Combination therapy for treating hematological cancers

Abstract

The present disclosure features a combination therapy useful for the treatment of AML and related hematological cancers.

Description

[0001] COMBINATION THERAPY FOR TREATING HEMATOLOGICAL CANCERS

[0002] BACKGROUND OF THE INVENTION

[0003] The present disclosure relates to combination therapies including N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof and an anti-hematological cancer agent for the treatment of AML and related hematological cancers. The combination therapies of the invention can reduce side effects, improve outcomes, decrease incidence of relapse, decrease leukemic stem cell levels, and / or reduce the dosing burden on the patient.

[0004] SUMMARY

[0005] The invention features a method of treating relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome in a subject in need thereof, the method including administering (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent, each in an amount that together is effective to treat the relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome, wherein: (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; (d) the subject is refractory to venetoclax and a hypomethylating agent, or (e) the subject has acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors.

[0006] The invention features a method of decreasing the amount of leukemic stem cells (e.g., cells expressing CD34, BRG1 , BCL2, CD123 / IL3RA, EGFL7, FAM30A, BAALC, RBPMS, HOPX, KRT18, SMIM24, SPINK2, CPXM1 , IGHM, EMP1 , CDK6, ZBTB46, DNMT3B, SOCS2, MMRN1 , AKR1C3, PROM1 , PPP1 R16B, ABCB1 , and / or LAPTM4B) in a subject (e.g., in the bone marrow or periphery, e.g., in a blood sample, of the subject) with acute myeloid leukemia or myelodysplastic syndrome, the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of leukemic stem cells in the subject is decreased by at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at by least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold). In some embodiments, the subject has relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. For example, the subject did not respond one or more initial therapies (e.g., intensive chemotherapy or venetoclax plus a hypomethylating agent such as azacytidine). In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. In some embodiments, the method further includes administering an anti-hematological cancer agent (e.g., decitabine or cytarabine), in an amount that together with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective to decrease the amount of leukemic stem cells in the subject.

[0007] The invention features a method of increasing the level of differentiated myeloid cells (e.g., cells expressing CD11 b, CD64, CD38, S100A8, S100A9, RBM47, LYZ, PTPRJ, NCF1 , FGR, FCN1 , and / or S100A11) in a subject (e.g., in the bone marrow or periphery, e.g., in a blood sample, of the sample) with acute myeloid leukemia or myelodysplastic syndrome, the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of differentiated myeloid cells in the subject is increased at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20- fold). In some embodiments, the subject has relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. For example, the subject did not respond one or more initial therapies (e.g., intensive chemotherapy or venetoclax plus a hypomethylating agent such as azacytidine). In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. In some embodiments, the method further includes administering an anti-hematological cancer agent (e.g., decitabine or cytarabine), in an amount that together with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective to increase the level of differentiated myeloid cells in the subject.

[0008] The invention features a method of differentiating leukemic stem cells in a subject (e.g., in the bone marrow or periphery, e.g., in a blood sample, of the subject) with acute myeloid leukemia or myelodysplastic syndrome, the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold) of the leukemic stem cells in the subject are differentiated. In some embodiments, the subject has relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. For example, the subject did not respond one or more initial therapies (e.g., intensive chemotherapy or venetoclax plus a hypomethylating agent such as azacytidine). In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. In some embodiments, the method further includes administering an anti-hematological cancer agent (e.g., decitabine or cytarabine), in an amount that together with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective differentiate leukemic stem cells in the subject.

[0009] The invention features a method of increasing the level of cells expressing CD11 b in a subject (e.g., in the bone marrow or periphery, e.g., in a blood sample, of the subject) with acute myeloid leukemia or myelodysplastic syndrome, the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the level of cells expressing CD11 b in the subject is increased at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold). In some embodiments, the subject has relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. For example, the subject did not respond one or more initial therapies (e.g., intensive chemotherapy or venetoclax plus a hypomethylating agent such as azacytidine). In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. In some embodiments, the method further includes administering an anti-hematological cancer agent (e.g., decitabine or cytarabine), in an amount that together with the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective to increase the amount of cells expressing CD11 b in the subject.

[0010] The invention features a method of increasing the level of cells expressing CD11 b, CD64, CD38, S100A8, S100A9, RBM47, LYZ, PTPRJ, NCF1 , FGR, FCN1 , S100A11 , or a combination thereof in a subject (e.g., in the bone marrow or periphery, e.g., in a blood sample, of the subject) with acute myeloid leukemia or myelodysplastic syndrome, the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the level of cells expressing CD11 b in the subject is increased. In some embodiments, the level of cells expressing CD64 in the subject is increased. In some embodiments, the level of cells expressing CD38 in the subject is increased. In some embodiments, the level of cells expressing S100A8 in the subject is increased. In some embodiments, the level of cells expressing S100A9 in the subject is increased. In some embodiments, the level of cells expressing LYZ in the subject is increased. In some embodiments, the level of cells expressing RBM47 in the subject is increased. In some embodiments, the level of cells expressing PTPRJ in the subject is increased. In some embodiments, the level of cells expressing NCF1 in the subject is increased. In some embodiments, the level of cells expressing FGR in the subject is increased. In some embodiments, the level of cells expressing FCN1 , S100A11 , or a combination thereof in the subject is increased. In some embodiments, the level of cells expressing CD11 b, CD64, CD38, S100A8, S100A9, RBM47, LYZ, PTPRJ, NCF1 , FGR, FCN1 , S100A11 , or a combination thereof in the subject is increased at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold). In some embodiments, the subject has relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. For example, the subject did not respond one or more initial therapies (e.g., intensive chemotherapy or venetoclax plus a hypomethylating agent such as azacytidine). In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. In some embodiments, the method further includes administering an anti-hematological cancer agent (e.g., decitabine or cytarabine), in an amount that together with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective to increase the amount of cells expressing CD11 b, CD64, CD38, S100A8, S100A9, RBM47, LYZ, PTPRJ, NCF1 , FGR, FCN1 , S100A11 , or a combination thereof in the subject.

[0011] The invention features a method of decreasing the level of cells expressing CD34 in a subject (e.g., in the bone marrow or periphery, e.g., in a blood sample, of the subject) with acute myeloid leukemia or myelodysplastic syndrome, the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the level of cells expressing CD34 in the subject is decreased at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold). In some embodiments, the subject has relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. For example, the subject did not respond one or more initial therapies (e.g., intensive chemotherapy or venetoclax plus a hypomethylating agent such as azacytidine). In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. In some embodiments, the method further includes administering an anti-hematological cancer agent (e.g., decitabine or cytarabine), in an amount that together with the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective to decrease the amount of cells expressing CD34 in the subject.

[0012] The invention features a method of decreasing the level of cells expressing CD34, BRG1 , BCL2, CD123 / IL3RA, EGFL7, FAM30A, BAALC, RBPMS, HOPX, KRT18, SMIM24, SPINK2, CPXM1 , IGHM, EMP1 , CDK6, ZBTB46, DNMT3B, SOCS2, MMRN1 , AKR1C3, PR0M1 , PPP1 R16B, ABCB1 , LAPTM4B, or a combination thereof in a subject (e.g., in the bone marrow or periphery, e.g., in a blood sample, of the subject) with acute myeloid leukemia or myelodysplastic syndrome, the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the level of cells expressing CD34 in the subject is decreased. In some embodiments, the level of cells expressing BRG1 in the subject is decreased. In some embodiments, the level of cells expressing BCL2 in the subject is decreased. In some embodiments, the level of cells expressing CD123 / IL3RA in the subject is decreased. In some embodiments, the level of cells expressing EGFL7 in the subject is decreased. In some embodiments, the level of cells expressing FAM30A in the subject is decreased. In some embodiments, the level of cells expressing BAALC in the subject is decreased. In some embodiments, the level of cells expressing RBPMS in the subject is decreased. In some embodiments, the level of cells expressing SMIM24 in the subject is decreased. In some embodiments, the level of cells expressing KRT18 in the subject is decreased. In some embodiments, the level of cells expressing SPINK2 in the subject is decreased. In some embodiments, the level of cells expressing IGHM in the subject is decreased. In some embodiments, the level of cells expressing CPXM1 in the subject is decreased. In some embodiments, the level of cells expressing AKR1 C3 in the subject is decreased. In some embodiments, the level of cells expressing CDK6 in the subject is decreased. In some embodiments, the level of cells expressing MMRN1 in the subject is decreased. In some embodiments, the level of cells expressing SOCS2 in the subject is decreased. In some embodiments, the level of cells expressing DNMT3B in the subject is decreased. In some embodiments, the level of cells expressing ZBTB46 in the subject is decreased. In some embodiments, the level of cells expressing EMP1 in the subject is decreased. In some embodiments, the level of cells expressing PROM1 , PPP1 R16B, ABCB1 , LAPTM4B, or a combination thereof in the subject is decreased. In some embodiments, the level of cells expressing CD34, BRG1 , BCL2, CD123 / IL3RA, EGFL7, FAM30A, BAALC, RBPMS, HOPX, KRT18, SMIM24, SPINK2, CPXM1 , IGHM, EMP1 , CDK6, ZBTB46, DNMT3B, SOCS2, MMRN1 , AKR1C3, PROM1 , PPP1 R16B, ABCB1 , LAPTM4B, or a combination thereof in the subject is decreased at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2- fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold). In some embodiments, the subject has relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. For example, the subject did not respond one or more initial therapies (e.g., intensive chemotherapy or venetoclax plus a hypomethylating agent such as azacytidine). In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. In some embodiments, the method further includes administering an anti- hematological cancer agent (e.g., decitabine or cytarabine), in an amount that together with the amount of N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective to decrease the amount of cells expressing CD34, BRG1 , BCL2, CD123 / IL3RA, EGFL7, FAM30A, BAALC, RBPMS, HOPX, KRT18, SMIM24, SPINK2, CPXM1 , IGHM, EMP1 , CDK6, ZBTB46, DNMT3B, SOCS2, MMRN1 , AKR1C3, PROM1 , PPP1 R16B, ABCB1 , LAPTM4B, or a combination thereof in the subject.

