A phase 2 trial presented at the 2024 American Society of Hematology Annual Meeting and Exposition (ASH) indicates that a combination of pirtobrutinib, venetoclax, and obinutuzumab shows promising results as a first-line treatment for chronic lymphocytic leukemia (CLL). The study, led by Nitin Jain, MD, reported high rates of undetectable minimal residual disease (uMRD), suggesting a potential new standard of care for CLL patients.
High Rates of Undetectable MRD
The trial (NCT05536349) assessed the efficacy of pirtobrutinib (Jaypirca) in combination with venetoclax (Venclexta) and obinutuzumab (Gazyva). Data from serial time points in blood and bone marrow analyses revealed significant uMRD rates. Specifically, at the end of cycle 7 (n = 66), the uMRD rate at less than 10-6 (uMRD6) was 79% in peripheral blood samples and 64% in bone marrow samples. Further analysis at the end of cycle 13 (n = 41) showed uMRD rates of 85% in peripheral blood and 80% in bone marrow.
According to Dr. Jain, professor at The University of Texas MD Anderson Cancer Center, “We report high rates of uMRD6 remission combined with pirtobrutinib, venetoclax, and obinutuzumab as first-line treatment for patients with CLL.”
Patient Demographics and Treatment Protocol
Between February 2023 and September 2024, the trial enrolled 80 patients with a median age of 63 years, with 26% being 70 years or older and 75% being male. A significant proportion of patients had high-risk genetic features, including 79% with unmutated IGHV status, 31% with NOTCH1 mutations, 21% with SF3B1 mutations, 14% with KRAS/NRAS mutations, 10% with BIRC3 mutations, and 13% with del(17p)/TP53 mutations.
The treatment protocol involved a combination of pirtobrutinib at 200 mg once daily, obinutuzumab, and a ramp-up dose of venetoclax. During cycle 1, obinutuzumab was administered at 100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15. Venetoclax was introduced with a weekly ramp-up dose during cycle 2, reaching 400 mg once daily from cycles 3 to 6. After cycle 7, patients continued with pirtobrutinib at 200 mg daily plus venetoclax at 400 mg once daily until cycle 13.
Safety Profile and Adverse Events
The safety analysis revealed that the most common grade 3/4 adverse effects were neutropenia (60%) and thrombocytopenia (14%), with 58% of patients requiring G-CSF. Neutropenic fever was reported in 4 patients. Dose reductions of pirtobrutinib were necessary in 21% of patients, while venetoclax dose reductions occurred in 31% of patients, primarily due to neutropenia. Two patients developed atrial fibrillation.
Clinical Implications
The results suggest that the combination of pirtobrutinib, venetoclax, and obinutuzumab could offer a highly effective first-line treatment option for CLL patients, particularly those with high-risk genetic features. The high rates of uMRD and the absence of disease progression at a median follow-up of 11.9 months underscore the potential of this triplet therapy to improve outcomes in CLL. Further studies with longer follow-up are needed to confirm these findings and assess the durability of response.
