Venetoclax Dosing Regimen Used in Combination with Azacitidine to Treat Myelodysplastic Syndromes

Abstract

The invention described herein relates to a therapeutic dosing regimen comprising administering venetoclax in combination with azacitidine for treating myelodysplastic syndromes (MDS).

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 201,749, filed May 11, 2021, the disclosure of which is incorporated by reference in its entirety herein.

[0002] The present invention relates to a method of treating myelodysplastic syndrome (MDS) in a human subject, comprising administering venetoclax in combination with azacitidine to the subject. [Background technology]

[0003] Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders with significant morbidity and high mortality. These syndromes are characterized by ineffective hematopoiesis, which manifests clinically as cytopenias and as transformation to acute myeloid leukemia (secondary or sAML) at various rates. Although approximately one-third of MDS patients subsequently develop AML, MDS is not considered to be the primary form of AML. The main cause of death in MDS patients is not AML transformation but bone marrow failure, particularly neutropenia leading to infections, including pulmonary hemorrhagic shock, or thrombocytopenia leading to bleeding.

[0004] Approximately half (45%) of MDS patients present with high MDS risk (International Prognostic Scoring System (IPSS) composite score >1.5) and have a median survival of less than 1 year with best supportive care. The only curative treatment for high-risk MDS is allogeneic stem cell or bone marrow transplantation. However, not all patients are eligible for this intensive treatment approach. When bone marrow transplantation is not possible, patients are usually treated with hypomethylating agents such as azacitidine. Currently, azacitidine is the only drug shown to extend survival in treatment-naive high-risk MDS, but overall results need to be improved.

[0005] Venetoclax is an oral small molecule inhibitor of B-cell lymphoma 2 (BCL-2) that rapidly induces multiple hallmarks of apoptotic cell death. Venetoclax has been investigated in clinical oncology studies as a monotherapy and in combination with various compounds for the treatment of a number of hematological malignancies, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, the dosing regimen used in the first clinical trial of venetoclax in MDS caused adverse side effects in certain patients. For example, two subjects developed fatal sepsis in the setting of severe neutropenia. Thus, there is a need in the art for dosing regimens for MDS patients who experience certain side effects. Summary of the Invention [Problem to be solved by the invention]

[0006] (Brief Summary of the Invention) The present disclosure relates to methods of treating myelodysplastic syndromes in human subjects, and in some embodiments, more particularly to methods of treating treatment-naïve high-risk myelodysplastic syndromes. [Means for solving the problem]

[0007] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75 × 10 / L or <75 × 10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% in the next 28-day dosing cycle. In some embodiments, the daily azacitidine dose is reduced according to bone marrow cellularity, absolute neutrophil count nadir decline, white blood cell count nadir decline, and platelet count nadir decline.

[0008] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, comprising administering to the human subject 75 mg / m 2 The daily azacitidine dose is reduced by ≦50% but not less than 33% in the next 28-day dosing cycle. 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75 × 10 / L or <75 × 10 9 / L. The human subject has no improvement in cell line differentiation, and the human subject has at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. In some embodiments, the daily dose of azacitidine is reduced according to bone marrow cellularity.

[0009] In certain embodiments, a method of treating myelodysplastic syndromes in a human subject is provided. The method comprises administering 400 mg of venetoclax per day for 14 days of a 28-day dosing cycle and 75 mg / m 2 of azacitidine per day for 7 days of a 28-day dosing cycle to the human subject, wherein the human subject has a baseline absolute neutrophil count of ≧1.5×10 9 / L, a baseline white blood cell count of ≧3×10 9 / L or a baseline platelet count of ≧75×10 9 / L and has at least one of the conditions selected from the group consisting of an absolute neutrophil count nadir of ≦1.5×10 9 / L and a platelet count nadir of ≦50×10 9 / L, the daily dose of azacitidine is reduced in the next 28-day dosing cycle to be ≦67% but ≧50% of 75 mg / m 2 .

[0010] In certain embodiments, a method of treating myelodysplastic syndromes in a human subject, the method comprising administering 400 mg of venetoclax per day for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle to the human subject, wherein the daily dose of azacitidine is reduced to 50% of 75 mg / m 2 in the next 28-day dosing cycle. The human subject has a baseline absolute neutrophil count of ≧1.5×10 9 / L, a baseline white blood cell count of ≧3×10 9 / L or a baseline platelet count of ≧75×10 9 / L. The human subject also has at least one of the conditions selected from the group consisting of an absolute neutrophil count nadir of ≦1.0×10 9 / L and a platelet count nadir of ≦50×10 9 / L.

[0011] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to ≦50 mg / m 2 However, 36 mg / m 2 Human subjects will be reduced to ≥ 1.5 × 10 9 Baseline absolute neutrophil count ≥ 75 × 10 / L or 9 / L and already have a complete, partial or complete marrow response at the start of the previous treatment cycle. 9 / L neutrophil count nadir, baseline platelets >100 × 10 9 / L, ≦50×10 9 / L platelet count nadir and baseline platelets ≤ 100 × 10 9 / L, <50% platelet count nadir. [Brief description of the drawings]

[0012] [Figure 1] Plot of mean absolute neutrophil counts by study day cycle. Number of observations are shown in Table 11. [Diagram 2] Plot of mean platelet counts by study day cycle. Number of observations are shown in Table 11. [Figure 3A] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3B]3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3C] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3D] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3E] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 3F] 3 is a bar graph of hematologic toxicities showing the number of patients with worsening common terminology criteria grade versus baseline per cycle. Table 3A is anemia. Table 3B is febrile neutropenia. Table 3C is leukopenia. Table 3D is neutropenia. Table 3E is thrombocytopenia. Table 3F is infection. [Figure 4A] 4A-4C are bar graphs of gastrointestinal toxicity showing the number of patients with Common Terminology Criteria grade deterioration versus baseline per cycle. FIG. 4A is diarrhea. FIG. 4B is vomiting. FIG. 4C is nausea. [Figure 4B] 4A-4C are bar graphs of gastrointestinal toxicity showing the number of patients with Common Terminology Criteria grade deterioration versus baseline per cycle. FIG. 4A is diarrhea. FIG. 4B is vomiting. FIG. 4C is nausea. [Figure 4C] 4A-4C are bar graphs of gastrointestinal toxicity showing the number of patients with Common Terminology Criteria grade deterioration versus baseline per cycle. FIG. 4A is diarrhea. FIG. 4B is vomiting. FIG. 4C is nausea. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present disclosure relates to a method of treating treatment-naïve, higher-risk myelodysplastic syndrome (MDS) in a human subject, comprising administering to the subject venetoclax in combination with azacitidine.

[0014] While venetoclax has been administered to patients with AML (sAML) with a prior history of MDS, this is the first disclosure to evaluate venetoclax in combination with azacitidine in subjects with MDS, and more specifically in subjects with treatment-naïve high-risk MDS, with the dosing regimen modified according to subjects who develop hematologic toxicity after initiation of treatment. Apart from the toxicity-specific dosing modifications disclosed herein, other significant differences for the administration of venetoclax in combination with azacitidine for MDS versus AML include a reduction in the duration of venetoclax administration from 28 days to 14 days in the 28-day cycle for MDS, as well as the absence of any dosing escalation in subjects with MDS.

[0015] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% in the next 28-day dosing cycle.

[0016] "Venetoclax" is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide. Venetoclax is a selective Bcl-2 inhibitor approved for adult patients with CLL and adult patients with newly diagnosed AML who are 75 years of age or older or who are ineligible for intensive induction chemotherapy.

[0017] Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. It is supplied in a sterile form to be reconstituted as a suspension for subcutaneous injection or as a solution that is further diluted for intravenous infusion.

[0018] The term "AE" as used herein refers to adverse event.

[0019] The term "AML," as used herein, refers to acute myeloid leukemia.

[0020] The term "ANC" as used herein refers to absolute neutrophil count.

[0021] The term "CLL" as used herein refers to chronic lymphocytic leukemia.

[0022] The term "CML" as used herein refers to chronic myeloid leukemia.

[0023] The term "CMML" as used herein refers to chronic myelomonocytic leukemia.

[0024] The term "CR" as used herein refers to complete response.

[0025] The term "CTC" as used herein refers to Common Terminology Criteria.

[0026] The term "ECOG" as used herein refers to the Eastern Cooperative Oncology Group.

[0027] The term "G-CSF" as used herein refers to granulocyte colony stimulating factor.

[0028] The term "HRQoL" as used herein refers to health-related quality of life.

[0029] The term "HMA" as used herein refers to a hypomethylating agent.

[0030] The term "HR-MDS" as used herein refers to high-risk myelodysplastic syndromes.

[0031] The term "IPSS" as used herein refers to the International Prognostic Scoring System.

[0032] The term "IPSS-R" as used herein refers to the Revised International Prognostic Scoring System.

[0033] The term "JMML" as used herein refers to juvenile myelomonocytic leukemia.

[0034] The term "mCR" as used herein refers to complete bone marrow remission.

[0035] The term "MDS" as used herein refers to myelodysplastic syndromes.

[0036] The term "MPN" as used herein refers to myeloproliferative neoplasms.

[0037] The term "OS" as used herein refers to overall survival.