[0013] The invention features a method of decreasing the amount of common myeloid progenitor cells in a subject (e.g., in the bone marrow or periphery, e.g., in a blood sample, of the subject) with acute myeloid leukemia or myelodysplastic syndrome, the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of common myeloid progenitor cells in the subject is decreased at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold). In some embodiments, the subject has relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. For example, the subject did not respond one or more initial therapies (e.g., intensive chemotherapy or venetoclax plus a hypomethylating agent such as azacytidine). In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. In some embodiments, the method further includes administering an anti-hematological cancer agent (e.g., decitabine or cytarabine), in an amount that together with the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective to decrease the amount of common myeloid progenitor cells in the subject.

[0014] The invention features a method of increasing the amount of monocytes in a subject (e.g., in the bone marrow or periphery, e.g., in a blood sample, of the subject) with acute myeloid leukemia or myelodysplastic syndrome, the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of monocytes in the subject is increased at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5- fold, at least 10-fold, at least 20-fold). In some embodiments, the subject has relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. For example, the subject did not respond one or more initial therapies (e.g., intensive chemotherapy or venetoclax plus a hypomethylating agent such as azacytidine). In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. In some embodiments, the method further includes administering an anti-hematological cancer agent (e.g., decitabine or cytarabine), in an amount that together with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective to increase the amount of monocytes in the subject.

[0015] The invention features a method of treating acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors (e.g., adverse cytogenetics or unfavorable risk factors) in a subject in need thereof, the method including administering (i) N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti- hematological cancer agent (e.g., decitabine or cytarabine), each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors. In some embodiments, the intermediate or adverse genetic risk factors include -5, 5q-, -7, 7q-, 11 q23 other than t(9;11), inv(3), t(3;3), t(6;9), t(9;22), and / or a complex karyotype. In some embodiments, the intermediate or adverse genetic risk factors include inv (3), del (7q t(4:7), -8, t(8;12), del (7q), del (7;12), and / or add(1). In some embodiments, the intermediate or adverse genetic risk factors include inv(3) o t(3;3), t(6;9), t(v;11)(v;q23), -5 or del(5q), ~7 and / or abn(17p). In some embodiments, the intermediate or adverse genetic risk factors include Inv(3)(q21q26) and / or t(3;3)(q21 ;q26). In some embodiments, the subject has a complex karyotype (e.g., a complex karyotype including > 4 unrelated abnormalities, but only in the absence t(15;17)(q22;q21), t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22), abn(3q), except for t(3;5)(q25;q34); inv(3)(q21 26) / t(3;3)(q21 ;q26); add(5q) / del(5q), -5; add(7q) / del(7q), -7; t(6;11)(q27;q23), t(10; 11)(p11 ~13;q23), other t(11 q23) with the exception of t(9;11)(p22;q23) and t(11 ;19)(q23;p13); t(9;22)(q34;q11); -17 and abn(17p) or > 3 abnormalities in the absence of t(8;21), inv(16) or t(16;16), t(15;17), t(9;11), t(v;11)(v;q23), t(6;9)(p23;q34) and inv(3) or t(3;3)). In some embodiments, intermediate or adverse genetic risk factors include deletion (i.e., loss) of part of chromosome 5 or 7, translocation or inversion of chromosome 3, translocation between chromosome 6 and 9, translocation between chromosome 9 and 22, abnormalities of chromosome 11 at the spot q23, loss of a chromosome so the cell has only one copy instead of the normal two, or complex changes (i.e., those involving 3 or more chromosomes). In some embodiments, the subject further has a tp53 alteration. In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent.

[0016] The invention features a method of treating acute myeloid leukemia or myelodysplastic syndrome with complex karyotype in a subject in need thereof, the method including administering (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent, each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with complex karyotype. In some embodiments, the complex karyotype includes > 4 unrelated abnormalities, but only in the absence t(15;17)(q22;q21), t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22), abn(3q), except for t(3;5)(q25;q34); inv(3)(q21q26) / t(3;3)(q21 ;q26); add(5q) / dei(5q), -5; add(7q) / del(7q), -7; t(6; 11 )(q27;q23), t(1O;11)(p11~13;q23), other t(11 q23) with the exception of t(9;11)(p22;q23) and t(11 ;19)(q23;p13); t(9;22)(q34;q11); -17 and abn(17p) or > 3 abnormalities in the absence of t(8;21), inv(16) or t(16;16), t(15;17), t(9;11), t(v;11)(v;q23), t(6;9)(p23;q34) and inv(3) o t(3;3). In some embodiments, the subject further has a tp53 alteration. In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent.

[0017] The invention features a method of treating acute myeloid leukemia or myelodysplastic syndrome with high EVI1 expression in a subject in need thereof, the method including administering (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)- 1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent, each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with high EVI1 expression. In some embodiments, the subject has cytogenetics including 3q26, inv (3) (q21q26) / t (3; 3) (q21 ; q26) / t (3, 21) (q26;q22) (7). In some embodiments, the subject has an MLL-ENL fusion. In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent.

[0018] The invention features a method of treating acute myeloid leukemia or myelodysplastic syndrome with a FLT3 mutation in a subject in need thereof, the method including administering (i) N- (1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) a FLT3 inhibitor (e.g., sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, or gilteritinib), each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with a FLT3 mutation. In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent. The invention features a method of treating acute myeloid leukemia or myelodysplastic syndrome with a MLL rearrangement and / or an NMP1 mutation in a subject in need thereof, the method including administering (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)- 3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) a menin inhibitor (e.g., revumenib or ziftomenib), each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with a MLL rearrangement and / or an NMP1 . In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent.

[0019] The invention features a method of treating acute myeloid leukemia or myelodysplastic syndrome with an IDH1 or IDH2 mutation in a subject in need thereof, the method including administering (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an IDH1 or IDH2 inhibitor (e.g., ivosidenib, enasidenib, olutasidenib, or AG-881), each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with an IDH1 or IDH2 mutation. In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent.

[0020] The invention features a method of decreasing the amount of blast cells in the spleen of a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome, or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors, the method including administering (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)- 3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an IDH1 or IDH2 inhibitor, each in an amount that together is effective to decrease the amount of blast cells in the spleen of the subject. In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent.

[0021] The invention features a method of slowing the growth of the spleen of a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome, or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors, the method including administering (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) second therapeutic agent, each in an amount that together is effective to slow the growth of the spleen of the subject. In some embodiments (a) the subject has not previously been administered a regimen of intensive chemotherapy; (b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse; (c) the subject is refractory to intensive chemotherapy; or (d) the subject is refractory to venetoclax and a hypomethylating agent.

[0022] In some of any of the foregoing aspects, the anti-hematological cancer agent is an FLT3 inhibitor. In some embodiments, the FLT3 inhibitor is sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib, quizartinib, and midostaurin. In some of any of the foregoing aspects, the anti- hematological cancer agent is a menin inhibitor. In some embodiments, the menin inhibitor is KO-539, SNDX-5613, revumenib, and DS-1594a. In some of any of the foregoing aspects, the anti- hematological cancer agent is an IDH1 inhibitor. In some of any of the foregoing aspects, the anti- hematological cancer agent is an IDH2 inhibitor. In some of any of the foregoing aspects, the anti- hematological cancer agent is an IDH1 or IDH2 inhibitor. In some of any of the foregoing aspects, the anti-hematological cancer agent is an IDH1 and IDH2 inhibitor. In some embodiments, the IDH1 inhibitor and / or IDH2 inhibitor is ivosidenib, enasidenib, olutasidenib, and AG-881 .

[0023] In some embodiments of any of the foregoing aspects, the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is between 1.5 mg and 10 mg per day (e.g., 1 .5 mg per day, 2.5 mg per day, 3 mg per day, 5 mg per day, 6 mg per day, 7.5 mg per day, or 10 mg per day).

[0024] In some embodiments of any of the foregoing aspects, the subject has RUNX1 , ASXL1 , BCOR, EZH2, TET2, CEBPA, AKL, CBL, ETV6, SMC1A, NRAS, KRAS, JAK2, TET2, ETNK1 , SF3B1 , KMT2A, FLT3-ITD, DNMT3A, U2AF1 , DDX41 , CUX1 , BRCA1 , MEN1 , CDKN1 Ap, C17Z1 , GATA2, ETV6, KDR, CBFB, NF1 , CBL, H1-B, NFE2, ASXL2, SRSF2, PTPN11 , WT1 , GRIN2AWT1 , CSF3R, PLCG2, ARHGEF28, BRD4, CDK12, KMT20, PARP1 , ZRSR1 , IRF8, MSH6, PPM1 D, IDH1 , EP300, STA2, KMT2C, NCOR1 , CBL, BCR / ABL, PMLRARA, and / or c-Kit mutation.

