Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)

Abstract 186

Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy

F is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m² daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m² bolus over 30 min followed by 40 mg/m² in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below.

Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens.