First-line regimen improves PFS in chronic lymphocytic leukemia
Key takeaways:
- Fixed-duration acalabrutinib plus venetoclax improved outcomes for untreated chronic lymphocytic leukemia compared with chemoimmunotherapy.
- Adding obinutuzumab to acalabrutinib-venetoclax improved survival, too.
SAN DIEGO — A multidrug combination significantly improved survival for certain patients with leukemia compared with standard chemoimmunotherapy, according to results of the randomized phase 3 AMPLIFY study.
Fixed-duration acalabrutinib (Calquence, AstraZeneca) plus venetoclax (Venclexta; AbbVie, Genentech) improved PFS 35% for individuals with previously untreated chronic lymphocytic leukemia, findings presented at ASH Annual Meeting and Exposition showed.
The addition of obinutuzumab (Gazyva, Genentech) to that regimen improved outcomes, as well, compared with standard care.
“The acalabrutinib-venetoclax [combination] is a very well-tolerated oral regimen, which is really going to be suitable for anyone and I think easy to use in the community, [It is] our first approved combination of Bruton tyrosine kinase [BTK] and BCL-2 [inhibitors],” researcher Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute and Worthington and Margaret Collette professor of medicine in the field of hematologic oncology at Harvard Medical School, said during a press briefing.
“If you add the obinutuzumab, it does add more work for the patient, it does add more toxicity, but that may be optimizing your progression free survival,” Brown added. “I see it for young, fit, maybe higher-risk patients [with unmutated disease] who really want to maximize that PFS.”
Background and methods
Continuous BTK inhibitor monotherapy and fixed-duration venetoclax-based combination regimens have been “highly effective” therapies for previously untreated CLL, according to researchers.
Fixed-duration treatment with first-generation BTK inhibitors have produced “deep, durable responses” for some patients, but it can cause cardiac toxicities, Brown said.
AMPLIFY is the first randomized study to evaluate a fixed-duration regimen with venetoclax plus a second-generation BTK inhibitor.
The ongoing, open-label trial enrolled 867 adults (median age, 61 years; interquartile range, 54-66; 64.5% men) with untreated CLL who did not have 17p deletion or TP53 mutations.
Researchers randomly assigned study participants to one of three regimens: acalabrutinib plus venetoclax (AV), AV plus obinutuzumab (AVO), or chemoimmunotherapy. The chemoimmunotherapy options included fludarabine, cyclophosphamide and rituximab (Rituxan; Genentech, Biogen), or a bendamustine-rituximab combination.
Patients assigned AV received 100 mg acalabrutinib orally twice a day for cycles 1 to 14, and oral venetoclax once daily in cycles 3 to 14, with a 5-week dose ramp-up of 20, 50, 100, 200 and 400 mg.
Patients assigned AVO received the same regimen plus IV obinutuzumab in cycle 2 (1,000 mg on days 1, 8 and 15), as well as cycles 3 to 7 (1,000 mg on day 1 of each cycle).
Blinded independent central review-assessed PFS served as the primary endpoint. Undetectable minimal residual disease rate and OS served as secondary endpoints.
Results and next steps
Median follow-up was 41 months.
Results showed improved PFS with AV vs. chemoimmunotherapy (HR = 0.65; 95% CI, 0.49-0.87), as well as improved PFS with AVO vs. chemoimmunotherapy (HR = 0.42; 95% CI, 0.3-0.59).Median PFS had not been reached in the AV or AVO groups. Median PFS in the chemoimmunotherapy group was 47.6 months.
Researchers observed higher 36-month PFS rates with AV (76.5%) and AVO (83.1%) than chemoimmunotherapy (66.5%).
Patients who received AV or AVO derived a PFS benefit regardless of IGHV status.
Among evaluable patients, results showed a higher undetectable minimal residual disease rate with AVO (95%) than chemoimmunotherapy (72.9%) or AV (45%).
Overall response rate per blinded independent central review assessment favored AV (92.8%) and AVO (92.7%) compared with chemoimmunotherapy (75.2%).
As of data cutoff on April 30, fewer deaths had occurred with AV (n = 18) than AVO (n = 37) or chemoimmunotherapy (n = 42).
After censoring for COVID-19 deaths, OS results favored AV vs. chemoimmunotherapy (HR = 0.27; 95% CI, 0.11-0.6) and AVO vs. chemoimmunotherapy (HR = 0.47; 95% CI, 0.22-0.95).
Neutropenia was the most common grade 3 adverse event across all cohorts (AV, 26.8%; AVO, 35.2%; chemoimmunotherapy, 32.4%).
A lower percentage of patients in the AV group experienced serious adverse events (24.7%) than in the chemoimmunotherapy (27.4%) or AVO (38.4%) groups.
Cardiac adverse events occurred more often with AV (9.3%) and AVO (12%) than chemoimmunotherapy (3.5%).
However, Brown described rates of atrial fibrillation and hypertension with AV (0.7% and 4.1%, respectively) and AVO (2.1% and 3.9%) as “low.” In the chemoimmunotherapy group, 0.8% of participants developed atrial fibrillation and 2.7% developed hypertension.
“The addition of obinutuzumab to acalabrutinib and venetoclax improved efficacy but also led to more adverse effects and more COVID deaths,” Brown said in an ASH press release. “Our next steps will include trying to better understand which patients get the most benefit from adding obinutuzumab and what factors lead to some patients relapsing sooner.”
Alexey Danilov, MD, PhD, hematologist-oncologist at City of Hope, said his patients prefer fixed-duration treatments to continuous therapies. The AV combination could “alleviate” some of their concerns, Danilov — who was not involved in the AMPLIFY study, said during a press briefing.
“As the study matures [and] as patients experience relapsed disease ... how they respond to subsequent therapies will be important,” Danilov said.
Perspective
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Although they didn’t compare [acalabrutinib plus venetoclax] with ibrutinib (Imbruvica; Janssen, Pharmacyclics) and venetoclax, AV or AVO appears to have a better safety profile than ibrutinib-venetoclax. It is well established that ibrutinib does cause atrial fibrillation, affecting approximately 15% of patients, with 10% grade 3 or higher incidence in the study of front-line ibrutinib-plus-venetoclax for CLL. In the acalabrutinib plus venetoclax study, 3% of patients developed any-grade atrial fibrillation. AV demonstrated good efficacy, with a 36-month PFS of 76%.
There may be other choices for BTK inhibitors combined with venetoclax. The Leukemia & Lymphoma Society is funding two studies to address this issue. Nitin Jain, MD, professor of medicine at The University of Texas MD Anderson Cancer Center, reported on the use of pirtobrutinib (Jaypirca, Eli Lilly & Co.), a noncovalent inhibitor of BTK, plus venetoclax and obinutuzumab for patients newly diagnosed with CLL. In this study of 27 patients, after 13 cycles, good efficacy was observed as determined by rate of MRD negativity.
Inhye Ahn, MD, senior physician at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, reports that zanubrutinib (Brukinsa, BeiGene) — a covalent inhibitor — plus venetoclax has demonstrated good efficacy among patients with relapsed or refractory disease. The use of zanubrutinib plus venetoclax for newly-diagnosed patients is being explored. Both zanubrutinib and pirtobrutinib are associated with low rate or cardiovascular side effects.
The new data with acalabrutinib plus venetoclax with or without obinutuzumab justify its use as first line therapy for treatment of CLL.
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Brown JR, et al. Abstract 1009. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.