[0025] In some embodiments of any of the foregoing aspects, the peripheral blast count in the subject is decreased by at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold).

[0026] In some embodiments of any of the foregoing aspects, the bone marrow blast counts in the subject are decreased by at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold).

[0027] In some embodiments of any of the foregoing aspects, the neutrophil count in the subject is increased by at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) or at least 2-fold (e.g., at least 5-fold, at least 10-fold, at least 20-fold).

[0028] In some embodiments of any of the foregoing aspects, the subject is red blood cell and / or platelet infusion independent after administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0029] In certain embodiments, (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) cytarabine, or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other, or are administered within 24 hours of each other, or are administered simultaneously.

[0030] In certain embodiments, (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the decitabine, or a pharmaceutically acceptable salt thereof, are administered within 7 days of each other, or are administered within 24 hours of each other, or are administered simultaneously.

[0031] In some embodiments, the method includes administering between about 5.0 mg and about

[0032] 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for six to eight days, followed by six to eight days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0033] In certain embodiments, the method includes administering between about 5.0 mg and about

[0034] 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for thirteen to fifteen days, followed by six to eight days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0035] In particular embodiments, the method includes administering between about 5.0 mg and about 22.5 mg per day of FHD N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for six to fifteen days, followed by six to eight days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the method includes administering between about 5.0 mg and about

[0037] 22.5 mg per day of FHD N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven days, followed by seven days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0038] In certain embodiments, the method includes administering between about 5.0 mg and about

[0039] 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for fourteen days, followed by seven days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0040] In particular embodiments, the method includes administering between about 5.0 mg and about 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven to fourteen days, followed by seven days without administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0041] In particular embodiments, the method includes administering 10 mg per day of N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven days, followed by seven days without administration of N-(1-((4- (6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0042] In particular embodiments, the method includes administering 20 mg per day of N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-l H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, to the subject at least once daily for seven days, followed by seven days without administration of N-(1-((4- (6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0043] For example, on dosing days the method can include (1) administering to the subject between about 5.0 mg and about 15 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (2) administering to the subject between about 5.0 mg and about 10 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (3) administering to the subject between about 5.0 mg and about 7.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (4) administering to the subject between about 7.5 mg and about 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (5) administering to the subject between about 7.5 mg and about 15 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (6) administering to the subject between about 7.5 mg and about 10 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (7) administering to the subject between about 10 mg and about 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (8) administering to the subject between about 10 mg and about 15 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (9) administering to the subject between about 15 mg and about 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, or can include (10) administering to the subject about 5.0 mg per day, about 7.5 mg per day, about 10 mg per day, about 15 mg per day, or about 22.5 mg per day of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2- yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments of any of the above methods, the invention provides a method of treating relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome, or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors in a subject, wherein continuous intravenous infusion of 100 mg / m2 / day, or less, of cytarabine, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered between about once a day for 10 days and about once every 4 days. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered once a day for 4 days. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof, is administered once every 4 days. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg / m2every 12 hours. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg / m2every 12 hours. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein the method can include administering to the subject between about 5.0 mg / m2and about 100 mg / m2per day of cytarabine, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the above methods, the invention provides a method of treating hematological cancer in a subject, wherein the method can include administering to the subject between about 10 mg / m2and about 75 mg / m2(or between about 10 mg / m2and about 50 mg / m2) per day of cytarabine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the cytarabine is administered for 1 to 10 days, after which only N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide is administered. In some embodiments, the method includes, at the initiation of combination therapy in the subject, administering to the subject at least one dose of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin- 2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfony l)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of cytarabine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is pretreated for 1 , 2, 3, 4, 5, 6, 7, or 8 days with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or one complete treatment cycle of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan- 2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide prior to the administration of cytarabine, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the method includes, at the completion of combination therapy in the subject, continuing to administer to the subject N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, without further administering to the subject cytarabine, or a pharmaceutically acceptable salt thereof. For example, the cytarabine treatment can be stopped after 1 to10 days of cytarabine administrations, after which the subject receives additional cycles of N-(1 - ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-l H-pyrrole-3-carboxamide therapy.

[0046] In some embodiments, the method comprises, or consists of, administering cytarabine for a period of 1 to 7 days, or 1 to 5 days.

[0047] In some embodiments, the method includes at least 21 days, 28 days, 2 months, 3 months, 4 months, or 6 months of treatment.

[0048] In some embodiments of any of the above methods, N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally.

[0049] In some embodiments of any of the above methods, cytarabine, or a pharmaceutically acceptable salt thereof, is administered intravenously.

[0050] In some embodiments of any of the above methods, the invention provides a method of treating relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome, or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors in a subject, wherein the decitabine is administered (low dose) at a dose of 15 mg / m2by continuous intravenous transfusion over 3 hours repeated every 8 hours for 3 days. The low dose decitabine cycle is optionally repeated every 6 weeks. In certain embodiments, the cycle is performed once, twice, or three times.

[0051] In certain embodiments of any of the above methods, the invention provides a method of treating relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome, or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors in a subject, wherein the decitabine is administered (high dose) at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days. The high dose decitabine cycle is optionally repeated every 4 weeks. In certain embodiments, the cycle is performed once, twice, or three times. In some embodiments, the method includes, at the initiation of combination therapy in the subject, administering to the subject at least one dose of the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, prior to administering to the subject a dose of decitabine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is pretreated for 1 , 2, 3, 4, 5, 6, 7, or 8 days with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or one complete treatment cycle of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide prior to the administration of decitabine, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, the method includes, at the completion of combination therapy in the subject, continuing to administer to the subject the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, without further administering to the subject decitabine, or a pharmaceutically acceptable salt thereof. For example, the decitabine treatment can be stopped after one, two, or three cycles of low dose decitabine or high dose decitabine administrations, after which the subject receives additional cycles of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide therapy.

[0053] In some embodiments, the method includes at least 21 days, 28 days, 2 months, 3 months, 4 months, or 6 months of treatment.

[0054] In some embodiments of any of the above methods, the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally.

[0055] In some embodiments of any of the above methods, the decitabine, or a pharmaceutically acceptable salt thereof, is administered intravenously.

[0056] In some embodiments, the invention provides a method of treating relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome, or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors in a subject, wherein the risk of developing differentiation syndrome is reduced in the subject relative to treatment with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with decitabine or cytarabine, or a pharmaceutically acceptable salt thereof, alone.

[0057] In some embodiments of any of the above methods, the invention provides a method of depleting or promoting differentiation of blast cells of the leukemia in a subject in need thereof, the method comprising administering to the subject (i) N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) continuous intravenous infusion of 100 mg / m2 / day, or less, of cytarabine, or a pharmaceutically acceptable salt thereof, each in an amount that together is effective in treating hematological cancer. In some embodiments of any of the above methods, the relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome, or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors is characterized by differentiation arrest.

[0058] In some embodiments of any of the above methods, the subject has been treated or is being treated for relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome, or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors is characterized by differentiation arrest.

[0059] In some embodiments, the invention provides a method of treating AML (acute myeloid) or MDS (myelodysplastic syndrome) in a subject. In some embodiments, the AML or MDS has or has been determined to have an inv(3) mutation. In some embodiments, the AML or MDS has or has been determined to have a -7 / del(7q) mutation. In some embodiments, the AML or MDS has or has been determined to have a SF3B1 mutation. In some embodiments, the AML or MDS has or has been determined to have a MLLr mutation. In some embodiments, the AML or MDS has or has been determined to have a RUNX1 mutation. In some embodiments, the AML or MDS has or has been determined to have an ASXL1 mutation. In some embodiments, the AML or MDS has or has been determined to have a JAK2 mutation. In some embodiments, the AML or MDS has or has been determined to have a NRAS mutation. In some embodiments, the AML or MDS has or has been determined to have a KRAS mutation. In some embodiments, the AML or MDS has or has been determined to have a TP53 mutation. In some embodiments, the AML or MDS has or has been determined to have a TET2 mutation. In some embodiments, the AML or MDS has or has been determined to have a DNMT3 mutation.

[0060] In some embodiments, the method of the invention includes administering an anti- hematological cancer agent, in an amount that together with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, that is effective to treat the acute myeloid leukemia or myelodysplastic syndrome. For example, (i) the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the anti- hematological cancer agent are administered within 28 days of each other, within 7 days of each other, within 24 hours of each other, or are administered simultaneously. The combination therapy is administered in amounts and at a frequency that permit both agents to be present at therapeutically effective levels in the plasma compartment of the subject.

[0061] In some embodiments of any of the methods of the invention, the anti-hematological cancer agent is a CD123 targeting agent. In some embodiments of any of the methods of the invention, the CD123 targeting agent is a CD123 antibody-drug conjugate (ADC). In some embodiments of any of the methods of the invention the CD123 ADC is pivekimab sunirine. In some embodiments of any of the methods of the invention, the CD123 ADC is VIP943.

[0062] In some embodiments of any of the method of the invention the subject is naive to intensive chemotherapy due to age or comorbidities. In certain embodiments of any of the method of the invention the subject is naive to intensive chemotherapy due to genetic markers.