[0038] The term "PR" as used herein refers to partial response.

[0039] The term "RAEB" as used herein refers to refractory anemia with excess blasts.

[0040] The term "sAML" as used herein refers to secondary acute myeloid leukemia.

[0041] The term "SE1" as used herein refers to Safety Expansion Cohort 1.

[0042] The term "SE2" as used herein refers to safety expansion cohort 2.

[0043] The term "TEAE" as used herein refers to treatment-emergent adverse events.

[0044] The term "tMDS" as used herein refers to treatment-related or therapy-related myelodysplastic syndrome.

[0045] Lack of improvement in cell line differentiation refers to a lack of clear improvement in cell differentiation at the time of the next cycle, e.g., a lower percentage of mature granulocytes and a lower absolute neutrophil count than at the start of the treatment cycle.

[0046] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% in the next 28-day dosing cycle.

[0047] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2 The daily azacitidine dose is reduced to 75% in the next 28 day dosing cycle, the human subject has 30-60% bone marrow cellularity, and the human subject has at least one of the conditions selected from the group consisting of: absolute neutrophil count nadir decrease of ≧75% from baseline absolute neutrophil count, white blood cell count nadir decrease of ≧75% from baseline white blood cell count, and platelet count nadir decrease of >75% from baseline platelet count. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0048] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2the daily dose of azacitidine is reduced to 75% in a next 28 day dosing cycle, the human subject has a bone marrow cellularity of 30-60%, the human subject has at least one of the conditions selected from the group consisting of a ≥ 75% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥ 75% decrease in white blood cell count nadir from baseline white blood cell count, and a > 75% decrease in platelet count nadir from baseline platelet count, and the human subject has at least one of the conditions selected from the group consisting of a next absolute neutrophil count above the neutrophil count nadir and that is ≤ 25% of the difference between the baseline absolute neutrophil count and the neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and that is ≤ 25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and that is ≤ 25% of the difference between the baseline platelet count and the platelet count nadir prior to the start of the next 28 day dosing cycle. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In yet other embodiments, the method further comprises a delay of ≧1 day before the next 28-day administration cycle.

[0049] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle.2 the daily dose of azacitidine is reduced to 75% in a next 28 day dosing cycle, the human subject has bone marrow cellularity of 30-60%, the human subject has at least one of the conditions selected from the group consisting of a ≥ 75% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥ 75% decrease in white blood cell count nadir from baseline white blood cell count, and a > 75% decrease in platelet count nadir from baseline platelet count, and the human subject maintains a next absolute neutrophil count above the neutrophil count nadir and that is ≤ 25% of the difference between the baseline absolute neutrophil count and the neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and that is ≤ 25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and that is ≤ 25% of the difference between the baseline white blood cell count and the white blood cell count nadir prior to the start of the next 28 day dosing cycle. and a subsequent platelet count that is ≦25% of the difference between the baseline platelet count and the platelet count nadir, and the daily dose of 400 mg of venetoclax is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle, and the human subject has, prior to the start of the subsequent 28-day dosing cycle, at least one of the conditions selected from the group consisting of a subsequent absolute neutrophil count above the absolute neutrophil count nadir and ≦25% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, a subsequent white blood cell count above the white blood cell count nadir and ≦25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a subsequent platelet count above the platelet count nadir and ≦25% of the difference between the baseline platelet count and the platelet count nadir. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of ≧1 day before the subsequent 28 day administration cycle.In still other embodiments, the method further comprises a delay of ≧1 day before the next 28 day administration cycle, and further comprises a delay of ≧1 day before the subsequent 28 day administration cycle.

[0050] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2 The daily dose of azacitidine is reduced to 50% in the next 28 day dosing cycle, the human subject has bone marrow cellularity of 15 to <30%, and the human subject has at least one of the conditions selected from the group consisting of: absolute neutrophil count nadir decrease of ≧50% from baseline absolute neutrophil count, white blood cell count nadir decrease of ≧50% from baseline white blood cell count, and platelet count nadir decrease of ≧50% from baseline platelet count. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0051] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2 the daily dose of azacitidine is reduced to 50% in a next 28 day dosing cycle, the human subject has a bone marrow cellularity of 15 to <30%, the human subject has at least one of the conditions selected from the group consisting of a ≥ 50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥ 50% decrease in white blood cell count nadir from baseline white blood cell count, and a ≥ 50% decrease in platelet count nadir from baseline platelet count, and the human subject has at least one of the conditions selected from the group consisting of a next absolute neutrophil count above the neutrophil count nadir and that is ≤ 25% of the difference between the baseline absolute neutrophil count and the neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and that is ≤ 25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and that is ≤ 25% of the difference between the baseline platelet count and the platelet count nadir prior to the start of the next 28 day dosing cycle. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In yet other embodiments, the method further comprises a delay of ≧1 day before the next 28-day administration cycle.

[0052] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 109 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2the daily dose of azacitidine is reduced by 50% in the next 28 day dosing cycle, the human subject has bone marrow cellularity of 15 to <30%, the human subject has at least one of the conditions selected from the group consisting of a ≥ 50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥ 50% decrease in white blood cell count nadir from baseline white blood cell count, and a ≥ 50% decrease in platelet count nadir from baseline platelet count, and the human subject achieves a next absolute neutrophil count above the neutrophil count nadir and that is ≤ 25% of the difference between the baseline absolute neutrophil count and the neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and that is ≤ 25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and that is ≤ 25% of the difference between the baseline white blood cell count and the white blood cell count nadir prior to the start of the next 28 day dosing cycle. and a subsequent platelet count that is ≦25% of the difference between the baseline platelet count and the platelet count nadir, and the daily dose of 400 mg venetoclax is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle, and the human subject has, prior to the start of the subsequent 28-day dosing cycle, at least one of the conditions selected from the group consisting of a subsequent absolute neutrophil count above the absolute neutrophil count nadir and ≦25% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, a subsequent white blood cell count above the white blood cell count nadir and ≦25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a subsequent platelet count above the platelet count nadir and ≦25% of the difference between the baseline platelet count and the platelet count nadir. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of ≧1 day before the subsequent 28 day administration cycle.In still other embodiments, the method further comprises a delay of ≧1 day before the next 28 day administration cycle, and further comprises a delay of ≧1 day before the subsequent 28 day administration cycle.

[0053] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2 The daily dose of azacitidine is reduced to 50% in the next 28-day dosing cycle, the human subject has bone marrow cellularity of 15 to <30%, the human subject has at least one of the conditions selected from the group consisting of a ≥50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥50% decrease in white blood cell count nadir from baseline white blood cell count, and a ≥50% decrease in platelet count nadir from baseline platelet count, and the human subject has at least one of the conditions selected from the group consisting of a >75% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a >75% decrease in white blood cell count nadir from baseline white blood cell count, and a >75% decrease in platelet count nadir from baseline platelet count. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0054] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2 The daily dose of azacitidine is reduced to 50% in the next 28 day dosing cycle, the human subject has bone marrow cellularity of 15 to <30%, the human subject has at least one of the conditions selected from the group consisting of a ≥50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥50% decrease in white blood cell count nadir from baseline white blood cell count, and a ≥50% decrease in platelet count nadir from baseline platelet count, the human subject has at least one of the conditions selected from the group consisting of a 50-75% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a 50-75% decrease in white blood cell count nadir from baseline white blood cell count, and a 50-75% decrease in platelet count nadir from baseline platelet count. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0055] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2 The daily dose of azacitidine is reduced to 33% in the next 28-day dosing cycle, the human subject has <15% bone marrow cellularity, and the human subject has at least one of the conditions selected from the group consisting of: absolute neutrophil count nadir decrease of ≧50% from baseline absolute neutrophil count, white blood cell count nadir decrease of ≧50% from baseline white blood cell count, and platelet count nadir decrease of ≧50% from baseline platelet count. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0056] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2 the daily dose of azacitidine is reduced to 33% in the next 28 day dosing cycle, the human subject has a bone marrow cellularity of <15%, the human subject has at least one of the conditions selected from the group consisting of a ≧50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≧50% decrease in white blood cell count nadir from baseline white blood cell count, and a ≧50% decrease in platelet count nadir from baseline platelet count, and the human subject has at least one of the conditions selected from the group consisting of a next absolute neutrophil count above the absolute neutrophil count nadir and that is ≦25% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and that is ≦25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and that is ≦25% of the difference between the baseline platelet count and the platelet count nadir prior to the start of the next 28 day dosing cycle. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In yet other embodiments, the method further comprises a delay of ≧1 day before the next 28-day administration cycle.

