Two pivotal phase III trials presented at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition mark a significant shift toward chemotherapy-free approaches in chronic lymphocytic leukemia (CLL), offering potentially more effective and tolerable treatment options for both front-line and relapsed or refractory disease.
In the relapsed or refractory setting, the BRUIN CLL-321 trial demonstrated that pirtobrutinib, a third-generation noncovalent Bruton’s tyrosine kinase (BTK) inhibitor, significantly improved progression-free survival and delayed the need for subsequent therapy in patients previously treated with covalent BTK inhibitors.1 The findings address an unmet need for heavily pretreated, high-risk patients, offering a well-tolerated option for sustained disease control.
In addition, the AMPLIFY trial provides the first phase III evidence supporting fixed-duration regimens of the BTK inhibitor acalabrutinib plus the BCL2 inhibitor venetoclax, with or without the monoclonal antibody obinutuzumab, in treatment-naive, fit patients with CLL.2 The study demonstrated superior progression-free and overall survival compared with chemoimmunotherapy, particularly in high-risk subgroups such as those with IGHV-unmutated disease.
BRUIN CLL-321: Pirtobrutinib in Relapsed or Refractory CLL
Jeff P. Sharman, MD
Presented by Jeff P. Sharman, MD, Director of Research at the Willamette Valley Cancer Institute and Director of Hematology Research for Sarah Cannon, the BRUIN CLL-321 trial is the first randomized phase III study to evaluate outcomes in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) following treatment with covalent BTK inhibitors. As Dr. Sharman explained, these patients often face poor outcomes and limited treatment options.
The study enrolled 238 high-risk patients who had previously been treated with first- or second-generation BTK inhibitors. Approximately 70% of the patients had discontinued prior BTK therapy because of disease progression, and more than half had TP53 abnormalities. The median number of prior therapies was three, with one-third of participants having received four or more lines of treatment. Patients were randomly assigned to receive either pirtobrutinib monotherapy or investigator’s choice of the kinase inhibitor idelalisib plus rituximab or bendamustine plus rituximab.
After a median follow-up of 17 months, the use of pirtobrutinib demonstrated a clear improvement in progression-free survival. Patients treated with pirtobrutinib achieved a median progression-free survival of 14 months compared with 8.7 months with the investigator’s choice treatment, representing a 46% reduction in the risk of disease progression or death (hazard ratio [HR] = 0.54, P = .0002).
In addition to progression-free survival, pirtobrutinib delayed the need for subsequent therapy or death. The median time to next treatment or death was approximately 2 years for patients receiving pirtobrutinib, extending to 2.5 years for those who had not previously received venetoclax. These results confirm the continued benefit of BTK inhibition, even after disease progression on earlier generations of BTK inhibitors, according to Dr. Sharman.
The safety profile of pirtobrutinib was found to be tolerable, with low rates of treatment discontinuation because of adverse events. A total of 5% of patients discontinued therapy for treatment-related toxicities. Of note, pirtobrutinib was associated with fewer gastrointestinal and hematologic toxicities, including neutropenia and diarrhea, compared with idelalisib or bendamustine-containing regimens. Adverse events of special interest, such as atrial fibrillation, remained infrequent, with cumulative rates consistent with earlier studies.
“Pirtobrutinib is an effective, well-tolerated agent among patients with difficult-to-treat disease and provides a clinically meaningful way to sustain BTK inhibition,” Dr. Sharman concluded.
AMPLIFY: Fixed-Duration Acalabrutinib and Venetoclax in Treatment-Naive CLL
Jennifer R. Brown, MD, PhD
Presented by Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute, the phase III AMPLIFY trial demonstrated that fixed-duration therapy with acalabrutinib and venetoclax, with or without obinutuzumab, significantly improved progression-free survival and overall survival compared with chemoimmunotherapy in treatment-naive, fit patients with CLL. The results position these regimens as effective, chemotherapy-free alternatives in the front-line setting, particularly for those with high-risk disease features.
The AMPLIFY trial enrolled 867 patients with treatment-naive CLL who were fit for therapy but had no TP53 aberrations. Patients were randomly assigned to receive either acalabrutinib and venetoclax for 14 cycles, acalabrutinib and venetoclax plus obinutuzumab for 14 cycles, or six cycles of standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab or bendamustine plus rituximab.
With a median follow-up of 40.8 months, the study’s primary endpoint of progression-free survival showed a clear benefit for both experimental arms vs chemoimmunotherapy. Patients receiving acalabrutinib and venetoclax achieved a 3-year progression-free survival rate of 76.5% (HR = 0.65), and those receiving acalabrutinib, venetoclax, and obinutuzumab reached a 3-year progression-free survival rate of 83.1% (HR = 0.42). In comparison, progression-free survival for patients receiving chemoimmunotherapy was 66.5%.
In the high-risk subgroup of patients with unmutated IGHV, there was a benefit to the regimen of acalabrutinib, venetoclax, and obinutuzumab. The 3-year progression-free survival rate for unmutated IGHV patients receiving this triplet was 83%, identical to outcomes seen in IGHV-mutated patients in the same arm. According to Dr. Brown, these findings suggest the addition of obinutuzumab may further enhance outcomes for patients with biologically aggressive disease.
