MRD-Guided Zanubrutinib/Venetoclax/Obinutuzumab Triplet Induces Deep Remissions in R/R CLL

Chronic Lymphocytic Leukemia
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Time-limited, minimal residual disease (MRD)–guided treatment with zanubrutinib (Brukinsa) plus venetoclax (Venclexta) and obinutuzumab (Gazyva) led to deep MRD responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), including those with TP53 mutations and/or previous exposure to a BTK inhibitor or venetoclax.

Findings from the phase 2 CLL2-BZAG study (NCT04515238), published in Blood, showed thatafter a median observation time of 21.5 months (interquartile range [IQR], 16.5-25.9), all patients in the full analysis set (n = 40) achieved an overall response, 7.5% of which were complete responses (CR) or CRs with incomplete marrow recovery (CRi) and 92.5% of which were partial responses.1,2

Over half of patients achieved undetectable MRD (uMRD) in peripheral blood (52.5%; 95% CI, 36.1%-68.5%), including 40% of patients with prior BTK inhibitor and/or venetoclax exposure and 53.3% of those with TP53 aberrations. Moreover, MRD responses deepened over the course of maintenance treatment. Detectable MRD was observed in 47.5% of patients at final restaging; this rate decreased to 23.5% of patients after cycle 1 of maintenance and 12.5% of patients after cycle 2.

The best uMRD rates—defined as uMRD achieved at any time—were 85%, 80%, and 80% for patients in the full analysis set, those with prior BTK inhibitor and/or venetoclax exposure, and those with TP53 aberrations, respectively. Notably, the rates of uMRD at final restaging and best uMRD were comparable between patients who received bendamustine debulking (52.6% and 89.5%, respectively) and those who did not (81% and 52.4%).

“This MRD-guided combination…shows promising efficacy in a relapsed/refractory CLL population enriched for patients with high-risk genetics and patients previously exposed to venetoclax/BTK inhibitors,” lead study authorMoritz Fürstenau, MD—a member of the faculty of medicine in the Department I of Internal Medicine at the University of Cologne in Germany, as well as a member of the German CLL Study Group—and colleagues wrote in the paper. “With a best uMRD rate of 85% and a substantial proportion of patients still receiving maintenance treatment, further deepening of responses and more conversions to uMRD with continued maintenance are expected, which might eventually translate into prolonged progression-free survival [PFS].”

Overview of CLL2-BZAG: Background and Trial Design

Triplet combinations incorporating BTK inhibitors, BCL2 inhibitors, and anti-CD20 antibodies have shown activity in frontline CLL. The phase 3 GAIA/CLL13 trial (NCT02950051) established the efficacy of venetoclax plus ibrutinib (Imbruvica) and obinutuzumab in treatment-naive patients, yielding high rates of uMRD and prolonged PFS. Findings from additional phase 2 studies support the use of such regimens, reporting robust outcomes in previously untreated patients. However, data in the relapsed/refractory setting—especially among patients with prior BTK inhibitor and/or venetoclax exposure—remain limited, with only 3 published phase 2 trials to date.

Given the growing preference for time-limited approaches in CLL, there is a need for such regimens that are effective in later lines, particularly for patients previously treated with BTK and/or BCL-2 inhibitors. To address this, the ongoing investigator-initiated CLL2-BZAG trial evaluated an MRD-guided regimen of venetoclax, zanubrutinib, and obinutuzumab following optional bendamustine debulking in patients with relapsed/refractory CLL.

The study completed enrollment in September 2022. Eligible patients were at least 18 years of age with previously treated, active CLL per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Patients who had previously progressed on BTK inhibitors and/or venetoclax or those who harbored resistance-associated BTK/BCL2 mutations were excluded.

Optional debulking with 2 cycles of intravenous (IV) bendamustine at 70 mg/m2 on days 1 and 2 was recommended for patients at high risk for tumor lysis syndrome (TLS). Induction was composed of the sequential initiation of IV obinutuzumab at 1000 mg on days 1 and/or 2, 8, and 15 of the first cycle, and on day 1 of the following cycles until the final restaging; 160 mg of oral zanubrutinib twice daily starting at the second induction cycle; and 400 mg of oral venetoclax added during the third induction cycle following the established 5-week ramp-up schedule, for a total of 8 induction cycles. Maintenance therapy included all 3 agents and continued until a CR or CR plus uMRD in peripheral blood was achieved in 2 consecutive assessments, or up to 24 months.

