Medicine for treating acute T lymphocytic leukemia and application thereof

Abstract

The invention provides application of chidamide or a derivative thereof in preparation of a medicine for preventing and / or treating acute T lymphocytic leukemia. According to statistics of curative effect data of grouped clinical patients, compared with an existing treatment scheme (the curative effect is 20-30%) for treating acute T-ALL, the pharmaceutical composition provided by the invention has the advantages that the curative effect can be improved to 75%, and remarkable clinical benefits are brought.

Description

Technical Field

[0001] This invention relates to the field of medicine, specifically to drugs for treating acute T-lymphoblastic leukemia and their applications. Background Technology

[0002] Acute T-cell acute lymphoblastic leukemia (T-ALL) is a pathological type of acute lymphoblastic leukemia (ALL), a hematologic malignancy caused by the malignant transformation and clonal expansion of T-cell precursor cells in the bone marrow and thymus. Due to the disruption of normal hematopoietic function and the aggregation of tumor cells, a series of clinical symptoms may occur, including infection, anemia, bleeding, and tissue infiltration.

[0003] T-ALL occurs more frequently in children and adolescents, but can also occur in adults. T-ALL accounts for approximately 10%–15% of ALL patients in children and approximately 20%–25% in adults. Historical research data shows that compared to B-ALL, T-ALL has a higher relapse rate, poorer remission rate, and lower long-term survival rate.

[0004] T-ALL often presents with a more aggressive clinical manifestation than other types of ALL and is prone to complications such as central nervous system leukemia (CNSL). Combined chemotherapy is the first-line treatment for T-ALL, but its efficacy is not ideal. Approximately 20% of children and 50% of adults with T-ALL fail to achieve durable complete remission and die due to disease progression. To improve efficacy and prognosis, more second-line treatment options, including hematopoietic stem cell transplantation (HSCT) and CAR-T (Chimeric antigen receptor T cells), have been applied in clinical trials and practice. However, these cell therapy methods are costly, complex to manage throughout the treatment process, and lack medical accessibility in some developing regions. Therefore, the high invasiveness of T-ALL, limited clinical treatment options, and poor prognosis remain a clinical challenge, necessitating further research into effective and relatively economical T-ALL treatments.

[0005] Based on domestic and international classifications, acute lymphoblastic leukemia (ALL) is generally classified into three types: high-risk, median, and low-risk. Referring to the 2023 ELN guidelines, high-risk T-ALL patients are defined as: ① Initially diagnosed WBC > 100 x 10^9 / L. ② Immunophenotype: Pro / Pre T, ETP, mature-T. ③ Cytogenetic: Ph+, t(4;14), subdiploid, complex karyotype (5 or more chromosomal abnormalities, excluding patients with confirmed translocations). ④ BCR-ABL1+, KMT2a-R. ⑤ Unmutated NOTCH1 / FBWX7 and normal RAS / PTEN. ⑥ Central nervous system involvement. ⑦ Mixed phenotype acute leukemia (MPAL). Currently, T-ALL treatment still follows the same chemotherapy regimen as B-ALL. The main induction therapy drugs include glucocorticoids, vincristine alkaloids, L-asparaginase, and anthracyclines. Because T-ALL is not sensitive to drugs during induction remission, high-intensity induction therapy is usually used in the early stages clinically. This strategy aims to significantly reduce the tumor burden in a short period to improve the success rate of induction therapy. However, despite high-intensity chemotherapy, the success rate of T-ALL induction remission is only 20-30%, and it also increases the incidence of adverse reactions.

[0006] Chidamide, an oral subtype-selective histone deacetylase (HDAC) inhibitor independently developed by Chipscreen Biosciences, primarily targets HDAC subtypes 1, 2, and 3 in class I and subtype 10 in class IIb. It not only regulates abnormal epigenetic functions in tumors and induces and activates novel cellular immune functions, but also overcomes drug resistance, making it a novel epigenetic drug. In 2014, Chidamide was approved by the China Food and Drug Administration (CFDA) for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).