[0063] In particular embodiments of any of the method of the invention the subject has failed prior treatment with intensive chemotherapy.

[0064] In some embodiments of any of the method of the invention the subject has failed prior treatment with venetoclax and a hypomethylating agent.

[0065] The invention features a method of treating relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome that failed to respond and / or progressed on a prior therapy in a patient in need thereof that, the method comprising administering to the subject N-(1-((4- (6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof in an amount sufficient to decrease the amount of leukemic stem cells and / or increase the amount of cells expressing CD11 b in the subject.

[0066] In some embodiments, the amount sufficient to decrease the amount of leukemic stem cells and / or increase the amount of cells expressing CD11 b in the subject is at least 5 mg daily. In some embodiments, the amount sufficient to decrease the amount of leukemic stem cells in the subject is 5 to 7.5 mg daily.

[0067] In some embodiment, the subject has a RUNX1 , ASXL1 , BCOR, EZH2, TET2, CEBPA, AKL, CBL, ETV6, SMC1A, NRAS, KRAS, JAK2, TET2, ETNK1 , SF3B1 , KMT2A, FLT3-ITD, DNMT3A, U2AF1 , DDX41 , CUX1 , BRCA1 , MEN1 , CDKN1 Ap, C17Z1 , GATA2, ETV6, KDR, CBFB, NF1 , CBL, H1-B, NFE2, ASXL2, SRSF2, PTPN11 , WT1 , GRIN2AWT1 , CSF3R, PLCG2, ARHGEF28, BRD4, CDK12, KMT20, PARP1 , ZRSR1 , IRF8, MSH6, PPM1 D, IDH1 , EP300, STA2, KMT2C, NCOR1 , CBL, BCR / ABL, PMLRARA, and / or c-Kit mutation.

[0068] In some embodiments, the relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome failed to respond and / or progress upon treatment with a FLT3 inhibitor, an IDH inhibitor, a menin inhibitor, cytarabine, decitabine, daunorubicin, idarubicin, mitoxintrone, azacitidine, venetoclax, and / or glasdegib, or combinations thereof.

[0069] In some embodiments, the method comprises administering N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof to the subject in combination with the prior therapy which the relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome failed to respond to and / or progressed on.

[0070] Definitions

[0071] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; and (iii) the terms “comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.

[0072] As used herein, the term “hematologic cancer,” refers to cancers that begin in blood-forming tissue, such as the bone marrow, or in the cells of the immune system, e.g., leukemias, lymphomas, and myelomas. Leukemias are cancers found in blood and bone marrow which are caused by rapid production of abnormal white blood cells. Lymphomas are cancers which affect the lymphatic system. Myelomas are cancers of the plasma cells. In most hematologic cancers, normal blood cell development is interrupted by uncontrolled growth of an abnormal type of blood cell. The abnormal blood cells prevent the blood from performing many of its functions. Hematologic cancers account for about 10% of all new cancer diagnoses. The 5-year relative survival rates for hematologic cancers range from about 50% to about 90%.

[0073] As used herein, “N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide” refers to the compound having the structure:

[0074] As used herein, the term “decitabine’ refers to 5-aza-2'-deoxycytidine. As used herein, decitabine has the structure:

[0075] As used herein, cytarabine refers to cytosine arabinoside. As used herein, cytarabine has the structure:

[0076] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

[0077] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.

[0078] As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not coformulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while an anti-hematological cancer agent of the combination may be administered orally.

[0079] The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human. Typically, a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.

[0080] A “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration.

[0081] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of a compound described herein. Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting a free base group with a suitable organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be, e.g., acid addition salts involving inorganic or organic acids, or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.

[0082] As used herein, the term “progression-free survival” as used herein, refers to the length of time during and after medication or treatment during which the disease being treated (e.g., cancer) does not get worse. The combination therapies of the invention can increase the likelihood of progression-free survival in a subject.

[0083] As used herein, the term “proliferation” as used in this application involves reproduction or multiplication of similar forms (cells) due to constituting (cellular) elements. The combination therapies of the invention can decrease proliferation of cancer cells.

[0084] As used herein, the term “subject” refers to any organism to which a composition in accordance with the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.

[0085] As used herein, the terms "treat," "treated," or "treating" mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. In the context of treating cancer, treatment may include slowing the spread of metastasis and / or extending progression-free survival in a population of treated subjects as compared to a population of untreated subjects. Compounds of the disclosure may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder.

[0086] As used herein, the term "intensive chemotherapy" refers to the so-called "7 + 3" method, which comprises inducible chemotherapy and is characterized by high dose or standard dose cytarabine for 7 days followed by 3 days of an agth g.gyg.iige or an anthmcenedigne, most often auncm bigm (can be substituted for oxcrybi n or idambigm or mitggganfggne). As used herein, the term “anti-hematological cancer agent” refers to an agent that is known to be useful for treatment of hematological malignancies (i.e., blood cancers). Hematological malignancies include, but are not limited to, acute myeloid leukemia or myelodysplastic syndrome. Examples of anti-hematological cancer agents include, but are not limited to, quizartinib, sunitinib, sorafenib, midosaurin, lestaurtinib, crenolanib, PLX3397, E6201 , AKN-028, ponatinib, ASP2215, KW- 2449, famatinib, DCC-2036, KO-539, SNDX-5613, revumenib, DS-1594a, ivosidenib, enasidenib, olutasidenib, and AG-881.

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0088] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[0089] BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Fig. 1 is a table depicting the reductions in blast counts in the periphery and bone marrow in subjects.

[0091] Fig. 2 is a table depicting the reductions in blast counts in the periphery and bone marrow in subjects.

[0092] Fig. 3 is an image illustrating the development of AML and the mechanism by which many current AML therapies treat the disease.

[0093] Fig. 4 is an image illustrating the cell marker on stem-like cells and the change in markers upon differentiation.

[0094] Fig. 5 is a table depicting the change in differentiation markers in subjects upon treatment.

[0095] Fig. 6 is a graph illustrating the differentiation of leukemic stem cells upon treatment as determined by single-cell RNAseq analysis.

[0096] Fig. 7 is a heatmap depicting cell densities of cells exposed to the combination therapies as in Figure 8, relative to DMSO control on day 14, over a range of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide concentrations as described in Example 3.

[0097] Fig. 8 is a depiction of genes with the greatest difference between LSC and CD11 b+ cells out of a total of 3,055 genes analyzed. Genes with the greatest difference were enriched for known LSC and mature myeloid markers, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0098] The present disclosure features combination therapies including N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide and decitabine for the treatment of AML and related hematological cancers. The combination therapies of the invention can reduce side effects, improve outcomes, and / or reduce the dosing burden on the patient. For example, using the methods described herein the risk of developing differentiation syndrome can be reduced in the subject relative to treatment with the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)- 1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, alone and / or relative to treatment with the decitabine, or a pharmaceutically acceptable salt thereof, alone. In some embodiments, the methods of the present disclosure result in one or more (e.g., two or more, three or more, four or more) of: (a) decrease blast count, (b) normal neutrophil counts, (c) normal platelet counts, (d) a bone marrow biopsy which reveals no clusters or collections of blast cells, (e) decreased tumor recurrence (f) increased survival of subject, (g) increased progression free survival of subject.

[0099] Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.

[0100] Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.

[0101] Exemplary acute myeloid leukemia or myelodysplastic syndrome that may be treated by the invention include, but are not limited to relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors.

[0102] The AML or MDS can be characterized as having an inv(3) mutation, a -7 / del(7q) mutation, a SF3B1 mutation, a MLLr mutation, a RUNX1 mutation, an ASXL1 mutation, a JAK2 mutation, a NRAS mutation, a KRAS mutation, a TP53 mutation, a TET2 mutation, and / or a DNMT3A mutation. The AML or MDS can be characterized as having an intermediate or adverse genetic risk factor, e.g., -5, 5q-, -7, 7q-, 11q23 other than t(9;11), inv(3), t(3;3), t(6;9), t(9;22), and / or a complex karyotype, in some embodiments, the intermediate or adverse genetic risk factors include inv (3), del (7q t(4:7), -8, t(8;12), del (7q), del (7;12), and / or add(1). The AML or MDS can be characterized as having an intermediate or adverse genetic risk factor, e.g., inv(3)(q21q26) and / or t(3;3)(q21 ;q26), a complex karyotype (e.g., a complex karyotype including > 4 unrelated abnormalities, but only in the absence t(15;17)(q22;q21), t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22), abn(3q), except for t(3;5)(q25;q34); inv(3)(q21q26) / t(3;3)(q21 ;q26); add(5q) / del(5q), -5; add(7q) / del(7q), -7; t(6;11)(q27;q23), t(10;11)(p11 ~13;q23), other t(11 q23) with the exception of t(9;11)(p22;q23) and t(11 ;19)(q23;p13); t(9;22)(q34;q11); -17 and abn(17p) or > 3 abnormalities in the absence of t(8;21), inv(16) or t(16;16), t(15; 17), t(9;11 ), t(v;11)(v;q23), t(6;9)(p23;q34) and inv(3) or t(3;3)). The AML or MDS can be characterized as having an intermediate or adverse genetic risk factor, e.g., deletion (i..e, loss) of part of chromosome 5 or 7, translocation or inversion of chromosome 3, translocation between chromosome 6 and 9, translocation between chromosome 9 and 22, abnormalities of chromosome 11 at the spot q23, loss of a chromosome so the cell has only one copy instead of the normal two, or complex changes (i.e., those involving 3 or more chromosomes), or a tp53 alteration.

