Expanding the Role of Venetoclax: Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia

The antiapoptotic protein B-cell leukemia/lymphoma-2 (BCL-2) has been a target of interest in treating B-cell lymphomas for several decades. Early attempts to inhibit BCL-2 with antisense RNA and small molecule inhibitors were unsuccessful until the discovery and development of navitoclax, a potent inhibitor of BCL-2, B-cell leukemia/lymphoma-XL (BCL-XL), and B-cell leukemia/lymphoma-w (BCL-w).¹  Despite its activity, this drug did not move forward in the clinic due to rate-limiting, high-grade, on-target (BCL-XL) thrombocytopenia. Fortunately, the discovery of venetoclax, a more specific and more potent BCL-2 inhibitor, soon followed. Based on its favorable safety profile and efficacy in high-risk, relapsed/refractory del(17p) chronic lymphocytic leukemia (CLL), it was approved by the U.S. Food and Drug Administration for this indication in 2016.²  As a single agent in CLL, venetoclax yielded responses in 79 percent of patients and complete responses (CRs) in 20 percent; the responses were durable with a two-year progression-free survival (PFS) of 62 percent, and were equivalent in high-risk del(17p) patients.^2,3  Responses in B-cell non-Hodgkin lymphoma (B-NHL) were also favorable, though not as promising, with a response rate of 44 percent across a variety of different diseases. Responses were significantly greater in mantle cell lymphoma (MCL) with 75 percent of patients responding and 21 percent of patients achieving a CR; median PFS was 14 months.⁴  Venetoclax has thus expanded the effective treatment options for patients with CLL and MCL who have exhausted other therapies including inhibition of the B-cell receptor pathway. On the heels of the clinical success of the single agent in the multiply-relapsed setting, this year has seen an expansion of the role of venetoclax with important and highly promising studies investigating new combinations in both CLL and MCL, the potential use of these combinations in earlier lines of therapy, and the potential for effective time-limited therapy.

Venetoclax was combined with rituximab based upon preclinical evidence of synergy⁵  and nonoverlapping toxicity profiles. In an early-phase study, this combination, when compared with historical controls, improved the CR rate and two-year PFS in CLL to 51 percent and 82 percent, respectively, and yielded minimal residual disease (MRD) negativity in 57 percent of patients.⁶  Eleven MRD-negative patients stopped therapy and maintained durable responses. It is based on these promising results that the phase 3 MURANO trial was born, randomizing 389 patients with relapsed/refractory CLL to either time-limited venetoclax-rituximab (venetoclax for up to 2 years plus rituximab for 6 months) or bendamustine-rituximab (for a total of 6 cycles).⁷  Forty-one percent of patients had received two or more prior lines of therapy, and high-risk characteristics including del(17p), TP53 mutations, and unmutated IGVH were found in 26.9 percent, 26.3 percent, and 68.3 percent of patients, respectively. At a median follow-up of 23.8 months, venetoclax-rituximab was associated with a two-year PFS of 84.9 percent compared with 36.3 percent for bendamustine-rituximab. This improvement was irrespective of adverse disease characteristics. Importantly, venetoclax-rituximab was associated with a high rate of MRD negativity (83.5%) at any time during the trial compared with 23.1 percent for bendamustine-rituximab. These improvements did translate to an overall survival (OS) benefit of two years for venetoclax-rituximab (91.9%) compared with bendamustine-rituximab (86.6%). The most common toxicity was neutropenia; however, although rates of high-grade neutropenia were more common in the venetoclax arm, rates of febrile neutropenia were more common in the bendamustine arm. This study defines venetoclax-rituximab as a significant and effective time-limited treatment option and improvement over conventional chemoimmunotherapy for patients with relapsed/refractory CLL. The question of how to sequence this regimen vis-à-vis Bruton tyrosine kinase (BTK) inhibition remains unanswered. It is known that venetoclax maintains its efficacy in the setting of BTK inhibitor resistance or intolerance, but the reverse is not known. However, the ability to offer time-limited therapy with what seems to be an improved safety and tolerability profile is highly appealing.

In MCL, there is even more room for improvement with combination strategies over single-agent venetoclax. As with venetoclax-rituximab, the observed preclinical synergy and lack of overlapping toxicity of dual BTK and BCL-2 inhibition led to a phase I study of venetoclax in combination with ibrutinib.⁸  Twenty-four patients were enrolled, treated with a median of two prior therapies; one patient was treated in the first line due to a chemotherapy contraindication. Three quarters of patients had high-risk disease by the MCL International Prognostic Index and half of the patients had alterations involving TP53; one patient had the blastoid or pleomorphic variant. CRs including positron emission tomography (PET) imaging were seen in 71 percent of patients, and 67 percent of patients were found to be MRD negative by flow cytometry. Estimated PFS at 12 and 18 months was 75 percent and 57 percent, respectively. The most common adverse events were diarrhea, nausea, and vomiting, but most were low grade. Responses were seen despite adverse prognostic factors, although a Ki-67 index of at least 30 percent was associated with an increased risk of nonresponse. Targeted sequencing was done on tumors from all patients; patients with mutations associated with BTK inhibitor resistance did respond (CR, 83%), as did patients with alterations in TP53 (CR, 50%). Based on these promising results, a randomized trial of venetoclax-ibrutinib versus ibrutinib alone in relapsed/refractory MCL is underway. Time-limited therapy was not tested in this study; there were three relapses in patients with a CR while on continued therapy, and two of these patients had had an MRD-negative CR. This suggests that, unlike in CLL, dual BTK and BCL-2 inhibition may need to be given continuously in MCL.

The persistent investigation into inhibiting BCL-2 despite a lack of initial success has been very fortuitous for patients with B-cell malignancies, especially high-risk CLL and MCL, two incurable diseases with limited treatment options and relatively short OS. The discovery of the potent and specific BCL-2 inhibitor venetoclax with its favorable toxicity profile and high response rates as a single agent in these diseases has provided additional options for patients. This year dovetailed on the initial success of this drug and identified two new, highly effective and safe combination partners, rituximab and ibrutinib, to move into the clinic, resulting in deeper and more durable remissions in a greater proportion of patients. These combinations overcome many adverse prognostic factors and resistance mechanisms to single agent therapy, and lead to MRD negativity in most patients. This translates into improved response duration and in the case of CLL, improved OS as well as the opportunity to offer time-limited rather than indefinite therapy. These two studies and these two combinations will undoubtedly benefit many patients and spur investigation of additional combinations that could be useful earlier in the disease course, hopefully changing their natural history.