[0007] Venetoclax is a BCL-2 inhibitor developed by AbbVie, Inc. It was first approved for marketing in the United States in April 2016 for the treatment of chronic lymphocytic leukemia. In December 2020, venetoclax was approved for marketing in China for the treatment of acute myeloid leukemia. Currently, venetoclax is marketed in multiple countries for various indications and is undergoing multiple clinical trials.

[0008] Azacitidine, commonly known as DNA methylation inhibitor, targets DNMT1. It was originally developed by Celgene Corp. and was first approved in the United States in May 2004 for the treatment of myelodysplastic syndromes. It was first approved in China for the same indication in April 2017.

[0009] There are currently no studies or reports on the use of chidamide in combination with veneclade and azacitidine for the prevention and / or treatment of acute T-lymphoblastic leukemia.

[0010] The technical problem that the invention aims to solve

[0011] The present invention aims to provide a novel pharmaceutical composition for the treatment of acute T-lymphoblastic leukemia, which has a synergistic effect and can significantly increase survival benefits. Summary of the Invention

[0012] A first aspect of the invention provides the use of chidamide or a derivative thereof in the preparation of a medicament for the prevention and / or treatment of T-lymphocytic leukemia; said medicament further comprising veneclade or a derivative thereof, azacitidine or a derivative thereof.

[0013] In some specific embodiments, the present invention provides the use of chidamide in the preparation of a medicament for the prevention and / or treatment of T-lymphocytic leukemia; said medicament further includes veneclade and azacitidine.

[0014] On the other hand, the present invention provides the use of chidamide or a derivative thereof in the preparation of a medicament for the prevention and / or treatment of T-lymphocytic leukemia in combination with verneclade or a derivative thereof and azacitidine or a derivative thereof.

[0015] In some specific embodiments, the present invention provides the use of chidamide in the preparation of a medicament for the prevention and / or treatment of T-lymphocytic leukemia in combination with verneclax and azacitidine.

[0016] A second aspect of the present invention provides a pharmaceutical composition comprising chidamide or a derivative thereof, veneclade or a derivative thereof, and azacitidine or a derivative thereof.

[0017] In some specific embodiments, the above-mentioned pharmaceutical composition comprises chidamide, veneclade, and azacitidine.

[0018] In some specific embodiments, the mass ratio of chidamide or its derivative, veneclade or its derivative, and azacitidine or its derivative in the above pharmaceutical composition is 5-60:100-400:75-150; the preferred ratio is 10-30:400:150, based on the mass of chidamide, veneclade, and azacitidine, respectively.

[0019] In some specific embodiments, the pharmaceutical composition described above is used for the prevention and / or treatment of T-lymphoblastic leukemia.

[0020] A third aspect of the invention provides a medicine box containing the pharmaceutical composition described above.

[0021] In some specific embodiments, the aforementioned medicine box contains chidamide or its derivatives, veneclade or its derivatives, and azacitidine or its derivatives in unit formulations with the same or different specifications.

[0022] In some specific embodiments, the aforementioned medicine box contains chidamide or its derivatives, veneclade or its derivatives, and azacitidine or its derivatives, either in the same container or in different containers.

[0023] In some specific implementations, the chidamide described herein is a gastrointestinal dosage form, preferably an oral formulation.

[0024] In some specific implementations, the Veneclair described herein is a gastrointestinal dosage form, preferably an oral formulation.

[0025] In some specific implementations, the azacitidine described herein is a gastrointestinal or parenteral dosage form, preferably an oral or injectable formulation, and more preferably an injectable formulation.

[0026] A fourth aspect of the invention provides a method for preventing and / or treating T-lymphoblastic leukemia, comprising administering to an individual in need a preventive and / or therapeutically effective amount of the pharmaceutical composition as described above.

