Venetoclax Achieves Durable and Deep Remissions in CLL


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Danielle Brander, MD

Danielle Brander, MD

Michael Keating, MD

Michael Keating, MD

Preliminary study results suggest that venetoclax (Venclexta) plus rituximab (Rituxan) is a highly active combination in relapsed/refractory chronic lymphocytic leukemia (CLL), achieving durable responses and minimal residual disease negativity in previously treated patients.

“The results of our phase Ib trial show it is possible to achieve treatment-free remission in this setting,” said lead author Danielle Brander, MD, of Duke Cancer Institute, Durham, North Carolina. “It is also possible to re-treat patients who have asymptomatic progression and achieve a complete response,” she added at the 2017 International Workshop on CLL (iwCLL) in New York.1

The results of our phase Ib trial show it is possible to achieve treatment-free remission in [patients with relapsed/refractory CLL.
— Danielle Brander, MD

Venetoclax is the first U.S. Food and Drug Administration (FDA)-approved drug to target the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell survival and is overexpressed in the vast majority of patients with CLL. The drug is approved for patients with CLL and 17p deletion (del[17p], an adverse prognostic factor) treated with at least one prior therapy. The National Comprehensive Cancer Network® (NCCN®) Guidelines for CLL recommend venetoclax for patients whose disease progresses on ibrutinib (Imbruvica) therapy.

Study Details

Study M13-365 was a phase Ib, open-label, dose-escalation trial of venetoclax plus rituximab in relapsed/refractory CLL or small lymphocytic leukemia. Over the first 5 weeks of the study, most patients were escalated to the cohort target daily dose of venetoclax (200–600 mg/d). The recommended phase II dose of venetoclax in this combination was 400 mg, identical to the approved single-agent dose.

Dr. Brander reported outcomes for the 49 patients enrolled in the trial. At baseline, median age was 68 years, median lymphocyte count was 58 × 109/L, 23 patients (47%) had node size > 5 cm, median number of prior therapies was 2, 90% had received prior rituximab-containing therapies, and 57%, prior fludarabine-containing regimens. Nine of 47 patients (19%) evaluable had del(17p), and 19 of 28 (68%) had unmutated IGHV.

The overall objective response rate was 86%, with 51% complete responses and 35% partial responses. Patients who are continuing on therapy have durable responses—a minimum of 31 months. One patient was not evaluable due to fatal tumor-lysis syndrome, a major adverse effect of concern with venetoclax. 


Minimal residual disease status can be used in decision-making, potentially as the endpoint of therapy.…
— John Seymour, MD, PhD

Bone marrow minimal residual disease–negative status was attained in 29 patients (59%), including 86% of those with a complete response and 47% of those with a partial response due to minor adenopathy. Of these 29 minimal residual disease–negative patients, 22 attained this level of response at 7 months and the remaining 7, at 12 to 22 months. 

Of the 49 patients enrolled in the trial, 28 are still on study. Reasons for treatment discontinuation were CLL progression in 7 patients, Richter’s transformation in 5 patients, and “other” in 5 patients. Median time to development of Richter’s transformation was 5 months; no patients developed the syndrome after 9 months. 

“Richter’s occurred early, and this should affect how we design our clinical trials. Central validation of Richter’s should be incorporated,” Dr. Brander said. 

If minimal residual disease–negative status was attained, the drug could be stopped. If disease progression occurred, the patient could re-start venetoclax and subsequent rituximab. 


It is very important at each line of therapy to check for del(17p). This is not widely done, but it should be.
— Susan O’Brien, MD

Sixteen patients who attained a deep response stopped therapy with venetoclax. Ten of 12 active patients remain progression-free after a median of 20 months. Three patients with del(17p) and 1 with mutant TP53 achieved minimal residual disease negativity and were progression-free at study discontinuation. After a median of 20 months (maximum 40 months and ongoing), none of the patients who achieved minimal residual disease negativity have had disease progression off therapy. 

Two patients who attained complete response with minimal residual disease–positive status had asymptomatic progression after 24 months off therapy. Both were re-treated with venetoclax; one achieved a partial response followed by progression after 19 months of retreatment, and the other achieved a complete response at 14 months of retreatment and remains on study.

