METHODS OF TREATING HEMATOLOGIC CANCERS USING PNP INHIBITORS SUCH AS FORODESINE IN COMBINATION WITH ALKYLATING AGENTS OR ANTI-CD20 AGENTS
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.