[0027] In some specific embodiments, as described herein, such as in treatment methods, the single dose of chidamide or its derivatives is 5-60 mg, preferably 10-30 mg, based on the mass of chidamide. Preferably, the unit dose strength of chidamide is 5 mg.

[0028] In some specific embodiments, as described herein, such as in treatment methods, a single dose of veneclade or a derivative thereof is 100-400 mg, preferably 400 mg, based on the weight of veneclade. Preferably, the unit dose strength of veneclade is 10 mg, 50 mg, or 100 mg.

[0029] In some specific embodiments, as described herein, such as in treatment methods, the single dose of azacitidine or its derivatives is 75-150 mg, preferably 150 mg, based on the mass of azacitidine. Preferably, azacitidine is available in 200 mg or 300 mg oral tablets or 100 mg injectable solutions.

[0030] In some specific implementations, such as in treatment methods, the chidamide or its derivatives, veneclade or its derivatives, and azacitidine or its derivatives are administered simultaneously, separately, or sequentially.

[0031] In some specific implementations, the derivatives described herein are selected from pharmaceutically acceptable salts, enantiomers, stereoisomers, or crystal forms of the active pharmaceutical ingredient.

[0032] CN03139760.3 discloses the structure of chidamide compounds and specifically discloses the in vitro inhibitory activity of this type of compound against histone deacetylases, as well as its growth inhibitory effect on different tumor cells. CN201210489178.8 discloses two crystalline forms of chidamide, namely chidamide crystal form A and chidamide crystal form B, as well as a new crystalline form of chidamide and a method for preparing an oral formulation of it as an active ingredient. CN201410136761.X discloses an E configuration of chidamide and specifically discloses its preparation method. The above-mentioned documents are incorporated herein by reference in their entirety as prior art and are integral parts of this invention.

[0033] In some specific implementations, the derivatives of dicamba described herein are selected from its pharmaceutically acceptable salts, crystal form A, or crystal form B.

[0034] In some specific implementations, the T-lymphocytic leukemia described herein is acute T-lymphocytic leukemia.

[0035] In some specific implementation schemes, the acute T-lymphoblastic leukemia described herein refers to high-risk acute T-lymphoblastic leukemia.

[0036] In some specific implementation schemes, the high-risk acute T-lymphoblastic leukemia described herein refers to newly diagnosed or relapsed / refractory leukemia.

[0037] In some specific implementations, the high-risk acute T-lymphoblastic leukemia described herein is relapsed, or refractory primary or secondary.

[0038] In some specific implementations, the derivatives of the drug described herein are pharmaceutically acceptable salts or crystal forms.

[0039] The beneficial effects of this invention are:

[0040] This application provides a pharmaceutical composition for treating acute T-ALL. According to the efficacy data of enrolled clinical patients, compared with existing treatment regimens for acute T-ALL (efficacy of 20-30%), the efficacy of the pharmaceutical composition provided in this application can be increased to 75%, bringing significant clinical benefits. Detailed Implementation

[0041] This invention discloses a drug for treating acute T-lymphoblastic leukemia and its uses. Those skilled in the art can refer to this document and make appropriate adjustments and improvements. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The drug for treating acute T-lymphoblastic leukemia and its uses described in this invention have been described through preferred embodiments. Those skilled in the art can obviously make modifications or appropriate changes and combinations to the applications and pharmaceutical compositions described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0042] Example 1: A multicenter, single-arm, open-label clinical trial of chidamide in combination with veneclade and azacitidine for the treatment of relapsed or refractory primary or secondary acute T-lymphoblastic leukemia.

[0043] I. Test Drugs

[0044] Chidamide, specification: 5mg / tablet, Shenzhen Chipscreen Biosciences Co., Ltd.

[0045] Venekra, strength: 100mg / tablet, AbbVie Ireland NL BV.

[0046] Azacitidine, specification: 100mg / vial, Huiyu Pharmaceutical.

