S98 EXABS-209-CLL The Case for Extending Treatment in MRD+ Patients on Venetoclax + Obinutuzumab Therapy Andrew Lipsky, MD1, and Nicole Lamanna, MD1,* 1Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY *Corresponding author: nl2129@cumc.columbia.edu Keywords Venetoclax, MRD, CLL14, CLL, therapy continuation Introduction Venetoclax + obinutuzumab (VenO) is a 12-cycle, fixed-duration treatment for adult patients with previously untreated chronic lymphocytic leukemia (CLL). Randomized trials have evaluated this combination in patients with (CLL14) and without (CLL13) coexisting conditions.1,2 Although many patients achieved high rates of undetectable minimal residual disease (uMRD) translating into improved PFS outcomes, relapse of disease still occurs and a subgroup of patients still demonstrates limited responses with detectable MRD levels ≥10−4. Notably, patients with higher-risk genetic features such as del(17p) and/or TP53 mutation (TP53 aberrancy) face higher rates of relapse. As the duration of venetoclax therapy was arbitrarily chosen, the optimal duration of treatment remains unknown. Here we review updated data for VenO in CLL and advocate for the extension of therapy in high-risk patients with detectable MRD levels at the end of treatment (EoT). Discussion At 5-years after randomization in the CLL14 study, patients receiving VenO had an estimated PFS rate of 62.6%.1 Importantly, EoT MRD levels in this study were also significantly associated with PFS and OS. Specifically, patients with MRD <10−6 at end of treatment had a longer PFS than patients with detectable MRD (HR 0.25). Patients with MRD ≥10−4 had a significantly shorter OS than patients with <10−4 (4-year OS rate 63.6% vs 89.2%).1 Although the majority of patients remain in remission according to iwCLL criteria, with extended follow-up at 48 months, only 18.1% of patients receiving VenO had maintained MRD levels below 10−4, demonstrating that VenO does not induce complete MRD eradication in most patients.1 It is well established that patients with high-risk features are at greater risk of inferior outcomes with time-limited therapy. For example, available data from patients with TP53 aberrancy in the CLL14 study had shorter PFS than those without, a 5-year-PFS 40.6% versus 65.8%.1 Notably, in cross-trial comparison, the median PFS for TP53 aberrant patients on VenO (49 months, approximately 4 years) compares unfavorably with data from pooled analysis of TP53 aberrant patients receiving continuous BTK inhibition, who at 4 years had a PFS of 79%.3 Furthermore, del(17p) is the only adverse parameter in the context of VenO treatment confirmed by multivariable PFS analysis and the only factor associated with significantly shorter OS.4 It is therefore this group that has the highest a priori likelihood of benefit from additional consolidation when receiving time-limited treatment. Various therapeutic approaches have been proposed for fixedduration therapy for patients who fail to achieve EoT uMRD, such as continuing therapy or amplifying treatment intensity with additional agents. Interestingly, amongst the 14 patients on CLL14 with MRD+ at 3 months after completing therapy, 50% exhibited a decline in MRD levels while under treatment (from cycle 7 to EoT), implying that there could be an ongoing advantage in maintaining venetoclax therapy in these patients.5 Not surprisingly differences in MRD outcomes on VenO are likely reflective of underlying disease biology with MRD+ (≥10−4) status associated with increased expression of multi-drug resistance gene ABCB1 (MDR1), whereas MRD6 (<10−6) is associated with BCL2L11 (BIM) expression.1 At present, there is limited prospective data evaluating MRDguided consolidation with additional venetoclax. Notably, a phase 2 study of venetoclax consolidation after standard frontline VenO therapy in the HOVON 139/GiVe trial read out as a “negative” study but was subject to several limitations.6 Here patients received either 12 additional cycles of venetoclax consolidation for only as long as MRD positivity was shown in peripheral blood (MRDguided consolidation group) or irrespective of MRD status (consolidation group). Notably, the MRD-guided group did not function as intended in this study as only 1/30 patients received additional venetoclax on account of a higher rate (97% already had uMRD) at the end of standard treatment pre-randomization. This likely occurred because the HOVON study regimen also included an additional two pre-induction cycles of obinutuzumab prior to initiating the standard CLL14 regimen. Similarly, the administration of a year of additional therapy to all-comers in the consolidation group (with only 5 TP53 aberrant patients) likely resulted in over-treatment, and does not exclude benefit for patients using a more narrowly-tailored extended consolidation.
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