Commentary

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Acalabrutinib With/Without Obinutuzumab Is Effective in Higher-Risk Chronic Lymphocytic Leukemia

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Acalabrutinib-containing regimens demonstrated long-term efficacy with a tolerable safety profile in higher-risk chronic lymphocytic leukemia.

Matthew S. Davids, MD, MMSc

Matthew S. Davids, MD, MMSc

Patients with higher-risk chronic lymphocytic leukemia (CLL) treated with acalabrutinib (Calquence)-based regimensexperienced long-term efficacy across all lines of treatment,according to findings from a pooled analysis of 5 prospective clinical studies published in Blood Advances.

At a median follow-up of 59.1 months (range, 1-82) in the treatment-naive cohort (n = 320) and 44.3 months (range, 0-88) in the relapsed/refractory cohort (n = 488), patients remained on treatment at last follow-up at rates of 51.3% and 26.8%, respectively. In patients with higher-risk disease in the treatment-naive cohort, the median progression-free survival (PFS) and overall survival (OS) were not reached (NR). In the relapsed/refractory cohort, patients with 17p deletion (del[17p])/TP53 mutations (n = 214), unmutated IGHV (n = 408), and complex karyotype (n = 146) experienced a median PFS of 38.6 months, 46.9 months, and 38.6 months, respectively, and a median OS of 60.6 months, NR, and NR, respectively.

Additionally, the overall response rates (ORR) in the treatment-naive cohort among patients with del(17p)/TP53 mutations (n = 64), unmutated IGHV (n = 287), and complex karyotype (n = 79) were 91% (95% CI, 81%-97%), 96% (95% CI, 93%-98%), and 91% (95% CI, 83%-96%), respectively. These respective rates in the subgroups of the relapsed/refractory cohort were 86% (95% CI, 81%-90%), 87% (95% CI, 84%-90%), and 84% (95% CI, 77%-89%). The respective complete response rates in the subgroups of the treatment-naive cohort were 23.4%, 19.9%, and 19.0%; in the relapsed/refractory cohort these rates were 5.1%, 7.8%, and 10.3%, respectively.

“Before targeted therapies, patients with higher-risk CLL, defined as del(17p) and/or TP53 mutation, unmutated IGHV, or complex karyotype, had poorer prognosis with chemoimmunotherapy,” Matthew S. Davids, MD, MMSc, director, clinical research, Division of Lymphoma, at Dana-Farber Cancer Institute, and an associate professor of medicine, at Harvard Medical School, both in Boston, Massachusetts, and coauthors wrote. “To better understand the impact of the second-generation BTK inhibitor acalabrutinib, we pooled data from 5 prospective clinical studies of acalabrutinib as monotherapy or in combination with obinutuzumab [Gazyva] in patients with higher-risk CLL in treatment-naive or relapsed/refractory cohorts.”

To conduct their analysis, investigators pooled data from the phase 3 ELEVATE-TN (NCT02475681), ELEVATE-RR (NCT02477696), and ASCEND (NCT02970318) studies, as well as the phase 1/2 ACE-CL-001 (NCT02029443) and phase 1 ACE-CL-003 (NCT02296918) trials. Patients included in the analysis (n = 808) received acalabrutinib at a dose of 100 mg twice daily until disease progression or unacceptable toxicity, apart from some patients in ACE-CL-001 and ACE-CL-003 who were initially treated at a dose of 200 mg once daily. Those in ACE-CL-003 and in the acalabrutinib plus obinutuzumab arm of ELEVATE-TN also received 6 cycles of obinutuzumab at a dose of 100 mg on day 1, followed by 900 mg on day 2, and 1000 mg on days 8 and 15 of cycle 2, plus 1000 mg on day 1 of cycles 3 to 7.

Study outcomes included PFS, OS, ORR, and safety. The median age of the overall cohort was 67 years (range, 32-89). Most patients were male (68%), had an ECOG performance status of 1 or less (93%), and had unmutated IGHV (88%). The median number of prior lines of treatment was 1 (range, 0-10) and the median follow-up was 49.1 months (range, 0-88).

In terms of safety, in the overall cohort 70.3% of patients experienced at least 1 grade 3 or greater treatment-emergent adverse effect (TEAE). The most common grade 3 or greater TEAEs included neutropenia (19.3%), pneumonia (9.5%), anemia (8.4%), thrombocytopenia (6.1%), and hypertension (5.4%). Patients discontinued treatment due to TEAEs at a rate of 16.5%, most commonly due to pneumonia (0.9%) and thrombocytopenia (0.6%).

Patients discontinued treatment due to disease progression (22%), AEs (15%), study termination (14%), death (4%), loss to follow-up (0.4%), Richter transformation (0.4%), and other reasons (8%). Deaths occurred in 10.6% and 23.4% of patients in the treatment-naive and relapsed/refractory cohorts, respectively.

“Overall, our results demonstrate the long-term benefit of acalabrutinib-based regimens in patients with CLL and higher-risk genomic features, regardless of line of therapy, with no new safety signals identified in the analysis,” Davids and coauthors wrote in conclusion. “Our data continue to support the approach of continuous acalabrutinib as a highly effective and well-tolerated option for treating a broad population of patients with CLL, particularly those with higher-risk genetic features. However, treatment optimization in patients with del(17p)/TP53 [mutations] is still an urgent unmet need, particularly in the relapsed/refractory setting.”

Reference

  1. Davids MS, Sharman JP, Ghia P, et al. Acalabrutinib-based regimens in frontline or relapsed/refractory higher-risk CLL: pooled analysis of 5 clinical trials. Blood Adv. 2024;8(13):3345-3359. doi:10.1182/bloodadvances.2023011307

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