Venetoclax is a highly selective, orally bioavailable inhibitor of BCL-2, a crucial regulator of apoptosis that is aberrantly overexpressed in a number of hematologic malignancies, including chronic lymphocytic leukemia (CLL). Venetoclax has been approved by FDA for a number of clinical settings, including CLL with 17p deletion (April 2016), combination with rituximab for previously treated CLL (June 2018), newly diagnosed acute myeloid leukemia or those ineligible for intensive induction chemotherapy (November 2018), and as part of a chemotherapy-free regimen for treatment-naïve CLL (May 2019).
The phase III MURANO study (NCT02005471) evaluated the 2-year fixed-duration combination of venetoclax plus rituximab versus the standard bendamustine-rituximab combination for 6 cycles in patients with relapsed or refractory CLL. A report detailing the first pre-planned analysis showed superior progression-free survival (PFS) for the venetoclax plus rituximab arm (N Engl J Med 2018;378:1107-1120). A subsequent follow-up report, after all participants with ongoing disease control had completed therapy in the venetoclax arm, showed continued benefit in PFS for patients in the venetoclax-rituximab arm (J Clin Oncol 2019; 37(4):269-277).
Two leading clinicians that participated in that trial and who are continuing to participate in the subsequent follow-up are John Seymour, MBBS, PhD, FRACP, from the Royal Melbourne Hospital, Peter MacCallum Cancer Centre and University of Melbourne, and Thomas J. Kipps, MD, PhD, at the UC San Diego Moores Cancer Center. At the 2019 ASH Annual Meeting, Seymour presented data from an analysis of patients with a median follow-up duration of 48 months, with patients in the venetoclax-rituximab arm a median of 22 months after treatment cessation (Abstract 355). Regarding this analysis, Seymour stated, “The hazard ratio (HR) associated with PFS in previous analyses has been 0.16, and in the current analysis, this figure remains similar at 0.19.”
As described in previous reports, patients in the venetoclax arm received 6 monthly infusions of rituximab in combination with venetoclax, followed by 400 mg venetoclax daily for a total of 2 years, while those in the control arm received 6 cycles of bendamustine-rituximab. Minimal residual disease (MRD) status in peripheral blood cells was assessed centrally at several different timepoints during the study and follow-up periods. MRD status was delineated into the following categories: undetectable MRD (uMRD), low-MRD, or high-MRD. Regarding the use of term MRD-negative, Kipps stated, “The use of this term should be discouraged; I would suggest we, as clinicians, should use uMRD, as this is the proper terminology to reflect our level of knowledge about that status of disease clearance.”
As of the data cutoff, May 8, 2019, the median follow-up from enrollment was 48 months, while the median follow-up period post-venetoclax completion was 22 months. “The PFS benefit for venetoclax-rituximab over bendamustine-rituximab was sustained, with 4-year PFS estimates of 57.3 percent (95% CI: 49.4-65.3%) and 4.6 percent (95% CI, 0.1 - 9.2%), respectively,” Seymour noted. A total of 130 patients completed 2 years of venetoclax therapy. In this population, the estimated 24-month post- cessation PFS value was 68.0 percent (95% CI 57.6 - 78.4%). Of these 130 patients, 35 have developed progressive disease to date.
The benefit for overall survival (OS) was also sustained for patients who received the venetoclax plus rituximab combination, as shown by the HR of 0.41 (95% CI: 0.26, 0.65; p<0.0001) and the 4-year OS rate—85.3 percent versus 66.8 percent. Notably, the OS benefit was observed even though 103 of the 142 patients treated with bendamustine-rituximab received additional treatment, which often included use of novel targeted therapies, such as drugs that inhibit Bruton tyrosine kinase, PI3K, or other targets.
“Across both treatment arms, the previously reported association between uMRD in peripheral blood at the end of treatment (EOT) response visit with improved PFS was maintained with this extended follow-up,” Seymour noted. Among venetoclax plus rituximab patients who had detectable peripheral blood MRD at the EOCT response visit and at end of therapy, low-MRD patients continued to display improved PFS values relative to patients with high-MRD.
Summarizing their main findings, Seymour stated, “Four-year data from MURANO demonstrate sustained PFS and OS benefits with the venetoclax plus rituximab relative to bendamustine-rituximab.
“The PFS rate at 24-months post-treatment cessation was 68.0 percent in those patients completing 2 years of venetoclax therapy,” he noted. “No new safety signals were noted in this analysis. One important observation was that patients who attained uMRD in peripheral blood and maintained this status at EOT showed particularly durable responses.
“An important thing to note about looking for disease in the peripheral blood is that, many times, residual CLL can be found in the bone marrow, particularly during or several months after treatment with anti-CD20 monoclonal antibodies” Kipps explained. “Quite often, there can be malignant cells in the marrow that are not seen in blood of patients treated with such antibodies. These marrow-located CLL cells may serve as the basis for recurrence of detectable MRD in the blood within a year of stopping such therapy.” Seymour then noted, “This is why potent clearance of these malignant cells from the marrow tend to provide the most durable clinical responses.”
“These follow-up data provide further support for the use of time-limited venetoclax plus rituximab in patients with relapsed or refractory CLL,” Kipps stated. Seconding this notion, Seymour said, “This analysis provides robust data supporting the shift to time-limited therapy with venetoclax in this population. The patients receiving venetoclax had ceased that therapy for a median of nearly 2 years.
“Time-limited therapy has the potential to confer several advantages over that of continuous therapy, including lowering the risk for developing drug resistance, lowering the costs of therapy, and lowering the risk for treatment-associated side effects, which generally increases the patient's quality of life,” Seymour added.
Richard Simoneaux is a contributing writer.