Commentary

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Dr Dorritie on the NCRI-FLAIR Trial of Ibrutinib Plus Venetoclax in Previously Untreated CLL

Kathleen A. Dorritie, MD, discusses the significance of results from the phase 3 NCRI-FLAIR study in previously untreated chronic lymphocytic leukemia.

Kathleen A. Dorritie, MD, hematologist/medical oncologist, the University of Pittsburgh Medical Center’s Hillman Cancer Center; assistant professor of medicine, Division of Oncology, Department of Medicine, University of Pittsburgh, discusses the significance of results from the phase 3 National Cancer Research Institute (NCRI) FLAIR study (ISRCTN01844152) of ibrutinib (Imbruvica) plus venetoclax (Venclexta) in previously untreated chronic lymphocytic leukemia (CLL).

The NCRI-FLAIR study compared ibrutinib and venetoclax with fludarabine, cyclophosphamide, and rituximab (FCR) in untreated CLL, and assessed whether a personalized treatment duration using peripheral blood minimal residual disease (MRD) response as a measure could optimize outcomes, Dorritie details. Unlike previous trials, NCRI-FLAIR excluded the higher-risk patients with TP53-mutated CLL and employed an adaptive design allowing patients to discontinue therapy upon achieving MRD negativity, she notes. The study's primary end point was investigator-assessed progression-free survival (PFS). Key secondary end points presented included overall survival (OS), IWCLL response, MRD, and safety. All appropriate end points were analyzed according to CLL prognostic sub-groups.

Results demonstrated substantially higher rates of MRD negativity with the ibrutinib plus venetoclax combination, reaching approximately 60% overall vs 40% with FCR across all MRD testing methods, Dorritie reports. Moreover, the majority of patients attained MRD negativity in peripheral blood with the ibrutinib plus venetoclax regimen, she says. This translated into superior overall response rates, prolonged PFS, and OS benefits. In the primary analysis, the PFS rate at 3 years was 97.2% in the ibrutinib plus venetoclax arm vs 76.8% in the FCR arm, for a hazard ratio of 0.13 (95% CI, 0.07-0.24; P < .0001).

Notably, high PFS rates were observed among higher risk IGHV-unmutated patients, a subgroup historically associated with poorer outcomes, Dorritie adds. This finding suggests that the combination therapy could potentially elevate the prognosis of these patients to a level comparable to that of standard-risk individuals, she concludes.

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