Initial findings from a multi-center, investigator-initiated, phase II study demonstrated that time limited therapy with zanubrutinib, obinutuzumab, and venetoclax (BOVen) is well-tolerated and achieves rapid undetectable minimum residual disease, according to data presented at the 2020 ASCO Annual Meeting (Abstract 8006).
"Time-limited therapy with obinutuzumab (CD20 antibody) and venetoclax (BCL2 inhibitor) induces minimum residual disease (MRD) undetectable responses. There is strong rationale to add the BTK inhibitor zanubrutinib to obinutuzumab and venetoclax," noted study author Jacob Drobnyk Soumerai, MD, from Massachusetts General Hospital.
"We initiated this study to determine whether MRD-directed, time-limited therapy with the BOVen regimen achieves frequent disease eradication in previously untreated patients," he explained.
Methods & Results
Eligible patients had previously untreated chronic lymphocytic leukemia (CLL). The researchers administered BOVen in 28-day cycles.
"Treatment duration was determined by a prespecified undetectable minimum residual disease endpoint (min 8 cycles). Minimum residual disease was assessed in peripheral blood (PB; flow cytometry, sensitivity >10-4) starting cycle 7, day 1, then every 2 cycles," the study authors wrote. "Once PB undetectable minimum residual disease was determined and confirmed in bone marrow (BM), treatment continued two additional cycles."
Adverse events (AE) were assessed per CTCAE v5. The primary endpoint was undetectable MRD, which was estimated using the Kaplan-Meier method.
Thirty-nine were enrolled on the trial with a median age of 59 years (23-73). The ratio of men to women was 3:1. Twenty-six (67%) patients had a CLL-International Prognostic Index score greater than 4. Other patient characteristics included unmutated IGHV (72%) and 17p del/TP53 mutated (10%). All patients were evaluable for toxicity and 37 were evaluable for efficacy, according to the study authors.
"BOVen achieved rapid undetectable MRD," Soumerai reported. "At a median follow-up of 11 months, 84 percent of patients are MRD undetectable in blood and 73 percent of patients are MRD undetectable in bone marrow.
"Treatment duration is determined by a prespecified MRD endpoint," he explained. "At a median follow-up of 11 months, 62 percent of patients have achieved the prespecified MRD endpoint and stopped therapy after a median of 8 months of treatment (6 months of the BOVen triplet)."
The most common treatment emergent AEs were neutropenia (49%), infusion-related reaction (41%), bruising (39%), and diarrhea (39%), the study authors noted in the abstract.
"Of 17 patients at high risk for tumor lysis syndrome (TLS) on cycle 1 day 1, 2 cycles of zanubrutinib and obinutuzumab reduced TLS risk to low/medium at venetoclax initiation in 15 (88%)."
"BOVen is well-tolerated, notably with a low rate of grade 3/4 neutropenia (15%)," Soumerai said. "Grade 3/4 neutropenia was seen in one-third to one-half of patients in prior studies evaluating venetoclax with other BTK inhibitors, so these data are encouraging."
Implications & Next Steps
The researchers will continue to evaluate the value of MRD-directed treatment duration with continued post-discontinuation follow-up, according to Soumerai.
"We will determine how frequently BOVen achieves minimal residual disease undetectable responses with additional follow-up of the patients still on active therapy," he explained. "We await ongoing correlative analyses. As an example, we are also evaluating depth of remission using the clonoSEQ assay.
"The BOVen regimen is well-tolerated and achieves frequent and rapid MRD eradication and warrants further evaluation as a frontline regimen in CLL," he concluded. "By incorporating an MRD-driven treatment duration strategy into this novel study design, we will determine the optimal duration of the BOVen regimen for future study."
Catlin Nalley is a contributing writer.
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