High Response Rate With Venetoclax in Relapsed/Refractory CLL


Two-thirds of patients with chronic lymphocytic leukemia that progressed on B-cell receptor pathway inhibitors had objective responses to treatment with venetoclax (Venclexta), results of a small open-label trial showed.

Jeffrey Jones, MD

Two-thirds of patients with chronic lymphocytic leukemia (CLL) that progressed on B-cell receptor pathway inhibitors had objective responses to treatment with venetoclax (Venclexta), results of a small open-label trial showed.

Overall, 67% of patients responded to the BCL2 inhibitor, including 70% of patients previously treated with ibrutinib (Imbruvica) and 62% treated with idelalisib (Zydelig). Peripheral blood analysis for a subset of patients showed that treatment with venetoclax led to minimal residual disease (MRD) status in 45% of cases, according to findings presented at the 2016 ASH Annual Meeting in San Diego.1

“Responses are thus far durable, and the median progression-free survival (PFS) and overall survival (OS) have not been reached after at least 12 months of follow-up,” said Jeffrey Jones, MD, assistant professor of internal medicine at Ohio State University in Columbus. “Venetoclax was well tolerated, and cytopenias were managed by dose adjustments and supportive care. No clinical tumor lysis syndrome was observed.

“This is the first prospective trial to demonstrate high rates of durable responses, including MRD negativity, in patients progressing after B-cell receptor signaling pathway antagonists.”

Treatment with ibrutinib and idelalisib has led to high response rates and survival in patients with CLL. However, patients whose disease progresses, relapses, or proves refractory to B-cell receptor signaling antagonists have a poor prognosis.

Venetoclax, which targets BCL2, has been shown to induce response rates of about 80% in patients with relapsed/refractory CLL.2,3

Continuing the evaluation of venetoclax in relapsed/refractory CLL, investigators conducted a phase II trial involving 64 patients with CLL that had progressed, relapsed, or proven refractory to ibrutinib (n = 43), idelalisib (n = 21), or both agents (n = 4).

The patients had a median age of about 66. About half the patients previously treated with ibrutinib had del(17p13.1), as did 2 of the patients treated with idelalisib. A majority (38/64) of the patients had bulky nodal disease. Patients in the ibrutinib subgroup had received a median of 4 prior therapies, whereas the idelalisib subgroup had received 3 prior regimens.

A third of the patients discontinued treatment with venetoclax, primarily because of disease progression (n = 15). Three patients discontinued because of adverse events. Jones said 26 patients required 2 or more dose interruptions, and 9 patients required dose reductions.

As assessed by independent reviewers, treatment with venetoclax led to objective responses in 30 of 43 patients in the ibrutinib group and 13 of 21 in the idelalisib group. One patient achieved a complete response.

The ibrutinib group had a 13-month median time on study, compared with 9 months in the idelalisib group. Median duration of response, PFS, or OS had yet to be reached after a median follow-up of 11.8 months. The estimated 12-month PFS for all 64 patients was 80% (95% CI, 67-89).

Peripheral blood assessment for 31 patients demonstrated MRD status at 24 to 48 weeks. Five patients had sustained MRD-negative status in peripheral blood, and subsequent bone marrow evaluations showed MRD-negative status in marrow.

The most common all-grade adverse events (AEs) were neutropenia (58%), thrombocytopenia (44%), diarrhea (42%), nausea (41%), anemia (36%), fatigue (31%, decreased white blood cells (22%), and hyperphosphatemia (22%). Grade 3/4 AEs included neutropenia in 45%, thrombocytopenia in 28%, and anemia in 22%.

Half the patients had serious AEs, the most common of which were febrile neutropenia (9%) and pneumonia (8%). Jones reported that 2 patients developed multiorgan failure during the study.


  1. Jones J, Choi MY, Mato AR, et al. Venetoclax (VEN) Monotherapy for Patients with Chronic Lymphocytic Leukemia (CLL) Who Relapsed after or Were Refractory to Ibrutinib or Idelalisib. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 637.
  2. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.N Engl J Med.2016;374(4):311-322.
  3. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study.Lancet Oncol.2016;17(6):768-778.
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