Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia

[Jm954]

Abstract report in New England Journal of Medicine Published February 5, 2025

No real new information here and I'm surprised anyone was recruited for this study as the control arm is chemoimmunotherapy and no account appears to have been taken for unmated IGHV or 17p/TP53 as the patients were randomly assigned, in a 1:1:1 . I'd like to see an end to clinical trials that include chemoimmunotherapy as it only has a niche use now in CLL and still carries the risk of AML and MDS some years out.

Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib–venetoclax, 83.1% with acalabrutinib–venetoclax–obinutuzumab, and 66.5% with chemoimmunotherapy.

Estimated 36-month overall survival was 94.1% with acalabrutinib–venetoclax, 87.7% with acalabrutinib–venetoclax–obinutuzumab, and 85.9% with chemoimmunotherapy. 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.

Its a short read here: nejm.org/doi/full/10.1056/N...

Jackie

[Maya2007]

Thanks v much for information.Not sure whether chemo-immunotherapy is still used as first-line treatment in the UK.The novel treatments seem to offer great hope.

[Skyshark]

Study started in February 2019, del(17p)/TP53 mutated were excluded. Very similar criteria to the 6 year UK FLAIR trial. In 2019 the standard of care for del(17p)/TP53 was Ibrutinib. Only the US had allowed everyone access to Ibrutinib in 2017. In the UK V+O was still nearly 2 years away and Acalabrutinib 3 years, both with restrictions on access to those with del(17p)/TP53 mutated or unsuitable for FCR/BR. The duration of CLL trials means many will be overtaken by changes to standard of care, then they have to resort to MAIC, matching adjusted indirect comparison.

This randomized, global, multicenter, open-label, Phase 3 study will evaluate the efficacy and safety of AV and AVG versus chemoimmunotherapy (FCR or BR) in subjects with previously untreated CLL without del(17p) or TP53.

clinicaltrials.gov/study/NC...

Except for highly mutated (<94% match) IgHV doing very well on FCR (BR is no longer recommended) IgHV mutated / unmutated has little bearing on selection of treatment.

AV+/-O (AV+/-G) is on the UK NICE to do list and is in progress.

nice.org.uk/guidance/indeve...

(I think you have to be in UK to see NICE documents.)

It may beat the extension of V+O (without CDF funding) to all untreated patients.

[Spark_Plug]

It may be just the ticket for the ones that need treatment and draw an Acalabrutinib Combination. Withdraw if they tell you chemo?

[julius_the_cat]

Review below described AMPLIFY as "practice changing" as it will likely result in FDA approval of an all oral alternative to V&O. Although TP53 patients were excluded, subsequent data supporting AVO for del 17p and TP53 are also now available.

Outside of trials, zanubrutinib & sonrotoclax or the BTK degraders (NX-5948 or BGB-16673) are a few years away, so this may be the non-trial preferred option for a while.

Cll Society discussion here: cllsociety.org/2025/01/ampl...

[dumbsaintmind]

TP53/del17p were included in this enriched study for AVO:

ascopubs.org/doi/10.1200/JC...

[Smakwater]

Some good news here. Unfortunately one way to get trial approval is to stack the deck, or in other words have a comparison that increases the focus drugs success probability.

Insurance companies use a similarly disapointing strategy when participating in coverages that their accounting algorithm deem most cost effective and least subject to liability. I am sure many of us are familiar with having to fail with the industry standard drug before insurance will participate in what the apparent most desirable choice is.

Fun and Games, AKA Politics and Regulation

JM