The study also demonstrated a significant benefit in undetectable measurable residual disease (MRD) rates, a critical endpoint in CLL. At the end of treatment, undetectable MRD was achieved in 66% of patients given acalabrutinib and venetoclax plus obinutuzumab and 34% in patients given acalabrutinib and venetoclax within the intention-to-treat population. Among evaluable patients, these rates were even higher, reaching 95% with the triplet and 45% with the doublet. Prolonged progression-free survival was strongly associated with undetectable MRD across all treatment arms, highlighting the importance of achieving deep responses.
Overall survival was also improved in the experimental arms vs chemoimmunotherapy. The primary analysis showed a survival benefit for acalabrutinib and venetoclax over chemoimmunotherapy, and when COVID-19–related deaths were censored, both acalabrutinib regimens demonstrated improved overall survival.
In terms of safety, the experimental arms demonstrated a favorable tolerability profile. The median duration of treatment was 13 months with the acalabrutinib regimens compared with 6 months for chemoimmunotherapy. Serious adverse events were more common with the regimen of acalabrutinib and venetoclax plus obinutuzumab, with neutropenia and infections being the most frequently reported toxicities. However, febrile neutropenia was notably lower with the acalabrutinib regimens than with chemoimmunotherapy. Cardiac events, a common concern with BTK inhibitors, remained infrequent, with atrial fibrillation rates of 0.7% in those given acalabrutinib and venetoclax and 2% in those given acalabrutinib and venetoclax plus obinutuzumab.
“These results confirm that fixed-duration acalabrutinib and venetoclax, with or without the addition of obinutuzumab, can achieve deep, durable responses while avoiding the cumulative toxicities of chemoimmunotherapy,” Dr. Brown concluded.
Expert Point of View
Matthew S. Davids, MD, MMSc
Matthew S. Davids, MD, MMSc, Associate Professor of Medicine at Harvard Medical School, and Director of Clinical Research in the Division of Lymphoma at Dana-Farber Cancer Institute, told The ASCO Post that both the BRUIN CLL-321 and AMPLIFY trials were likely to lead to full approval of these regimens by the U.S. Food and Drug Administration (FDA).
“The AMPLIFY trial provides strong evidence to support the registration of both acalabrutinib plus venetoclax as well as acalabrutinib, venetoclax, and obinutuzumab for front-line treatment of chronic lymphocytic leukemia [CLL] in fit patients,” said Dr. Davids, a co-investigator of the study. “One of the unique aspects is that acalabrutinib plus venetoclax represents an all-oral, time-limited therapy option, which we currently don’t have approved in the United States. That’s a major step forward for patients.”
Commenting on the BRUIN CLL-321 trial, Dr. Davids underscored its significance for patients with relapsed or refractory disease who have previously received covalent BTK inhibitors. “The trial is likely to lead to full FDA approval of pirtobrutinib for relapsed or refractory CLL in patients after covalent BTK inhibitors,” he said. “It’s the first randomized phase III trial to focus exclusively on this growing population, and the data are impressive, given the difficulty of treating these patients after covalent BTK inhibitors.”
Dr. Davids highlighted the long time to next treatment observed in the BRUIN CLL-321 trial, particularly in patients who were venetoclax-naive: “The durability of benefit from pirtobrutinib stood out, with the time to next treatment approaching 30 months for venetoclax-naive patients. That’s a meaningful result for a group with limited treatment options.”
Although the study specifically evaluated pirtobrutinib in patients who had prior covalent BTK inhibitors, Dr. Davids noted that the FDA’s final label could be broader: “If the FDA aligns with the trial design, approval will likely focus on post–covalent BTK inhibitor patients,” he proposed. “However, there is a chance it could extend to all patients with relapsed or refractory CLL, depending on the agency’s interpretation of the data.”
DISCLOSURE: Dr. Sherman reported financial relationships with AbbVie, Eli Lilly, BeiGene, AstraZeneca, BMS, Genentech, Merck, Genmab, ADC Therapeutics, TG Therapeutics, and Pharmacyclics. Dr. Brown reported financial relationships with Pharmacyclics, Grifols Therapeutics, Gilead Sciences, Pfizer, Numab Therapeutics, Merck, Loxo/Lilly, iOnctura, Kite Pharma, InnoCare Pharma, Genentech/Roche, MEI Pharma, TG Therapeutics, UpToDate, Bristol Myers Squibb, BeiGene, Alloplex Biotherapeutics, Acerta/AstraZeneca, and AbbVie. Dr. Davids reported financial relationships with Merck, MEI Pharma, AbbVie, Eli Lilly, AstraZeneca, BeiGene, Ascentage Pharma, TG Therapeutics, Adaptive Biosciences, Janssen, Genmab, BMS, Galapagos, Novartis, Nuvalent, and Genentech.
REFERENCES
- Sharman JP, Munir T, Grosicki S, et al: BRUIN CLL-321: Randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma. 2024 ASH Annual Meeting. & Exposition Abstract 886. Presented December 9, 2024.
- Brown JR, Seymour JF, Jurczak W, et al: Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: Interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. 2024 ASH Annual Meeting & Exposition. Abstract 1009. Presented December 9, 2024.
