ASH 2024 AMPLIFY supports second-generation BTK inhibitor combination for first-line CLL treatment

medwireNews: Phase 3 trial results indicate that first-line chronic lymphocytic leukemia (CLL) treatment with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib plus venetoclax (AV) improves progression-free survival (PFS) compared with chemoimmunotherapy. Presenting author Jennifer Brown (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) told delegates at the 66th Annual ASH Meeting & Exposition in San Diego, California, USA, that “AMPLFIY provides the first phase 3 evidence of fixed-duration therapy combining a second-generation BTK inhibitor with venetoclax with or without anti-CD20 in treatment-naïve CLL.” The trial included 867 adults with treatment-naïve CLL without del(17p) or TP53 alterations and low comorbidity who were randomly assigned to receive 14 28-day cycles of acalabrutinib 100 mg twice daily plus venetoclax 400 mg/day given on cycles 3–14 alone (n=291) or in combination with obinutuzumab (O) 1000 mg for cycles 2–7 (n=286), or to receive six cycles of fludarabine, cyclophosphamide, and rituximab or bendamustine plus rituximab (n=290). The median age of the patients was 61 years, with 27% in each group aged over 65 years, and 61–69% were men. The majority (63%) were based in Europe and the remainder in North America or other regions. Advanced Rai stage III–IV disease was diagnosed in 41–47% of the treatment arms, 16–20% had the del(11q) aberration, 57–59% had an unmutated immunoglobulin heavy chain variable region (IGHV) gene, and 15–16% had a complex karyotype with at least three aberrations. Compared with standard chemoimmunotherapy, AV significantly improved the primary endpoint of independent review committee–assessed PFS, with a hazard ratio (HR) for disease progression or death of 0.65. This endpoint in a secondary analysis of AVO versus chemoimmunotherapy was also significantly improved with an HR of 0.42 in favor of AVO. The 3-year PFS rates for the AV, AVO, and chemoimmunotherapy arms were 76.5%, 83.1%, and 66.5%, respectively, and, after a median follow-up of 40.8 months, median PFS was unreached for the AV and AVO groups versus 47.6 months with chemoimmunotherapy. There was also a significant increase in PFS with AV and AVO versus chemoimmunotherapy among the subgroup of patients with unmutated IGHV, with HRs for disease progression or death of 0.69 and 0.35, respectively, and median PFS of 51.5, unreached, and 43.3 months, respectively. And among patients with mutated IGHV, the HRs for AV and AVO versus chemoimmunotherapy were 0.67 and 0.58, respectively, and the median PFS was unreached in all three treatment arms. Brown highlighted that the 3-year PFS rate was “essentially identical” among the patients without and with IGHV mutations who were given AVO, at 82.8% and 83.6%, respectively, “suggesting that the unmutated patients may derive particular benefit from the addition of obinutuzumab.” The presenter noted that the trial coincided with the COVID-19 pandemic and adverse events (AEs) related to COVID-19 occurred in 22.0% of patients given AV, 24.3% given AVO, and 3.9% of those given chemoimmunotherapy, resulting in discontinuation of a study treatment in a corresponding 2.4%, 8.1%, and 1.2%, and deaths in 3.4%, 8.7%, and 7.2%. However, the results of a prespecified analysis of PFS after censoring for COVID-19-related deaths were “consistent with the primary analysis,” Brown said. Rates of undetectable minimal residual disease (MRD), as measured by flow cytometry of the peripheral blood, were highest in the AVO arm, followed by the chemoimmunotherapy arm, and then the AV arm, at 94.1%, 77.9%, and 32.0%, respectively, among patients whose samples were taken on a prespecified endpoint for each treatment. A similar pattern was also seen among these patients when MRD was measured at the end of treatment and 3 weeks after treatment. Among patients with undetectable MRD at the end of treatment, PFS was significantly better for both the AV and AVO groups versus the chemoimmunotherapy arm (HR=0.43 and 0.27, respectively), with 3-year PFS rates of 90.4%, 87.1%, and 74.8%. There was also a significant PFS benefit for AV versus chemoimmunotherapy among MRD-positive patients (HR=0.44) and although the HR of 0.70 was not significant for the AVO arm, the presenter pointed out that this was “not really assessable” because of the small number of MRD-positive patients given the triple therapy. Overall survival (OS) was significantly “prolonged” with AV versus chemoimmunotherapy, with an HR for death of 0.33, and there was a trend toward better OS with AVO. After censoring for COVID-related deaths, the HR for OS was significant for both AV and AVO (HR=0.27 and 0.47, respectively). Turning to safety findings, Brown said that the AV and AVO treatment arms each had a median exposure of 12.9 months versus 5.6 months with chemoimmunotherapy. Grade 3 and more severe AEs occurred in 53.6%, 69.4%, and 60.6% of patients, respectively, with fatal AEs seen in a corresponding 3.4%, 6.0%, and 3.5%. AEs led to discontinuation in 7.9%, 20.1%, and 10.8% of patients, respectively. She noted that although neutropenia was the most common AE, febrile neutropenia at grade 3 or more severe was “rare” in the AV and AVO arms compared with the chemoimmunotherapy arm (1.7 and 2.5 versus 9.3%). AV and AVO were associated with any-grade headache (35.1 and 28.2 vs 7.7%), while any-grade infusion-related reactions occurred only in the AVO and chemoimmunotherapy groups (19.7 vs 32.8%). Cardiac events at any grade occurred in 9.3% of the AV arm, 12.0% of the AVO arm, and 3.5% of the chemoimmunotherapy arm, but atrial fibrillation was “rare” affecting 0.7%, 0.8% and 0.8% of the groups, respectively. Infections at any grade occurred in 50.9% of patients given AV, 53.9% of those given AVO, and 31.7% of patients treated with chemoimmunotherapy, while tumor lysis syndrome occurred in 0.3%, 0.4%, and 3.1%, respectively. “The incidence of cardiac AEs remained low in both the AV and AVO regimens,” the presenter concluded. medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group ASH Annual Meeting & Exposition 2024; San Diego, California, USA: 7–10 December

Podcast | Air pollution and CVD

Advanced Search

Search Operators:

Springer Medicine

ASH 2024 AMPLIFY supports second-generation BTK inhibitor combination for first-line CLL treatment

Please log in to get access to this content

Keynote webinar | Spotlight on progress in colorectal cancer