[0103] N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2- yl)-1 -(methylsulfonyl)-1H-pyrrole-3-carboxamide

[0104] Methods for synthesizing N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)- 3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide are described in International Application No. PCT / US2021 / 015876, the content of which is incorporated herein by reference in its entirety. Methods of treatment of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide are described in International Application No. PCT / US2021 / 015876, the content of which is incorporated herein by reference in its entirety. Methods of treating cancer by N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide are described in International Application No. PCT / US23 / 17829, the content of which is incorporated herein by reference in its entirety.

[0105] In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 22.5 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 15 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 10 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 5.0 mg and about 7.5 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 22.5 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 15 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 7.5 mg and about 10 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 10 mg and about 22.5 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 10 mg and about 15 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of between about 15 mg and about 22.5 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 5.0 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 7.5 mg per day. In some embodiments, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 10 mg per day. In some embodiments, N-(1-((4- (6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 15 mg per day. In some embodiments, N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of the disclosure is administered in total dose of about 22.5 mg per day.

[0106] Additional details are provided in the Examples.

[0107] Relapsed or Refractory AML

[0108] There is a large population of patients whose disease relapses after achieving first morphological complete remission. A 3-year study of 1 ,069 patients who did not undergo aSCT, conducted at MD Anderson Cancer Center, showed that the probability of relapse-free survival at 3 years was 29%. The patients had a median age of 55 years, included 22% with favorable cytogenetics, 64% with intermediate risk cytogenetics, and a 14% with adverse cytogenetics. Younger age and more favorable karyotype were associated with significantly increased rates of relapse-free survival at 1 year (Mangan, 2011). The prognosis of relapsed or refractory AML is poor and the median survival is approximately 6 months (Ferrara, 2004; Giles, 2005; Ritchie, 2013; Craddock, 2014; Plever, 2014).

[0109] For some patients with relapsed or refractory disease treated with chemotherapy alone, there is the potential for long-term disease-free survival, however this is most likely due to hematopoietic stem cell therapy (HSCT). HSCT in first relapse may be successful if a suitable donor can be identified, and the patient can proceed to transplant in a timely fashion. However, when treated patients with relapsed or refractory disease, challenges include accurately assessing the following: prognosis of disease, whether remission can be achieved, and the ability of patients to tolerate aggressive salvage therapies, choosing a successful salvage therapy, and ultimately identifying suitable patients for HSCT. The prognosis in relapsed AML patients is generally poor but depends largely on the timing of relapse (early versus late) and the possibility of allogeneic hematopoietic stem cell transplantation. For patients potentially eligible for hematopoietic stem cell transplantation post- HSCT is frequent, and in spite of salvage attempts, less than 20% of these patients are alive after 5 years (Thol. F., Ganser, A., 2020). For those patients that are not eligible for HSCT, hypomethylating agents, low-dose AraC, and increasingly combination therapy of venetoclax with demethylating agents achieve encouraging response rates. However, there are patients that did not respond to one or more initial therapies (e.g. intensive chemotherapy, venetoclax, or hypomethylating agent, such as azacytidine).

[0110] Decitabine

[0111] Methods of treatment of decitabine are described in US Application No. US20050222076A1 , the content of which is incorporated herein by reference in its entirety. Decitabine is approved for use by the FDA under the name DACOGEN®.

[0112] In some embodiments, decitabine or a pharmaceutically acceptable salt thereof is administered at a dose of 15 mg / m2by continuous intravenous transfusion over 3 hours repeated every 8 hours for 3 days (i.e. , low dose decitabine) in a cycle optionally repeated every 6 weeks. In some embodiments, decitabine or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg / m2by continuous intravenous transfusion over 1 hour repeated daily for 5 days (i.e., high dose decitabine) in a cycle optionally repeated every 4 weeks. The combination therapy can include, one, two, three, or more cycles of decitabine administered in combination with N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-l H-pyrrole-3-carboxamide treatment.

[0113] Cytarabine

[0114] Methods of treatment of cytarabine are described in "Nicholas D. Reese, Gary J. Schiller; Curr Hematol Malig Rep. 2013, 141-148," and Methods of treatment of low dose cytarabine are described in “Jehn U, Goldel N, Vehling-Kaiser U. Low-dose cytosine arabinoside (LD-Ara C) treatment in dysmyelopoietic syndromes (DMPS) and acute myelogenous leukemia (AML). Anticancer Res. 1987. :505-8.” Cytarabine is approved for use by the FDA under the name Cytosar-U®.

[0115] In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of less than 100 mg / m2intravenous daily for a period of 1 to 10 days. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg / m2by continuous intravenous transfusion every 12 hours. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg / m2by continuous intravenous transfusion every 12 hours. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered between about once a day for 4 days and about once every 4 days. In some embodiments, cytarabine, or a pharmaceutically acceptable salt thereof is administered at a dose of between about 5.0 mg / m2and about 100 mg / m2per day (on days cytarabine is dosed).

[0116] FLT3 Inhibitors

[0117] In one embodiment, the invention features a combination therapy including (i) N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of, and (ii) a FLT3 inhibitor. The term "FLT3 pathway inhibitor" or "FLT3 targeting compound" or "FLT3 inhibitor" refers to a compound that specifically binds to and inhibits FLT3, which interferes with the activation of FLT3 - mediated signal transduction pathways and reduces cell proliferation in cancer cells that overexpress FLT3. In certain embodiments, a FLT3 inhibitor is a compound that specifically binds to and inhibits wild type FLT3. In certain embodiments, a FLT3 inhibitor is a compound that specifically binds to and inhibits mutant FLT3, for example, FLT3-ITD (an internal tandem duplication mutation in the JM domain-coding sequence of the FLT3 gene) and / or FLT3-KDM (a missense point mutation at the D835 residue and point mutations, deletions and insertions in the codons surrounding D835 within a TK domain of FLT3).

[0118] Exemplary FLT3 inhibitors for use herein include, but are not limited to quizartinib (AC220), sunitinib (SU11248), sorafenib (BAY 43-9006), midostaurin (PKC412), lestaurtinib (CEP-701), crenolanib (CP- 868596), PLX3397, E6201 , AKN-028, ponatinib (AP24534), ASP2215, KW- 2449, famitinib and DCC- 2036.

[0119] Menin Inhibitors

[0120] In one embodiment, the invention features a combination therapy including (i) N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of, and (ii) a menin inhibitor. The term "menin pathway inhibitor" or "menin targeting compound" or "menin inhibitor" refers to a compound that specifically binds to and inhibits menin, which inhibits the protein-protein interaction of menin with an MLL protein (e.g. MLL1 , MLL2, or MLL fusion protein). In certain embodiments, a menin inhibitor is a compound that specifically binds to and inhibits wild type menin. In certain embodiments, a menin inhibitor is a compound that specifically binds to and inhibits mutant menin, for example, menin-NPM1 (a mutation in the NPM1 gene in exon 12 of the NPM1 gene or a frameshift mutation, where the mutation can be an insertion of two to nine bases or a deletion of nucleotides 965 through 969 (GGAGG)) and or menin-DNMT3A (a mutation in the DNMT3A gene in R882, a frameshift deletion, missense mutation, nonsense mutation, splice-site substitution, splicesite deletion, or whole-gene deletion). Exemplary menin inhibitors for use herein include, but are not limited to, KO-539, SNDX-5613, revumenib, and DS-1594a.

[0121] IDH1 Inhibitor

[0122] In one embodiment, the invention features a combination therapy including (i) N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of, and (ii) an IDH1 inhibitor. The term "IDH1 inhibitor" or "IDH1 targeting compound" refers to a compound that specifically binds to and inhibits wild-type or mutant IDH1 , which inhibits the formation of a dimer, e.g., a homodimer of IDH1 wild-type subunits, a homodimer of IDH1 mutant subunits, or a heterodimer of a mutant and wildtype subunit. In certain embodiments, an IDH1 inhibitor is a compound that specifically binds to inhibits mutant IDH1 , for example, mlDK1 (somatic mutation in IDH1). In certain embodiments, the IDH1 inhibitor also inhibits IDH2. in certain embodiments, iDHI inhibitor binds to an IDH1 mutant subunit anti inhibits neoactivitiy. In some embodiments, the neoactivity inhibition is at least about 60%, 70%, 80%, 90%, 95% or 99% as compared to the activity in the absence of the mutant IDH1 inhibitor. Exemplary IDH1 inhibitors for use herein include, but are not limited to ivosidenib, enasidenib, olutasidenib, and AG-881.

[0123] IDH2 inhibitor

[0124] In one embodiment, the invention features a combination therapy including (i) N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of, and (ii) an IDH2 inhibitor. The term "IDH2 inhibitor" or "IDH2 targeting compound" refers to a compound that specifically binds to and inhibits wild-type or mutant IDH2, which inhibits the formation of a dimer, e.g., a homodimer of IDH2 wild-type subunits, a homodimer of IDH2 mutant subunits, or a heterodimer of a mutant and wildtype subunit. In certain embodiments, an IDH2 inhibitor is a compound that specifically binds to inhibits mutant IDH2, for example, mlDH2 (somatic mutation in IDH2). In certain embodiments, the IDH2 inhibitor also inhibits IDH1 . In certain embodiments, IDH2 inhibitor binds to an IDH2 mutant subunit and inhibits neoactivitiy. In some embodiments, the neoactivity inhibition is at least about 60%, 70%, 80%, 90%, 95% or 99% as compared to the activity in the absence of the mutant IDH1 inhibitor. Exemplary IDH2 inhibitors for use herein include, but are not limited to ivosidenib, enasidenib, olutasidenib, and AG-881.

