Method for treating hematopoietic neoplasms

Abstract

This invention relates to methods for treating a hematopoietic neoplasm comprising administering a therapeutically effective amount of a combretastatin compound, or a pharmaceutically acceptable salt thereof, to a subject having a hematological malignancy, wherein the combretastatin compound comprises a catechol or quinone moiety and is capable of forming a reactive oxygen species (ROS) in vivo. The method may further comprise co-administering a second chemotherapeutic agent.

We claim: 
     
         1 . A method of treating a myeloid neoplasm comprising administering a therapeutically effective amount of a combretastatin compound comprising combretastatin A-1 diphosphate (CA1dP): 
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable salt of CA1dP, combretastatin A-4 phosphate (CA4P): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of CA4dP, to a subject having a malignancy comprising a myeloid neoplasm. 
       
     
     
         2 . The method of  claim 1 , wherein the combretastatin compound is a pharmaceutically acceptable salt of combretastatin A-1 diphosphate (CA1dP). 
     
     
         3 . The method of  claim 2 , wherein the cation of the salt can be either a divalent cation or two monovalent cations. 
     
     
         4 . The method of  claim 2 , wherein, the divalent cation is a divalent metal cation. 
     
     
         5 . The method of  claim 2 , wherein, the monovalent cation is an alkali metal, an aliphatic amine or an ammonium. 
     
     
         6 . The method of  claim 2 , wherein, the monovalent cation is selected from the group consisting of sodium, TRIS, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)-ethylamine, choline, and hydrabamine. 
     
     
         7 . The method of  claim 1 , wherein the combretastatin compound is a pharmaceutically acceptable salt of combretastatin A-4 phosphate (CA4P). 
     
     
         8 . The method of  claim 1 , wherein the myeloid neoplasm is an acute myeloid leukemia (AML). 
     
     
         9 . The method of  claim 1 , wherein the myeloid neoplasm is a refractory organ-infiltrating leukemia. 
     
     
         10 . The method of  claim 1 , wherein the pharmaceutically acceptable salt is a potassium salt of combretastatin A-1 diphosphate. 
     
     
         11 . The method of  claim 1 , further comprising co-administering a chemotherapeutic agent to the subject having a myeloid neoplasm. 
     
     
         12 . The method of  claim 11 , wherein the chemotherapeutic agent is Ara-C, etoposide, thioguanine or cyclophosphamide. 
     
     
         13 . The method of  claim 1 , wherein the therapeutically effective amount includes a dose of 1.0 mg to 1000 mg of compound. 
     
     
         14 . A method of treating acute myeloid leukemia (AML) comprising administering a therapeutically effective amount of a combretastatin compound comprising combretastatin A-1 diphosphate (CA1dP): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, to a subject having acute myeloid leukemia. 
       
     
     
         15 . The method of  claim 14 , wherein the combretastatin compound is a pharmaceutically acceptable salt of combretastatin A-1 diphosphate (CA1dP). 
     
     
         16 . The method of  claim 15 , wherein the cation of the salt can be either a divalent cation or two monovalent cations. 
     
     
         17 . The method of  claim 15 , wherein, the divalent cation is a divalent metal cation. 
     
     
         18 . The method of  claim 15 , wherein, the monovalent cation is an alkali metal, an aliphatic amine or an ammonium. 
     
     
         19 . The method of  claim 15 , wherein, the monovalent cation is selected from the group consisting of sodium, TRIS, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)-ethylamine, choline, and hydrabamine. 
     
     
         20 . A method of treating a myeloid neoplasm comprising administering a therapeutically effective amount of a combretastatin compound to a subject having a malignancy comprising a myeloid neoplasm, wherein the combretastatin compound is a compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein
 each R 1  independently is selected from C 1-6  alkoxy, halogen and halo-substituted C 1-6  alkyl; 
 R 2  is selected from C 1-6  alkoxy, halogen and halo-substituted C 1-6  alkyl; 
 R 3  and R 4  each independently is selected from hydroxyl or 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein
 each Y independently is OR 5  or NHR 5 , or O − , wherein each R 5  independently is selected from hydrogen and C 1-6  alkyl; and Z is O or S. 
 
           
         
       
     
     
         21 . The method of  claim 20 , wherein the myeloid neoplasm is an acute myeloid leukemia (AML).