In an interim analysis of a phase III, open-label AMPLIFY study conducted in fit patients with previously untreated chronic lymphocytic leukaemia (CLL), fixed-duration acalabrutinib-venetoclax with or without obinutuzumab significantly prolonged progression-free survival (PFS) as compared with chemoimmunotherapy. Overall survival (OS) was significantly prolonged with acalabrutinib-venetoclax as compared with chemoimmunotherapy.
Continued follow-up will determine the durability of survival benefits with fixed-duration combination treatment with this second generation Bruton’s tyrosine kinase (BTK) inhibitor and venetoclax with or without obinutuzumab according to Dr. Jennifer R. Brown of the Dana-Farber Cancer Institute in Boston, MA, US and colleagues, who reported the findings on 5 February 2025 in The New England Journal of Medicine.
Although fixed-duration chemoimmunotherapy can lead to durable remission in some patients, continuous treatment with a BTK inhibitor with or without an anti-CD20 antibody has shown superior efficacy in patients with previously untreated CLL. Fixed-duration venetoclax combinations with obinutuzumab, ibrutinib, or both have led to high rates of undetectable measurable residual disease (MRD) and prolonged PFS in patients with previously untreated CLL.
Current fixed-duration therapies have important limitations. Chemoimmunotherapy regimens require intravenous administration and lead to prolonged immunosuppression, myelosuppression, a risk of a second primary cancer or a myeloid cancer, and inferior efficacy among patients with unmutated IGHV.
Venetoclax-obinutuzumab is administered intravenously, has been shown to result in shorter PFS among patients with unmutated IGHV than among patients with mutated IGHV, and is associated with a risk of tumour lysis syndrome, which warrants monitoring that can be burdensome.
Ibrutinib-venetoclax combinations are associated with safety concerns, particularly ibrutinib-related cardiovascular side effects, among older patients with coexisting conditions. Acalabrutinib is a second generation BTK inhibitor with a better safety profile than ibrutinib, including reduced cardiovascular side effects.
The AMPLIFY investigators reported in their article the results from the first prespecified interim analysis of this phase III study evaluating fixed-duration acalabrutinib-venetoclax with or without obinutuzumab as compared with chemoimmunotherapy comprising of the investigator’s choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab in fit patients with previously untreated CLL without a 17p deletion or TP53 mutation.
Patients 18 years of age or older who had an ECOG performance status score of 0 to 2 and who did not have a 17p deletion or TP53 mutation were included in the study. Patients were randomly assigned in a 1:1:1 ratio to receive acalabrutinib-venetoclax, acalabrutinib-venetoclax-obinutuzumab, or chemoimmunotherapy. The primary endpoint was PFS for acalabrutinib-venetoclax versus chemoimmunotherapy in the intention-to-treat population, assessed by blinded independent central review.
A total of 867 patients underwent randomisation with 291 assigned to receive acalabrutinib-venetoclax, 286 acalabrutinib-venetoclax-obinutuzumab, and 290 chemoimmunotherapy of whom 143 received fludarabine-cyclophosphamide-rituximab and 147 bendamustine-rituximab. The median age of the patients was 61 years (range, 26 to 86), 64.5% were men, and 58.6% had unmutated IGHV.
At a median follow-up of 40.8 months, estimated 36-month PFS was 76.5% with acalabrutinib-venetoclax, 83.1% with acalabrutinib-venetoclax-obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib-venetoclax versus chemoimmunotherapy 0.65, 95% confidence interval 0.49 to 0.87, p = 0.004; for the comparison of acalabrutinib-venetoclax-obinutuzumab with chemoimmunotherapy, p < 0.001).
Results for PFS suggest that the benefit of adding obinutuzumab to acalabrutinib-venetoclax was most apparent in the subgroup with unmutated IGHV, which had results that were similar to those in the subgroup with mutated IGHV. Continued follow-up will be essential to clarify which patients would be most suitable for acalabrutinib-venetoclax and which for acalabrutinib-venetoclax-obinutuzumab.
Estimated 36-month OS was 94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab, and 85.9% with chemoimmunotherapy. In the AMPLIFY study, a larger percentage of patients in the acalabrutinib-venetoclax-obinutuzumab group than in the chemoimmunotherapy group had undetectable MRD in peripheral blood as measured by means of flow cytometry at 3 months after the end of treatment (94.4% versus 77.9% in patients who could be evaluated).
Neutropenia, the most common adverse event of clinical interest of grade 3 or higher, was reported in 32.3%, 46.1%, and 43.2% in the three groups, respectively. Death from COVID19 was reported in 10, 25, and 21 patients in the three groups. The higher incidence of deaths due to COVID19 observed in the two groups receiving regimens containing an anti-CD20 antibody, obinutuzumab or rituximab in the chemoimmunotherapy group, suggests that the clinical benefit of deeper responses with these drugs comes with the risk of greater immunocompromise, which was particularly evident at the height of a worldwide pandemic. Few patients overall had atrial fibrillation or hypertension.
The study was funded by AstraZeneca.
Reference
Brown JR, Seymour JF, Jurczak W, et al. for the AMPLIFY investigators. Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. NEJM; Published online 5 February 2025. DOI: 10.1056/NEJMoa2409804