[0125] CD123 Targeting Agent

[0126] In one embodiment, the invention features a combination therapy including (i) N-(1-((4-(6- (2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide or pharmaceutically acceptable salt of, and (ii) a CD123 targeting agent. The term "CD123 targeting agent" refers to a compound that specifically binds to CD123, e.g., a CD123 antibody or a CD123 antibody-drug conjugate (ADC). A CD123 ADC is typically composed of a monoclonal antibody (mAbs) that binds to an epitope of CD123 covalently attached to a cytotoxic drug via a chemical linker. Exemplary CD123 targeting agents for use herein include, but are not limited to, pivekimab sunirine and VIP943.

[0127] Pharmaceutical Compositions

[0128] The compounds of the present disclosure may be formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include an active agent as described herein and a physiologically acceptable excipient (e.g., a pharmaceutically acceptable excipient). Formulation principles for the compounds disclosed herein may be those described, e.g., in W02020 / 160180, the disclosure of which is incorporated by reference herein in its entirety.

[0129] The compounds of the disclosure may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. Preferably, the compound is administered orally.

[0130] Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP / NF (United States Pharmacopeia and the National Formulary).

[0131] In one embodiment, N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide may be formulated into a unit dosage form for oral administration (e.g., a capsule) as described in Table 1 .

[0132] Table 1. Formulation of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1 -oxopropan-2-yl)-1 -(methylsulfonyl)-l H-pyrrole-3-carboxamide

[0133] Examples

[0134] Example 1. Phase 1 Monotherapy Dose Escalation Study

[0135] N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan- 2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide was studied in relapsed or refractory acute myeloid leukemia and relapsed or refractory myelodysplastic syndrome subjects who had exhausted all treatment options. Doses tested were 2.5 mg, 5 mg, 7.5 mg, and 10 mg orally once daily. Forty subjects were enrolled in the study. Thirty-six subjects had been diagnosed with relapsed or refractory acute myeloid leukemia and four subjects had been diagnosed with relapsed or refractory myelodysplastic syndrome. 67.5% of the subjects had received at least three prior lines of therapy. 82.5% had an abnormal karyotype and 65% had poor genetic risk factors, i.e., adverse genetic status and a broad range of mutations.

[0136] The most common treatment related adverse effects were dry mouth, increased blood bilirubin, increased ALT, and rash. The most common grade 3 or higher treatment related adverse effects were increased blood bilirubin, hypocalcemia, differentiation syndrome, stomatitis, and increased ALT. An expert adjudication committee identified one relapsed or refractory acute myeloid leukemia subject as having definitive differentiation syndrome due to treatment. This subject also had two events of investigator-reported differentiation syndrome. The committee also adjudicated five relapsed or refractory acute myeloid leukemia subjects as indeterminate for differentiation syndrome. Two of these five subjects had at least one event of investigator reported differentiation syndrome. The range of onset of differentiation syndrome was 4 to 42 days. The potential differentiation syndrome symptoms included pleural effusion, pericardial effusion, volume overload, weight gain, elevated WBC counts, hypotension, ground glass opacities and / or pulmonary infiltrates on imaging without documentation of positive cultures, hypoxia, pyrexia, and / or multi-organ involvement (lung, heart, and / or kidneys).

[0137] The detailed characteristics of the subjects in the trial are shown in Table 2. Table 2. Subject Characteristics

[0138] The safety summary of the subjects in the trial are shown in Table 3.

[0139] Table 3. Safety Summary

[0140]

[0141] The summary of grade 3 or higher treatment related adverse effects of the subjects in the trial are shown in Table 4.

[0142] Table 4. Grade 3 or Higher Treatment Related Adverse Effect Summary

[0143] As shown in FIGs. 1 and 2, peripheral blood and bone marrow blast count reduction was observed in a majority of patients with available samples. These reductions were observed across mutation status, cytogenic risk, and dose levels. Several subjects were also found to have neutrophil recovery which is a sign of clinical benefit.

[0144] Example 2. Differentiation of Leukemic Stem Cells in Subjects

[0145] Acute myeloid leukemia is often caused by mutations in hematopoietic stem cells resulting in leukemic stem cells which differentiate into blast cells. As shown in FIG. 3, current AML therapies target proliferative blast leaving the leukemic stem cells behind driving relapse in patients. A combined approach targeting both leukemic stem cells and blasts could theoretically prevent relapse. As shown in FIG. 4, CD34 is a marker of sternness in hematopoietic cells that can differentiate into mature myeloid cells that express CD11 b. During the differentiation process, CD11 b levels increase and CD34 levels decrease.

[0146] Subject samples were analyzed by single-cell RNAseq to determine if any changes to leukemic stem cell levels occurred during treatment. The analysis was conducted as follows:

[0147] Starting with a combined single-cell RNA-seq dataset including all AML patients at screening and treated timepoints, label all leukemic stem cells and CD11 b+ cells. For LSCs, the markers used for this are CD34+ / CD123+ / CD38-. For CD11 b cells, the only marker is CD11 b. Cells are considered positive if they express counts > 0 for the markers. T-cells and erythroid cells prior to combining the single-cell dataset for the above, since we were not interested in those types for the analysis. Run differential expression analysis at single-cell level between the labeled LSCs and the CD11 b+ cells (using Seurat FindMarkers function). Rank genes by the difference in the percentage of cells expressing the gene (LSC percentage - CD11 b+ percentage). Take the top 50 ranked genes upregulated in LSCs as the LSC signature set. Take the top 50 ranked genes upregulated in CD11 b+ cells as the differentiation signature set. To make the single-cell plots per patient, for each cell, take the average counts of the 50 LSC genes — this is the LSC signature score. For each cell, do the same for the 50 differentiation genes — this is the differentiation signature score. For a given patient, for each cell, plot the LSC signature score vs the differentiation signature score. Color by timepoint (either screening or treated). Genes from the 50-gene LSC signature include CD34, EGFL7, FAM30A, BAALC, RBPMS, SMIM24, HOPX, KRT18, TFPI, IGHM, SPINK2, PPP1 R16B, PROM1 (CD133), ABCB1 , BRG1 , BCL2, CD123 / IL3RA, CPXM1 , EMP1 , CDK6, ZBTB46, DNMT3B, SOCS2, MMRN1 , AKR1C3, and LAPTM4B (FIG. 8). Genes from the 50-gene differentiation signature include ITGAM (CD11 b), S100A8, S100A9, LYZ, RBM47, PTPRJ, NCF1 , FGR, FCN1 , S100A11 , CD64, and CD38 (FIG. 8).

[0148] As shown in FIG. 5, biopsies demonstrated that differentiation as measured by CD34 and CD11 b in subjects treated with N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide. Further, as shown in FIG. 6, subject samples showed loss of leukemic stem cell identity and transformation to differentiated marrow. These effects were seen across mutational status, cytogenic risk status, and dose levels.

[0149] Example 3. In vitro study of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide and standard of care cytotoxic agents.

[0150] The AML cell lines were cultured as described in cell culture methods. To determine the concentrations of the combination agents to be used, prior to the study, each cell line was exposed to combination agent of varying doses alone for 7 days. Cell viability was assessed on Day 7 using CellTiter-Glo (Promega #G7571) per manufacturer protocol, from which half-maximal inhibitory concentration (IC50) curves were generated.

[0151] On Day 0, cells were seeded in 6-well plates at the indicated densities (Table 5) and then exposed to DMSO (control) or N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide alone for 7 days, at which time flow cytometric assessment of cell density, CD11 b, and Ki67 was performed. Combination agents (cytarabine, decitabine, or venetoclax) were then added at 3 predetermined concentrations as shown in Figure 9 (1 at the IC50 value and 1 each above and below it); DMSO-only cells were exposed to each cytotoxic agent or DMSO alone for an additional 7 days, while the N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide -only cells were exposed to N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide in combination with each cytotoxic agent or DMSO for an additional 7 days as shown in Figure 8. Flow cytometric analysis of cell density was performed in all cell lines on Days 7 (prior to combination agent addition) and 14 (7 days after combination agent addition) as shown in Figure 10.

[0152] Results: As shown in FIG. 7, treatment of AML cells with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide and standard of care cytotoxic agents can result in more reduction of the cell densities and less cell proliferation over treatment with N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)-

[0153] 1 H-pyrrole-3-carboxamide alone. N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)- 3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide can also sensitize the AML cells to the standard cytotoxic agents. The decitabine combination can be more effective than the venetoclax combination.

[0154] Table 5: Test Article Concentrations

[0155] Abbreviation: IC50 = half-maximal inhibitory concentration.

[0156] Note: Concentrations of combination agent were predetermined by exposing cell lines to combination agent of varying doses alone for 7 days, at which time cell viability was assessed using CellTiter-Glo reagent and IC50 curves were generated.

