Abstract
PurposeDinaciclib inhibits cyclin-dependent kinases 1, 2, 5, and 9 with a better therapeutic index than flavopiridol in preclinical studies. This study assessed the activity of dinaciclib in acute leukemia both in the clinic and in vitro.MethodsAdults with relapsed/refractory acute myeloid leukemia (n = 14) and acute lymphoid leukemia (n = 6) were treated with dinaciclib 50 mg/m2 given as a 2-h infusion every 21 days.ResultsMost patients had dramatic but transient reduction in circulating blasts; however, no remissions were achieved on this schedule. The most common toxicities were gastrointestinal, fatigue, transaminitis, and clinical and laboratory manifestations of tumor lysis syndrome, including one patient who died of acute renal failure. Dinaciclib pharmacokinetics showed rapid (2 h) achievement of maximum concentration and a short elimination/distribution phase. Pharmacodynamic studies demonstrated in vivo inhibition of Mcl-1 expression and induction of PARP cleavage in patients’ peripheral blood mononuclear cells 4 h after dinaciclib infusion, but the effects were lost by 24 h and did not correlate with clinical outcome. Correlative in vitro studies showed that prolonged exposures to dinaciclib, at clinically attainable concentrations, result in improved leukemia cell kill.ConclusionsWhile dinaciclib given as a 2-h bolus did not exhibit durable clinical activity, pharmacokinetic and pharmacodynamic data support the exploration of prolonged infusion schedules in future trials in patients with acute leukemias. Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-013-2249-z) contains supplementary material, which is available to authorized users.
Highlights
Uncontrolled proliferation and deregulated cell cycle progression are hallmarks of many human cancers, including acute leukemias
Pharmacodynamic studies demonstrated in vivo inhibition of Mcl-1 expression and induction of PARP cleavage in patients’ peripheral blood mononuclear cells 4 h after dinaciclib infusion, but the effects were lost by 24 h and did not correlate with clinical outcome
Single-agent dinaciclib 50 mg/m2 given as a 2-h infusion has potent, but short-lived, cytoreductive activity, without objective responses observed in our patients with advanced acute leukemia
Summary
Uncontrolled proliferation and deregulated cell cycle progression are hallmarks of many human cancers, including acute leukemias. Cyclin-dependent kinases (CDKs) are serine/threonine kinases that primarily regulate the mammalian cell cycle and represent an appealing therapeutic target [1,2,3]. Progression through the cell cycle is a complex process that depends on synchronized activity of different CDKs (CDK1, CDK2, CDK4, CDK6), their phosphorylation status, and association with cyclins and endogenous Cip/Kip or INK4 inhibitors [4,5,6,7]. Inhibition of transcriptional CDKs may induce cell death through down-regulation of several short-lived proteins, including the anti-apoptotic proteins Mcl-1 and XIAP [13,14,15,16]
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