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Acalabrutinib Combos Improve PFS vs CIT in First-Line CLL

Key Takeaways

  • Acalabrutinib-venetoclax combinations significantly improved PFS over CIT in treatment-naïve CLL patients, with a 35% risk reduction in disease progression or death.
  • The acalabrutinib-venetoclax-obinutuzumab regimen showed the largest PFS benefit, especially in patients with unmutated IGHV, despite not achieving the highest OS.
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Acalabrutnib plus venetoclax, with or without obinutuzumab, improved progression-free survival (PFS) compared with chemoimmunotherapy (CIT) in patients with untreated chronic lymphocytic leukemia (CLL), meeting the phase 3 AMPLIFY study’s primary endpoint.

Acalabrutnib-based combination regimens given for a fixed period of time outperformed chemoimmunotherapy (CIT) among fit, treatment-naïve patients with chronic lymphocytic leukemia (CLL), initial findings from a late-stage study, published in the New England Journal of Medicine suggest.1

The data readout from the prespecified interim analysis of the phase 3 AMPLIFY study (NCT03836261) showed that the fixed-duration combination of acalabrutinib (Calquence; AstraZeneca) and venetoclax (Venclexta; AbbVie and Genentech), with or without obinutuzumab (Gazyva; Genentech), led to improved progression-free survival (PFS) compared with CIT, meeting the study’s primary end point.

Acalabrutinib is a second-generation BTKi with reduced cardiovascular toxicity and an overall better safety profile compared with ibrutinib. | Image credit: Laszlo - stock.adobe.com

Acalabrutinib is a second-generation BTKi with reduced cardiovascular toxicity and an overall better safety profile compared with ibrutinib. | Image credit: Laszlo - stock.adobe.com

Findings of the study, funded by AstraZeneca, point to a 35% reduction in the risk of disease progression or death with acalabrutinib-venetoclax compared with CIT (HR, 0.65; 95% CI, 0.49-0.87; P = 0.004, and P < 0.001 for acalabrutinib-venetoclax-obinutuzumab compared with CIT).

Currently, venetoclax is approved in combination with obinutuzumab as a fixed-duration regimen for untreated CLL,2 though the combination has shown less improvement in PFS among patients with unmutated IGHV. The BCL-2 inhibitor has also been assessed in combination with ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi) associated with cardiovascular toxicity.

Acalabrutinib is a second-generation BTKi with reduced cardiovascular toxicity and an overall better safety profile compared with its first-generation counterpart. Acalabrutinib got the green light from the FDA for CLL in 2019. The approval for use as monotherapy or in combination with obinutuzumab was based on two phase 3 trials showing favorable PFS.3

Now tested alongside venetoclax with or without obinutuzumab, acalabrutinib as part of fixed-duration combinations was studied among a total of 867 patients.1 Patients were randomized 1:1:1 to receive 1 of the 2 acalabrutinib regimens or CIT, which consisted of either fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab.

After a median follow-up of 40.8 months, the estimated 36-month PFS was 76.5% (95% CI, 71-81.1) among patients receiving acalabrutinib-venetoclax and 83.1% (95% CI, 78.1 to 87.1) with acalabrutinib-venetoclax-obinutuzumab. Among the CIT arm, PFS was 66.5% (95% CI, 59.8-72.3). Notably, adding the anti-CD20 antibody to acalabrutinib-venetoclax showed the largest PFS benefit in patients with unmutated IGHV.

While the goal of the trial was not to compare outcomes between the two acalabrutinib-venetoclax combination arms, the researchers highlighted that the most favorable PFS was seen with the acalabrutinib-venetoclax-obinutuzumab arm, though the triplet did not yield the highest estimate of overall survival (OS).

Estimated 36-month OS was 94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab, and 85.9% with CIT. The researchers noted that the difference in PFS and OS results was largely attributable to deaths during the COVID-19 pandemic in the triplet arm, as screening and randomization occurred between February 2019 and April 2021.

“The higher incidence of deaths due to COVID-19 observed in the 2 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,” explained the group.

The most common grade 3 or higher adverse events observed in the trial included neutropenia, occurring in 32.3% of patients receiving acalabrutinib plus venetoclax, 46.1% of patients receiving acalabrutinib plus venetoclax and obinutuzumab, and 43.2% of patients receiving CIT.

"In this interim analysis of the AMPLIFY trial in fit patients with previously untreated CLL, fixed-duration acalabrutinib-venetoclax (with or without obinutuzumab) significantly prolonged progression-free survival as compared with chemoimmunotherapy," the authors concluded. "...Continued follow-up will determine the durability of survival benefits with fixed-duration combination therapy with a second-generation Bruton tyrosine kinase inhibitor and venetoclax with or without obinutuzumab."

References

  1. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762.
  2. FDA approved venetoclax for CLL and SLL. News release. FDA. Published May 15, 2019. Accessed April 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-venetoclax-cll-and-sll
  3. Calquence approved in the US for adult patients with chronic lymphocytic leukaemia. News release. AstraZeneca. Published November 21, 2019. Accessed April 15, 2025. https://www.astrazeneca.com/media-centre/press-releases/2019/calquence-approved-in-the-us-for-adult-patients-with-chronic-lymphocytic-leukaemia-21112019.html#
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