[0157] Example 4. Treatment of patients with FLT3-resistant AML

[0158] Subjects with FLT3-resistant cancer (e.g., subjects who previously received FLT-3 inhibitors as a monotherapy and who became resistant to their FLT-3 treatment over time) are treated with dose of FLT3 inhibitors and dose of FHD 286, both administered orally. FLT3 inhibitors have been approved for the treatment of AML but leukemia relapse remains to be a major cause of treatment failure. A combination therapy of FLT3 inhibitors and FHD 286 could theoretically prevent relapse or prolong relapse-free survival. The subjects, who are previously treated with FLT3 inhibitors, relapse with FLT3- resistant AML after an initial complete remission. The subjects, who are not previously treated with FHD 286, commence therapy with the regimen of an FLT3 inhibitor and FHD 286.

[0159] The dose of FLT3 inhibitors, or a pharmaceutically acceptable salt, is administered orally with an average daily dose of 100 mg to 1 ,400 mg QD to the subject for a period of at least one to twenty-eight days.

[0160] The dose of FHD 286, or a pharmaceutically acceptable salt thereof, is administered orally with an average daily dose of between 1 .5 mg and 22.5 mg QD to the subject for a period of at least one to twenty-eight days.

[0161] The combination therapy of FLT3 inhibitors and FHD 286 can be dosed in a cyclical on / off dosing regimen. The dose of FLT3 inhibitors is administered to the subject for a period of at least 1 -6 months. The dose of FLT3 inhibitors is repeated multiple times, as needed. The dose of FHD 286 is administered to the subject for a period of at least 1 -6 months. The dose of FHD 286 is repeated multiple times, as needed.

[0162] For some responsive patients, the dosing of FLT3 inhibitor is discontinued after five cycles, four cycles, three cycles, two cycles, or one cycle, after which the patients continue to receive the dosing of FHD 286 alone for a period of at least one month, two months, three months, four months, six months, 1 year, 2 years, 5 years, 10 years or 20 years.

[0163] Subjects receiving combination of FLT3 inhibitor and FHD 286 can reduce rick of relapse or prolong relapse-free survival, relative to a steady high-dose treatment with FLT3 inhibitor alone. Other Embodiments

[0164] While the invention has been described in connection with specific embodiments thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0165] Other embodiments are in the claims.

Claims

What is claimed is:CLAIMS1. A method of treating relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome in a subject in need thereof, the method including administering (i) N-(1-((4-(6- (2, 6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1 -(methylsulfonyl)- 1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent, each in an amount that together is effective to treat the relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome, wherein(a) the subject has not previously been administered a regimen of intensive chemotherapy;(b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse;(c) the subject is refractory to intensive chemotherapy;(d) the subject is refractory to venetoclax and a hypomethylating agent; or(e) the subject has acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors.

2. A method of decreasing the amount of leukemic stem cells in a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome; or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors; the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3- methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the amount of leukemic stem cells in the subject is decreased by at least 50% .

4. The method of claim 2 or 3, wherein the amount of leukemic stems cells in the subject is decreased in the bone marrow of the subject.

5. The method of any one of claims 2-4, wherein the amount of leukemic stems cells in the subject is decreased in the blood of the subject.

6. The method of any one of claims 2-5, wherein:(a) the subject has not previously been administered a regimen of intensive chemotherapy;(b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse;(c) the subject is refractory to intensive chemotherapy; or(d) the subject is refractory to venetoclax and a hypomethylating agent.

7. The method of any one of claims 2-6, wherein the method further includes administering an anti-hematological cancer agent in an amount that together, with the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of leukemic stem cells in the subject.

8. A method of increasing the level of differentiated myeloid cells in a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome; or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors; the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the amount of differentiated myeloid cells in the subject is increased by at least 50%.

10. The method of claim 8 or 9, wherein the amount of differentiated myeloid cells in the subject is increased in the bone marrow of the subject.

11. The method of any one of claims 8-10, wherein the amount of differentiated myeloid cells in the subject is increased in the blood of the subject.

12. The method of any one of claims 8-11 , wherein:(a) the subject has not previously been administered a regimen of intensive chemotherapy;(b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse;(c) the subject is refractory to intensive chemotherapy; or(d) the subject is refractory to venetoclax and a hypomethylating agent.

13. The method of any one of claims 8-12, wherein the method further includes administering an anti-hematological cancer agent in an amount that together with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the level of differentiated myeloid cells in the subject.

14. A method of differentiating leukemic stem cells in a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome; or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors; the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein at least 50% of the leukemic stem cells in the subject are differentiated.

16. The method of claim 14 or 15, wherein the leukemic stem cells in the bone marrow of the subject are differentiated.

17. The method of any one of claims 14-16, wherein the leukemic stem cells in the blood of the subject are differentiated.

18. The method of any one of claims 14-17, wherein:(a) the subject has not previously been administered a regimen of intensive chemotherapy;(b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse;(c) the subject is refractory to intensive chemotherapy; or(d) the subject is refractory to venetoclax and a hypomethylating agent.

19. The method of any one of claims 14-18, wherein the method further includes administering an anti-hematological cancer agent in an amount that together with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective differentiate leukemic stem cells in the subject.

20. A method of increasing the level of cells expressing CD11 b in a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome; or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors; the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

21. The method of claim 20, wherein the level of cells expressing CD11 b in the subject is increased by at least 50%.

22. The method of claim 20 or 21 , wherein the amount of cells expressing CD11 b in the subject is increased in the bone marrow of the subject.

23. The method of any one of claims 20-22, wherein the amount of cells expressing CD11 b in the subject is increased in the blood of the subject.

24. The method of any one of claims 20-23, wherein:(a) the subject has not previously been administered a regimen of intensive chemotherapy;(b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse;(c) the subject is refractory to intensive chemotherapy; or(d) the subject is refractory to venetoclax and a hypomethylating agent.

25. The method of any one of claims 20-24, wherein the method further includes administering an anti-hematological cancer agent in an amount that together, with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of cells expressing CD11 b in the subject.

26. A method of decreasing the level of cells expressing CD34 in a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome; or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors; the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein the level of cells expressing CD34 in the subject is decreased by at least 50%.

28. The method of claim 26 or 27, wherein the amount of cells expressing CD34 in the subject is decreased in the bone marrow of the subject.

29. The method of any one of claims 26-28, wherein the amount of cells expressing CD34 in the subject is decreased in the blood of the subject.

30. The method of any one of claims 26-29, wherein:(a) the subject has not previously been administered a regimen of intensive chemotherapy;(b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse;(c) the subject is refractory to intensive chemotherapy; or(d) the subject is refractory to venetoclax and a hypomethylating agent.31 . The method of any one of claims 26-30, wherein the method further includes administering an anti-hematological cancer agent in an amount that together, with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to decrease the amount of cells expressing CD34 in the subject.

32. A method of decreasing the amount of common myeloid progenitor cells in a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome; or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors; the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the amount of common myeloid progenitor cells in the subject is decreased by at least 50%.

34. The method of claim 32 or 33, wherein the amount of common myeloid progenitor cells in the subject is decreased in the bone marrow of the subject.

35. The method of any one of claims 32-34, wherein the amount of common myeloid progenitor cells in the subject is decreased in the blood of the subject.

36. The method of any one of claims 32-35, wherein:(a) the subject has not previously been administered a regimen of intensive chemotherapy;(b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse;(c) the subject is refractory to intensive chemotherapy; or(d) the subject is refractory to venetoclax and a hypomethylating agent.

37. The method of any one of claims 32-36, wherein the method further includes administering an anti-hematological cancer agent, in an amount that together with the amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof is effective to decrease the amount of common myeloid progenitor cells in the subject.

38. A method of increasing the amount of monocytes in a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome; or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors; the method comprising administering to the subject an effective amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1- oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

39. The method of claim 38, wherein the amount of monocytes in the subject is increased by at least 50%.

40. The method of claim 38 or 39, wherein the amount of monocytes in the subject is increased in the bone marrow of the subject.41 . The method of any one of claims 38-40, wherein the amount of monocytes in the subject is increased in the blood of the subject.

42. The method of any one of claims 38-41 , wherein:(a) the subject has not previously been administered a regimen of intensive chemotherapy;(b) the subject has not previously been administered venetoclax and a hypomethylating agent after relapse;(c) the subject is refractory to intensive chemotherapy; or(d) the subject is refractory to venetoclax and a hypomethylating agent.

43. The method of any one of claims 38-42, wherein the method further includes administering an anti-hematological cancer agent in an amount that together, with the amount of N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to increase the amount of monocytes in the subject.

44. A method of treating acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors in a subject in need thereof, the method including administering (i) N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti- hematological cancer agent, each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors.

45. The method of claim 44, wherein the intermediate or adverse genetic risk factors include -5, 5q~, -7, 7q~, 11q23 other than t(9;11), inv(3), t(3;3), t(6;9), t(9;22), and / or a complex karyotype.

46. The method of claim 44, wherein the intermediate or adverse genetic risk factors include inv (3), del (7q t(4:7), -8, t(8;12), del (7q), del (7;12), and / or add(1).

47. The method of claim 44, wherein the intermediate or adverse genetic risk factors include inv(3) or t(3;3), t(6;9), t(v;11)(v;q23), -5 or del(5q), -7 and / or abn(17p).

48. The method of claim 44, wherein the intermediate or adverse genetic risk factors include inv(3)(q21q26) and / or t(3;3)(q21 ;q26).

