The "hybrid" administration of flavopiridol followed in a time sequence by arabinoside (Ara-C) and mitoxantrone showed significant clinical activity in adults with relapsed and refractory leukaemias, reports the phase I "hybrid FLAM" study in Blood.

Flavopiridol is a protein bound cytotoxic cyclin-dependent kinase inhibitor that inhibits cell cycle progression by targeting multiple cyclin-dependent kinases, inducing checkpoint arrest, interrupting transcriptional elongation and triggering cell death via multiple mechanisms.

The hypothesis-driven design of the FLAM regimen was that administration of flavopiridol to marrow leukaemic blasts followed sequentially by Ara-C should result in synergistic enhancement of Ara-C related blast cell apoptosis.

In an attempt to overcome human serum protein binding of flavopiridol, a hybrid schedule of flavopiridol administration was developed involving a 30 minute bolus of approximately one-third to one-half of the total dose followed by a four hour infusion of the remainder.

Clinical data in high-risk CLL patients has already demonstrated that this administration schedule induced an acute tumour lysis syndrome (TLS) characterized by massive hyperkalemia, hyperphosphatemia, and increases in lactic dehydrogenase (LDH), with a dramatic and durable clinical response in 40 to 50% of refractory patients, including those with poor-risk genetic features and/or bulky disease.

Judith Karp and colleagues, from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (Baltimore, MD), conducted a phase 1 trial of "Hybrid FLAM" to explore the hybrid bolus-infusion flavopiridol schedule in a dose-escalation fashion. The purpose of their study was to determine the maximal tolerated dose (MTD) of "hybrid" flavopiridol administration used in timed sequence with Ara-C and mitoxantrone, as well as to explore the pharmacokinetics and pharmacodynamics of the schedule.

Between May 2007 and January 2009, 55 adults with relapsed/refractory acute leukaemias started treatment at a total flavopiridol dose of 50 mg/m ² per day three times ( 20 mg/m ² bolus, 30-mg/m² infusion).

Results showed that the dose limiting toxicity occurred at level 6 ( involving 30-mg/m² bolus and 70-mg/m ²" infusion) with tumour lysis, hyperbilirubinemia and mucositis. Death occurred in five patients (9%), with complete remission in 22 (44%) across all doses and the overall and disease-free survivals for complete remission patients were more than 60% at more than two years. The authors recommended a "hybrid" dose bolus of 30mg/m ² followed by infusions of 60mg/m ² daily for three days.

In the current study, target modulation occurred to various degrees in the majority of the 12 patients' leukaemia blast populations with HMGA1, STAT-3, E2F-1, POLr2A , and VEGF-A m RNA down regulation occurring in 67 to 83% of patients. The finding that flavopiridol inhibits transcription of HMGA1 mRNA, write the authors, sheds new light on the mechanisms by which flavopiridol may exert its antileukemic effects at the level of the leukaemia stem cell.

Article: JE Karp, B Douglas Smith, LS Resar, et al. Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukaemias. Blood. 2011: 117: 3302-3310.