Moderator Michael Keating, MD, of The University of Texas MD Anderson Cancer Center, Houston, noted, “It is remarkable that in this relatively short study, some patients discontinue therapy and are controlled for a long time. We haven’t seen this with other therapy.” 

Additional Comments

At a separate symposium on the treatment of relapsed/refractory CLL held during the 2017 iwCLL meeting, experts had additional comments about venetoclax.2 Although the drug is not approved in the first-line setting, two of the four panelists at this symposium said they might start treatment with venetoclax in patients with del(17p).

John G. Gribben, DSc, FRCP, FRCPath, FMedSci

John G. Gribben, DSc, FRCP, FRCPath, FMedSci

Michael Hallek, MD

Michael Hallek, MD

Panelists agreed that depth of response and achievement of minimal residual disease–negative status mattered. “Complete response and minimal residual disease negativity predict improved long-term outcomes,” said John Seymour, MD, PhD, of Peter MacCallum Cancer Centre, Melbourne.

Several panelists mentioned that del(17p) may not be present at diagnosis but can develop later. “Clonal evolution occurs over time. It is very important at each line of therapy to check for del(17p). This is not widely done, but it should be,” stated symposium moderator Susan O’Brien, MD, of the University of California Irvine Health.

Tumor-lysis syndrome is a potential concern with venetoclax. With more experience in using the drug, investigators have amended protocols to start at low doses of 20 mg, with weekly dose escalation to 400 mg by 5 weeks. “Careful assessment at each dosing level has improved safety,” said John G. Gribben, DSc, FRCP, FRCPath, FMedSci, of Barts Cancer Institute and Queen Mary University of London. “This includes risk assessment, assessment of tumor burden, prophylaxis, and blood chemistry,” he added.

Michael Hallek, MD, of the Center for Integrated Oncology and University of Cologne, Germany, proposed using combination therapy to gain rapid control of disease and achieve minimal residual disease–negative status. “The idea is to debulk the tumor with bendamustine or fludarabine to render the clone smaller, then move to induction therapy with ibrutinib, obinutuzumab (Gazyva), or a BCL-2 inhibitor, then to minimal residual disease–tailored maintenance,” he said.

Venetoclax Update

  • Venetoclax, a BCL-2 inhibitor, is highly active in CLL and effective in patients with del(17p). 
  • A phase Ib trial evaluating the combination of venetoclax plus rituximab in relapsed/refractory CLL showed deep and durable remissions, with a high percentage of patients attaining minimal residual disease–negative status.

Dr. Hallek subsequently told The ASCO Post that the combination of venetoclax plus obinutuzumab may be the most efficient approach to CLL therapy currently. “In fact, a recent study published in a letter to Blood has already used venetoclax and obinutuzumab in first-line therapy for CLL, with impressive results regarding efficacy.”3 

“Minimal residual disease status can be used in decision-making, potentially as the endpoint of therapy, demonstrating eradication of disease on therapy, as well as to determine the length of therapy,” Dr. Seymour said.

Dr. Seymour mentioned a poster presentation at the 2017 iwCLL showing results of a phase II trial in patients with untreated or relapsed/refractory CLL.4 The study used sequential treatment as described by Dr. Hallek, with bendamustine followed by obinutuzumab and venetoclax, and achieved minimal residual disease–negative status in 89% of the enrolled CLL patients. “This is efficacy beyond anything I have seen so far,” Dr. Seymour said.

“Venetoclax gained accelerated approval by the FDA based on an overall response rate of 80%. We will need randomized trials for full approval of this drug,” Dr. O’Brien stated. ■

DISCLOSURE: Drs. Brander, Keating, Seymour, O’Brien, Gribben, and Hallek reported no conflicts of interest.

REFERENCES

1. Brander D, et al: Durability of responses on continuous therapy and following drug cessation in deep responders with venetoclax and rituximab. 2017 International Workshop on CLL. Presented May 15, 2017.

2. Evolution of Treatment in Relapsed/Refractory CLL (AbbVie-sponsored symposium). 2017 International Workshop on CLL. Presented May 15, 2017.

3. Fischer K, et al: Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood 129:2702-2705, 2017

4. Cramer P, et al: Sequential treatment with bendamustine, followed by obinutuzumab and venetoclax in patients with chronic lymphocytic leukemia. 2017 International Workshop on CLL. Abstract 156. Presented May 14, 2017.


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