Combination Treatment for Hematological Cancers

Abstract

The present invention relates to a combination treatment for hematological cancers. More specifically; a combination of a telomerase inhibitor and a Bcl-2 inhibitor are useful in treating hematological cancers, including AML. In certain embodiments, the telomerase inhibitor is imetelstat or imetelstat sodium and the Bcl-2 inhibitor is ABT-199.

What is claimed is: 
     
         1 . A method of treating a hematological cancer comprising administering a telomerase inhibitor and a Bcl-2 inhibitor in combination to a subject in need thereof. 
     
     
         2 . The method of  claim 1  wherein the hematological cancer is acute myeloid leukemia, essential thrombocythemia, polycythemia vera, primary myelofibrosis, systemic mastocytosis, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, type 1, refractory anemia with excess blasts, type 2, myelodysplastic syndrome (MDS) with isolated del (5q), MDS unclassifiable, chronic myelomonocytic leukemia (CML), atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, myeloproliferative/myelodysplastic syndromes—unclassifiable, B lymphoblastic leukemia/lymphoma, T lymphoblastic leukemia/lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma/leukemia, follicular lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, Mantle cell lymphoma, marginal zone lymphomas, post-transplant lymphoproliferative disorders, HIV-associated lymphomas, primary effusion lymphoma, intravascular large B-cell lymphoma, primary cutaneous B-cell lymphoma, hairy cell leukemia, monoclonal gammopathy of unknown significance, smoldering multiple myeloma, and solitary plasmacytomas (solitary bone and extramedullary). 
     
     
         3 . The method of  claim 1  wherein the hematological cancer is acute myeloid leukemia. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the telomerase inhibitor is imetelstat. 
     
     
         5 . The method of  claim 4  wherein imetelstat is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising:
 (a) intravenous administration of about 7-10 mg/kg imetelstat once every four weeks; 
 (b) intravenous administration of about 7-10 mg/kg imetelstat once weekly for four weeks; 
 (c) intravenous administration of about 2.5-10 mg/kg imetelstat once every three weeks; or 
 (d) intravenous administration of about 0.5-9.4 mg/kg imetelstat once every four weeks. 
 
     
     
         6 . The method of  claim 5 , wherein imetelstat is imetelstat sodium. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the Bcl-2 inhibitor is ABT-199. 
     
     
         8 . The method of  claim 7 , wherein ABT-199 is administered at a dose of
 (a) about 50-400 mg ABT-199 daily;   (b) about 2 mg ABT-199 on day 1 with daily escalation to a final dose of about 800 mg on day 6 and daily thereafter; or   (c) about 25 mg ABT-199 on day 1 with daily escalation to a final dose of about 400 mg on day 5 and daily thereafter.   
     
     
         9 . The method of  claim 8  wherein the administration of ABT-199 is one day before, one day after, or the same day as, the administration of the telomerase inhibitor. 
     
     
         10 . A method of inducing apoptosis in a hematologic cancer cell comprising contacting the cell with a therapeutically effective amount of a telomerase inhibitor and contacting the cell with a therapeutically effective amount of a Bcl-2 inhibitor. 
     
     
         11 . The method of  claim 10 , wherein the telomerase inhibitor is imetelstat. 
     
     
         12 . The method of  claim 11 , wherein imetelstat is imetelstat sodium. 
     
     
         13 . The method of any of  claims 10 - 12 , wherein the Bcl-2 inhibitor is ABT-199. 
     
