Phosphorylation of GSK3β is Prognostic for Inferior Survival in Acute Myeloid Leukemia

Abstract

Background: Midostaurin (PKC412) is a FLT3 kinase inhibitor with activity in acute myeloid leukemia (AML). Hypomethylating agents play an important role in the treatment of AML and MDS. We investigated the safety (phase I) and clinical activity (phase II) of combination of 5-azacytidine (AZA) and PKC412 in pts with R/R AML and MDS. Method: Pts 18 years with MDS, CMML or AML, who failed prior therapies with performance status 2, adequate liver (bilirubin 2x ULN, ALT 2.5x ULN) and renal (creatinine 2x ULN) functions were eligible. Pts received AZA 75 mg/m subcutaneously or intravenously for 7 days of each cycle (Days 1-7) and PKC412 at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8-21). Pts planned to receive up to 12 cycles if benefit from treatment. Supportive care was standard. Results: 14 pts included in phase I. 1 pt was inevaluable for DLT (withdrawal before completing cycle#1). 6 pts treated in cohort 1 and 7 in cohort 2. 1 pt in cohort 2 received PKC412 dose as per cohort 1 dose by pt error. Pt characteristics and responses are summarized in table 1. The overall response rate (ORR) was 3/13(21%) 2 with CRi, 1 pt dropped BM blasts form 27% to 7% after 2 cycles and went to transplant. 1/4 with FLT3-ITD achieved CRi, 2 of the non-responders received prior FLT3 inhibitors (1 had developed FLT3 D835). All toxicities were grade 1 (nausea 1 pt, vomiting 1 pt, dry skin 1 pt, and rash 1 pt) with no difference between the 2 groups. No DLT was identified. Conclusion: PKC412+AZA is safe and well tolerated at the intended doses with good ORR in high risk pts with R/R AML. Phase II study is enrolling pts with FLT3-ITD. Updated result will be presented. Table 1 Patients Characteristics and Responses Parameter