[0057] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 109 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2the daily dose of azacitidine is reduced to 33% in the next 28 day dosing cycle, the human subject has <15% bone marrow cellularity, the human subject has at least one of the conditions selected from the group consisting of a ≥50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥50% decrease in white blood cell count nadir from baseline white blood cell count, and a ≥50% decrease in platelet count nadir from baseline platelet count, and the human subject achieves a next absolute neutrophil count above the neutrophil count nadir and that is ≤25% of the difference between the baseline absolute neutrophil count and the neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and that is ≤25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and that is ≤25% of the difference between the baseline white blood cell count and the white blood cell count nadir, prior to the start of the next 28 day dosing cycle. and a subsequent platelet count that is ≦25% of the difference between the line platelet count and the platelet count nadir, and the daily dose of 400 mg venetoclax is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle, and the human subject has at least one of the following conditions selected from the group consisting of a subsequent absolute neutrophil count above the neutrophil count nadir and >25% of the difference between the baseline absolute neutrophil count and the neutrophil count nadir, a subsequent white blood cell count above the white blood cell count nadir and >25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a subsequent platelet count above the platelet count nadir and >25% of the difference between the baseline platelet count and the platelet count nadir prior to the start of the subsequent 28-day dosing cycle. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of ≧1 day before the subsequent 28 day administration cycle.In still other embodiments, the method further comprises a delay of ≧1 day before the next 28 day administration cycle, and further comprises a delay of ≧1 day before the subsequent 28 day administration cycle.

[0058] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2the daily dose of azacitidine is reduced to 33% in the subsequent 28 day dosing cycle, the human subject has <15% bone marrow cellularity, the human subject has at least one of the conditions selected from the group consisting of a ≥50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥50% decrease in white blood cell count nadir from baseline white blood cell count, and a ≥50% decrease in platelet count nadir from baseline platelet count, and the daily dose of 400 mg venetoclax is reduced to 33% in the subsequent 28 day dosing cycle, and the human subject has at least one of the following conditions selected from the group consisting of: a subsequent absolute neutrophil count above the neutrophil count nadir and >25% of the difference between the baseline absolute neutrophil count and the neutrophil count nadir, a subsequent white blood cell count above the white blood cell count nadir and >25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a subsequent platelet count above the platelet count nadir and >25% of the difference between the baseline platelet count and the platelet count nadir prior to the start of a subsequent 28-day administration cycle. In some embodiments, the azacitidine is administered intravenously. In other embodiments, the azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of ≥1 day prior to the subsequent 28-day administration cycle. In still other embodiments, the method further comprises a delay of ≥1 day prior to the next 28-day administration cycle, and further comprises a delay of ≥1 day prior to the subsequent 28-day administration cycle.

[0059] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2 The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2 The daily dose of azacitidine is reduced to 33% in the next 28-day dosing cycle, the human subject has a bone marrow cellularity of <15%, the human subject has at least one of the conditions selected from the group consisting of a ≥50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥50% decrease in white blood cell count nadir from baseline white blood cell count, and a ≥50% decrease in platelet count nadir from baseline platelet count, and the human subject has at least one of the conditions selected from the group consisting of a >75% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a >75% decrease in white blood cell count nadir from baseline white blood cell count, and a >75% decrease in platelet count from baseline platelet count. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0060] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, no improvement in cell line differentiation, and at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir. 2The daily azacitidine dose is reduced by ≦75% but not less than 33% to 75 mg / m2 in the next 28-day dosing cycle. 2 The daily azacitidine dose is reduced to 33% in the next 28 day dosing cycle, the human subject has <15% bone marrow cellularity, the human subject has at least one of the conditions selected from the group consisting of a ≥50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a ≥50% decrease in white blood cell count nadir from baseline white blood cell count, and a ≥50% decrease in platelet count nadir from baseline platelet count, the human subject has at least one of the conditions selected from the group consisting of a 50-75% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count, a 50-75% decrease in white blood cell count nadir from baseline white blood cell count to white blood cell count nadir, and a 50-75% decrease in platelet count nadir from baseline platelet count. In some embodiments, the azacitidine is administered intravenously. In other embodiments, the azacitidine is administered subcutaneously.

[0061] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 is reduced by ≦50% but not less than 33% in the next 28-day dosing cycle, and human subjects are <1.5×10 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, the human subject has no improvement in cell line differentiation, and the human subject has at least one of the conditions selected from the group consisting of a ≧50% reduction in absolute neutrophil count nadir, a ≧50% reduction in white blood cell count nadir, and a ≧50% reduction in platelet count nadir.

[0062] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 is reduced by ≦50% but not less than 33% in the next 28-day dosing cycle, and human subjects are <1.5×10 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, the human subject has no improvement in cell line differentiation, and the human subject has at least one of the conditions selected from the group consisting of a ≧50% reduction in absolute neutrophil count nadir, a ≧50% reduction in white blood cell count nadir, and a ≧50% reduction in platelet count nadir.

[0063] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 is reduced by ≦50% but not less than 33% in the next 28-day dosing cycle, and human subjects are <1.5×10 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, the human subject has no improvement in cell line differentiation, the human subject has at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir, and is receiving a daily dose of 75 mg / m2 of azacitidine. 2is reduced to 50% in the next 28 day dosing cycle and the human subject has bone marrow cellularity of 15-50%. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0064] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, comprising administering to the human subject 75 mg / m 2 The daily azacitidine dose is reduced by ≦50% but not less than 33% in the next 28-day dosing cycle, and the human subject receives <1.5×10 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, the human subject has no improvement in cell line differentiation, the human subject has at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir, 2 the daily dose of azacitidine is reduced by 50% but not less than 33% in the next 28 day administration cycle, the human subject has a bone marrow cellularity of 15-50%, and the human subject has at least one of the following conditions selected from the group consisting of a next increase in absolute neutrophil count above the absolute neutrophil count nadir and <50% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next increase in white blood cell count above the white blood cell count nadir and <50% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next increase in platelet count above the platelet count nadir and <50% of the difference between the baseline platelet count and the platelet count nadir prior to the start of the next 28 day administration cycle. In some embodiments, the azacitidine is administered intravenously. In other embodiments, the azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of ≧1 day prior to the next 28 day administration cycle.

[0065] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, comprising administering to the human subject 75 mg / m 2 The daily azacitidine dose is reduced by ≦50% but not less than 33% in the next 28-day dosing cycle, and the human subject receives <1.5×10 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, the human subject has no improvement in cell line differentiation, the human subject has at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir, 2the daily dose of azacitidine is reduced by 50% in a next 28 day dosing cycle, the human subject having a bone marrow cellularity of 15-50%, and the human subject, prior to the start of the next 28 day dosing cycle, experiencing at least one of the following conditions selected from the group consisting of an increase in absolute neutrophil count above the absolute neutrophil count nadir and <50% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, an increase in white blood cell count above the white blood cell count nadir and <50% of the difference between the baseline white blood cell count and the white blood cell count nadir, and an increase in platelet count above the platelet count nadir and <50% of the difference between the baseline platelet count and the platelet count nadir. and the daily dose of 400 mg of venetoclax is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle, and the human subject has at least one of the following conditions selected from the group consisting of: absolute neutrophil count above absolute neutrophil count nadir and a subsequent white blood cell count above white blood cell count nadir and a subsequent white blood cell count above white blood cell count nadir and a subsequent platelet count above platelet count nadir and a subsequent platelet count above platelet count nadir and a subsequent platelet count above platelet count nadir and a subsequent platelet count above platelet count nadir. In some embodiments, the azacitidine is administered intravenously. In other embodiments, the azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of ≧1 day before the subsequent 28-day dosing cycle. In still other embodiments, the method further comprises a delay of ≧1 day before the next 28 day administration cycle, and further comprises a delay of ≧1 day before the subsequent 28 day administration cycle.

[0066] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2is then reduced by ≦50% but not less than 33% in a 28-day dosing cycle, and human subjects are <1.5×10 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, the human subject has no improvement in cell line differentiation, the human subject has at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir, and is receiving a daily dose of 75 mg / m2 of azacitidine. 2 is reduced to 33% in the next 28 day dosing cycle and the human subject has <15% bone marrow cellularity. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0067] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, comprising administering to the human subject 75 mg / m 2 The daily azacitidine dose is reduced by ≦50% but not less than 33% in the next 28-day dosing cycle, and the human subject receives <1.5×10 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, the human subject has no improvement in cell line differentiation, the human subject has at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir, 2 The daily azacitidine dose was reduced by 33% to 75 mg / m in the next 28-day treatment cycle. 2The daily dose of azacitidine is reduced to 33% in the next 28-day administration cycle, the human subject has a bone marrow cellularity of <15%, and the human subject has at least one of the following conditions selected from the group consisting of a next absolute neutrophil count increase above the absolute neutrophil count nadir and <50% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count increase above the white blood cell count nadir and <50% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count increase above the platelet count nadir and <50% of the difference between the baseline platelet count and the platelet count nadir prior to the start of the next 28-day administration cycle. In some embodiments, the azacitidine is administered intravenously. In other embodiments, the azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of ≧1 day prior to the next 28-day administration cycle.