[0047] II. Selection Criteria

[0048] Inclusion criteria: ① Age ≥ 18 years, gender not limited; ② Diagnosis meets the T-ALL diagnostic criteria in the "Guidelines for the Diagnosis and Treatment of Acute Lymphoblastic Leukemia in Chinese Adults" (2021 Edition); ③ Patients understand and voluntarily participate in this study and sign an informed consent form.

[0049] III. Treatment Plan

[0050] All enrolled patients received a dual-phenomenal, multi-target regimen, specifically: chidamide 30 mg biw, orally; azacitidine 75 mg / m². 2 Subcutaneous injection on days 1-7; Veneclair 100mg on day 1, 200mg on day 2, 300mg on day 3, and 400mg once daily (ddd4-d14), orally; Dexamethasone 10mg intravenously on days 1-7 / day 1-10 (to reduce tumor burden), 14 days as one course of treatment, efficacy evaluation after one or two courses of treatment.

[0051] IV. Dosage Adjustment

[0052] The specific dosage should be adjusted according to the patient's physical condition. If bone marrow suppression occurs, the medication should be stopped immediately and the original dosage should be resumed after the indicators return to normal.

[0053] V. Therapeutic Indicators

[0054] After one or two cycles of this chemotherapy regimen (dual-phenomenological multi-target regimen), all patients underwent follow-up blood tests, bone marrow smears, minimal residual disease (MRD) in the bone marrow, and MRD in cerebrospinal fluid. Treatment response was evaluated according to the "Guidelines for the Diagnosis and Treatment of Acute Lymphoblastic Leukemia in Chinese Adults" (2021 edition). Efficacy can be categorized as follows:

[0055] CR: ① No blast cells in peripheral blood, no extramedullary leukemia; ② Recovery of hematopoiesis in the bone marrow (three lineages), with blast cells <5%; ③ Absolute neutrophil count (ANC) >1.0×10⁻⁶. 9 / L; ④PLT>100×10 9 / L; ⑤ No recurrence within 4 weeks.

[0056] CRi:PLT≤100×10 9 / L and / or ANC ≤ 1.0 × 10 9 / L, the rest meet CR standards.

[0057] Overall reaction rate (ORR) = CR + Cri.

[0058] VI. Research Process

[0059] Four high-risk T-ALL patients admitted to the Department of Hematology, Sichuan Provincial People's Hospital from April 2023 to May 2024 were included in this study. One of them was refractory T-ALL. All patients received a dual-phenomenal, multi-target treatment regimen. Baseline data of the patients were collected through the electronic medical record system, and baseline characteristics of the enrolled patients were analyzed using SPSS 27.0 statistical software. Treatment response was assessed after 1-2 cycles of treatment with this regimen, and patients' treatment responses were observed. Follow-up was conducted through follow-up visits, telephone inquiries, and medical record reviews, and long-term survival was assessed based on the follow-up results.

[0060] VII. Test Results

[0061] The clinical trial results are shown in Table 1:

[0062] Table 1

[0063]

[0064] Note: CR: Complete remission; CRi: Complete remission with incomplete hematologic recovery; PR: Partial remission; MRD: Minimal residual disease.

[0065] Table 1 shows that 4 patients were enrolled and underwent 2 courses of treatment. All 4 patients achieved complete remission (CR), with a CR rate of 100%. 3 patients achieved MRD negativity, with an MRD negativity rate of 75%. The overall effective rate was 100% (4 / 4).

[0066] According to literature reports, the current efficacy rate for acute T-lymphoblastic leukemia is 20-30%, while the efficacy rate of this trial protocol can be increased to over 75%, bringing significant clinical benefits.

Claims

1. Use of chidamide or its derivatives in the preparation of a medicament for the prevention and / or treatment of T-lymphocytic leukemia in combination with verneclax or its derivatives and azacitidine or its derivatives.

