Letters to Blood To the editor: Efficacy and safety of dinaciclib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia Paolo Ghia, 1,2, * Lydia Scarf ` o, 1,2, * Susan Perez, 3 Kumudu Pathiraja, 3 Martha Derosier, 3 Karen Small, 3 Christine McCrary Sisk, 3 and Nigel Patton 4 1 Universit ` a Vita-Salute San Raffaele, Milan, Italy; 2 IRCCS Istituto Scientifico San Raffaele, Milan, Italy; 3 Merck & Company, Incorporated, Kenilworth, NJ; and 4 Auckland City Hospital, Auckland, New Zealand Novel approaches targeting molecules involved in intracellular path- ways that are crucial for the survival and proliferation of the leuke- mic clone have been recently approved for the treatment of chronic lymphocytic leukemia (CLL) patients. Nevertheless, CLL remains incurable outside of allogeneic stem cell transplant, and novel treat- ment options for relapsed/refractory patients remain an unmet clinical need. Cyclin-dependent kinases (CDKs), key regulators of cell cycle progression, have become attractive therapeutic targets in oncology and hematology, 1,2 given the role of aberrant cell cycle regulation in the pathogenesis of many cancers, including leukemias. CDK inhibitors offer the potential of simultaneous blockade of cell cycle progression and transcription, facilitating the induction of apoptosis and reactivation of the TP53 tumor suppressor mechanism. These agents have shown potent activity in patients with CLL. 3 The pan-CDK inhibitor fla- vopiridol demonstrated clinical efficacy 4,5 but was associated with tumor lysis syndrome (TLS), which occurred in 25% of patients, some of whom required hemodialysis. 6 Dinaciclib is a novel, potent, small-molecule CDK inhibitor that selectively inhibits CDK1, 2, 5, and 9 at 50% inhibitory concentration values in the 1- to 4-nM range. 7,8 In in vitro studies, dinaciclib induced apoptosis and/or cell growth arrest in various solid and hematopoietic tumor cell models. 9-11 Additionally, dinaciclib produces caspase- independent downregulation of messenger RNA and protein expres- sion of the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which is essential for CLL cell survival. 12 In murine xenograft models, dinaciclib exhibited a superior therapeutic index compared with flavopiridol. 9 Phase 1 studies of dinaciclib demonstrated acceptable toxicity, with typical adverse events (AEs) represented by cytopenias, transient laboratory abnormalities, and TLS. 13,14 A phase 1 study of dinaciclib in patients with CLL showed a partial response rate of ;63% in pretreated subjects at the recommended phase 2 dose (14 mg/m 2 ), 13 including responses in high-risk subgroups, such as patients with deletion of 17p (del17p). 13 Ofatumumab is a fully humanized type I anti-CD20 monoclo- nal antibody, 15,16 which binds to a different epitope of CD20 than rituximab. 17 A phase 1/2 study in relapsed/refractory CLL demon- strated that ofatumumab had an overall response rate (ORR) of 50% and was generally well tolerated, even at high doses. 18 Ofatumumab has shown activity in subjects with fludarabine- and alemtuzumab- refractory and bulky fludarabine-refractory CLL, irrespective of prior treatment with rituximab. 19 However, the phase 3 RESONATE trial demonstrated a remarkably lower ORR in patients with relapsed/ refractory CLL treated with ofatumumab (4.1%; used as control arm vs ibrutinib). 20 Here, we present the results of a randomized, open-label, phase 3 trial designed to compare the efficacy and tolerability of dinaciclib with ofatumumab in patients with relapsed/refractory CLL (registered at www.clinicaltrials.gov as #NCT01580228; study P012). At the time of study initiation, ofatumumab was the only therapy specifically approved for refractory CLL patients and was therefore selected as the comparison arm. Patients with confirmed CLL, as defined by the 2008 International Workshop on CLL criteria, 21 and no response or disease relapse within 6 or 24 months after fludarabine or chemoimmunother- apy, respectively, were enrolled. Dinaciclib was administered IV at escalating doses of 7 to 10 to 14 mg/m 2 (on days 1, 8, and 15, respectively) in cycle 1 and 14 mg/m 2 in cycle 2 and thereafter (1 cycle 5 28 days) for 12 cycles. Ofatumumab was administered IV once weekly for 8 weeks starting in cycle 1 on day 1, followed by 9 monthly doses as follows: 300 mg in cycle 1 on day 1; 2000 mg in cycle 1 on days 8, 15, and 22 and cycle 2 on days 1, 8, 15, and 22, and every 4 weeks starting from 5 weeks later on day 1 of cycles 4 to 12. Table 1. Baseline demographics and disease characteristics Dinaciclib (n 5 20) Ofatumumab (n 5 22) Total (n 5 42) Sex (male) 15 (75.0) 17 (77.3) 32 (76.2) Age, mean 6 SD, y 60.1 6 8.6 62.3 6 9.1 61.2 6 8.8 Race White 19 (95.0) 20 (90.9) 39 (92.9) Other 1 (5.0) 2 (9.0) 3 (7.2) Rai stage I 1 (5.0) 2 (9.1) 3 (7.1) II 4 (20.0) 8 (36.4) 12 (28.6) III 1 (5.0) 5 (22.7) 6 (14.3) IV 13 (65.0) 7 (31.8) 20 (47.6) Missing 1 (5.0) 0 (0.0) 1 (2.4) Number of prior therapies, median (range) 2 (1-6) 3 (1-20) 3 (1-20) Prior fludarabine 18 (90.0) 21 (95.5) 39 (92.9) Prior rituximab 19 (95.0) 22 (100.0) 41 (97.6) Bulky disease* 12 (60.0) 12 (54.5) 24 (57.1) ECOG ,1 18 (90.0) 22 (100.0) 40 (95.2) Del17p 7 (35.0) 9 (40.9) 16 (38.1) Refractory/relapse Chemoimmunotherapy #6 mo 14 (70.0) 13 (59.1) 27 (64.3) Fludarabine refractory 3 (15.0) 3 (13.6) 6 (14.3) Chemoimmunotherapy .6 to 24 mo 3 (15.0) 6 (27.3) 9 (21.4) Data are presented as n (%) of patients, unless otherwise indicated. ECOG, Eastern Cooperative Oncology Group. *Defined as any lymph node .5 cm by physical exam or computed tomography scan. 1876 BLOOD, 30 MARCH 2017 x VOLUME 129, NUMBER 13 Downloaded from http://ashpublications.org/blood/article-pdf/129/13/1876/1399124/blood748210.pdf by guest on 07 June 2022