     
         14 . The method of  claim 10 , wherein the hematological cancer cell is cell selected from the following types of hematological cancer: acute myeloid leukemia; essential thrombocythemia; polycythemia vera; primary myelofibrosis; systemic mastocytosis; chronic myeloid leukemia; chronic neutrophilic leukemia; chronic eosinophilic leukemia; refractory anemia with ringed sideroblasts; refractory cytopenia with multilineage dysplasia; refractory anemia with excess blasts; type 1; refractory anemia with excess blasts; type 2; myelodysplastic syndrome (MDS) with isolated del (5q); MDS unclassifiable; chronic myelomonocytic leukemia (CML); atypical chronic myeloid leukemia; juvenile myelomonocytic leukemia; myeloproliferative/myelodysplastic syndromes—unclassifiable; B lymphoblastic leukemia/lymphoma; T lymphoblastic leukemia/lymphoma; diffuse large B-cell lymphoma; primary central nervous system lymphoma; primary mediastinal B-cell lymphoma; Burkitt lymphoma/leukemia; follicular lymphoma; chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma; B-cell prolymphocytic leukemia; lymphoplasmacytic lymphoma/Waldenström macroglobulinemia; Mantle cell lymphoma; marginal zone lymphomas; post-transplant lymphoproliferative disorders; HIV-associated lymphomas; primary effusion lymphoma; intravascular large B-cell lymphoma; primary cutaneous B-cell lymphoma; hairy cell leukemia; monoclonal gammopathy of unknown significance; smoldering multiple myeloma; and solitary plasmacytomas (solitary bone and extramedullary). 
     
     
         15 . The method of  claim 10  wherein the hematological cancer cell is an acute myeloid leukemia (AML) cell. 
     
     
         16 . A kit, comprising:
 (a) a dose of a telomerase inhibitor, in an amount effective, when administered, to induce apoptosis in a hematologic cancer cell; and   (b) a dose of a Bcl-2 inhibitor, in an amount effective, when administered, to induce apoptosis in a hematologic cancer cell.   
     
     
         17 . The kit of  claim 16 , wherein the telomerase inhibitor is imetelstat, and wherein the Bcl-2 inhibitor is ABT-199. 
     
     
         18 . A method of treating acute myeloid leukemia comprising administering imetelstat and ABT-199 to a subject having acute myeloid leukemia. 
     
     
         19 . An in vitro method of inducing apoptosis in an acute myeloid leukemia (AML) cell comprising: contacting the cell with a therapeutically effective amount of imetelstat sodium; and contacting the cell with a therapeutically effective amount of ABT-199. 
     
     
         20 . A pharmaceutical composition comprising imetelstat and ABT-199. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the imetelstat is imetelstat sodium. 
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein the composition is formulated for treatment of acute myeloid leukemia. 
     
     
         23 . Use of imetelstat or imetelstat sodium for treating a hematological cancer in a patient undergoing BCL inhibition therapy. 
     
     
         24 . Use of ABT-199 for treating a hematological cancer in a patient undergoing telomerase inhibition therapy. 
     
     
         25 . A telomerase inhibitor for use in a method of treating hematological cancer, the method comprising administering the telomerase inhibitor and a Bcl-2 inhibitor in combination to a subject in need thereof. 
     
     
         26 . A combination comprising a telomerase inhibitor and a Bcl-2 inhibitor for use in a method of treating hematological cancer, the method comprising administering the combination to a subject in need thereof. 
     
     
         27 . The telomerase inhibitor for use according to  claim 25  or the combination for use according to  claim 26  wherein the hematological cancer is acute myeloid leukemia (AML), essential thrombocythemia, polycythemia vera, primary myelofibrosis, systemic mastocytosis, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, type 1, refractory anemia with excess blasts, type 2, myelodysplastic syndrome (MDS) with isolated del (5q), MDS unclassifiable, chronic myelomonocytic leukemia (CML), atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, myeloproliferative/myelodysplastic syndromes—unclassifiable, B lymphoblastic leukemia/lymphoma, T lymphoblastic leukemia/lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma/leukemia, follicular lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, Mantle cell lymphoma, marginal zone lymphomas, post-transplant lymphoproliferative disorders, HIV-associated lymphomas, primary effusion lymphoma, intravascular large B-cell lymphoma, primary cutaneous B-cell lymphoma, hairy cell leukemia, monoclonal gammopathy of unknown significance, smoldering multiple myeloma, and solitary plasmacytomas (solitary bone and extramedullary). 
     
     
         28 . The telomerase inhibitor for use according to  claim 25  or the combination for use according to  claim 26 , wherein the hematological cancer is acute myeloid leukemia. 
     
