Assays and methods for selecting a treatment regimen for a subject with leukemia

Abstract

Diagnostic methods for identifying cancer bearing subjects appropriate for treatment with CPX-351 include genetic and ex vivo testing of cells from a candidate subject. Combination treatment with CPX-351 and FLT-3 inhibitors improve CPX-351 uptake and toxicity.

1 . A method to determine the susceptibility of a hematologic cancer-bearing subject to treatment with a liposomal formulation, the method comprising assaying a biological sample of the subject to determine:
 (a) the presence or absence of a mutation in the Fms-like tyrosine receptor kinase 3 (FLT-3) gene in the subject; and/or   (b) the presence or absence of a mutation in the nucleophosmin 1 (NPM-1) gene in the subject; and/or   (c) the presence or absence of a mutation in the CCAAT enhancer binding protein alpha (CEBPα) gene in the subject; and/or   (d) the genotype of the subject as favorable risk, intermediate-I, intermediate-II, or adverse risk,   
       wherein the liposomal formulation comprises cytarabine and daunorubicin co-encapsulated at a synergistic molar ratio. 
     
     
         2 . The method of  claim 1 , wherein the liposomal formulation comprises cytarabine and daunorubicin co-encapsulated at a 5:1 molar ratio. 
     
     
         3 . The method of  claim 1 , wherein the liposomal formulation is a low-cholesterol liposomal formulation. 
     
     
         4 . The method of  claim 1 , wherein the hematologic cancer is selected from the group consisting of acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPNs), and lymphomas. 
     
     
         5 . The method of  claim 1 , wherein the biological sample comprises blood, serum, plasma, saliva, or blast cells. 
     
     
         6 . The method of  claim 1 , wherein the method comprises determining the presence or absence of a mutation in the Fms-like tyrosine receptor kinase 3 (FLT-3) gene in the subject. 
     
     
         7 . The method of  claim 6 , wherein the mutation is an FLT-3 activating mutation. 
     
     
         8 . The method of  claim 6 , wherein the mutation is an FLT-3-ITD or FLT-3-TKD. 
     
     
         9 . The method of  claim 1 , wherein the method further comprises exposing hematologic cancer cells from the subject to the liposomal formulation in a cell culture ex vivo and measuring the responsiveness of the hematologic cancer cells to exposure to the liposomal formulation. 
     
     
         10 . The method of  claim 9 , wherein the responsiveness of the hematologic cancer cells is determined by measuring the IC 50  or IC 90  of the liposomal formulation of the cells in the cell culture. 
     
     
         11 . The method of  claim 9 , wherein the responsiveness of the hematologic cancer cells is determined by measuring the uptake of the liposomal formulation by the cells in the cell culture. 
     
     
         12 . A method to treat a hematologic cancer in a cancer-bearing subject, the method comprising:
 (a) exposing hematologic cancer cells from the subject to a liposomal formulation in a cell culture ex vivo; and   (b) measuring the responsiveness of the hematologic cancer cells to exposure to the liposomal formulation; and   (c) administering a therapeutically effective amount of the liposomal formulation to a subject whose cells respond to the exposure,   
       wherein the liposomal formulation comprises cytarabine and daunorubicin co-encapsulated at a synergistic molar ratio. 
     
     
         13 . The method of  claim 12 , wherein the liposomal formulation comprises cytarabine and daunorubicin co-encapsulated at a 5:1 molar ratio. 
     
     
         14 . The method of  claim 12 , wherein the liposomal formulation is a low-cholesterol liposomal formulation. 
     
     
         15 . The method of  claim 12 , wherein the hematologic cancer is selected from the group consisting of acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPNs), and lymphomas. 
     
     
         16 . The method of  claim 15 , wherein the responsiveness of the hematologic cancer cells is determined by measuring the IC 50  or IC 90  of the liposomal formulation of the cells in the cell culture. 
     
     
         17 . The method of  claim 15 , wherein the responsiveness of the hematologic cancer cells is determined by measuring the uptake of the liposomal formulation by the cells in the cell culture.