2. The use as described in claim 1, wherein the derivative is selected from pharmaceutically acceptable salts, enantiomers, stereoisomers, or crystal forms of the active pharmaceutical ingredient; Preferably, the derivative of chidamide is selected from its pharmaceutically acceptable salt, crystal form A, or crystal form B.

3. The use of chidamide in the preparation of a medicament for the prevention and / or treatment of T-lymphocytic leukemia in combination with verneclax and azacitidine, as described in claim 1.

4. The use as described in any one of claims 1-3, wherein the T-lymphoblastic leukemia is acute T-lymphoblastic leukemia; Preferably, the acute T-lymphoblastic leukemia is high-risk acute T-lymphoblastic leukemia; Preferably, the high-risk acute T-lymphoblastic leukemia is newly diagnosed or relapsed / refractory. Preferably, the high-risk acute T-lymphoblastic leukemia is relapsed or refractory primary or secondary.

5. A pharmaceutical composition, characterized in that, It contains chidamide or its derivatives, veneclade or its derivatives, and azacitidine or its derivatives; Preferably, the derivative is selected from pharmaceutically acceptable salts, enantiomers, stereoisomers, or crystal forms of the active pharmaceutical ingredient. Preferably, the derivative of cidamide is selected from its pharmaceutically acceptable salt, crystal form A, or crystal form B; Preferably, the pharmaceutical composition comprises chidamide, veneclade, and azacitidine; Preferably, the mass ratio of chidamide or its derivative, veneclade or its derivative, and azacitidine or its derivative is 5-60:100-400:75-150; the preferred ratio is 10-30:400:150, based on the mass of chidamide, veneclade, and azacitidine, respectively.

6. The pharmaceutical composition of claim 5, for the prevention and / or treatment of T-lymphoblastic leukemia; Preferably, the T-lymphoblastic leukemia is acute T-lymphoblastic leukemia; Preferably, the acute T-lymphoblastic leukemia is high-risk acute T-lymphoblastic leukemia; Preferably, the high-risk acute T-lymphoblastic leukemia is newly diagnosed or relapsed / refractory. Preferably, the high-risk acute T-lymphoblastic leukemia is relapsed or refractory primary or secondary.

7. A pillbox comprising the pharmaceutical composition as described in claim 5 or 6; Preferably, the chidamide or its derivative, verneclade or its derivative, and azacitidine or its derivative are unit formulations with the same or different specifications; Preferably, the chidamide or its derivative, veneclade or its derivative, and azacitidine or its derivative are placed in the same container or in different containers. Preferably, chidamide is a gastrointestinal dosage form, and more preferably an oral formulation; Preferably, veneclade is a gastrointestinal dosage form, and more preferably an oral formulation; Preferably, azacitidine is a gastrointestinal or parenteral dosage form, preferably an oral or injectable formulation, and more preferably an injectable formulation.

8. A method for preventing and / or treating T-lymphoblastic leukemia, comprising administering to an individual in need a preventive and / or therapeutically effective amount of the pharmaceutical composition as described in claim 5; Preferably, the single dose of chidamide or its derivative is 5-60 mg, more preferably 10-30 mg, based on the mass of chidamide; Preferably, the single dose of veneclade or its derivative is 100-400 mg, preferably 400 mg, based on the mass of veneclade; Preferably, the single dose of azacitidine or its derivative is 75-150 mg, preferably 150 mg, based on the mass of azacitidine; Preferably, the chidamide or its derivative, veneclade or its derivative, and azacitidine or its derivative are administered simultaneously, separately, or sequentially. Preferably, the T-lymphoblastic leukemia is acute T-lymphoblastic leukemia; Preferably, the acute T-lymphoblastic leukemia is high-risk acute T-lymphoblastic leukemia; Preferably, the high-risk acute T-lymphoblastic leukemia is newly diagnosed or relapsed / refractory. Preferably, the high-risk acute T-lymphoblastic leukemia is relapsed or refractory primary or secondary.

Images