From the Journals

Ibrutinib + venetoclax: High-risk features don’t lessen CLL response


 

FROM CLINICAL CANCER RESEARCH

High-risk genetic features do not diminish the response to first-line, fixed-dose ibrutinib (Imbruvica) plus venetoclax (Venclexta) for chronic lymphocytic leukemia (CLL), according to the latest report from AbbVie’s CAPTIVATE trial.

In the new analysis, published in Clinical Cancer Research, investigators compared outcomes in 66 adults without genetic risk factors to 129 with deletion of 17p, mutated TP53, and/or unmutated immunoglobulin heavy chain, all of which are associated with poor outcomes and poor responses to chemoimmunotherapy.

Over 95% of patients responded regardless of risk factors, with complete response in 61% of patients with and 53% of subjects without high-risk features. Progression free-survival (PFS) lasted at least 3 years in 88% of the high-risk group and 92% of low-risk patients, with over 95% of patients in both groups alive at 3 years

“Since high-risk genetic features inform treatment selection, understanding the efficacy of fixed-duration ibrutinib plus venetoclax in patients with high-risk CLL is important to determine how this regimen fits in the first-line treatment algorithm for the disease,” hematologic oncologist John Allan, MD, a CLL specialist at Weill Cornell Medical Center in New York and the lead investigator, said in a press release from American Association for Cancer Research, publisher of CCR.

Although the analysis was not powered to perform statistical comparisons between the two groups, Dr. Allan said the results “support fixed-duration ibrutinib plus venetoclax as a treatment approach for this patient population.”

The press release also noted that the outcomes “compare favorably” to other upfront targeted therapy approaches for CLL.

Experts respond

Asked for comment, Thomas LeBlanc, MD, a hematologic oncologist at Duke University in Durham, N.C., said “the advent of some fixed duration regimens with novel therapies has been an exciting thing for patients especially, recognizing that at the start of treatment one already knows the completion date, and one can also thus forgo much of the potentially cumulative physical, psychological, and financial toxicity of an indefinite oral therapy.”

As for the new findings, he said they show “that even in this high-risk population ... we can achieve remarkable remission rates and levels of [minimal residual disease] negativity by combining the two best drug classes to date in CLL: BTK inhibitors and venetoclax.”

Another expert, hematologic oncologist John Byrd, MD, a leukemia specialist at the University of Cincinnati, was more cautious.

“These findings confirm the results of many other prior studies of targeted therapies where high complete response rates with absence of detectable disease is observed,” he said.

However, while “such therapeutic combinations for sure enable treatment discontinuation,” Dr. Byrd noted, they “lack long-term follow-up. Given the added toxicities associated with these combinations and lack of long-term follow up, use of treatments such as those brought forth in the CAPTIVATE trial should be considered only in the context of a well-designed clinical trial.”

Study details

The new findings follow previous reports of CAPTIVATE, which found strong first-line response across CLL patients but did not focus as specifically on patients with high-risk genetic features.

Subjects received three 28-day cycles of ibrutinib 420 mg/day followed by twelve 28-day cycles of ibrutinib plus venetoclax, with a 5-week venetoclax ramp-up to 400 mg/day.

Side effects were similar regardless of high-risk features and included, most commonly, diarrhea, neutropenia, nausea, and arthralgia. The most common grade 3/4 treatment-emergent adverse events were neutropenia in 36% of patients in both groups and hypertension in 9% of patients with and 3% of patients without high-risk features.

The study was funded by Pharmacyclics/AbbVie, maker/marketer of both ibrutinib and venetoclax. Investigators had numerous ties to the companies, including Dr. Allan, who reported grants and/or personal fees. Dr. LeBlanc reported speaker/consulting honoraria from AbbVie as well as institutional research funding. Dr. Byrd did not have any connections to the companies.

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