Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias

Abstract

Purpose: Dinaciclib 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.

Methods: Adults with relapsed/refractory acute myeloid leukemia (n = 14) and acute lymphoid leukemia (n = 6) were treated with dinaciclib 50 mg/m(2) given as a 2-h infusion every 21 days.

Results: Most 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.

Conclusions: While 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.

Figures

Fig. 1

The effects of dinaciclib on circulating WBCs, pharmacokinetics, and pharmacodynamics. a Graph demonstrating rapid decline in the WBC count in AML patients after treatment with dinaciclib, followed by gradual recovery, usually by day 15. b Graph demonstrating rapid decline in the WBC count in ALL patients after treatment with dinaciclib. c Population pharmacokinetic (PPK) model-based prediction of plasma concentration versus time profiles following a single 2-h infusion of 50 mg/m2 dinaciclib. d Western blot analysis of protein lysates obtained from PBMC collected prior to and at 4 and 24 h after dinaciclib infusion to measure the expression of p-Rb and Mcl-1 and induction of PARP cleavage. β-actin controls are shown to document equivalent loading and transfer of proteins. Lanes were loaded with 8–25 μg of protein

Fig. 2

Prolonged exposure to dinaciclib effectively inhibits proliferation, induces apoptosis, and down-regulates Mcl-1 and phospho-Rb expression in primary leukemia cells. a Six primary AML samples were exposed to DMSO (control) or dinaciclib (0.0004–10 μM) for 24 h and the IC50 values were estimated using the WST-1 assay. b Primary AML cells (AML 08) were exposed to dinaciclib (2, 20, and 200 nM) for the indicated times and the extent of cell death was monitored by measuring Annexin V/PI staining by flow cytometry. c Five primary AML and ALL samples were exposed to DMSO (control) and dinaciclib (20 and 200 nM) for 6 and/or 24 h, after which whole cells were lysed and proteins extracted, and subjected to Western blot analysis to measure the expression of PARP, Mcl-1, p-Rb. β-actin controls are shown to document equivalent loading and transfer of proteins. Lanes were loaded with 8–25 μg of protein