[0068] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of azacitidine for 7 days of a 28-day dosing cycle, comprising administering to the human subject 75 mg / m 2 The daily azacitidine dose is reduced by ≦50% but not less than 33% in the next 28-day dosing cycle, and the human subject receives <1.5×10 9 Baseline absolute neutrophil count / L, <3 × 10 9 Baseline white blood cell count <75×10 / L or <75×10 9 / L, the human subject has no improvement in cell line differentiation, the human subject has at least one of the conditions selected from the group consisting of a ≥ 50% reduction in absolute neutrophil count nadir, a ≥ 50% reduction in white blood cell count nadir, and a ≥ 50% reduction in platelet count nadir, 2the daily dose of azacitidine is reduced to 33% in a next 28 day dosing cycle, the human subject has <15% bone marrow cellularity, and the human subject, prior to the start of the next 28 day dosing cycle, experiences at least one of the following conditions selected from the group consisting of: an increase in absolute neutrophil count above the absolute neutrophil count nadir and <50% relative to the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir; an increase in white blood cell count above the white blood cell count nadir and <50% relative to the difference between the baseline white blood cell count and the white blood cell count nadir; and an increase in platelet count above the platelet count nadir and <50% relative to the difference between the baseline platelet count and the platelet count nadir. and a daily dose of 400 mg of venetoclax is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle, and the human subject has at least one of the following conditions selected from the group consisting of: an absolute neutrophil count above the absolute neutrophil count nadir and a subsequent white blood cell count that is <50% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, an absolute white blood cell count above the white blood cell count nadir and a subsequent platelet count that is <50% of the difference between the baseline white blood cell count and the white blood cell count nadir, and an absolute platelet count above the platelet count nadir and a subsequent platelet count that is <50% of the difference between the baseline platelet count and the platelet count nadir prior to the start of the subsequent 28-day dosing cycle. In some embodiments, the azacitidine is administered intravenously. In other embodiments, the azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of ≧1 day prior to the subsequent 28-day dosing cycle. In still other embodiments, the method further comprises a delay of ≧1 day before the next 28 day administration cycle, and further comprises a delay of ≧1 day before the subsequent 28 day administration cycle.

[0069] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28 day dosing cycle, 9 Baseline absolute neutrophil count ≥ 3 × 10 / L 9 Baseline white blood cell count of ≥ 75 × 10 / L or 9has a baseline platelet count of / L and ≤ 1.5 × 10 9 the absolute neutrophil count nadir of / L and ≤ 50 × 10 9 / L platelet count nadir, when having at least one of the conditions selected from the group consisting of, the daily dose of azacitidine is reduced from 75 mg / m in the next 28-day dosing cycle 2 to ≤ 67% but ≥ 50%.

[0070] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, the myelodysplastic syndrome being treatment-naive high-risk myelodysplastic syndrome. The method includes administering to the human subject a daily dose of 400 mg of venetoclax over 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine over 7 days of a 28-day dosing cycle, wherein the human subject has a baseline absolute neutrophil count of ≥ 1.5 × 10 9 / L, a baseline white blood cell count of ≥ 3 × 10 9 / L or a baseline platelet count of ≥ 75 × 10 9 / L and, when having at least one of the conditions selected from the group consisting of a nadir absolute neutrophil count of ≤ 1.5 × 10 9 / L and a nadir platelet count of ≤ 50 × 10 9 / L, the daily dose of azacitidine is reduced from 75 mg / m in the next 28-day dosing cycle 2 to ≤ 67% but ≥ 50%.

[0071] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, the myelodysplastic syndrome being treatment-naive high-risk myelodysplastic syndrome. The method includes administering to the human subject a daily dose of 400 mg of venetoclax over 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine over 7 days of a 28-day dosing cycle, wherein the human subject has a baseline absolute neutrophil count of ≥ 1.5 × 10 9 / L, a baseline white blood cell count of ≥ 3 × 10 9 / L or a baseline platelet count of ≥ 75 × 10 9has a baseline platelet count of / L and ≤ 1.5×10 9 the absolute neutrophil count nadir of / L and ≤ 50×10 9 / L of the platelet count nadir, when having at least one of the states selected from the group consisting of, the daily dose of azacitidine is, in the next 28-day administration cycle, 75 mg / m 2 from ≤ 67% but reduced by 50% or more, the daily dose of azacitidine is reduced from 75 mg / m 2 to 67%, and the human subject has an absolute neutrophil count nadir of 0.5×10 9 / L to 1.5×10 9 / L and a platelet count nadir of 25×10 9 / L to 50×10 9 / L, and has at least one of the states selected from the group consisting of. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0072] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, the myelodysplastic syndrome being treatment-naive high-risk myelodysplastic syndrome. The method comprises administering to the human subject a daily dose of 400 mg of venetoclax over 14 days of a 28-day administration cycle and a daily dose of 75 mg / m 2 of azacitidine over 7 days of a 28-day administration cycle, wherein the human subject has a baseline absolute neutrophil count of ≥ 1.5×10 9 / L, a baseline white blood cell count of ≥ 3×10 9 / L or a baseline platelet count of ≥ 75×10 9 / L and has at least one of the states selected from the group consisting of a nadir absolute neutrophil count of ≤ 1.5×10 9 / L and a nadir platelet count of ≤ 50×10 9 / L, when having at least one of the states selected from the group consisting of, the daily dose of azacitidine is, in the next 28-day administration cycle, 75 mg / m 2 from ≤ 67% but reduced by 50% or more, the daily dose of azacitidine is reduced from 75 mg / m 2 to 67%, and the human subject has an absolute neutrophil count nadir of 0.5×10 9 / L ~ 1.5×10 9 / L and the platelet count nadir is 25×10 9 / L ~ 50×10 9 / L, having at least one of the states selected from the group consisting of, the human subject, prior to the start of the following 28-day dosing cycle, ≤ 1.5×10 9 / L of the following absolute neutrophil count and ≤ 50×10 9 / L of the following platelet count, having at least one of the states selected from the group consisting of. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In still other embodiments, the method further includes a delay of ≥ 1 day prior to the following 28-day dosing cycle.

[0073] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, the myelodysplastic syndrome being treatment-naive high-risk myelodysplastic syndrome. The method includes administering to the human subject a daily dose of 400 mg of venetoclax over 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine over 7 days of a 28-day dosing cycle, the human subject having a baseline absolute neutrophil count of ≥ 1.5×10 9 / L, a baseline white blood cell count of ≥ 3×10 9 / L or a baseline platelet count of ≥ 75×10 9 / L, having at least one of the states selected from the group consisting of an absolute neutrophil count nadir of ≤ 1.5×10 9 / L and a platelet count nadir of ≤ 50×10 9 / L, when the daily dose of azacitidine is reduced by ≤ 67% but ≥ 50% from 75 mg / m 2 in the next 28-day dosing cycle, the daily dose of azacitidine is reduced to 67% from 75 mg / m 2 and the human subject has an absolute neutrophil count nadir of 0.5×10 9 / L ~ 1.5×10 9 / L and the platelet count nadir is 25×10 9 / L ~ 50×10 9Having at least one of the states selected from the group consisting of, a human subject has, prior to the start of the next 28-day dosing cycle, ≤ 1.5 × 10 9 / L of the following absolute neutrophil count and ≤ 50 × 10 9 / L of the following platelet count, having at least one of the states selected from the group consisting of, the 400 mg daily dose of venetoclax is reduced from 14 days to 7 days in the subsequent 28-day dosing cycle, and a human subject has, prior to the start of the subsequent 28-day dosing cycle, ≤ 1.5 × 10 9 / L of the subsequent absolute neutrophil count and ≤ 50 × 10 9 / L of the subsequent platelet count. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In still other embodiments, the method further includes a delay of ≥ 1 day prior to the subsequent 28-day dosing cycle. In still other embodiments, the method further includes a delay of ≥ 1 day prior to the next 28-day dosing cycle and a delay of ≥ 1 day prior to the subsequent 28-day dosing cycle.

[0074] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, the myelodysplastic syndrome being treatment-naive high-risk myelodysplastic syndrome. The method includes administering to the human subject a 400 mg daily dose of venetoclax over 14 days of a 28-day dosing cycle and a 75 mg / m 2 of azacitidine over 7 days of a 28-day dosing cycle, the human subject having ≥ 1.5 × 10 9 / L of baseline absolute neutrophil count, ≥ 3 × 10 9 / L of baseline white blood cell count or ≥ 75 × 10 9 / L of baseline platelet count, and having at least one of the states selected from the group consisting of ≤ 1.5 × 10 9 / L of the nadir absolute neutrophil count and ≤ 50 × 10 9 / L of the nadir platelet count, the daily dose of azacitidine is reduced to ≤ 67% but ≥ 50% from 75 mg / m 2 in the next 28-day dosing cycle, and the daily dose of azacitidine is 75 mg / m2 is reduced to 50% from, and the human subject has at least one of the states selected from the group consisting of an absolute neutrophil count nadir of <0.5×10 9 / L and a platelet count nadir of <25×10 9 / L. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously.

[0075] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, the myelodysplastic syndrome being treatment-naive high-risk myelodysplastic syndrome. The method includes administering to the human subject a 400 mg dose of venetoclax over 14 days of a 28-day dosing cycle and a 75 mg / m 2 dose of azacitidine over 7 days of a 28-day dosing cycle, the human subject having a baseline absolute neutrophil count of ≧1.5×10 9 / L, a baseline white blood cell count of ≧3×10 9 / L or a baseline platelet count of ≧75×10 9 / L, and having at least one of the states selected from the group consisting of an absolute neutrophil count nadir of ≦1.5×10 9 / L and a platelet count nadir of ≦50×10 9 / L, wherein the daily dose of azacitidine is reduced to ≦67% but 50% or more from 75 mg / m 2 in the next 28-day dosing cycle, the daily dose of azacitidine is reduced to 50% from 75 mg / m 2 , the human subject has at least one of the states selected from the group consisting of an absolute neutrophil count nadir of <0.5×10 9 / L and a platelet count nadir of <25×10 9 / L, and the human subject has a next absolute neutrophil count of ≦1.5×10 9 / L and a next platelet count of ≦50×10 9It has at least one of the states selected from the group consisting of the following platelet counts per μL. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In still other embodiments, the method further includes a delay of ≧1 day prior to the following 28-day dosing cycle.

