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A novel triplet regimen led to improved outcomes and was well tolerated in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a phase II trial found.

After a median follow-up of 25.8 months, the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) combined with obinutuzumab (Gazyva) and venetoclax (Venclexta) resulted in undetectable minimal residual disease (MRD) in the peripheral blood and bone marrow in 33 of 37 patients (89%) -- meeting the prespecified criteria to stop therapy -- with a median treatment duration of 10 months, reported Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City.

Additionally, 94% of the patients maintained undetectable MRD status after a median surveillance of 15.8 months post-treatment, they noted in .

The regimen had a safety profile that was favorable in comparison with combinations of venetoclax and other BTK inhibitors, with or without a CD20 antibody.

The most common adverse events with the triplet were thrombocytopenia (59%), fatigue (54%), neutropenia (51%), and bruising (51%). Seven of 39 patients in the intent-to-treat population experienced grade 3 or higher neutropenia.

These results "warrant further study of this regimen as a first-line therapy" for CLL and SLL, Zelenetz and team wrote.

The study authors addressed "two important points" -- whether undetectable MRD can be used as a primary study endpoint and as the measure that defines duration of therapy, and the safety of this novel triplet combination, pointed out Davide Rossi, MD, and Joyce Marques De Almeida, both of the Oncology Institute of Southern Switzerland and Ente Ospedaliero Cantonale in Bellinzona, Switzerland, in an .

"The high rate of [unmeasurable] MRD in both peripheral blood and bone marrow observed with the zanubrutinib, venetoclax, and obinutuzumab combination is highly encouraging, especially given that patients received a median treatment duration of just ten 1-month cycles," they wrote.

This study is the first reported prospective trial in CLL or SLL to use MRD as the principal determinant of treatment duration and discontinuation, as well as the first to report the safety, tolerability, and activity of venetoclax and obinutuzumab combined with zanubrutinib in this disease setting, Zelenetz and colleagues said.

"Venetoclax and obinutuzumab is the standard of care for treatment of newly diagnosed chronic lymphocytic leukemia, which achieves undetectable minimal residual disease that is durable," Zelenetz said in an , noting that zanubrutinib is a second-generation BTK inhibitor that -- unlike ibrutinib -- minimally inhibits interleukin-2-inducible T-cell kinase and is an appealing option to add to the venetoclax/obinutuzumab backbone.

The study included 39 patients (median age 62 years, 77% men), 37 of whom received at least two cycles of therapy and underwent MRD and response assessment.

The triplet was administered in 28-day cycles (oral zanubrutinib at 160 mg twice daily starting in cycle 1 on day 1; intravenous obinutuzumab at 1,000 mg on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2 to 8; and oral venetoclax ramped up to 400 mg daily starting in cycle 3 on day 1), and discontinued after eight to 24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow.

As for other findings, the median time to undetectable MRD in the bone marrow was 8 months. All 37 patients had an overall response, while 21 (57%) had a complete response or complete response with incomplete marrow recovery. Median progression-free survival was not reached, with only one patient having progressive disease.

"Although MRD is a promising surrogate for survival in CLL and SLL, its real potential is as a biomarker for guiding treatment," Zelenetz and colleagues observed.

In a post-hoc analysis, they found that early MRD response kinetics identified a cohort of patients (40%) with high-risk biology, independent of traditional biomarkers for CLL or SLL, and who exhibited delayed bone marrow clearance despite longer duration of treatment. Thus, "we plan to prospectively validate early-MRD-response kinetics as a biomarker to guide treatment duration," they wrote.

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