Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia

Abstract

Flavopiridol, a cyclin-dependent kinase inhibitor, is cytotoxic to leukemic blasts. In a Phase II study, flavopiridol 50 mg/m 2 was given by 1-hour infusion daily × 3 beginning Day 1 followed by 2 gm/ m 2 /72 hr ara-C beginning Day 6 and 40 mg/m 2 mitoxantrone on Day 9 (FLAM) to 45 adults with newly diagnosed acute myelogenous leukemia (AML) with multiple poor risk features. Thirty patients (67%) achieved complete remission (CR) and 4 (9%) died. Twelve (40%) received myeloablative allogeneic bone marrow transplant (BMT) in first CR. Median OS and DFS are not reached (67% alive 12.5-31 months, 58% in CR 11.4-30 months), with median follow-up 22 months. Sixteen received FLAM in CR, with median OS and DFS 9 and 13.1 months, and 36% alive at 21-31 months. Short OS and DFS correlated with adverse cytogenetics, regardless of age or treatment in CR. The addition of allogeneic BMT in CR translates into long OS and DFS in the majority of eligible patients.

Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia

“…19 In order to mitigate imbalance in randomization, patients were stratified by presence or absence of secondary AML, antecedent MDS or MPD six months or more prior to AML transformation, and therapy for antecedent disorder. 29,30 As in previous FLAM trials, [16][17][18][19] a 72-h continuous infusion of ara-C 2 gms/m 2 (667 mg/m 2 /24 h) began Day 6 and mitoxantrone 40 mg/m 2 was administered as an intravenous bolus over 60-120 min on Day 9, 12 h after completing ara-C. Patients who achieved CR after cycle 1 were eligible to receive a second cycle of FLAM beginning 21±7 days following hospital discharge from the first cycle.…”

“…[5][6][7][8][9][10][11][12][13][14][15] We have conducted longitudinal clinical-laboratory studies of flavopiridol followed in a timed sequential manner by ara-C and mitoxantrone (FLAM). [16][17][18][19] The hypothesis-driven design of FLAM was generated in an in vitro model where flavopiridol followed by ara-C enhanced ara-C related apoptosis in marrow leukemic blasts. 20,21 Serial trials of FLAM in poor-risk AML [16][17][18] have documented reproducible and durable CRs and low morbidity and mortality.…”

“…[16][17][18][19] The hypothesis-driven design of FLAM was generated in an in vitro model where flavopiridol followed by ara-C enhanced ara-C related apoptosis in marrow leukemic blasts. 20,21 Serial trials of FLAM in poor-risk AML [16][17][18] have documented reproducible and durable CRs and low morbidity and mortality. For newly diagnosed, poor-risk patients, 67% achieved CR, 9% died in the first 60 days, and median overall survival (OS) and disease-free survival (DFS) for patients achieving CR were 12.6 and 13.3 months, respectively.…”

“…For newly diagnosed, poor-risk patients, 67% achieved CR, 9% died in the first 60 days, and median overall survival (OS) and disease-free survival (DFS) for patients achieving CR were 12.6 and 13.3 months, respectively. 18 Flavopiridol is highly protein-bound in human serum. [22][23][24][25] To overcome binding, Byrd and Grever 26 developed a pharmacologically-modeled 'hybrid' schedule of flavopiridol administration of a 30-min bolus of between one-third and half the total dose, followed by a 4-h infusion of the remainder.…”

“…The 'hybrid' schedule yielded dramatic responses in more than 50% of refractory chronic lymphocytic leukemia (CLL) patients, accompanied by severe tumor lysis syndrome. [26][27][28] Based on our phase II data using 1-h bolus flavopiridol in FLAM, [16][17][18] and the results of single-agent hybrid flavopiridol in CLL, we conducted a phase I trial of 'hybrid FLAM' built on the template of previous trials. 19 Dose-limiting toxicity occurred with 100 mg/m 2 (30 mg/m 2 bolus, 70 mg/m 2 infusion), with tumor lysis, hyperbilirubinemia and mucositis.…”