     
         29 . The telomerase inhibitor for use according to  claim 25  or the combination for use according to  claim 26 , wherein the telomerase inhibitor is imetelstat. 
     
     
         30 . The telomerase inhibitor for use according to  claim 29  or the combination for use according to  claim 29 , wherein the telomerase inhibitor is imetelstat sodium. 
     
     
         31 . The telomerase inhibitor for use according to  claim 29  or the combination for use according to  claim 29 , wherein imetelstat is administered for administration for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising:
 (a) intravenous administration of about 7-10 mg/kg imetelstat once every four weeks; 
 (b) intravenous administration of about 7-10 mg/kg imetelstat once weekly for four weeks; or
 c) intravenous administration of about 2.5-7 mg/kg imetelstat once every three weeks; or 
 
 (c) intravenous administration of about 0.5-9.4 mg/kg imetelstat once every four weeks. 
 
     
     
         32 . The telomerase inhibitor for use according to  claim 25  or the combination for use according to  claim 26 , wherein the Bcl-2 inhibitor is ABT-199. 
     
     
         33 . The telomerase inhibitor for use according to  claim 32  or the combination for use according to  claim 32 , wherein the ABT-199 is for administration at a dose of:
 (a) 50-400 mg ABT-199 daily; 
 (b) 2 mg ABT-199 on day 1 with daily escalation to a final dose of 800 mg on day 6 and daily thereafter; or 
 (c) 25 mg ABT-199 on day 1 with daily escalation to a final dose of 400 mg on day 5 and daily thereafter. 
 
     
     
         34 . The telomerase inhibitor for use according to  claim 25  or the combination for use according to  claim 26 , wherein the administration of ABT-199 is one day before, one day after, or the same day as, the administration of the telomerase inhibitor. 
     
     
         35 . The telomerase inhibitor for use according to  claim 25  or the combination for use according to  claim 26 , wherein the combination of telomerase inhibitor and Bcl-2 inhibitor induces apoptosis of hematologic cancer cells. 
     
     
         36 . Imetelstat sodium for use in a method of treating acute myeloid leukemia (AML), the method comprising administering imetelstat sodium and ABT-199 in combination to a subject in need thereof. 
     
     
         37 . ABT-199 for use in a method of treating acute myeloid leukemia (AML), the method comprising administering ABT-199 and imetelstat sodium in combination to a subject in need thereof. 
     
     
         38 . A combination comprising imetelstat sodium and ABT-199 for use in a method of treating acute myeloid leukemia (AML), the method comprising administering the combination to a subject in need thereof. 
     
     
         39 . Imetelstat sodium for use according to  claim 36 , ABT-99 for use according to  claim 37  or the combination for use according to  claim 38 , wherein imetelstat sodium is for administration for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising:
 (a) intravenous administration of about 7-10 mg/kg imetelstat sodium once every four weeks; 
 (b) intravenous administration of about 7-10 mg/kg imetelstat sodium once weekly for four weeks; 
 (c) intravenous administration of about 2.5-7 mg/kg imetelstat sodium once every three weeks; or 
 (d) intravenous administration of about 0.5-9.4 mg/kg imetelstat sodium once every four weeks. 
 
     
     
         40 . Imetelstat sodium for use according to  claim 36 , ABT-99 for use according to  claim 37  or the combination for use according to  claim 38 , wherein the ABT-199 is for administration at a dose of:
 (a) about 50-400 mg ABT-199 daily; 
 (b) about 2 mg ABT-199 on day 1 with daily escalation to a final dose of about 800 mg on day 6 and daily thereafter; or 
 (c) about 25 mg ABT-199 on day 1 with daily escalation to a final dose of about 400 mg on day 5 and daily thereafter. 
 
     
     
         41 . Imetelstat sodium for use according to  claim 36 , ABT-99 for use according to  claim 37  or the combination for use according to  claim 38 , wherein the administration of ABT-199 is one day before, one day after, or the same day as, the administration of imetelstat sodium.