Early Study Signals Promising Role for Venetoclax in Treatment of Relapsed CLL

Jeffrey A. Jones, MD

Adding the oral BCL-2 inhibitor venetoclax (Venclexta) to obinutuzumab (Gazyva) and ibrutinib (Imbruvica) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) is safe and is demonstrating encouraging signs of efficacy, according to early results from a phase Ib study.

Objective responses have been observed in all 12 patients assessed after 8 cycles of the combination regimen, and no dose-limiting toxicities were recorded at any of the venetoclax doses evaluated, reported lead investigator Jeffrey A. Jones, MD, at the 2016 ASH Annual Meeting.

“These drugs can be safely administered in combination at doses that are standard for all 3 for the treatment of CLL,” said Jones, an assistant professor of internal medicine, Division of Hematology, Department of Internal Medicine, at the Ohio State University Wexner Medical Center.

Promising evidence of potential synergy between venetoclax and ibrutinib in the treatment of CLL provided the rationale for exploring whether the combination could more efficiently achieve a deep response in these patients and facilitate treatment discontinuation, Jones said.

He reported results from this single-institution study (NCT02427451) involving 11 men and 1 woman (median age, 57 years) who had an ECOG performance status ≤1 and their CLL had relapsed after at least 1 prior therapy. Laboratory assessments revealed 11 patients with unmutated IGVH status and 5 with complex abnormal karyotype. Other baseline genetic risk information included 1 patient with a del17p alteration and 8 with del11q. Importantly, Jones noted, patients who were eligible for the study had creatinine clearance ≥50 mL/min/1.73m².

To determine the maximum tolerated dose (MTD) of venetoclax, patients were assigned to 3 cohorts: 100 mg (n = 3), 200 mg (n = 3), and 400 mg (n = 6). Obinutuzumab was given at its licensed dose in the first month, and in the second month patients also received ibrutinib (420 mg). In cycle 3, and without discontinuation of either drug, once-daily venetoclax was added and sequentially ramped up to the 400 mg MTD, Jones explained.

All patients on this study will receive no more than fourteen 28-day cycles of therapy, he said, with responses assessed after cycle 8 and then 2 months after therapy discontinuation, using radiographic imaging, bone marrow biopsies, and assessments of peripheral blood and minimal residual disease (MRD).

In his presentation at ASH, Jones reported that 11 patients remain on therapy, and 1 patient had completed the 14 cycles of therapy but had not yet undergone the formal response assessments.

Grade 3/4 nonhematologic adverse events (AEs) included hypertension in 3 patients that was manageable in all cases, Jones said, and hypophosphatemia, also in 3 patients; and 1 patient had a grade 3/4 infusion reaction. Grade 1/2 nonhematologic AEs occurring in ≥5 patients included bruising in all patients, and 9 experienced hypocalcemia and infusion-related reactions—the latter not unusual with obinutuzumab, Jones noted. In addition to no dose-limiting toxicities, no cases of laboratory or clinical tumor lysis syndrome were observed, and elevated electrolyte levels were not significant, Jones reported.

“In general, I would say that the toxicities are similar to those experienced in patients who are treated with the single agents, and nothing has yet emerged that seems specific to the combination.”

Treatment-related hematologic AEs were expected and occurred in all patients on the study, Jones said. Neutropenia was common, including 8 patients with grade 1 infection, but there were no grade 3/4 infections or cases of febrile neutropenia. Five patients received at least 1 dose of G-CSF during the course of therapy.

In terms of early signals of efficacy, Jones reported that all patients have responded to the combination, and 2 have experienced a complete response. Four patients achieved MRD negativity by flow assessment in both their peripheral blood and bone marrow, with investigators observing a trend toward MRD negativity at the full 400-mg dose.

Jones reported that accrual is nearly complete for a parallel phase II cohort evaluating venetoclax at the now-established 400-mg dose, and he hopes the findings will be equally promising. This phase of the research will involve 25 patients with R/R CLL and an equal number of treatment-naïve patients.

Jones JA, Woyach J, Awan FT, et al. Phase 1b results of a phase 1b/2 study of obinutuzmab, ibrutinib, and venetoclax in relapsed/refractory chronic lymphocytic leukemia (CLL). Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 639.

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