The study’s primary end point was uMRD rate in peripheral blood at final restaging after 6 cycles of induction therapy. Secondary end points included overall response rate, CR rate, PFS, overall survival (OS), and safety. Exploratory analyses included MRD and circulating tumor DNA (ctDNA) dynamics and subgroup efficacy outcomes. The data cutoff for the primary end point analysis was June 5, 2023.

Between November 2020 and September 2022, a total of 42 patients were enrolled onto the study after screening, comprising the intention-to-treat (ITT) population. Of these patients, 19 received bendamustine debulking therapy; 15 completed both planned cycles, and 4 received only 1 cycle. Notably, 7.5% of patients discontinued induction treatment early due to adverse effects (AEs)—2 from COVID-19 and 1 from elevated hepatic enzyme levels.

All patients in the ITT population received induction therapy, with 40 patients completing at least 2 full cycles of induction therapy. These patients were included in the full analysis set. All patients who received 1 or more doses of the study drug were included in the safety population. During induction, 35% of patients required at least 1 venetoclax dose modification, and 25% of patients received a dose modification of zanubrutinib due to AEs.

Maintenance therapy was administered to 34 patients, 2 of whom discontinued treatment early due to AEs, 17 of whom completed study treatment per protocol with confirmed uMRD, and 1 of whom who was lost to follow-up due to noncompliance. As of the data cutoff, 15 patients remained on treatment, and 18 patients were in follow-up. The median duration of treatment was 14.3 months (IQR, 11.2-16.7). Among the 22 patients who completed treatment, the median duration of treatment was 14.9 months (IQR, 12.9-17.5).

“The patient cohort enrolled in this trial embodies this clinical diversity in the relapsed/refractory setting with a broad range of prior treatment lines, including 50.0% of patients with prior exposure to BTK inhibitors and/or venetoclax and a high variability in the genetic risk profile,” the authors continued.

Within the full analysis set, the median age was 64 years (IQR, 57-70), and 67.5% of patients were male. The median cumulative illness rating scale score was 3 (IQR, 2.0-5.8), and the median creatinine clearance was 82.1 mL/min (IQR, 58.4-100.5). The median number of prior therapies was 1 (range, 1-5), with 45%, 17.5%, and 12.5% of patients having received a prior BTK inhibitor, prior venetoclax, or both, respectively. Half of patients had prior exposure to BTK inhibitors and/or venetoclax, primarily through time-limited regimens; 17 of 18 patients had completed such regimens as planned, and 2 patients had discontinued prior continuous BTK inhibitor monotherapy due to intolerance. Additionally, 2 had patients discontinued prior BTK inhibitor monotherapy early with no further time-limited venetoclax–containing regimens due to intolerance. High-risk genomic features included 17p deletions and/or TP53 mutations in 37.5% of patients, unmutated IGHV in 77.5% of patients, and complex karyotype (≥ 3 aberrations) in 50% of patients.

Additional Efficacy and ctDNA Data

The median PFS in the full analysis set was 29.1 months, and the estimated 18-month PFS rate was 96.0%. Comparable 18-month PFS rates were observed among patients who had prior BTK inhibitor and/or venetoclax exposure (90%), harbored TP53 aberrations (100%), undergone debulking therapy (92.9%), and had not undergone debulking therapy (100%). Two patients experienced disease progression per iwCLL criteria at 9 months after stopping maintenance due to uMRD and 12 months after early treatment discontinuation due to infections, respectively. Investigators noted that neither patient required subsequent CLL therapy.

The median OS was not reached, and the estimated 18-month OS rate was 96.8%. One patient died 11 months after early discontinuation due to fungal pneumonia following prolonged SARS-CoV-2 infection. A second COVID-19–related death occurred in a patient excluded from the full analysis set.

