There is still a pressing need to find effective therapy for patients with relapsed or refractory CLL, especially those with genetically high-risk disease, such as with complex abnormal karyotype or del17p. Dinaciclib is a selective inhibitor of cyclin-dependent kinases, which resulted in an ORR of 54% in a phase 1 study of 52 patients with relapsed/refractory CLL (Flynn JMM, et al. Blood. 2013;122. Abstract 871). In an effort to improve ORR and to reduce the risk for hyperacute tumor lysis syndrome (TLS), a phase 1b/2 study was conducted by Jones and colleagues to investigate the safety and efficacy of dinaciclib when given with ofatumumab in patients with relapsed or refractory CLL (Blood. 2014;124. Abstract 329). The treatment plan included 3 stages: cycle 1 consisted of ofatumumab on days 1, 8, 15, and 22; cycle 2 consisted of ofatumumab as in cycle 1 plus dinaciclib on days 2, 8, and 15; cycles 3 to 7 consisted of ofatumumab on day 1 plus dinaciclib on days 1, 8, and 15.
At the time the data were reported at ASH 2014, 36 patients had been treated with a median of 4 cycles, and 15 had completed all planned therapy. Early discontinuation was reported in patients as a result of AEs (N = 5), intercurrent illness (N = 4), disease progression (N = 6), choice of alternate therapy (N = 4), or death (N = 1). The main toxicities observed with this regimen were neutropenia, anemia, thrombocytopenia, infection, hyperglycemia, hypertension, hypophosphatemia, hypoalbuminemia, diarrhea, and hypokalemia. TLS was observed in only 1 patient. The treatment responses were reported as partial response in 42% of the patients, with stable disease in 44% of patients. The median PFS was 10.38 months, which is not significantly different from other therapies used in this patient population.
Although it appears that dinaciclib can be safely administered with ofatumumab to patients with relapsed/refractory CLL in a stepwise dose-escalation protocol, further study with this agent in combination with other targeted agents is warranted to increase efficacy.
