Chronic lymphocytic leukemia (CLL) is one of the most common hematologic malignancies in the world, with an incidence of 23,690 cases per year in the U.S.1,2 With respect to management, depending on the lens through which one views this malignancy, CLL was the first to use targeted therapies in the frontline (1L) setting versus chemoimmunotherapy (CIT). Current treatment options for most 1L patients vacillate between continuous use of single-agent Bruton tyrosine kinase inhibitors (BTKis)3-6 and fixed-duration therapy with venetoclax and obinutuzumab (VO).7-9 Both options have unique downsides, with VO requiring intravenous infusion and being associated with increased risk of neutropenia, while BTKis are generally given indefinitely and, with chronic use, increase patients’ risk of bleeding, chronic joint discomfort, and cardiovascular issues.6,10,11 For those with p53 aberrations (TP53 mutations or 17p deletions), there is generally a lean toward use of BTKis; however, some of the benefit of this class compared to VO is invariably related to duration of treatment (fixed vs. indefinite). As more studies have evaluated combinations of these classes of drugs, questions arise concerning whether you can stop both drugs and when is the most appropriate time to do so.
In the non-randomized arm D of the SEQUOIA study,12 Mazyar Shadman, MD, MPH, and colleagues looked to evaluate the efficacy of venetoclax and the BTKi zanubrutinib in patients with TP53-aberrant CLL. This cohort included patients aged 65 and older (or those younger than 65 with comorbidities). Patients were assigned to receive zanubrutinib starting on day 1 of cycle 1. Venetoclax started on day 1 of cycle 4, with escalation up to a dose of 400 mg. Patients remained on both agents through cycle 28. Thereafter, patients continued treatment with zanubrutinib until progressive disease (PD), toxicity, or reaching undetectable minimal residual disease (uMRD) stopping criteria.
Of the 114 enrolled patients receiving zanubrutinb, only 110 received both drugs from November 2019 through July 2022. At the data cutoff, 110 patients had stopped venetoclax and 29 (25%) had stopped zanubrutinib. After 60 patients with TP53-aberrant disease were enrolled, the study was amended to enroll 50 patients without TP53-aberrant disease unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab.
With a median follow-up of 31.2 months (range: 0.4-58.0 months), the median progression-free survival (PFS) had not been reached for the intention-to-treat (ITT) population; the 24-month PFS rate was 92% (95% CI 85%-96%). For those with p53-aberrant disease, the 24-month PFS rate was 94% (95% CI 85%-98%) and the 36-month PFS rate was 88% (95% CI 75%-94%). The overall response rate (ORR) was 97% in the ITT population, with 55 patients (48%) obtaining a complete response (CR)/complete response with incomplete hematopoietic recovery (CRi) confirmed by bone marrow biopsy. For those with p53-aberrant disease, the ORR was 99% with a CR/CRi of 47%. MRD analysis was obtained from the peripheral blood in 112 (98%) of the enrolled patients, including 65 patients with p53-aberrant disease. Eleven patients were able to stop treatment due to meeting uMRD-guided stopping criteria. This required patients to have completed at least 27 cycles of zanubrutinib, obtain CR/CRi, have uMRD results on their two most recent peripheral blood (PB) samples, and have uMRD results in two bone marrow (BM) samples obtained at least 12 weeks apart. Of those 11 patients, nine remained in ongoing remission with sustained PB uMRD.
Treatment-emergent adverse events (TEAEs) of any grade occurred in 112 patients (98%), with grade 3 or higher TEAEs occurring in 62 patients (54%). The most common TEAE of any grade was COVID-19 infection, which was noted in 54% of the patients on study, while the most common grade 3 or higher TEAE was neutropenia, which was noted in 17% of patients.
Several studies have been conducted lately examining fixed-duration regimens using BTKis and venetoclax,13-16 with overall efficacy of these studies being comparable irrespective of the BTKi used (ibrutinib, acalabrutinib, or zanubrutinib). The most important aspect of these studies remains the durability of response given the incurable nature of CLL. In just evaluating the p53-aberrant patient population treated in the SEQUOIA study, the PFS appears comparable to other doublet trials that were not enriched for patients with p53 alterations. Additionally, the SEQUOIA study demonstrates impressive rates of uMRD in enrolled patients with p53-aberrant disease, although lower than reported from the triplet studies of acalabrutinib plus VO and ibrutunib plus VO.15,16 Despite the lower rates of uMRD compared to those regimens, the PFS rates from arm D of the SEQUOIA study are comparable to those of these fixed-duration triplet combinations.
With respect to other doublet studies and durability of response in p53-aberrant patients, time on treatment might be an important point to consider. As reported in this trial, the time to achieve a uMRD in those with p53-aberrant disease was substantially shorter than those without this aberrancy. Given this fact, only a few of the enrolled patients have been able to meet the rigorous criteria needed to stop therapy. Taken in sum, despite best efforts, continuous therapy might be the best approach for this patient population given that few if any real-world patients would be willing to undergo the amount of testing required to meet the SEQUOIA stopping criteria. One big caveat to all of this will always be if patients, including those with p53 aberrancy, are able to positively respond to a repeat challenge to BTKi-based therapy. If abbreviated therapy does not eliminate the sensitivity of the malignant cell to a covalent BTKi (cBTKi), there is in some ways less pressure to maximize the duration of the first remission. If ongoing studies can demonstrate that this is indeed true, we will need to look beyond the first PFS reported. Future studies will need to consider the duration of second remission to a cBTKI. Further, any quality-of-life improvements noted with time off of treatment will ultimately be most important for determining the true benefit of continuous versus fixed-duration therapy in all patients, particularly high-risk patients who have an inferior OS on average as compared to others with CLL.
In Brief
Arm D of the SEQUOIA study is one of the few cohorts to evaluate the efficacy of a cBTKi and venetoclax doublet in a patient population enriched for those with p53 aberrations. Given the efficacy of single-agent cBTKi and venetoclax in combination with obinutuzumab, the allure of doublets like those used in the SEQUOIA study is leveraging the benefit of these targeted therapies with the possibility of stopping the cBTKi. To that end, most of these studies have incorporated fixed-duration therapy. Whether that is ultimately the best way to manage patients with p53 aberrations is yet to be determined. What we can glean from arm D of the SEQUOIA study is that the combination of zanubrutinib and venetoclax is indeed effective in this patient population, achieving similar results in those with and without a p53 aberration. The major difference is the time needed to achieve a uMRD, a marker that has been used as a correlative for deeper remissions. Those with p53 aberrations took several months longer to achieve a uMRD rate compared to wild-type patients. Additionally, using a rigorous method for ensuring the depth and durability of uMRD (testing both the PB and BMBx at multiple time points), the authors were able to stop treatment in a small subset of patients, most of whom remain in clinical and molecular remission. The hope is that longer follow-up on this study and others will clarify this current dilemma and provide a clearer path on the best way to manage patients with high-risk CLL.
Disclosure Statement
Dr. Phillips indicated no relevant conflicts of interest.