[0076] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, where the myelodysplastic syndrome is treatment-naive high-risk myelodysplastic syndrome. The method includes administering to the human subject a 1-day dose of 400 mg of venetoclax over 14 days of a 28-day dosing cycle and a 1-day dose of 75 mg / m 2 of azacitidine over 7 days of a 28-day dosing cycle, wherein the human subject has a baseline absolute neutrophil count of ≧1.5×10 9 / μL, a baseline white blood cell count of ≧3×10 9 / μL or a baseline platelet count of ≧75×10 9 / μL, and has at least one of the states selected from the group consisting of an absolute neutrophil count nadir of ≦1.5×10 9 / μL and a platelet count nadir of ≦50×10 9 / μL, in which case the 1-day dose of azacitidine is reduced by ≦67% but by 50% or more from 75 mg / m 2 in the next 28-day dosing cycle, the 1-day dose of azacitidine is reduced to 50% from 75 mg / m 2 , the human subject has at least one of the states selected from the group consisting of an absolute neutrophil count nadir of <0.5×10 9 / μL and a platelet count nadir of <25×10 9 / μL, the human subject has at least one of the states selected from the group consisting of the next absolute neutrophil count of ≦1.5×10 9 / μL and the next platelet count of ≦50×10 9 / μL prior to the start of the next 28-day dosing cycle, the 1-day dose of 400 mg of venetoclax is reduced from 14 days to 7 days in subsequent 28-day dosing cycles, and the human subject has at least one of the states selected from the group consisting of the next absolute neutrophil count of ≦1.5×10 9 / L and subsequent absolute neutrophil count ≤ 50 × 10 9 / L and subsequent platelet count. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of ≧1 day before the subsequent 28 day administration cycle. In still other embodiments, the method further comprises a delay of ≧1 day before the next 28 day administration cycle and further comprises a delay of ≧1 day before the subsequent 28 day administration cycle.

[0077] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to 50%, and human subjects have a 9 Baseline absolute neutrophil count ≥ 3 × 10 / L 9 Baseline white blood cell count of ≥ 75 × 10 / L or 9 / L and the human subject has a baseline platelet count of ≦1.0×10 9 / L neutrophil count nadir and ≦50×10 9 / L platelet count nadir.

[0078] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to 50%, and human subjects have a 9Baseline absolute neutrophil count ≥ 3 × 10 / L 9 Baseline white blood cell count of ≥ 75 × 10 / L or 9 / L and the human subject has a baseline platelet count of ≦1.0×10 9 / L neutrophil count nadir and ≦50×10 9 and a platelet count nadir of 0.01 to 0.05 / L. In some embodiments, the azacitidine is administered intravenously. In other embodiments, the azacitidine is administered subcutaneously.

[0079] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to 50%, and human subjects have a 9 Baseline absolute neutrophil count ≥ 3 × 10 / L 9 Baseline white blood cell count of ≥ 75 × 10 / L or 9 / L and the human subject has a baseline platelet count of ≦1.0×10 9 / L neutrophil count nadir and ≦50×10 9 and a platelet count nadir of 100 / L, and the human subject has at least one of the conditions selected from the group consisting of a subsequent absolute neutrophil count increase above the absolute neutrophil count nadir and <50% relative to the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, and a subsequent platelet count increase above the platelet count nadir and <50% relative to the difference between the baseline platelet count and the platelet count nadir, prior to the start of the next 28-day administration cycle. In some embodiments, the azacitidine is administered intravenously. In other embodiments, the azacitidine is administered subcutaneously. In yet other embodiments, the method further comprises a delay of ≧1 day prior to the next 28-day administration cycle.

[0080] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to 50%, and human subjects have a 9 Baseline absolute neutrophil count ≥ 3 × 10 / L 9 Baseline white blood cell count of ≥ 75 × 10 / L or 9 / L and the human subject has a baseline platelet count of ≦1.0×10 9 / L neutrophil count nadir and ≦50×10 9and a platelet count nadir of 0.1 mg / L, and the human subject has at least one of the conditions selected from the group consisting of an increase in absolute neutrophil count above the absolute neutrophil count nadir and a subsequent increase in absolute neutrophil count that is <50% relative to the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, and a subsequent increase in platelet count above the platelet count nadir and a subsequent increase in platelet count that is <50% relative to the difference between the baseline platelet count and the platelet count nadir, prior to the start of a next 28-day dosing cycle, The 400 mg daily dose of is reduced from 14 days to 7 days in a subsequent 28-day administration cycle, and the human subject has at least one of the following conditions selected from the group consisting of: a subsequent increase in absolute neutrophil count above the neutrophil count nadir and <50% relative to the difference between the baseline absolute neutrophil count and the neutrophil count nadir, and a subsequent increase in platelet count above the platelet count nadir and <50% relative to the difference between the baseline platelet count and the platelet count nadir, prior to the start of the subsequent 28-day administration cycle. In some embodiments, azacitidine is administered intravenously. In other embodiments, azacitidine is administered subcutaneously. In still other embodiments, the method further comprises a delay of >1 day before the subsequent 28-day administration cycle. In still other embodiments, the method further comprises a delay of ≥1 day before the next 28-day administration cycle, and further comprises a delay of ≥1 day before the subsequent 28-day administration cycle.

[0081] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided. The method includes administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to ≦50 mg / m 2 However, 36 mg / m 2 and human subjects are reduced to ≥ 1.5 × 10 9 Baseline absolute neutrophil count ≥ 75 × 10 / L or 9 / L, the human subject already had a complete, partial or bone marrow complete response at the start of the previous dosing cycle, and the human subject has a baseline platelet count of ≦0.500×10 9 / L neutrophil count nadir, baseline platelets >100 × 10 9 / L, ≦50×10 9 / L platelet count nadir and baseline platelets ≤ 100 × 10 9 / L, <50% platelet count nadir.

[0082] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to ≦50 mg / m 2 However, 36 mg / m 2 and human subjects are reduced to ≥ 1.5 × 10 9 Baseline absolute neutrophil count ≥ 75 × 10 / L or 9 / L, the human subject already had a complete, partial or bone marrow complete response at the start of the previous dosing cycle, and the human subject has a baseline platelet count of ≦0.500×10 9 / L neutrophil count nadir, baseline platelets >100 × 10 9 / L, ≦50×10 9 / L platelet count nadir and baseline platelets ≤ 100 × 10 9 / L, <50% platelet count nadir.

[0083] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to ≦50 mg / m 2 However, 36 mg / m 2 and human subjects are reduced to ≥ 1.5 × 10 9 Baseline absolute neutrophil count ≥ 75 × 10 / L or 9 / L, the human subject already had a complete, partial or bone marrow complete response at the start of the previous dosing cycle, and the human subject has a baseline platelet count of ≦0.500×10 9 / L neutrophil count nadir, baseline platelets >100 × 10 9 / L, ≦50×10 9 / L platelet count nadir and baseline platelets ≤ 100 × 10 9 / L, <50% platelet count nadir, and the daily dose of azacitidine is 75 mg / m 2 to 50 mg / m 2 is reduced to

[0084] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to ≦50 mg / m 2 However, 36 mg / m 2 and human subjects are reduced to ≥ 1.5 × 10 9Baseline absolute neutrophil count ≥ 75 × 10 / L or 9 / L, the human subject already had a complete, partial or bone marrow complete response at the start of the previous dosing cycle, and the human subject has a baseline platelet count of ≦0.500×10 9 Absolute neutrophil count nadir / L and baseline platelets >100×10 9 / L, ≦50×10 9 / L platelet count nadir, baseline platelets ≤ 100 × 10 9 / L, <50% platelet count nadir, and the daily dose of azacitidine is 75 mg / m 2 to 50 mg / m 2 and the daily azacitidine dose was reduced to 50 mg / m2 for successive 28-day dosing cycles. 2 to 36 mg / m 2 is reduced to

[0085] In certain embodiments, a method is provided for treating myelodysplastic syndrome in a human subject, where the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. The method comprises administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle and a daily dose of 75 mg / m 2 of azacitidine to a human subject for 7 days of a 28-day dosing cycle, wherein the daily dose of azacitidine is 75 mg / m 2 to ≦50 mg / m 2 However, 36 mg / m 2 and human subjects are reduced to ≥ 1.5 × 10 9 Baseline absolute neutrophil count ≥ 75 × 10 / L or 9 / L, the human subject already had a complete, partial or bone marrow complete response at the start of the previous dosing cycle, and the human subject has a baseline platelet count of ≦0.500×10 9 Absolute neutrophil count nadir of 0.05–0.15 / L and baseline platelets >100×10 9 / L, ≦50×10 9 / L platelet count nadir, baseline platelets ≤ 100 × 109 / L, <50% platelet count nadir, and the daily dose of azacitidine is 75 mg / m 2 to 50 mg / m 2 and the daily azacitidine dose was reduced to 50 mg / m2 for successive 28-day dosing cycles. 2 to 36 mg / m 2 and the daily dose of 400 mg of venetoclax is reduced from 14 days to 7 days in the subsequent 28-day dosing cycle.

