from the group consisting of mercaptopurine, azathioprine, and thioguanine, which is used in combination with azacitidine. This medicine is used in the dosages (2) to (4) above.
  • the present invention it is possible to effectively treat high-risk (advanced stage) MDS for which there has been no effective therapeutic means so far.
  • the medicament of the present invention can treat high-risk (advanced stage) MDS for which there has been no effective therapeutic means by using a pharmaceutical ingredient that has been used clinically and has established safety.
  • FIG. 1 shows changes in the white blood cell count (/ ⁇ L: on the graph) and the neutrophil count (/ ⁇ L: on the graph) after the start of treatment with azacitidine and mercaptopurine.
  • FIG. 2 shows the transition of the platelet count (10,000 / ⁇ L) after the start of treatment with azacitidine and mercaptopurine.
  • FIG. 3 shows the transition of the hemoglobin number (10,000 / ⁇ L) after the start of treatment with azacitidine and mercaptopurine.
  • the present invention relates to a pharmaceutical agent for treating myelodysplastic syndrome, which comprises administering azacitidine and thiopurine in combination.
  • a pharmaceutical agent for treating myelodysplastic syndrome which comprises administering azacitidine and thiopurine in combination.
  • MDS myelodysplastic syndromes
  • the "myelodysplastic syndromes [MDS]" according to the present invention is one of hematopoietic malignant tumors in which tumorized hematopoietic cells proliferate in the bone marrow, and abnormal blood cell formation. This name is used because of (dysplasia) and blood cell depletion. MDS often progresses to acute myeloid leukemia (it has been proposed that a diagnosis of acute myeloid leukemia occurs when myeloblasts exceed 20%), so it is sometimes referred to as a pre-leukemic state.
  • MDS is classified into refractory anemia, iron blast refractory anemia, refractory anemia with polycytic dysplasia, and iron blast refractory anemia with polycytic dysplasia, depending on the ratio of bone marrow to blast. , Precursor-increasing refractory anemia, 5q-syndrome, and unclassifiable myelodysplastic syndrome. Unless otherwise specified, the term MDS in the present invention includes all of these.
  • the medicament of the present invention is characterized in that it exerts an effect on high-risk (advanced stage) MDS in which conventional MDS therapy such as a chemotherapeutic agent does not respond sufficiently.
  • Azacitidine is a nucleotide analog in which the carbon atom at the 5-position of the pyrimidine ring of cytidine is replaced with a nitrogen atom, and is used as a therapeutic agent for myelodysplastic syndrome by inhibiting DNA methylation and inducing cell differentiation. ..
  • azacitidine preparation (trade name: Vidaza (registered trademark)) approved in Japan
  • 75 mg / m 2 (body surface area) of azacitidine is subcutaneously administered once daily for 7 days or for 10 minutes to adults. Intravenous infusion over the drug and withdrawal for 3 weeks.
  • the standard administration method of azacitidine is to set this as one cycle and repeat the administration.
  • Azacitidine shows a certain effect on about half of MDS patients with increased myeloblasts, but the effect often lasts for about a year.
  • the medicament of the present invention can effectively treat high-risk (advanced stage) MDS by using this azacitidine in combination with thiopurine.
  • a thiopurine or a thiopurine preparation is a purine antimetabolite used for the treatment of leukemia, autoimmune diseases (Crohn's disease, rheumatoid arthritis, etc.), and post-organ transplantation.
  • thiopurine preparations are azathioprine, mercaptopurine (6-mercaptopurine), and thioguanine (6-thioguanine) (in Japan, only azacitidine and mercaptopurine), all of which are 6-thio in the body. It is metabolized to guanine nucleoside (6-TGN) and exerts its action.
  • Mercaptopurine is a thiopurine preparation used as a therapeutic agent for malignant tumors such as acute and chronic myelogenous leukemia and acute lymphocytic leukemia, and inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Is.
  • the amount of remission introduced is usually 1 adult as mercaptopurine hydrate.
  • the typical treatment protocol is to administer mercaptopurine daily for 2 weeks during consolidation / intensive therapy, 70 days for intermittent maintenance therapy, and 12 to 16 months daily for long-term maintenance therapy (The above-mentioned "Blood Tumor Protocol Collection” that is useful in the field).
  • the effect can be expected by daily administration for 12 to 17 weeks, and if the effect is obtained, further continuous administration is performed (Nielsen et al., Supra). ..
  • the mercaptopurine preparation (trade name: Purinehol, Leukerin) currently used is an oral tablet, but mercaptopurine can also be used intravenously (van der Werff Ten Bosch Jet al. Value). of intravenous 6-mercaptopurine during continuing treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG. Therefore, as will be described later, mercaptopurine can be formulated as an injection together with azacitidine.
