The Bruton’s tyrosine kinase (BTK) inhibitors have been one of the most exciting advances in the treatment of patients with chronic lymphocytic leukemia (CLL) and have led to the development of chemotherapy-free treatments for both treatment-naive as well as relapsed or refractory CLL based on studies where these novel agents were directly compared with chemoimmunotherapy. ASCEND is the first trial to directly compare two targeted agents in a phase III study.1 The trial met its primary endpoint on interim analysis, showing prolonged progression-free survival with acalabrutinib monotherapy vs investigator’s choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR).
Seema A. Bhat, MD
Jennifer A. Woyach, MD
Final Results: No Role for Chemoimmunotherapy
In the final results of this international phase III trial, presented during the ASCO20 Virtual Scientific Program,2 the investigators demonstrated continued superior progression-free survival with acalabrutinib monotherapy compared with IdR or BR in adults with relapsed or refractory CLL who had received at least one prior line of treatment. As expected, patients who had previously received treatment with novel targeted agents were excluded; however, patients who had previously received bendamustine were eligible provided the duration of the prior response was at least 24 months. Of the 310 study participants, 155 were treated with acalabrutinib monotherapy, where treatment was continuous until disease progression or unacceptable
toxicity. In the standard arm, of the 155 patients, 119 patients received IdR, which was continued until disease progression, and 36 patients received BR for six cycles. This imbalance between the two regimens in the standard arm reflects the increasing preference of physicians to prescribe novel agent–based therapies in comparison to chemoimmunotherapy for patients with relapsed CLL.
The results of this study suggest that chemoimmunotherapy has no role in relapsed CLL. In the final results, at a median follow-up of 22 months, acalabrutinib significantly prolonged investigator-assessed progression-free survival vs the standard arm (median = not reached vs 16.8 months, hazard ratio = 0.27, P < .0001). The 18-month rates were 82% with acalabrutinib and 48% with IdR/BR, and the progression-free survival benefit of acalabrutinib was consistent across prespecified high-risk genomic subgroups, including those with unmutated IGHV and del(17p)/TP53 mutation. Overall response rates were similar between the two arms (80% with acalabrutinib vs 84% with IdR/BR), but as the results depicted, responses with IdR and BR were not durable. In addition, based upon previous studies with BTK inhibitors in CLL, we can expect the overall response rate to continue to increase with longer follow-up.
These positive results are not surprising, given the established role of BTK inhibition in the treatment of CLL. An overall survival difference was not seen, and presumably will not be seen, given the crossover design of the study. As of the data cutoff for this study, 23% of patients initially randomly assigned to investigator’s choice crossed over to receive acalabrutinib at disease progression.
“In addition to improved progression-free survival, therapy with acalabrutinib was associated with fewer adverse effects.”— Seema A. Bhat, MD, and Jennifer A. Woyach, MD
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Less Toxicity With Acalabrutinib
In addition to improved progression-free survival, therapy with acalabrutinib was associated with fewer adverse effects. The rates of adverse events leading to drug discontinuation were 16% with acalabrutinib, 56% with IdR, and 17% with BR. Acalabrutinib is a second-generation, highly specific BTK inhibitor with less effect on other kinases, which may translate into fewer side effects.
The most common adverse events with acalabrutinib were diarrhea, neutropenia, and headache, but they were generally manageable and short-lasting. Headache is a unique toxicity with acalabrutinib, and we usually warn our patients about this possibility and reassure them it is transient and treatable with acetaminophen, hydration, or caffeine. The frequency of adverse events of clinical interest usually reported with BTK inhibition (including atrial fibrillation, hypertension, and major bleeding) was low and lower than what has been reported with ibrutinib.
These results are highly encouraging, since in previous studies with ibrutinib we have seen a high rate of treatment discontinuation due to these adverse effects. Indeed, Byrd et al recently presented results from the phase II ACE-CL-001 trial during the ASCO20 Virtual Scientific Program confirming the long-term safety and tolerability of acalabrutinib in treatment-naive CLL; 86% of patients remained on treatment at a median follow-up of more than 4 years.3 In addition, Awan et al have previously demonstrated that patients with CLL who discontinued ibrutinib due to intolerance were able to tolerate acalabrutinib well and achieve promising disease control.4 A head-to-head trial comparing acalabrutinib with ibrutinib is currently underway (ELEVATE-R/R, ClinicalTrials.gov identifier NCT02477696).
The final ASCEND results with additional follow-up confirm earlier findings, thus adding to the growing number of novel agents approved for patients with CLL who have relapsed disease (idelalisib, ibrutinib, venetoclax, duvelisib, and acalabrutinib). Acalabrutinib is also the first drug to receive simultaneous U.S. Food and Drug Administration approval for both upfront as well as relapsed or refractory disease indications based on the ELEVATE-TN study and the interim results of the ASCEND study, respectively. Although CLL remains an incurable disease, this study adds another effective agent to the treatment armamentarium with the potential to improve the quality and quantity of life for our patients with this disease.
Drs. Bhat and Woyach are oncologists on staff at The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus.
DISCLOSURE: Dr. Bhat has served as a consultant or advisor to Pharmacyclics. Dr. Woyach has served as a consultant or advisor to ArQule, AstraZeneca, Janssen, and Pharmacyclics and has received research funding from AbbVie, Janssen, Karyopharm Therapeutics, Loxo, MorphoSys, and Verastem.
1. Ghia P, Pluta A, Wach M, et al: ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 38:2849-2861, 2020.
2. Ghia P, Pluta A, Wach M, et al: Acalabrutinib vs idelalisib plus rituximab or bendamustine plus rituximab in relapsed/refractory chronic lymphocytic leukemia: ASCEND final results. ASCO20 Virtual Scientific Program. Abstract 8015.
3. Byrd JC, Woyach JA, Furman RR, et al: Acalabrutinib in treatment-naive chronic lymphocytic leukemia. ASCO20 Virtual Scientific Program. Abstract 8024.
4. Awan FT, Schuh A, Brown JR, et al: Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv 3:1553-1562, 2019.