[0086] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, the method comprising: (a) obtaining a baseline absolute neutrophil count, a baseline white blood cell count, and a baseline platelet count from the human subject; (b) treating the human subject with an initial dose of venetoclax and an initial dose of azacitidine in a first treatment cycle; (c) comparing the baseline absolute neutrophil count, the baseline white blood cell count, and the baseline platelet count with a subsequent absolute neutrophil count, a subsequent white blood cell count, and a subsequent platelet count obtained after the first treatment cycle; and (d) treating the human subject with an azacitidine dose that is ≦75% but not less than 33% of the initial dose of azacitidine in a subsequent treatment cycle if the subsequent absolute neutrophil count nadir is ≧50% of the baseline neutrophil count, the subsequent white blood cell count nadir is ≧50% of the baseline neutrophil count, or the subsequent platelet count nadir is ≧50% of the baseline platelet count. In some embodiments, the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. In other embodiments, the initial dose of venetoclax is 400 mg and the initial dose of azacitidine is 75 mg / m 2 In yet other embodiments, the dosing cycle is 28 days. In yet other embodiments, the human subject is administered a daily dose of venetoclax for 14 days in a 28 day dosing cycle, with a daily dose of 75 mg / m 2of azacitidine is administered for 7 days in a 28-day dosing cycle. In yet another embodiment, the daily dose of 400 mg of venetoclax is reduced from 14 days to 7 days in a further subsequent 28-day dosing cycle if the human subject has at least one of the following conditions selected from the group consisting of: a next absolute neutrophil count above the absolute neutrophil count nadir and a next white blood cell count that is ≦25% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and a next platelet count that is ≦25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and a next platelet count that is ≦25% of the difference between the baseline platelet count and the platelet count nadir prior to the start of a further subsequent 28-day dosing cycle. In yet another embodiment, azacitidine is administered intravenously. In yet another embodiment, azacitidine is administered subcutaneously.

[0087] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, the method comprising: (a) obtaining a baseline absolute neutrophil count, a baseline white blood cell count, and a baseline platelet count from the human subject; (b) treating the human subject with an initial dose of venetoclax and an initial dose of azacitidine in a first treatment cycle; (c) comparing the baseline absolute neutrophil count, the baseline white blood cell count, and the baseline platelet count with a subsequent absolute neutrophil count, a subsequent white blood cell count, and a subsequent platelet count obtained after the first treatment cycle; and (d) treating the human subject with an azacitidine dose that is ≦50% but not less than 33% of the initial dose of azacitidine in a subsequent treatment cycle if the subsequent absolute neutrophil count nadir is ≧50% of the baseline neutrophil count, the subsequent white blood cell count nadir is ≧50% of the baseline neutrophil count, or the subsequent platelet count nadir is ≧50% of the baseline platelet count. In some embodiments, the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. In other embodiments, the initial dose of venetoclax is 400 mg and the initial dose of azacitidine is 75 mg / m 2In yet other embodiments, the dosing cycle is 28 days. In yet other embodiments, the human subject is administered a daily dose of venetoclax for 14 days in a 28 day dosing cycle, with a daily dose of 75 mg / m 2 of azacitidine is administered for 7 days in a 28-day dosing cycle. In yet another embodiment, the daily dose of 400 mg of venetoclax is reduced from 14 days to 7 days in a further subsequent 28-day dosing cycle if the human subject has at least one of the following conditions selected from the group consisting of: a next absolute neutrophil count above the absolute neutrophil count nadir and a next white blood cell count that is ≦25% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and a next platelet count that is ≦25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and a next platelet count that is ≦25% of the difference between the baseline platelet count and the platelet count nadir prior to the start of a further subsequent 28-day dosing cycle. In yet another embodiment, azacitidine is administered intravenously. In yet another embodiment, azacitidine is administered subcutaneously.

[0088] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, the method comprising: (a) obtaining a baseline absolute neutrophil count, a baseline white blood cell count, and a baseline platelet count from the human subject, (b) treating the human subject with an initial dose of venetoclax and an initial dose of azacitidine in a first treatment cycle, (c) comparing the baseline absolute neutrophil count, baseline white blood cell count, and baseline platelet count with a subsequent absolute neutrophil count, subsequent white blood cell count, and subsequent platelet count obtained after the first treatment cycle, and (d) determining whether the human subject has a baseline absolute neutrophil count of ≧1.5×10 9 Baseline absolute neutrophil count ≥ 3 × 10 / L 9 Baseline white blood cell count of ≥ 75 × 10 / L or 9 / L and a baseline platelet count of ≤1.5 × 10 9 / L neutrophil count nadir and ≦50×10 9 and a platelet count nadir of 0.05 mg / m2 / L, the dose of azacitidine is increased to 75 mg / m2 / L in the next 28-day dosing cycle.2 to ≦67% but ≧50%. In some embodiments, the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. In other embodiments, the initial dose of venetoclax is 400 mg and the initial dose of azacitidine is 75 mg / m 2 In yet other embodiments, the dosing cycle is 28 days. In yet other embodiments, the human subject is administered a daily dose of venetoclax for 14 days in a 28 day dosing cycle, with a daily dose of 75 mg / m 2 of azacitidine is administered for 7 days in a 28-day dosing cycle. In yet another embodiment, the daily dose of 400 mg of venetoclax is reduced from 14 days to 7 days in a further subsequent 28-day dosing cycle if the human subject has at least one of the following conditions selected from the group consisting of: a next absolute neutrophil count above the absolute neutrophil count nadir and a next white blood cell count that is ≦25% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and a next platelet count that is ≦25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and a next platelet count that is ≦25% of the difference between the baseline platelet count and the platelet count nadir prior to the start of a further subsequent 28-day dosing cycle. In yet another embodiment, azacitidine is administered intravenously. In yet another embodiment, azacitidine is administered subcutaneously.

[0089] In certain embodiments, a method of treating myelodysplastic syndrome in a human subject is provided, comprising: (a) obtaining a baseline absolute neutrophil count, a baseline white blood cell count, and a baseline platelet count from the human subject, (b) treating the human subject with an initial dose of venetoclax and an initial dose of azacitidine in a first treatment cycle, (c) comparing the baseline absolute neutrophil count, baseline white blood cell count, and baseline platelet count with a subsequent absolute neutrophil count, subsequent white blood cell count, and subsequent platelet count obtained after the first treatment cycle, and (d) determining whether the baseline absolute neutrophil count, baseline white blood cell count, and baseline platelet count are greater than or equal to 1.5×10 9 Baseline absolute neutrophil count ≥ 3 × 10 / L 9 Baseline white blood cell count of ≥ 75 × 10 / L or 9 / L and a baseline platelet count of ≤1.0 × 10 9 / L neutrophil count nadir and ≦50×10 9 / L and a daily dose of azacitidine of 75 mg / m 2 In some embodiments, the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome. In other embodiments, the initial dose of venetoclax is 400 mg and the initial dose of azacitidine is 75 mg / m 2 In yet other embodiments, the dosing cycle is 28 days. In yet other embodiments, the human subject is administered a daily dose of venetoclax for 14 days in a 28 day dosing cycle, with a daily dose of 75 mg / m 2 of azacitidine is administered for 7 days in a 28-day dosing cycle. In yet another embodiment, the daily dose of 400 mg of venetoclax is reduced from 14 days to 7 days in a further subsequent 28-day dosing cycle if the human subject has at least one of the following conditions selected from the group consisting of: a next absolute neutrophil count above the absolute neutrophil count nadir and a next white blood cell count that is ≦25% of the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir, a next white blood cell count above the white blood cell count nadir and a next platelet count that is ≦25% of the difference between the baseline white blood cell count and the white blood cell count nadir, and a next platelet count above the platelet count nadir and a next platelet count that is ≦25% of the difference between the baseline platelet count and the platelet count nadir prior to the start of a further subsequent 28-day dosing cycle. In yet another embodiment, azacitidine is administered intravenously. In yet another embodiment, azacitidine is administered subcutaneously. EXAMPLES

[0090] In order that the invention described herein may be more fully understood, the following examples are set forth.

[0091] A multicenter, nonrandomized Phase 1b study was initiated in adults with previously untreated high-risk MDS, defined as IPSS risk classification intermediate-2 or high (IPSS pooled score ≥ 1.5). The initial protocol randomized patients to one of three treatment arms: venetoclax 800 mg + azacitidine, venetoclax 400 mg + azacitidine, and azacitidine monotherapy. In the initial protocol, venetoclax was administered on days 1 through 28 of each 28-day cycle, with dosing initiated according to the cycle 1 escalation dosing. This dosing schedule resulted in two patients developing fatal sepsis in the setting of severe neutropenia, after which the study was placed on partial clinical hold and enrollment was temporarily halted. The partial clinical hold was lifted based on a revised protocol, which ultimately resulted in a low incidence of infections and cases of leukopenia.