  • Tioguanine (6-thioguanine) is a trade name of Tabroid® for maintaining remission of acute lymphocytic leukemia and as a second-line treatment for myelogenous leukemia, acute myelogenous monocytic leukemia, and chronic myelogenous leukemia.
  • Mercaptopurine is metabolized to 6-TGN in the body and exerts its action, but thioguanine is its active metabolite and can be expected to have the same action as mercaptopurine.
  • Azathioprine is a trade name of Imran (registered trademark), and is a thiopurine preparation used for immunosuppressive drugs, induction and maintenance of remission of steroid-dependent Crohn's disease, treatment-resistant rheumatic diseases, autoimmune hepatitis, etc. Is. Azathioprine is a prodrug of mercaptopurine, which is metabolized non-enzymatically in the body to mercaptopurine, which is further metabolized to 6-TGN to exert its action.
  • azacitidine is preferably 50 to 100 mg / m 2 (body surface area) per day, more preferably 70 to 80 mg / m 2 (body surface area) per day, and most preferably. 75 mg / m 2 (body surface area) daily administered subcutaneously or intravenously. The dose may be appropriately reduced depending on the patient's condition.
  • the frequency of administration of azacitidine is once to three times a day, preferably once or twice a day, and more preferably once a day every day.
  • the administration period is 3 to 7 days, preferably 5 to 7 days, more preferably 7 days, 7 to 30 days, preferably 14 to 28 days, more preferably 21 days, and 1 to 3 cycles. , Preferably 4 to 10 cycles, more preferably repeated administration as long as the effect is observed. In effective cases, discontinuation of treatment can lead to relapse of cytopenia and poor prognosis.
  • thiopurine is preferably 2 to 20 mg / m 2 (body surface area) per day, more preferably 5 to 8 mg / m per day as mercaptopurine hydrate when administered subcutaneously or intravenously. It is administered at a dose comparable to 2 (body surface area), most preferably 6.4 mg / m 2 (body surface area) daily. The dose may be reduced as appropriate according to the patient's condition.
  • the number of administrations of thiopurine is once to three times a day, preferably once or twice a day, and more preferably once a day every day.
  • the administration period is 3 to 7 days, preferably 5 to 7 days, more preferably 7 days, 7 to 30 days, preferably 14 to 28 days, more preferably 21 days, and 1 to 3 cycles. , Preferably 4 to 10 cycles, more preferably repeated administration as long as the effect is observed.
  • the mercaptopurine hydrate is preferably 0.5 to 2 mg / kg (body weight) per day, more preferably 0.75 to 1.5 mg / kg (body weight) per day, and most preferably 0.8 to 1.2 per day. It is administered at a dose comparable to mg / kg (body weight). The dose may be reduced as appropriate depending on the patient's condition.
  • the number of administrations of thiopurine is once to three times a day, preferably once or twice a day, and more preferably once a day every day.
  • the administration period is 3 to 7 days, preferably 5 to 7 days, more preferably 7 days, 7 to 30 days, preferably 14 to 28 days, more preferably 21 days, and 1 to 3 cycles. , Preferably 4 to 10 cycles, more preferably repeated administration as long as the effect is observed.
  • the dose as mercaptopurine hydrate is described, but in the case of azathioprine and thioguanine, it can be used in a dosage and administration that is metabolized to give an equivalent amount of 6-TGN. That is, “comparable dose” means a dose that gives an equivalent amount of active metabolite (6-TGN) in the body.
  • azacitidine 75 mg / day m 2 (body surface area) is administered intravenously and, per day mercaptopurine hydrate 40 mg / m 2 (body surface area) is (if 1 day to about 60 ⁇ 85 mg of an adult male (about 110 ⁇ 160 mg per day for an adult male) ) Orally administered for 7 consecutive days, withdrawal for 21 days.
  • azacitidine 75 mg / day m 2 (body surface area) is administered intravenously and, per day mercaptopurine hydrate 40 mg / m 2 (body surface area) is (if 1 day to about 60 ⁇ 85 mg of an adult male (about 110 ⁇ 160 mg per day for an adult male) ) Orally administered for 7 consecutive days, withdrawal for 21 days.
  • the form of the medicament of the present invention is characterized in that azacitidine and thiopurine are administered in combination.
  • administering azacitidine and thiopurine in combination includes all of simultaneous administration, separate administration, continuous administration, or administration at regular time intervals.
  • azacitidine and thiopurine may be separate preparations (pharmaceutical composition), one preparation (pharmaceutical composition), or separate preparations contained in one package. It may be a kit formulation.
