Patients with high-risk chronic lymphocytic leukemia may benefit from treatment with ibrutinib plus venetoclax

First-line ibrutinib (Imbruvica) plus venetoclax (Venclexta) led to high response rates and survival in patients with chronic lymphocytic leukemia (CLL) whether or not their cancer harbors high-risk genetic characteristics commonly associated with poor outcomes, according to results published in Clinical Cancer ResearchJournal of the American Association for Cancer Research (AACR).

Patients with high-risk CLL defined by 17p deletion, mutated TP53, and/or unmutated immunoglobulin heavy chain (IGHV) have historically had a greater risk of disease progression and death than patients whose CLL does not contain these features. For many years, patients with high-risk CLL had limited treatment options due to lack of response to chemoimmunotherapy, the former standard of care for CLL.

Recently, the standard of care for CLL has moved away from chemoimmunotherapy to first-line targeted therapy regimens, such as those involving Bruton’s tyrosine kinase (BTK) or BCL-2 inhibitors with or without CD20-targeted antibody therapy, explained John Allen, MD, Associate Professor of Clinical Medicine at Weill Cornell Medicine.

Allen and colleagues reported previously results from the phase II CAPTIVATE trial showing that patients with CLL had a durable response to first-line, fixed-duration treatment with the BTK inhibitor ibrutinib in combination with venetoclax. Unlike continuous treatment, fixed-duration treatment is given for a limited period of time to reduce the risk of toxicity or resistance to treatment.

While the trial results suggest that fixed-duration ibrutinib plus venetoclax may be a useful first-line treatment for CLL, the benefit of this regimen for patients with high-risk CLL remains unclear.

Because high-risk genetic characteristics inform treatment choice, understanding the efficacy of fixed-duration ibrutinib plus venetoclax in patients with high-risk CLL is important to determine how this regimen fits into the first-line treatment algorithm for the disease.

John Allen, MD, Associate Professor of Clinical Medicine at Weill Cornell Medicine

The latest publication reports the results of a subset of patients in the CAPTIVATE trial who were treated with fixed-duration ibrutinib plus venetoclax and whose baseline genetic risk characteristics were known. Of the 195 patients included in this subgroup, 129 had high-risk CLL and 66 had low-risk CLL.

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

Eighty-eight percent of patients with high-risk CLL and 92% of patients without high-risk CLL survived PFS of at least 36 months. Furthermore, more than 95% of patients with and without high-risk CLL are alive 36 months after starting treatment.

“Previously reported results from the CAPTIVATE trial demonstrated deep and durable responses with prolonged PFS after fixed-duration therapy with ibrutinib plus venetoclax for first-line treatment of CLL,” said Allen. “The current analysis builds on these results by demonstrating that these clinical outcomes are maintained at these early time points in CLL patients carrying high-risk genomic features.” Although further follow-up is needed to understand long-term results, these results are supportive Fixed-duration ibrutinib plus venetoclax as a treatment approach for this patient population.”

Allen noted that the results seen in this study compare favorably with historical data with other targeted therapy approaches, but he cautioned that differences in patient population and study design preclude a direct comparison.

Ibrutinib and fixed-duration venetoclax lead to similar side effects regardless of the presence of high-risk genetic characteristics, Allen added. The most common adverse reactions were diarrhea, neutropenia, nausea, and arthralgia in both groups. Serious adverse events were observed in 22% and 21% of patients with and without high-risk CLL, respectively.

A limitation of the study is that it is exploratory in nature and cannot make statistical comparisons between patients with and without high-risk features of CLL.

The study was funded by Pharmacyclics LLC, an AbbVie company. Alan has received grants and/or personal fees from Pharmacyclics LLC, AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, Lilly, Genentech, Janssen, and TG Therapeutics.