“With regard to the interpretation of PFS data, it is still too early to draw definitive conclusions, but the 18-month PFS and OS results also compare well with [those observed with] other standard regimens in the relapsed/refractory setting,” the investigators added.

An exploratory analysis comparing plasma-based digital droplet PCR (ddPCR) assays targeting patient-specific immunoglobulin variable diversity joining rearrangements with conventional multicolor flow cytometry for MRD monitoring was conducted. Concordance between both methods—defined as either both undetectable (uMRD/ctDNA negative) or both detectable (MRD/ctDNA positive)—was observed in 87.2% of the 281 samples analyzed. Discordant results occurred in 12.8% of samples, with 63.9% of samples showing persistent ctDNA despite uMRD by flow cytometry, and 36.1% of samples showing MRD positivity by flow cytometry in the absence of detectable ctDNA. Moreover, ddPCR did not detect any known resistance mutations in BTK or BCL2 genes. One PLCG2 S707F mutation was identified 11 months after treatment in 1 patient who had not been previously exposed to a BTK inhibitor.

Safety Analysis

All patients who received 1 or more doses of study treatment were included in the safety population (n = 42). As of the data cutoff, a total of 445 AEs were reported; of these, 8.8%, 68.1%, 18.9%, and 4.3% occurred during debulking, induction, maintenance, and follow-up, respectively. In total, 18% of patients required dose modification of at least 1 study drug; this included 22 dose reductions, 65 temporary interruptions, and 7 permanent discontinuations.

“No unexpected toxicities were observed in this study so far. Hematological toxicities were anticipated and occurred in most patients; however, no patients experienced febrile neutropenia,” the authors stated.

The most frequently reported any-grade AEs were COVID-19 (61.9%), diarrhea (35.7%), infusion-related reactions (35.7%), thrombocytopenia (33.3%), neutropenia (28.6%), nausea (28.6%), fatigue (28.6%), constipation (21.4%), dizziness (21.4%), hematoma (19.0%), headache (16.7%), pneumonia (16.7%), rash (16.7%), arthralgia (14.3%), leukopenia (11.9%), pyrexia (11.9%), back pain (11.9%), vomiting (11.9%), hyperuricemia (10.0%), anemia (7.1%), TLS (7.1%), and sepsis (2.4%).

Grade 3 or higher AEs included neutropenia (23.8%), COVID-19 (21.4%), thrombocytopenia (16.7%), pneumonia (11.9%), anemia (7.1%), TLS (7.1%), leukopenia (9.5%), and individual cases of constipation, hematoma, hyperuricemia, infusion-related reaction, and sepsis (each 2.4%/n = 1). Notably, 2 patients experienced grade 3 or higher cardiac toxicities: 1 with a grade 3 non–ST-elevation myocardial infarction, and 1 with 2 episodes of grade 3 atrial fibrillation in the setting of pre-existing atrial fibrillation.

Regarding study limitations, the investigators noted that, “although the early efficacy data of this regimen look promising and compare well with continuous BTK inhibitor monotherapy in this setting, it is important to acknowledge that this study cohort consists of rather young and fit patients with CLL mostly treated at large academic centers.”

The interpretation of these data is also constrained by the timing of the primary end point analysis, which was scheduled relatively early and resulted in lower uMRD rates compared with those observed at subsequent time points; the exclusion of 2 patients who discontinued treatment early and achieved suboptimal outcomes from the efficacy analysis; and the heterogeneity of the study population, which comprised 2 cohorts of patients who underwent slightly different treatment regimens.

“Given the potential of this MRD-driven, individualized treatment approach to achieve deep remissions in most patients even when pre-exposed to targeted treatments, this time-limited triple combination warrants further exploration in relapsed/refractory CLL,” the authors concluded.

Reference

Fürstenau M, Robrecht S, Schneider C, et al. MRD-guided zanubrutinib, venetoclax, and obinutuzumab in relapsed CLL: primary end point analysis from the CLL2-BZAG trial. Blood. 2025;145(suppl 12):1282-1292. doi:10.1182/blood.2024026685