Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy

Abstract Venetoclax is approved as monotherapy and in combination with rituximab for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Two Phase 1 studies (M12‐175 [NCT01328626]; M13‐365 [NCT01682616]) were conducted in which patients who initially responded and then progressed on venetoclax monotherapy could receive added rituximab. Ten patients were evaluated (M12‐175, n = 8; M13‐365, n = 2), and five (50%) responded again upon addition of rituximab, including three complete and two partial responses. Responses were ongoing after 5–10 months of follow‐up. Addition of rituximab was well tolerated. These findings indicate potential clinical benefit with rituximab added to venetoclax post‐progression in some patients with R/R CLL.

antibody [1]. Although responses are achieved in approximately 75% of patients with monotherapy in the relapsed/refractory (R/R) setting, most patients will develop progressive disease (PD) while on continuous venetoclax after a median duration of 3 years [2,3]. Including rituximab from the outset induces high response rates (92%) and more frequent deep responses when indirectly compared with venetoclax monotherapy in patients with R/R CLL/SLL [4]; however, it is unknown whether the later addition of rituximab after PD on venetoclax can improve outcomes.
The primary analyses of two phase 1 dose-escalation studies of venetoclax in R/R CLL/SLL (M12-175 and M13-365) have been previously reported [5,6]. During long-term follow-up in these studies, patients who progressed on venetoclax monotherapy could, at investigator discretion, receive added rituximab while continuing venetoclax [5,6]. Here, we report efficacy and safety outcomes for these patients. Per protocol amendments, patients with CLL PD while on venetoclax monotherapy could remain on venetoclax and receive rituximab (375 mg/m 2 followed by 500 mg/m 2 monthly for 5 months) after PD, per iwCLL criteria [7]. Tumor lysis syndrome (TLS) prophylaxis was not mandated for rituximab treatment after progression; low-risk standard TLS prophylaxis was followed for some patients. Adverse events (AEs)

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were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events. In this patient series, we recorded clinicopathological factors both at study commencement and at the time of CLL progression. We evaluated responses and described the duration of clinical benefit following rituximab treatment. AEs occurring after starting additional rituximab were summarized.

RESULTS AND DISCUSSION
Adding rituximab to continuous venetoclax therapy after documented CLL progression was not mandatory per study protocols and occurred at investigator discretion. The case studies (Supplementary Materials) include patients who had achieved durable responses to venetoclaxbased therapy, had indolent CLL relapse on venetoclax monotherapy, and opted to continue therapy and receive rituximab. Ten patients (M12-175: n = 8; M13-365: n = 2) had rituximab added to ongoing venetoclax after developing PD per iwCLL criteria (n = 9) or rising MRD in PB (>1 log increase; n = 1) while on continuous venetoclax monotherapy. Progression was characterized by lymphadenopathy in seven of 10 patients, although none had bulky disease; the median of the largest node size was 3.2 cm (range, 2.0-3.9 cm). No patient had clinically aggressive relapse or Richter transformation. In one of six evaluable patients in this series, an emergent BCL2 mutation (Gly101Val) was detected at CLL progression; the mutation in this patient was the major clone and has been previously described [9].
The characteristics of this cohort and responses after adding rituximab to venetoclax therapy are summarized in Table 1  Another responder with a BCL2 mutation detected at CLL PD conferring putative venetoclax resistance [9], achieved MRD-negative CR on completion of rituximab therapy. This mutation (Gly101Val) was found to reduce sensitivity to venetoclax in vitro; however, full resistance requires additional changes to the microenvironment, which varies between patients [9]. As of the data cutoff, CLL response was ongoing in all four patients, providing additional clinical benefit ranging from 5.4+ to 9.8+ months; one patient developed PD after database cutoff. Four patients did not achieve a response following rituximab treatment; one patient who has not yet had a formal response assessment remains on venetoclax monotherapy with stable disease with ongoing clinical benefit as judged by the treating hematologist.
Both patients in M13-365 who initially received venetoclax in combination with rituximab achieved PR to initial therapy in dose escalation (dose < 400 mg once daily) and subsequently received 400 mg once daily after the RP2D was determined. These patients developed PD at 36 and 55 months, and both received an increase in venetoclax dose to 600 mg without CLL response. One patient achieved a PR shortly after being re-treated with rituximab, then attained CR with undetectable MRD in BM 12 months later, with ongoing undetectable MRD. The second patient did not achieve disease response following rituximab re-treatment and discontinued the study due to PD. Despite the durable responses that can be achieved by venetoclax with rituximab in the R/R setting [10], options for treating patients with CLL who progress on venetoclax are limited. Bruton tyrosine kinase inhibitors (BTKis) can be effective in BTKi-naive patients [11,12] or in patients ceasing initial BTKi therapy because of intolerance; however, interventions that prolong the clinical benefit of venetoclax are desirable. One option for achieving this is to re-treat patients with rituximab or other anti-CD20 antibodies such as obinutuzumab, which has been shown to be a more effective antibody to partner with chemotherapy than rituximab in the frontline setting [13,14] and has an acceptable safety profile with venetoclax [15]. In this era of novel CLL therapies [4,16], this case series provides insight into the potential ben-

ACKNOWLEDGMENTS
We would like to thank the patients and their families, study coordinators, and support staff. Venetoclax is being developed in collaboration between AbbVie and Genentech Inc. AbbVie and Genentech funded the study and participated in the study design, research, analysis, data collection, interpretation of data, as well as the writing, review,

DATA AVAILABILITY STATEMENT
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