Methods of treating hematologic cancers using pnp inhibitors such as forodesine in combination with alkylating agents or anti-cd20 agents

Abstract

The present application relates to treatment of hematologic cancers, which treatments can include, e.g., administration of a purine nucleoside phosphorylase (PNP) inhibitor, an alkylating agent and/or an anti-CD20 agent, and related compositions and kits.

1 . A method of treating a hematologic cancer in a subject comprising the steps of:
 (a) administering to the subject an effective amount of a purine nucleoside phosphorylase (PNP) inhibitor; and   (b) administering to the subject an effective amount of an alkylating agent or an anti-CD20 agent.   
     
     
         2 . The method of  claim 1 , wherein the PNP inhibitor is Forodesine. 
     
     
         3 . The method of  claim 1 , wherein the alkylating agent is selected from a mustard derivative, a nitrosourea derivative, a platinum compound, and an imidazole carboxamide compound. 
     
     
         4 . The method of  claim 3 , wherein the alkylating agent is a mustard derivative. 
     
     
         5 . The method of  claim 4 , wherein the alkylating agent is Bendamustine. 
     
     
         6 . The method of  claim 1 , wherein the anti-CD20 agent is Rituximab. 
     
     
         7 . The method of  claim 1 , wherein the PNP inhibitor and alkylating agent or anti-CD20 agent are administered concurrently. 
     
     
         8 . The method of  claim 1 , wherein the PNP inhibitor and alkylating agent or anti-CD20 agent are administered sequentially. 
     
     
         9 . The method of  claim 8 , wherein the alkylating agent or anti-CD20 agent is administered one or more times prior to administration of the PNP inhibitor. 
     
     
         10 . The method of  claim 1 , wherein the hematologic cancer is selected from chronic lymphocytic leukemia and acute lymphoblastic leukemia. 
     
     
         11 . The method of  claim 10 , wherein the hematologic cancer is chronic lymphocytic leukemia. 
     
     
         12 . The method of  claim 10 , wherein the hematologic cancer is acute lymphoblastic leukemia. 
     
     
         13 . The method of  claim 1 , wherein an effective amount of an alkylating agent is administered to the subject. 
     
     
         14 . The method of  claim 1 , wherein an effective amount of an anti-CD20 agent is administered to the subject. 
     
     
         15 . The method of  claim 1 , wherein the method comprises administering to the subject an effective amount of a PNP inhibitor, an effective amount of an alkylating agent, and an effective amount of an anti-CD20 agent. 
     
     
         16 . The method of  claim 15 , wherein the PNP inhibitor, alkylating agent and anti-CD20 agent are administered concurrently. 
     
     
         17 . The method of  claim 15 , wherein the PNP inhibitor, alkylating agent and anti-CD20 agent are administered sequentially. 
     
     
         18 . The method of  claim 17 , wherein the alkylating agent and anti-CD20 agents are administered one or more times prior to administration of the PNP inhibitor. 
     
     
         19 . A method of treating a hematologic cancer in a subject resistant to one or more chemotherapeutic agents comprising the steps of:
 (a) identifying a subject resistant to one or more chemotherapeutic agents; and   (b) administering to the subject a PNP inhibitor.   
     
     
         20 . The method of  claim 19 , wherein the PNP inhibitor is Forodesine. 
     
     
         21 . The method of  claim 19 , wherein the subject is resistant to one or more chemotherapeutic agents selected from the group consisting of an alkylating agent and a purine nucleoside analogue. 
     
     
         22 . The method of  claim 21 , wherein the alkylating agent is Bendamustine. 
     
     
         23 . The method of  claim 21 , wherein the purine nucleoside analogue is Fluradadine. 
     
     
         24 . The method of  claim 21 , wherein the hematologic cancer is selected from chronic lymphocytic leukemia and acute lymphoblastic leukemia. 
     
     
         25 . The method of  claim 24 , wherein the hematologic cancer is chronic lymphocytic leukemia. 
     
     
         26 . The method of  claim 24 , wherein the hematologic cancer is acute lymphoblastic leukemia. 
     
     
         27 . A method of treating a subject with a hematologic cancer comprising the steps of:
 (a) detecting a p53 deletion in one or more cancer cells in a sample from the subject; and   (b) administering to the subject a PNP inhibitor.   
     
     
         28 . The method of  claim 27 , wherein the PNP inhibitor is Forodesine. 
     
     
         29 . The method of  claim 27 , further comprising detecting the presence of a 17p deletion. 
     
     
         30 . The method of  claim 27 , further comprising determining if one or more cancer cells in the sample are resistant to one or more chemotherapeutic agents. 
     
     
         31 . The method of  claim 30 , wherein the cancer cell or cells are resistant to one or more chemotherapeutic agents selected from the group consisting of an alkylating agent and a purine nucleoside analogue. 
     
     
         32 . The method of  claim 27 , wherein the hematologic cancer is selected from chronic lymphocytic leukemia and acute lymphoblastic leukemia. 
     
     
         33 . The method of  claim 32 , wherein the hematologic cancer is chronic lymphocytic leukemia. 
     
     
         34 . The method of  claim 32 , wherein the hematologic cancer is acute lymphoblastic leukemia. 
     
     
         35 . A pharmaceutical composition comprising a PNP inhibitor and an alkylating agent or an anti-CD20 agent. 
     
     
         36 . The composition of  claim 35 , wherein the PNP inhibitor is Forodesine. 
     
     
         37 . The composition of  claim 35  that comprises Forodesine and Bendamustine. 
     
     
         38 . The composition of  claim 35  that comprises Forodesine and Rituximab. 
     
     
         39 . The composition of  claim 35  that comprises a PNP inhibitor, an alkylating agent, and an anti-CD20 agent. 
     
     
         40 . The composition of  claim 39  that comprises Forodesine, Bendamustine and Rituximab. 
     
     
         41 . A kit comprising a PNP inhibitor and an alkylating agent or an anti-CD20 agent. 
     
     
         42 . The kit of  claim 41 , further comprising a delivery system for the PNP inhibitor, the alkylating agent, the anti-CD20 agent, or any combination thereof. 
     
     
         43 . The kit of  claim 41 , further comprising instructions for treating a subject. 
     
     
         44 . The kit of  claim 41  comprising a PNP inhibitor and an alkylating agent. 
     
     
         45 . The kit of  claim 41  comprising a PNP inhibitor and an anti-CD20 agent. 
     
     
         46 . The kit of  claim 41  wherein the PNP inhibitor is Forodesine. 
     
     
         47 . The kit of  claim 41  that comprises Forodesine and Bendamustine. 
     
     
         48 . The kit of  claim 41  that comprises Forodesine and Rituximab. 
     
     
         49 . The kit of  claim 41  that comprises a PNP inhibitor, an alkylating agent, and an anti-CD20 agent. 
     
     
         50 . The kit of  claim 49  that comprises Forodesine, Bendamustine and Rituximab. 
     
     
         51 . A kit that comprises a PNP inhibitor. 
     
     
         52 . The kit of  claim 51 , further comprising a label that indicates that the contents are to be administered to a subject that is resistant to an alkylating agent. 
     
     
         53 . The kit of  claim 51 , further comprising a label that indicates that the contents are to be administered to a subject with a p53 deletion. 
     
     
         54 . The kit of  claim 51 , further comprising a label that indicates that the contents are to be administered with an alkylating agent or an anti-CD20 agent.