Time‐Limited Triplet Therapy Induces Rapid Undetectable MRD Responses in CLL

Short abstract

Zanubrutinib, obinutuzumab, and venetoclax (BOVen), given on a treatment schedule driven by minimal residual disease milestones, is a promising approach to previously untreated chronic lymphocytic leukemia, according to new findings from an investigator‐initiated phase II study.

Combination time‐limited therapy with obinutuzumab, an anti‐CD20 antibody, and venetoclax, a B‐cell lymphoma 2 (BCL2) inhibitor, has emerged as a standard frontline option for previously untreated chronic lymphocytic leukemia (CLL). In a recent phase III trial, fixed‐duration treatment with obinutuzumab plus venetoclax induced undetectable minimal residual disease (uMRD) responses in the majority of patients with newly diagnosed CLL, with uMRD rates of 76% and 57% in the peripheral blood (PB) and bone marrow (BM), respectively [1].

Additional early‐phase data support the combination of venetoclax with a Bruton's tyrosine kinase (BTK) inhibitor as frontline therapy for CLL. In two recent phase II trials, frontline treatment with ibrutinib plus venetoclax induced uMRD responses of 65%–75% in patients with previously untreated CLL [2, 3]. Zanubrutinib is a second‐generation BTK inhibitor currently approved for the treatment of relapsed/refractory mantle cell lymphoma. With fewer off‐target kinase‐inhibitory effects than first‐generation BTK inhibition, zanubrutinib is associated with durable responses and a favorable safety profile [4].

Building on these findings, the novel three‐drug combination of zanubrutinib, obinutuzumab, and venetoclax (BOVen) combines a BTK inhibitor, anti‐CD20 antibody, and BCL2 inhibitor. The current investigator‐initiated trial was designed to test the hypothesis that MRD‐directed, time‐limited treatment with BOVen will lead to frequent disease eradication and durable responses in patients with previously untreated CLL.

Phase II Study Design

To date, the trial has enrolled 39 patients with previously untreated CLL or small lymphocytic lymphoma (SLL) with leukemic involvement who require treatment per the International Workshop on CLL (iwCLL) criteria. Eligible patients were required to have an Eastern Cooperative Group (ECOG) performance score <3, absolute neutrophil count (ANC) ≥1,000, and a platelet count ≥75,000/mm³ (or ANC ≥ and platelet count ≥20,000/mm³ if due to CLL/SLL).

All patients were treated with BOVen in 28‐day cycles with the following approach:

• Zanubrutinib 160 mg twice daily starting on day 1 of cycle 1

• Obinutuzumab 1,000 mg IV starting on day 1 of cycle 1 (or split on days 1, 2, 8, and 15 of cycle 1), followed by day 1 of cycles 2‐8

• Venetoclax titrating to a target dose of 400 mg once daily starting on day 1 of cycle 3

After patients completed a minimum of 8 cycles, the prespecified uMRD endpoint determined the remaining duration of treatment. Starting on day 1 of cycle 7, and then every 2 cycles thereafter, MRD was assessed in PB by flow cytometry (sensitivity >10^‐4). Once uMRD was determined in the PB and confirmed in BM patients, 2 additional cycles were completed for a maximum total of 24 cycles.

The primary endpoint was the frequency of uMRD confirmed in the PB and BM. Secondary endpoints included time on therapy to achieve uMRD, the proportion of patients who successfully discontinued BOVen, the impact of the zanubrutinib‐obinutuzumab lead‐in on tumor lysis syndrome (TLS) risk assessment, and safety and tolerability.

The median patient age was 59 years (range, 23–73 years), and the ratio of men to women was 3:1. The majority of patients (72%) had high‐risk or very high‐risk disease according to CLL‐International Prognostic Index criteria. Baseline genetic testing showed unmutated IGHV in 72% of patients and TP53 aberrations in 15%. The median follow‐up was 11 months.

Jacob Soumerai, M.D., from Massachusetts General Hospital, presented preliminary findings from the ongoing multicenter phase II trial.

Key Findings

Frontline treatment with BOVen induced rapid uMRD responses. At a median follow‐up of 11 months, 62% of patients had achieved the prespecified uMRD endpoint, enabling them to stop therapy after a median of 8 months (i.e., 2 cycles of zanubrutinib plus obinutuzumab and 6 cycles of BOVen). In total, 83.8% of patients achieved uMRD in the blood and 73.0% percent achieved uMRD in the BM.

Among patients evaluable for best response by iwCLL criteria (n = 37), the overall response rate (ORR) was 100%, including a complete response (CR) or CR with incomplete hematologic recovery (CRi) in 43% of patients. Among those who were able to discontinue BOVen (n = 23), the ORR was 100% and the CR/CRi rate was 57% at the time of treatment discontinuation.

The most common treatment‐emergent adverse events (TEAEs) were neutropenia (51%), thrombocytopenia (46%), infusion‐related reaction (41%), bruising (41%), and diarrhea (41%). Among TEAEs of special interest, grade 3–4 neutropenia occurred in 15.4% of patients. According to the study authors, the rate of grade 3–4 neutropenia with BOVen was lower than that observed in patients treated with venetoclax in combination with other BTK inhibitors.

The zanubrutinib and obinutuzumab lead‐in strategy successfully reduced TLS risk. On day 1 of cycle 1, 49% and 43% of patients had medium and high TLS risk, respectively. After 2 cycles of zanubrutinib and obinutuzumab, the proportion at medium and high risk decreased to 24% and 5%, respectively. No patients developed laboratory or clinical TLS.

Looking ahead, the research team will continue to assess the value of MRD‐directed treatment duration with additional follow‐up of patients who have discontinued BOVen. Several correlative analyses are also under way, including an evaluation of the depth of remission using the clonoSEQ® MRD assay, which has a sensitivity of 1 CLL cell in 1,000,000 cells (or 10^–6). With these analyses, Soumerai and colleagues aim to determine the optimal duration of BOVen for future frontline CLL studies.