Anti-cancer effects of jak2 inhibitors in combination with thalidomide derivatives and glucocorticoids

Abstract

The present invention provides methods of treatment for hematological malignancies involving synergistic combination of a JAK2 inhibitor and a glucocorticoid or a JAK2 inhibitor, thalidomide or thalidomide derivative, and a glucocorticoid. The compositions and methods provide an unexpected efficacy in the treatment for hematological disorders. The hematological disorders treated by the current invention include multiple myeloma, and may also include hematological disorders that are refractory to prior cancer treatments, or a relapsed hematologic disorder.

1 . A method of treating or preventing a hematological malignancy in a subject comprising administering to the subject a JAK2 inhibitor, and thalidomide or a derivative thereof. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the hematological malignancy is selected from the group consisting of: multiple myeloma, chronic lymphocytic leukemia, or B-cell non-Hodgkin lymphoma. 
     
     
         4 . The method  claim 1 , wherein the JAK2 inhibitor is selected from the group consisting of: ruxolitinib, fedratinib, baricitinib, Pacritinib, AZD1480, XL019, LY2784544, BMS-911543, NS-018, CYT387, atiprimod dihydrochloride, CP 690550, Cucurbitacin I, 1,2,3,4,5,6-Hexabromocyclohexane, Lestaurtinib, NSC 33994, and SD 1008. 
     
     
         5 . The method of  claim 1 , wherein the JAK2 inhibitor comprises ruxolotinib, baricitinib, Pacritinib, CYT387, and CP 690550. 
     
     
         6 . The method of  claim 1 , wherein the thalidomide or the derivative thereof is selected from the group consisting of: thalidomide, lenalidomide, pomalidomide, linomide, CC-1088, CDC-501, and CDC-801. 
     
     
         7 . The method of  claim 1 , wherein the thalidomide or the derivative thereof comprises-lenalidomide or pomalidomide. 
     
     
         8 .- 11 . (canceled) 
     
     
         12 . The method of  claim 1 , comprising administering:
 a) ruxolotinib and lenalidomide;   b) ruxolitinib and pomalidomide;   c) baricitinib and lenalidomide;   d) bariticinib and pomalidomide; or   e) CYT387 and pomalidomide   to the subject.   
     
     
         13 .- 43 . (canceled) 
     
     
         44 . A method of treating a hematological malignancy in a subject comprising administering to the subject, a JAK2 inhibitor, thalidomide or a derivative thereof, and a glucocorticoid. 
     
     
         45 . (canceled) 
     
     
         46 . The method  claim 44 , wherein the hematological malignancy is selected from the group consisting of: multiple myeloma, chronic lymphocytic leukemia, or B-cell non-Hodgkin lymphoma. 
     
     
         47 . The method of  claim 44 , wherein the subject was previously treated with a chemotherapeutic agent. 
     
     
         48 . The method of  claim 44 , wherein the subject was previously treated with doxorubicin or a derivative thereof, melphalan, etoposide, cytarabine, and bendamustine. 
     
     
         49 . The method of  claim 44 , wherein the subject was previously treated with a proteasome inhibitor. 
     
     
         50 . The method of  claim 44 , wherein the subject was previously treated with bortezomib. 
     
     
         51 . The method of  claim 44 , wherein the subject was previously treated with thalidomide or a derivative thereof. 
     
     
         52 . The method of  claim 44 , wherein the subject was previously treated with a glucocorticoid. 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 44 , wherein the JAK2 inhibitor is selected from the group consisting of: ruxolitinib, fedratinib, baricitinib, Pacritinib, AZD1480, XL019, LY2784544, BMS-911543, XL019, NS-018, CYT387, atiprimod dihydrochloride, CP 690550, Cucurbitacin I, 1,2,3,4,5,6-Hexabromocyclohexane, Lestaurtinib, NSC 33994, and SD 1008. 
     
     
         56 . The method of  claim 44 , wherein the JAK2 inhibitor comprises ruxolitinib baricitinib, pacritinib, CYT387, and CP 690550. 
     
     
         57 . The method of  claim 44 , wherein thalidomide or the derivative thereof is selected from the group consisting of: thalidomide, lenalidomide, pomalidomide, linomide, CC-1088, CDC-501, and CDC-801. 
     
     
         58 . The method of  claim 44 , wherein thalidomide or the derivative thereof comprises lenalidomide or pomalidomide. 
     
     
         59 . The method of  claim 44 , wherein the glucocorticoid is selected from the group consisting of: hydroxycortisone, cortisone, desoxycorticosterone, fludrocortisone, betamethasone, dexamethasone, prednisolone, prednisone, methylprednisolone, methylprednisone, paramethasone, triamcinolone, flumethasone, fluocinolone, fluocinonide, fluprednisolone, halcinonide, flurandrenolide, meprednisone, medrysone, and esters and mixtures thereof. 
     
     
         60 . The method of  claim 44 , wherein the glucocorticoid comprises dexamethasone. 
     
     
         61 . The method of  claim 44 , wherein the glucocorticoid comprises methylprednisolone, methylprednisone or prednisone. 
     
     
         62 . (canceled) 
     
     
         63 . The method of  claim 44 , wherein;
 a) ruxolitinib, lenalidomide, and dexamethasone; or   b) CP 690550, lenalidomide, and dexamethasone;   are administered to the subject.   
     
     
         64 .- 72 . (canceled) 
     
     
         73 . The method of  claim 1 , wherein the subject was previously treated with a chemotherapeutic agent. 
     
     
         74 . The method of  claim 1 , wherein the subject was previously treated with doxorubicin or a derivative thereof, melphalan, etoposide, cytarabine, and bendamustine. 
     
     
         75 . The method of  claim 1 , wherein the subject was previously treated with a proteasome inhibitor. 
     
     
         76 . The method of  claim 1 , wherein the subject was previously treated with bortezomib. 
     
     
         77 . The method of  claim 1 , wherein the subject was previously treated with thalidomide or a derivative thereof. 
     
     
         78 . The method of  claim 1 , wherein the subject was previously treated with a glucocorticoid. 
     
     
         79 . The method of  claim 1 , wherein the subject was previously treated with thalidomide or a derivative thereof, and a glucocorticoid.