  • the medicament of the present invention is a fixed dose combination drug or a time-prepared preparation containing a fixed amount of azacitidine and thiopurine mixed in a single preparation. It may be present, or a separate preparation (pharmaceutical composition) containing each active ingredient may be administered at the same time.
  • azacitidine and thiopurine are separate preparations, it is indicated on the packaging, package insert, etc. that the pharmaceutical composition containing thiopurine as an active ingredient and / or the pharmaceutical composition containing azacitidine as an active ingredient are used in combination with each other. However, such labeling is not always required.
  • the medicament of the present invention is prepared to achieve the desired dosage of the active ingredient: azacitidine or thiopurine described above.
  • the dosage form of the medicament of the present invention is not particularly limited, and can be used in conventionally used modes such as oral administration and intravenous administration.
  • azacitidine is preferably an injection (eg, subcutaneous injection, intravenous injection).
  • Thiopulin can be injectable (eg, subcutaneous, intravenous) or orally administrable, especially solid (eg, tablets, powders, granules, capsules, pills, dry syrup, etc.). It is preferable to have.
  • a preparation (pharmaceutical composition) containing azacitidine and / or thiopurine may contain a pharmaceutically acceptable carrier (additive) in addition to the active ingredient, and such a carrier includes, for example, an excipient.
  • a pharmaceutically acceptable carrier includes, for example, an excipient.
  • the carrier is not limited to these, and other commonly used carriers can be used as appropriate.
  • sugar starch, dextrin, sucrose, tragant, etc. can be used as the excipient.
  • binder examples include pregelatinized starch, gelatin, gum arabic, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like.
  • lubricant examples include fatty acid salts such as stearic acid and stearate, talc, and silicates.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • disintegrant examples include low-degree-of-substitution hydroxypropyl cellulose, chemically modified cellulose and starches.
  • solubilizing agent examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc .; for example, polyvinyl alcohol, polyvinylpyrrolidone. , Hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.
  • tonicity agent examples include sodium chloride, potassium chloride, glucose, D-sorbitol, D-mannitol, glycerin, urea and the like.
  • stabilizer examples include polyethylene glycol, sodium dextran sulfate, and other amino acids.
  • Examples of the pain-relieving agent include benzyl alcohol and the like.
  • the buffer examples include a buffer solution such as phosphate, acetate, carbonate, and citrate.
  • preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidant examples include sulfites, ascorbic acid, ⁇ -tocopherol, ethylenediaminetetraacetic acid (EDTA) and the like.
  • flavoring and odorant examples include sweeteners and flavors normally used in the pharmaceutical field, and examples of the colorant include colorants normally used in the pharmaceutical field.
  • a preferred form of the medicament of the present invention is an injectable preparation containing azacitidine and thiopurine.
  • the formulation contains a lyophilized fixed amount of azacitidine and a fixed amount of thiopurine in combination with additives such as D-mannitol and lactose in one vial or in separate vials.
  • the above-mentioned preparation is suspended or dissolved in water for injection at the time of use, and in the case of intravenous drip infusion, it is further mixed with physiological saline or Ringer's lactate solution.
  • the injectable formulation may be prepared as a ready-to-use syringe filling formulation.
  • the present invention also provides the use of azacitidine and / or thiopurine in the manufacture of therapeutic pharmaceuticals (compositions) for MDS.
  • the use of azacitidine in the manufacture of a therapeutic drug for MDS which is characterized by being used in combination with thiopurine, is characterized by being used in combination with azacitidine.
  • inventions relating to the use of thiopurine in the manufacture of a therapeutic agent for MDS are provided.
  • the present invention provides an invention relating to the use of azacitidine and thiopurine in the manufacture of a therapeutic drug for MDS.
  • the medicaments of the present invention are sufficiently effective for high-risk (advanced) MDS, but depending on the patient's symptoms, existing therapies such as ESA, androgen, and lenalidomide may be used. It can be expected that more preferable results can be obtained by using in combination with the above. If inflammation in the bone marrow is involved in the pathology, corticosteroids such as prednisolone may be used in combination.
  • Table 1 summarizes the results of typical examples (4 cases), and the details are described in Examples 1 to 4.
  • the precursor cell ratio increased to 20% or more during the vidaza treatment, and it was judged that the vidaza was refractory and this treatment was started.
  • the efficacy of the treatment was judged by 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 were completely relieved. Has been determined.
  • Example 1 63 year old male.
  • the diagnosis at the start of azacitidine is MDS, EB-2.
  • Six courses of azacitidine treatment (75 mg / m2 per body surface area once daily, subcutaneous injection for 7 days, withdrawal for 4 weeks) were performed, but cytopenia and bone marrow examination showed an increase in myeloblasts, resulting in vidaza refractory. I decided.