[0092] Test Design Inclusion criteria Subjects aged 18 years or older with a diagnosis of treatment-naïve IPSS intermediate-2 or high-risk myelodysplastic syndrome with ECOG ≤ 2 were enrolled. In this study, inclusion criteria included: 1. Subjects must be ≥ 18 years of age. 2. The target is: a. Have an International Prognostic Scoring System (IPSS) risk classification of intermediate-2 or high (i.e., a minimum IPSS score of 1.5) or a Revised IPSS (IPSS-R) classification of intermediate, high, or very high (score >3); and b. Presence of <20% myeloblasts per bone marrow biopsy / aspirate; Must have a documented diagnosis of previously untreated de novo MDS. 3. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance score of ≦2.

[0093] According to the International Prognostic Scoring System, patients with myelodysplastic syndromes are divided into two main risk groups: low risk and high risk. High-risk myelodysplastic syndromes, as used herein, are defined as International Prognostic Scoring System (IPSS) risk classification intermediate-2 or high (i.e., minimum IPSS score of 1.5), or revised IPSS (IPSS-R) classification intermediate, high, or very high (combined score >3).

[0094] [Table 1]

[0095] Subjects with high-risk MDS are classified into intermediate, high, and very high in the revised International Prognostic Scoring System (IPSS-R) classification. This patient population roughly corresponds to the IPSS intermediate-2 and high-risk groups, and the World Health Organization (WHO) histological subtypes of refractory anemia with excess blasts (RAEB)-1 and RAEB-2. The IPSS-R is also currently considered to be a well-validated assessment tool to identify patients who are generally considered clinically appropriate to undergo aggressive treatment. The revised International Prognostic Scoring System (IPSS-R) is shown in Table 2 and includes a high-precision classification of cytogenetic abnormalities, more specific cutoffs for bone marrow blast count and cytopenias, weighted by their severity. The revised International Prognostic Scoring System risk groups for myelodysplastic syndromes are defined based on the integrated score. The integrated score is calculated as the sum of the blast score, cytogenetic score, hemoglobin score, platelet score, and absolute neutrophil count score.

[0096] [Table 2]

[0097] ECOG performance status was assessed using the criteria in Table 3.

[0098] [Table 3]

[0099] Main Exclusion Criteria 1. Subject has previously been treated for MDS.

[0100] 2. Subject has previously been treated with a BH3 mimetic.

[0101] 3. The target is: MDS with IPSS low or intermediate-1 risk classification (IPSS combined score < 1.5), b. Treatment-related MDS (t-MDS), C. MDS that has evolved from a previously existing myeloproliferative neoplasm (MPN), d. MDS / MPN, including chronic myelomonocytic leukemia (CMML), atypical chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia (JMML), and unclassified MDS / MPN have a previously untreated diagnosis other than de novo MDS, including

[0102] 4. Subject has received a strong or moderate CYP3A inducer within 7 days prior to the first dose of study drug.

[0103] 5. Subjects enrolled in dose escalation cohorts, except for the safety expansion cohort, have received a strong or moderate CYP3A inhibitor within 3 days prior to the first dose of study drug.

[0104] Azacitidine 75 mg / m 2(daily intravenously or subcutaneously) for 7 days and venetoclax at 400 mg for 14 days of each 28-day cycle. In both cohorts, dose modifications in cycle 1 were not recommended. Dose modifications in subsequent cycles were prescribed for adverse events. In safety expansion cohort 1 (SE1), venetoclax was initially reduced due to significant neutrophil or platelet toxicity. Per protocol dose reductions were 33% for azacitidine or 50% for venetoclax during the 14 days of each cycle. In subsequent cycles, the duration of venetoclax could be shortened to 9 days in each cycle. In safety expansion cohort 2 (SE2), dose modification guidelines were revised to initially reduce the azacitidine dose (initially 50 mg / m 2 , followed by 36 mg / m 2 ), followed by a 7-day duration taper (venetoclax 400 mg) with each cycle of venetoclax was recommended. The impact of each dose modification strategy on safety and efficacy in SE1 and SE2 was compared. Worsening from baseline in treatment-emergent adverse event grades was analyzed by cycle. Response was assessed using IWG 2006 criteria. Analyses included all subjects who received ≥1 dose of study drug.

[0105] [Table 4]

[0106] Treatment dose reduction may be indicated following prior interruption of treatment, delay in initiation of the next cycle, occurrence of adverse events with hematological toxicity, significant reduction in neutrophils or significant reduction in platelets. A stepwise azacitidine dose modification was performed, followed by an adjustment of venetoclax treatment from 14 days to 7 days in the final step after all azacitidine dose modification steps had been performed. Venetoclax and azacitidine were resumed on the same day following any delay or interruption in treatment.

[0107] Absolute neutrophil count score <1.5 × 10 9 / L neutropenia or platelets <75×10 9Subjects who begin a treatment cycle with thrombocytopenia of ≥ 1.5 × 10 / L may be particularly susceptible to cytopenia due to abnormal hematopoiesis caused by underlying absolute neutrophil counts. Thus, such subjects typically do not require dose reduction in response to uncomplicated nadir cytopenia. However, subjects with absolute neutrophil counts ≥ 1.5 × 10 9 / L and platelets ≥ 75 × 10 9 Subjects who begin a treatment cycle of 100 mg / L and who are already in complete, partial, or complete bone marrow remission should have a subsequent absolute neutrophil count nadir of <0.500 x 10 9 / L or baseline >100 × 10 9 / L, nadir platelet count <50 × 10 9 / L or baseline ≤100 × 10 9 / L, dose reduction may be necessary if platelets are <50%.

[0108] result: Baseline characteristics of SE1 and SE2 are shown in Table 5 . Twenty-two subjects with SE1 and 21 subjects with SE2 were compared with a median (range) follow-up of 7.5 (1.0–8.9) and 7.9 (1.8–10.1) months, respectively, as shown in Table 6 .

[0109] [Table 5]

[0110] [Table 6]

[0111] A summary of adverse events in >20% of subjects is shown in Table 7. Similar frequencies of grade ≥3 hematological treatment-emergent adverse events (approximate %) were reported in SE1 and SE2, respectively, including anemia (14% and 33%), febrile neutropenia (46% and 48%), leukopenia (36% and 19%), neutropenia (55% and 48%), and thrombocytopenia (32% and 38%). Infections (59% and 38%) and leukopenia (36% and 19%) were more frequent in SE1 than in SE2.

[0112] [Table 7]

[0113] The deterioration of treatment-emergent adverse event grade from baseline was analyzed for each cycle. As shown in Figures 3A-3F and 4A-4C, the progression of adverse events remains low after the first few cycles, e.g., cycles 1 and 2. Figures 3A-3F are hematological toxicity showing the number of patients with a deterioration of Common Terminology Criteria grade from baseline per cycle. Figures 4A-4C are gastrointestinal toxicity showing the number of patients with a deterioration of Common Terminology Criteria grade from baseline per cycle.

[0114] Response rates were the same for SE1 and SE2, with 86% of subjects in both SE1 and SE2 having a complete response (CR) or marrow complete response (mCR), as shown in Table 8. In subjects with mCR, hematologic improvement occurred in 50% of SE1 subjects and 46% of SE2 subjects.

[0115] [Table 8]

[0116] A summary of cycle delays is shown in Table 9. Cycle delays were comparable for SE1 and SE2, with SE1 being slightly longer in duration in early cycles.

[0117] [Table 9]

[0118] The mean absolute neutrophil and platelet counts are shown in Figures 1 and 2, respectively. The observed number of counts by day of the study cycle for both absolute neutrophil and platelet counts is shown in Table 10.

[0119] [Table 10]

[0120] 86% of both SE1 and SE2 patients had a complete response or bone marrow complete response.

[0121] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and should not be construed as limiting the scope of the invention, which is defined solely by the appended claims and equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including those related to the method of use of the invention, can be made without departing from the spirit and scope of the invention. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A pharmaceutical composition comprising venetoclax, The pharmaceutical composition is for use in combination with azacitidine in a method of treating myelodysplastic syndrome in a human subject, The method includes administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle, and a daily dose of 75 mg / m ２ for 7 days of a 28 day dosing cycle, The human subject <1.5 x 10 ９ Baseline absolute neutrophil count of <3×10 / L ９ Baseline white blood cell count of 0.01 / L or <75 x 10 ９ / L of baseline platelet count, There was no improvement in cell line differentiation, a. ≥ 50% reduction in absolute neutrophil count nadir; b. A ≥ 50% reduction in white blood cell count nadir; and c. A ≥ 50% reduction in platelet count nadir When the patient has at least one of the conditions selected from the group consisting of: 75 mg / m ２ wherein the daily dose of azacitidine is reduced by ≦75% but not less than 33% in a subsequent 28 day dosing cycle.

2. The pharmaceutical composition according to claim 1, wherein the myelodysplastic syndrome is a treatment-naïve high-risk myelodysplastic syndrome.

