12 June 2023

First-line ibrutinib combined with venetoclax could benefit patients with high-risk chronic lymphocytic leukaemia (CLL), a new US study has suggested.

A team from Weill Cornell Medicine say fixed duration ibrutinib plus venetoclax led to high response and survival rates, whether or not patients’ cancer harboured high-risk genetic features that are associated with poor outcomes.

Patients with high-risk CLL, defined by deletion of 17p, mutated TP53, and/or unmutated immunoglobulin heavy chain (IGHV), have a greater risk of disease progression and death than patients whose CLL does not contain these features, the researchers report.

The treatment options are limited, they say, due to a lack of response to chemoimmunotherapy, but the standard of care for CLL has moved away from chemoimmunotherapy to first-line targeted therapy regimens, such as those involving inhibitors of Bruton’s tyrosine kinase (BTK) or BCL-2 with or without CD20-directed antibody therapy.

Dr John Allan, associate professor of clinical medicine at Weill Cornell Medicine, and colleagues have previously reported results from the phase II CAPTIVATE trial. This showed that patients with CLL experienced durable responses to fixed-duration first-line treatment with the BTK inhibitor ibrutinib in combination with venetoclax.

While the trial results suggested fixed-duration ibrutinib plus venetoclax may be a good first-line treatment for CLL, the benefit for patients with high-risk CLL remained unclear.

The latest study, published in Clinical Cancer Research, has examined the outcomes of a subgroup of patients in the CAPTIVATE trial who were treated with fixed duration ibrutinib plus venetoclax and whose baseline genetic risk features were known. Of the 195 patients included in this subgroup, 129 had high-risk CLL and 66 had low-risk CLL. 

More than 95% had responses to the combination therapy, regardless of whether their CLL harboured high-risk genetic features, and 61% and 53% of patients with and without high-risk disease, respectively, had complete responses.

Most patients – 88% with high-risk CLL and 92% without high-risk CLL – experienced progression-free survival (PFS) of at least 36 months. More than 95% of patients with and without high-risk CLL were alive 36 months after beginning treatment.

Dr Allan said: “Previously reported results from the CAPTIVATE study demonstrated deep and durable responses with sustained PFS after fixed-duration therapy with ibrutinib plus venetoclax for first-line treatment of CLL.

“The current analysis builds upon those results by demonstrating that these clinical outcomes are maintained at these early time points in patients with CLL harbouring high-risk genomic features. While further follow-up is required to understand longer term outcomes, these results support fixed duration ibrutinib plus venetoclax as a treatment approach for this patient population.”

Study limitations included the fact that it was exploratory in nature and not powered to perform statistical comparisons between patients with and without high-risk CLL features.


Allan JN, Flinn IW, Siddiqi T, Ghia P, Tam CS, Kipps TJ, Barr PM, Elinder Camburn A, Tedeschi A, Badoux XC, Jacobs R, Kuss BJ, Trentin L, Zhou C, Szoke A, Abbazio C, Wierda WG. (2023) “Outcomes in Patients with High-Risk Features after fixed-duration ibrutinib plus venetoclax may benefit patients with high-risk chronic lymphocytic leukemia.” Clinical Cancer Research, doi: 10.1158/1078-0432.CCR-22-2779

Link: https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-2779/726933/Outcomes-in-Patients-with-High-Risk-Features-after

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