49. The method of any one of claims 44-48, wherein the subject further has a tp53 alteration.

50. A method of treating acute myeloid leukemia or myelodysplastic syndrome with complex karyotype in a subject in need thereof, the method including administering (i) N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent, each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with complex karyotype.

51. The method of claim 50, wherein the complex karyotype includes(i) > 4 unrelated abnormalities, but only in the absence of t(15;17)(q22;q21), t(8;21)(q22;q22), Inv(16)(p13q22) or t(16;16)(p13;q22), abn(3q), except for t(3;5)(q25;q34); Inv(3)(q21q26) / t(3;3)(q21 ;q26); add(5q) / del(5q), -5; add(7q) / del(7q), -7; t(6;11)(q27;q23), t(10;11)(p11 -13;q23), other t(11q23) with the exception of t(9;11)(p22;q23) and t(11 ;19)(q23;p13); t(9;22)(q34;q11); -17 and abn(17p), or(ii) > 3 abnormalities in the absence oft(8;21), inv(16) ort(16;16), t(15;17), t(9;11), t(v;11)(v;q23), t(6;9)(p23;q34) and inv(3) or t(3;3).

52. The method of claim 50 or 51 , wherein the subject further has a tp53 alteration.

53. A method of treating acute myeloid leukemia or myelodysplastic syndrome with high EVI1 expression in a subject in need thereof, the method including administering (i) N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent, each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with high EVI1 expression.

54. The method of claim 53 wherein the subject has cytogenetics including 3q26, inv (3) (q21q26) / t (3; 3) (q21 ; q26) / t (3, 21) (q26;q22) (7).

55. The method of claim 53 or 54 wherein the subject has an MLL-ENL fusion.

56. The method of any one of claims 1 -55, wherein the subject has a RUNX1 , ASXL1 , BCOR, EZH2, TET2, CEBPA, AKL, CBL, ETV6, SMC1A, NRAS, KRAS, JAK2, TET2, ETNK1 , SF3B1 , KMT2A, FLT3-ITD, DNMT3A, U2AF1 , DDX41 , CUX1 , BRCA1 , MEN1 , CDKN1 Ap, C17Z1 , GATA2, ETV6, KDR, CBFB, NF1 , CBL, H1-B, NFE2, ASXL2, SRSF2, PTPN11 , WT1 , GRIN2AWT1 , CSF3R, PLCG2, ARHGEF28, BRD4, CDK12, KMT20, PARP1 , ZRSR1 , IRF8, MSH6, PPM1 D, IDH1 , EP300, STA2, KMT2C, NCOR1 , CBL, BCR / ABL, PMLRARA, and / or c-Kit mutation.

57. A method of treating acute myeloid leukemia or myelodysplastic syndrome with an FLT3 mutation in a subject in need thereof, the method including administering (i) N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent that is a FLT3 inhibitor, each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with a FLT3 mutation.

58. A method of treating acute myeloid leukemia or myelodysplastic syndrome with a MLL rearrangement and / or an NMP1 mutation in a subject in need thereof, the method including administering (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 - (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti- hematological cancer agent that is a menin inhibitor, each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with a MLL rearrangement and / or an NMP1 .

59. A method of treating acute myeloid leukemia or myelodysplastic syndrome with an IDH1 or IDH2 mutation in a subject in need thereof, the method including administering (i) N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent that is an IDH1 or IDH2 inhibitor, each in an amount that together is effective to treat the acute myeloid leukemia or myelodysplastic syndrome with an IDH1 or IDH2 mutation.

60. A method of decreasing the amount of blast cells in the spleen of a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors, the method including administering (i) N-(1 -((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1 - oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent that is an IDH1 or IDH2 inhibitor, each in an amount that together is effective to decrease the amount of blast cells in the spleen of the subject.61 . A method of slowing the growth of the spleen of a subject with relapsed / refractory acute myeloid leukemia or myelodysplastic syndrome or acute myeloid leukemia or myelodysplastic syndrome with intermediate or adverse genetic risk factors, the method including administering (i) N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) an anti-hematological cancer agent that is an IDH1 or IDH2 inhibitor, each in an amount that together is effective to slow the growth of the spleen of the subject.

62. The method of any one of claims 1 -61 , wherein the amount of N-(1 -((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is between 1.5 mg and 10 mg per day.

63. The method of claim 62, wherein the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin- 2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfony l)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is 1 .5 mg per day.

64. The method of claim 62, wherein the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin- 2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfony l)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is 2.5 mg per day.

65. The method of claim 62, wherein the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin- 2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfony l)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is 3 mg per day.

66. The method of claim 62, wherein the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin- 2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfony l)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is 5 mg per day.

67. The method of claim 62, wherein the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin- 2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfony l)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is 6 mg per day.

68. The method of claim 62, wherein the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin- 2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfony l)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is 7.5 mg per day.

69. The method of claim 62, wherein the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin- 2-yl)thiazol-2-yl)amino)-3-methoxy-1 -oxopropan-2-yl)-1 -(methylsulfony l)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is 10 mg per day.

70. The method of any one of claims 1-69, wherein the peripheral blast count in the subject is decreased by at least 50%.

71. The method of any one of claims 1-70, wherein the bone marrow blast counts in the subject are decreased by at least 50%.

72. The method of any one of claims 1-71 , wherein the neutrophil count in the subject is increased by at least 50%.

73. The method of any one of claims 1-72, wherein the subject is red blood cell and / or platelet infusion independent after administration of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2- yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

74. The method of any one of claims 2-6, 8-12, 14-18, 20-24, 26-30, 32-36, 38-42, and 62-73, wherein the method further includes administering an anti-hematological cancer agent in an amount that together, with the amount of N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, is effective to treat the acute myeloid leukemia or myelodysplastic syndrome.

75. The method of any one of claim 1 , 7, 13, 19, 25, 31 , 37, 43, 44-61 or 74, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the anti-hematological cancer agent, are administered within 28 days of each other.

76. The method of claim 75, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the anti-hematological cancer agent, are administered within 7 days of each other.

77. The method of claim 76, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the anti-hematological cancer agent, are administered within 24 hours of each other.

78. The method of claim 77, wherein (i) the N-(1-((4-(6-(2,6-dimethylmorpholino)pyridin-2- yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof, and (ii) the anti-hematological cancer agent, are administered simultaneously.

79. The method of any one of claims 2-6, 8-12, 14-18, 20-24, 26-30, 32-36, 38-42, and 62-78, wherein the anti-hematological cancer agent is a CD123 targeting agent.

80. The method of claim 79, wherein the CD123 targeting agent is a CD123 antibody-drug conjugate (ADC).81 . The method of claim 80, wherein the CD123 ADC is pivekimab sunirine.

82. The method of any one of claims 1 -81 , wherein the subject is naive to intensive chemotherapy due to age or comorbidities.

83. The method of any one of claims 1 -81 , wherein the subject is naive to intensive chemotherapy due to genetic markers.

84. The method of any one of claims 1 -81 , wherein the subject has failed prior treatment with intensive chemotherapy.

85. The method of any one of claims 1 -81 , wherein the subject has failed prior treatment with venetoclax and a hypomethylating agent.

86. A method of treating relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome that failed to respond and / or progressed on a prior therapy in a patient in need thereof that, the method comprising administering to the subject N-(1-((4-(6-(2,6- dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1 H- pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof in an amount sufficient to decrease the amount of leukemic stem cells and / or increase the amount of cells expressing CD11 b in the subject.

87. The method of claim 86, wherein the amount sufficient to decrease the amount of leukemic stem cells and / or increase the amount of cells expressing CD11 b in the subject is at least 5 mg daily.

88. The method of claim 86 or 87, wherein the amount sufficient to decrease the amount of leukemic stem cells in the subject is 5 to 7.5 mg daily.

89. The method of any one of claims 86-88, wherein the subject has a RUNX1 , ASXL1 , BCOR, EZH2, TET2, CEBPA, AKL, CBL, ETV6, SMC1A, NRAS, KRAS, JAK2, TET2, ETNK1 , SF3B1 , KMT2A, FLT3-ITD, DNMT3A, U2AF1 , DDX41 , CUX1 , BRCA1 , MEN1 , CDKN1 Ap, C17Z1 , GATA2, ETV6, KDR, CBFB, NF1 , CBL, H1-B, NFE2, ASXL2, SRSF2, PTPN11 , WT1 , GRIN2AWT1 , CSF3R, PLCG2, ARHGEF28, BRD4, CDK12, KMT20, PARP1 , ZRSR1 , IRF8, MSH6, PPM1 D, IDH1 , EP300, STA2, KMT2C, NCOR1 , CBL, BCR / ABL, PMLRARA, and / or c-Kit mutation.

90. The method of any one of claims 86-89, wherein the relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome failed to respond and / or progress upon treatment with a FLT3 inhibitor, an IDH inhibitor, a menin inhibitor, cytarabine, decitabine, daunorubicin, idarubicin, mitoxintrone, azacitidine, venetoclax, and / or glasdegib, or combinations thereof.

91. The method of any one of claims 86-90, wherein the method comprises administering N-(1- ((4-(6-(2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1- (methylsulfonyl)-1 H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof to the subject in combination with the prior therapy which the relapsed / refractory acute myeloid leukemia or relapsed / refractory myelodysplastic syndrome failed to respond to and / or progressed on.