Venetoclax (VEN), a once-daily oral inhibitor of BCL2, achieves high response rates and acceptable toxicity in patients with relapsed or refractory and treatment-naïve (TN) chronic lymphocytic leukemia (CLL), both as a single agent and in combination with anti-CD20 monoclonal antibodies such as obinutuzumab (OBIN), where minimal residual disease (MRD)-negative responses have been observed in the majority of patients.1 Preclinical data suggest that concurrent treatment with the Bruton tyrosine kinase inhibitor ibrutinib (IBR) may further potentiate sensitivity to VEN.2 At ASH 2017, the authors reported on the initial results from the phase 2 cohort of TN patients from a phase 1b/2 study of the combination of OBIN, IBR, and VEN in CLL.3
A total of 25 patients with TN, symptomatic CLL meeting International Working Group on CLL 2008 guideline indications for therapy were treated for 14 cycles of 28 days each with OBIN, IBR, and VEN started sequentially over the first 3 cycles. OBIN was started at cycle 1, IBR in cycle 2, and VEN in cycle 3. Baseline risk characteristics in these patients included unmutated IGHV in 17 (71%) patients, complex karyotype in 6 (24%), del(17p) in 3 (12%), del(11q) in 5 (20%), del(13q) in 5 (20%), and tri(12) in 3 (12%).
The most common grade 1/2 treatment-related adverse events (TRAEs) were infusion reactions (76%), nausea (60%), bruising (56%), oral mucositis (52%), and dyspepsia (48%). The most common grade 3/4 TRAEs were thrombocytopenia (48%), lymphopenia (44%), leukopenia (40%), hypertension (36%), and neutropenia (28%). There were no cases of neutropenic fever or tumor lysis syndrome.
Of the 25 patients who reached the first (post-cycle 8) response, 96% had an objective response, with a 52% rate of complete remission (CR), including with incomplete marrow recovery (CRi). MRD-negative status in both blood and bone marrow was achieved in 14 (58%) patients: 3 CR, 5 CRi, and 6 partial remission.
The authors concluded that the combination of OBIN, IBR, and VEN can be given safely and appears highly effective as initial therapy for CLL after response assessment. Objective responses, including MRD-negative CR, have been achieved in all patients to date. Results for the primary end point of MRD-negative CR after cycle 14 are expected in May 2018.
- Gentile M, et al. Expert Opin Investig Drugs. 2017;26:1307-1316.
- Jayappa KD, et al. Blood Adv. 2017;1:933-946.
- Rogers KA, et al. ASH 2017. Abstract 431.