Among patients with chronic lymphocytic leukemia (CLL) who cannot tolerate Bruton tyrosine kinase (BTK) or phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors, umbralisib appears to be safe and efficacious, according to research published in Blood.
Kinase inhibition has drastically improved outcomes in CLL, with several approved inhibitors – including BTK and PI3K inhibitors – significantly extending progression-free survival (PFS) and overall survival (OS) compared with older therapeutic regimens. Despite these improvements, kinase inhibitors are associated with significant toxicity. Widely used kinase inhibitors, including ibrutinib and idelalisib, are linked with adverse events (AEs) leading to treatment discontinuation in more than half of treated patients.
Because of this common issue in patients with CLL, novel treatments that benefit patients who are intolerant to BTK and PI3K inhibitors are badly needed. Umbralisib, a dual PI3Kδ/CK1 epsilon inhibitor with greater selectivity for the delta isoform, has previously been associated with lower toxicity. For this phase 2 study, researchers evaluated the safety and efficacy of umbralisib among patients with CLL intolerant to BTK or PI3Kδ inhibitor therapy.
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Overall, 51 patients were enrolled, among whom 51 were evaluable for safety and 50 were evaluable for PFS. The median patient age was 70 years (range, 48-96), 28 patients were male, 47 patients had a performance status of 0 or 1, and the median number of prior therapy lines was 2 (range, 1-7). The most common AEs that led to kinase inhibitor discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%).
The median PFS in the population was 23.5 months (95% CI, 13.1-not estimable), and 58% of patients were able to continue treatment for longer than with previous kinase inhibitor therapy.
The most common AEs that occurred in at least 5% of patients were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). While 6 (12%) patients discontinued umbralisib treatment because of an AE, 8 (16%) with dose reduction successfully had a therapy rechallenge.
“Given the noncurative nature of CLL therapy, adding effective lines of therapy to each patient’s treatment sequence is likely to improve outcomes,” the authors wrote in their report. “These data may be particularly relevant because the combination of umbralisib and ublituximab is being studied in a randomized phase 3 study with potential indications in the frontline and [relapsed/refractory] settings.”
Reference
Mato AR, Ghosh N, Schuster SJ, et al. Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy. Blood. 2021;137(20):2817-26. doi:10.1182/blood.2020007376