  • the first course of this treatment was started on April 12. That is, in addition to the same amount of Vidaza, oral administration of mercaptopurine (60 mg as mercaptopurine hydrate, corresponding to 1 mg / kg per body weight) was performed once a day for 7 days.
  • mercaptopurine 60 mg as mercaptopurine hydrate, corresponding to 1 mg / kg per body weight
  • mercaptopurine was orally administered as a powder ( corresponding to 40 mg / m 2 per body surface area), but when administered intravenously, mercaptopurine hydration was converted from the absorption rate of mercaptopurine (16%). As a substance, 6.4 mg / m 2 per body surface area can be administered intravenously.
  • Anti-leukemia chemotherapeutic agents such as Kiroside have no effect on advanced-stage MDS, and azacitidine is the only effective.
  • the new treatment method using azacitidine and mercaptopurine in combination is used for patients who do not respond to azacitidine, and has been shown to be effective in many of the administered cases, which can be said to be an epoch-making therapeutic effect.
  • Example 2 64-year-old man.
  • the diagnosis at the start of azacitidine is MDS, EB-2.
  • Twelve courses of azacitidine treatment (75 mg / m2 per body surface area, subcutaneous injection for 7 days, withdrawal for 3 weeks) were performed, but cytopenia and bone marrow examination showed an increase in myeloblasts.
  • the patient was judged to be refractory to Vidaza and started this treatment. That is, in addition to the same amount of Vidaza, oral administration of mercaptopurine (60 mg as mercaptopurine hydrate, corresponding to 0.85 mg / kg per body weight) was performed once a day for 7 days. When this treatment was repeated for 4 courses, it was judged to be in complete remission according to international evaluation criteria.
  • Example 3 75 year old male.
  • the diagnosis at the start of azacitidine is MDS, EB-2.
  • Three courses of azacitidine treatment (75 mg / m2 per body surface area, subcutaneous injection for 7 days, withdrawal for 3 weeks) were performed, but myeloblasts increased on bone marrow examination.
  • the patient was judged to be refractory to Vidaza and started this treatment. That is, in addition to the same amount of Vidaza, oral administration of mercaptopurine (60 mg as mercaptopurine hydrate, corresponding to 1 mg / kg per body weight) was performed once a day for 8 days. After 5 courses of this treatment, the patient was judged to be in complete remission according to international evaluation criteria. After that, this treatment was repeated every month, and although it was the 32nd course, complete remission was maintained.
  • mercaptopurine 60 mg as mercaptopurine hydrate, corresponding to 1 mg / kg per body weight
  • azacitidine 81 year old male.
  • the diagnosis at the start of azacitidine is MDS, RCMD (refractory cytopenia with multiple systems).
  • Due to blood transfusion-dependent anemia azacitidine treatment (75 mg / m 2 per body surface area once daily, subcutaneous injection for 7 days, withdrawal for 3 weeks) was started.
  • Anemia improved and azacitidine treatment was continued, but cytopenia progressed after 40 courses of azacitidine treatment, and myeloblasts increased on bone marrow examination.
  • the patient was judged to be refractory to Vidaza and started this treatment.
  • the medicament of the present invention is also useful for the treatment of high-risk (advanced stage) MDS and MDS that do not respond to azacitidine, for which there has been no effective therapeutic means so far.

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Abstract

La présente invention concerne une nouvelle méthode de traitement du syndrome myélodysplasique, ladite méthode étant caractérisée par l'utilisation combinée d'azacitidine et de thiopurine. En particulier, la présente invention concerne un médicament pour le traitement du syndrome myélodysplasique, ledit médicament étant caractérisé en ce que : l'azacitidine est administrée par voie sous-cutanée ou intraveineuse en une dose de 50-100 mg/m2 (surface corporelle) par jour ; et la thiopurine est administrée par voie orale sous la forme d'hydrate de mercaptopurine en une dose équivalente à 0,5-2,0 mg/kg (poids corporel) par jour, ou est administrée par voie sous-cutanée ou intraveineuse sous la forme d'hydrate de mercaptopurine en une dose équivalente à 2-20 mg/m2 (surface corporelle) par jour.
PCT/JP2020/047149 2019-12-18 2020-12-17 Agent thérapeutique pour le syndrome myélodysplasique à haut risque WO2021125261A1 (fr)

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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HISAMATSU TADAKAZU: "6-Thiopurine/Azathioprine", THE JOURNAL OF PRACTICAL PHARMACY, vol. 67, no. 6, 2016, pages 2149 - 2153 *
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