Treatment with acalabrutinib, umbralisib, ublituximab shows potential in CLL
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Key takeaways:
- Time-limited, dual B-cell receptor inhibitor therapy seems promising in treatment-naive and relapsed/refractory CLL.
- Immune-related adverse events required dose reduction of umbralisib in some patients, but most stayed on therapy.
Time-limited dual B-cell receptor inhibitor therapy with acalabrutinib, umbralisib and ublituximab showed potential in treatment-naive and relapsed/refractory chronic lymphocytic leukemia, according to data presented at ASH Annual Meeting.
In this investigator-sponsored, phase 2 trial, Inhye E. Ahn, MD, of Dana-Farber Cancer Institute, and colleagues assessed time-limited dual B-cell receptor inhibitor therapy with acalabrutinib (a Bruton tyrosine kinase inhibitor) and umbralisib (a PI3K-delta inhibitor), with the addition of ublituximab, a glycoengineered anti-CD20 antibody, initiated during cycle 7. The primary endpoint was complete response after cycle 24, but researchers also examined minimal residual disease (MRD).
Patients with treatment-naive or relapsed/refractory CLL received up to 24 cycles of acalabrutinib, umbralisib (Ukoniq, TG Therapeutics) and ublituximab (Briumvi, TG Therapeutics). Each cycle was 28 days, and daily oral doses of acalabrutinib (100 mg twice a day) and umbralisib (800 mg once a day) began on cycle 1 day 1, according to the abstract. Patients continued on acalabrutinib and umbralisib until cycle 24 unless they achieved complete response, when they stopped after cycle 12. They received IV ublituximab starting on cycle 7 for six cycles. However, when umbralisib was withdrawn from drug development in March 2023, patients receiving study therapy at the time remained on acalabrutinib monotherapy until cycle 24.
Of 29 patients enrolled in the study, 72% were treatment-naive and 79% had unmutated IGHV. Relapsed or refractory patients had received a median of one prior line of therapy. Additionally, many patients had genetic alterations. At a median follow-up of 23 months, seven patients were still receiving therapy prior to reaching cycle 24, with no deaths, Richter’s transformations or CLL progression events.
Researchers found that a complete response rate of 33%, undetectable MRD in bone marrow of 44% and undetectable MRD in peripheral blood of 67% at best response. At best response, they observed no statistically significant differences in complete response and undetectable MRD rates between treatment-naive and relapsed/refractory groups.
Complete response and undetectable MRD rates in bone marrow improved during the second year of therapy, with a complete response rate of 11% after cycle 12 and 28% after cycle 24, and a bone marrow undetectable MRD rate of 22% after cycle 12 and 39% after cycle 24. The undetectable MRD rate in peripheral blood remained unchanged at 44%. In addition, the median time from the last undetectable MRD to detectable MRD in peripheral blood was 3 months, and 80% of patients with MRD conversion had partial response or detectable MRD in bone marrow at best response.
Importantly, due to frequent immune-related adverse events, 38% of patients required dose reduction of umbralisib, after which most were then able to stay on therapy, according to the abstract. Notable adverse events included diarrhea or colitis, bruising, transaminitis, COVID-19 infection, hypertension, rash and pneumonitis. Additionally, two patients had temporary dose reduction of acalabrutinib to avoid drug-drug interaction.
“Longer follow-up is required to determine durability of remission off therapy,” Ahn said in the presentation.
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