3. 75 mg / m ２ the daily azacitidine dose is reduced by 75% in the next 28-day dosing cycle; the human subject has 30-60% bone marrow cellularity; The human subject a. A ≥ 75% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count; b. A ≥ 75% decrease in white blood cell count nadir from baseline white blood cell count; and c. A >75% decrease in platelet count nadir from baseline platelet count.

2. The pharmaceutical composition of claim 1, wherein the patient has at least one of the conditions selected from the group consisting of:

4. 2. The pharmaceutical composition of claim 1, wherein the azacitidine is administered intravenously.

5. 2. The pharmaceutical composition of claim 1, wherein the azacitidine is administered subcutaneously.

6. Prior to the start of the next 28-day dosing cycle, the human subject a. An absolute neutrophil count that is above the absolute neutrophil count nadir and is ≦25% relative to the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir; b. The following white blood cell counts are above the white blood cell count nadir and are ≦25% relative to the difference between the baseline white blood cell count and the white blood cell count nadir: c. A subsequent platelet count above the platelet count nadir and that is ≦25% of the difference between the baseline platelet count and the platelet count nadir The pharmaceutical composition of claim 3, wherein the patient has at least one of the conditions selected from the group consisting of:

7. The pharmaceutical composition of claim 6, wherein the method further comprises a delay of ≧1 day before the next 28-day administration cycle.

8. the venetoclax 400 mg daily dose is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle; Prior to the start of a subsequent 28-day administration cycle, a. a subsequent absolute neutrophil count above the absolute neutrophil count nadir and that is ≦25% relative to the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir; b. The following white blood cell counts are above the white blood cell count nadir and are ≦25% relative to the difference between the baseline white blood cell count and the white blood cell count nadir: c. A subsequent platelet count above the platelet count nadir and that is ≦25% of the difference between the baseline platelet count and the platelet count nadir The pharmaceutical composition of claim 6, wherein the patient has at least one of the conditions selected from the group consisting of:

9. 75 mg / m ２ the daily azacitidine dose is reduced by 50% in the next 28-day dosing cycle; The human subject has 15 to <30% bone marrow cellularity, The human subject a. A ≥ 50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count; b. A ≥ 50% decrease in white blood cell count nadir from baseline white blood cell count; and c. A ≥ 50% decrease in platelet count nadir from baseline platelet count.

2. The pharmaceutical composition of claim 1, wherein the patient has at least one of the conditions selected from the group consisting of:

10. 10. The pharmaceutical composition of claim 9, wherein the azacitidine is administered intravenously.

11. 10. The pharmaceutical composition of claim 9, wherein the azacitidine is administered subcutaneously.

12. Prior to the start of the next 28-day dosing cycle, the human subject a. An absolute neutrophil count that is above the absolute neutrophil count nadir and is ≦25% relative to the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir; b. The following white blood cell counts are above the white blood cell count nadir and are ≦25% relative to the difference between the baseline white blood cell count and the white blood cell count nadir: c. A subsequent platelet count above the platelet count nadir and that is ≦25% of the difference between the baseline platelet count and the platelet count nadir 10. The pharmaceutical composition of claim 9, wherein the patient has at least one of the conditions selected from the group consisting of:

13. The pharmaceutical composition of claim 12, wherein the method further comprises a delay of ≧1 day before the next 28-day administration cycle.

14. the venetoclax 400 mg daily dose is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle; Prior to the start of a subsequent 28-day administration cycle, a. a subsequent absolute neutrophil count above the absolute neutrophil count nadir and that is ≦25% relative to the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir; b. A subsequent white blood cell count that is above the white blood cell count nadir and is ≦25% relative to the difference between the baseline white blood cell count and the white blood cell count nadir; and c. A subsequent platelet count beyond the platelet count nadir and that is ≦25% relative to the difference between the baseline platelet count and the platelet count nadir. The pharmaceutical composition of claim 12, wherein the patient has at least one of the conditions selected from the group consisting of:

15. 75 mg / m ２ The daily azacitidine dose is reduced by 33% in the next 28-day dosing cycle, The human subject has <15% bone marrow cellularity, The human subject a. A ≥ 50% decrease in absolute neutrophil count nadir from baseline absolute neutrophil count; b. A ≥ 50% decrease in white blood cell count nadir from baseline white blood cell count; and c. A ≥ 50% decrease in platelet count nadir from baseline platelet count.

2. The pharmaceutical composition of claim 1, wherein the patient has at least one of the conditions selected from the group consisting of:

16. 16. The pharmaceutical composition of claim 15, wherein the azacitidine is administered intravenously.

17. 16. The pharmaceutical composition of claim 15, wherein the azacitidine is administered subcutaneously.

18. Prior to the start of the next 28-day dosing cycle, the human subject a. An absolute neutrophil count that is above the absolute neutrophil count nadir and is ≦25% relative to the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir; b. The following white blood cell counts are above the white blood cell count nadir and are ≦25% relative to the difference between the baseline white blood cell count and the white blood cell count nadir: c. A subsequent platelet count above the platelet count nadir and that is ≦25% of the difference between the baseline platelet count and the platelet count nadir 16. The pharmaceutical composition of claim 15, having at least one of the conditions selected from the group consisting of:

19. The pharmaceutical composition of claim 18, wherein the method further comprises a delay of ≧1 day before the next 28-day administration cycle.

20. the venetoclax 400 mg daily dose is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle; Prior to the start of a subsequent 28-day administration cycle, a. A subsequent neutrophil count above the absolute neutrophil count nadir and >25% relative to the difference between the baseline absolute neutrophil count and the absolute neutrophil count nadir; b. A subsequent white blood cell count that is above the white blood cell count nadir and is >25% relative to the difference between the baseline white blood cell count and the white blood cell count nadir; and c. A subsequent platelet count beyond the platelet count nadir and that is >25% relative to the difference between the baseline platelet count and the platelet count nadir.

20. The pharmaceutical composition of claim 18, wherein the patient has at least one of the conditions selected from the group consisting of:

21. A pharmaceutical composition comprising venetoclax, The pharmaceutical composition is for use in combination with azacitidine in a method of treating myelodysplastic syndrome in a human subject, The method includes administering a daily dose of 400 mg of venetoclax for 14 days of a 28-day dosing cycle, and a daily dose of 75 mg / m ２ for 7 days of a 28 day dosing cycle, The human subject ≧1.5×10 ９ Baseline absolute neutrophil count of / L; ≧3×10 ９ Baseline white blood cell count of / L or ≧75×10 ９ Baseline platelet count of / L having a.≦1.5×10 ９ / L absolute neutrophil count nadir and b.≦50×10 ９ Platelet count nadir of / L When the patient has at least one of the conditions selected from the group consisting of: The daily dose of azacitidine is 75 mg / m2 in the next 28-day dosing cycle. ２ from ≦67% but reduced by 50% or more.

22. The pharmaceutical composition of claim 21, wherein the myelodysplastic syndrome is treatment-naïve high-risk myelodysplastic syndrome.

23. The daily dose of azacitidine is 75 mg / m ２ to 67%. The human subject a. Absolute neutrophil count nadir is 0.5 x 10 ９ / L ~ 1.5 x 10 ９ / L and b. Platelet count nadir is 25 x 10 ９ / L~50x10 ９ / L 22. The pharmaceutical composition of claim 21, having at least one of the conditions selected from the group consisting of:

24. Prior to the start of the next 28-day dosing cycle, the human subject a.≦1.5×10 ９ Absolute neutrophil count and b.≦50×10 ９ Platelet count next to / L 22. The pharmaceutical composition of claim 21, having at least one of the conditions selected from the group consisting of:

25. The pharmaceutical composition of claim 24, wherein the method further comprises a delay of ≧1 day before the next 28-day administration cycle.

26. the venetoclax 400 mg daily dose is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle; Prior to the start of a subsequent 28-day administration cycle, a.≦1.5×10 ９ / L subsequent absolute neutrophil count and b.≦50×10 ９ / L subsequent platelet count 22. The pharmaceutical composition of claim 21, having at least one of the conditions selected from the group consisting of:

27. The daily dose of azacitidine is 75 mg / m ２ to 50%. The human subject a. Absolute neutrophil count nadir <0.5 x 10 ９ / L and b. Platelet count nadir <25 x 10 ９ / L 22. The pharmaceutical composition of claim 21, having at least one of the conditions selected from the group consisting of:

28. Prior to the start of the next 28-day dosing cycle, the human subject a.≦1.5×10 ９ Absolute neutrophil count and b.≦50×10 ９ Platelet count next to / L 28. The pharmaceutical composition of claim 27, having at least one of the conditions selected from the group consisting of:

29. The pharmaceutical composition of claim 28, wherein the method further comprises a delay of ≧1 day before the next 28-day administration cycle.

30. the venetoclax 400 mg daily dose is reduced from 14 days to 7 days in a subsequent 28-day dosing cycle; Prior to the start of a subsequent 28-day administration cycle, a.≦1.5×10 ９ / L subsequent absolute neutrophil count and b.≦50×10 ９ / L subsequent platelet count 29. The pharmaceutical composition of claim 28, having at least one of the conditions selected from the group consisting of:

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