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MRD-Directed Combo of Ibrutinib Plus Venetoclax Improves PFS, OS Among Patients With Treatment-Naïve CLL

December 5, 2023

January 2024

Anna Azvolinsky, PhD

Anna Azvolinsky, PhD, is a freelance medical and science journalist based in New York City.

Findings from the U.K.-based phase III FLAIR trial, presented at the 65th ASH Annual Meeting and Exposition, provide data on the efficacy of the combination of venetoclax plus ibrutinib for patients with treatment-naïve chronic lymphocytic leukemia (CLL).

In Europe, a fixed duration combination of ibrutinib, a Bruton tyrosine kinase inhibitor, and venetoclax, a BCL2 inhibitor, is approved for the treatment of patients with previously untreated CLL. The approval is based in part on the phase III GLOW trial that compared treatment with ibrutinib plus venetoclax to chlorambucil plus obinutuzumab.

“The FLAIR trial is the first randomized phase III trial in CLL that has individualized the duration of targeted therapy by assessment of measurable residual disease (MRD). Patients treated with the combination of ibrutinib plus venetoclax were treated for double the time each patient took to reach undetectable MRD, between two and six years,” said presenter Peter Hillmen MD, of St. James’s University Hospital and the Leeds Institute of Medical Research in the U.K.

The phase III FLAIR trial tested whether ibrutinib plus venetoclax is more effective for patients with previously untreated CLL compared to the fludarabine, cyclophosphamide, and rituximab (FCR) regimen and whether a personalized treatment duration using peripheral blood MRD response as a measure could optimize outcomes.

“The results demonstrated that ibrutinib plus venetoclax was significantly better than FCR chemotherapy in terms of progression-free survival (PFS) and overall survival (OS). The results of MRD-directed therapy are exceptional, with 97.2% patients remaining progression-free at three years compared to 76.8% for FCR,” Dr. Hillmen said.

At a median 43.7 months, there were 87 progressions — 75 in the FCR and 12 in the ibrutinib plus venetoclax arm — among previously untreated patients. The hazard ratio for PFS for ibrutinib plus venetoclax versus FCR is 0.13 (95% CI 0.07-0.24; p<0.0001).

A total of 523 patients were randomized: 263 to FCR and 260 to ibrutinib plus venetoclax. Patients’ MRD status was assessed at 12 months of treatment and then every six months. If a patient had undetectable MRD, MRD status was repeated after three months and then another three months in peripheral blood and the bone marrow. When a patient achieved MRD-negative status, the duration of ibrutinib plus venetoclax was double the time between the start of the combination therapy and the time of the initial MRD-negative status.

At three years, the OS rate is 98.0% in the ibrutinib plus venetoclax arm and 93.0% in the FCR arm, with nine and 25 deaths, respectively. The hazard ratio for OS is 0.31 (95% CI 0.15-0.67; p=0.0029).

Notably, patients who traditionally do worse with conventional CLL therapies, including patients with unmutated IGHV genes and those with a deletion of chromosome 11q, responded well to the combination therapy.

Ibrutinib plus venetoclax generally had a toxicity profile that was consistent with prior studies with no unexpected adverse events.

“MRD is one of the strongest prognostic markers in CLL and is a requirement if we are aiming . Our modelling indicated that we needed to treat beyond undetectable CLL to achieve deep enough remissions to optimize outcomes,” Dr. Hillmen said.

“MRD is standardized and can be performed by most hematopathology laboratories. MRD is not routinely performed in the U.K. or the U.S. for CLL, although it is assessed for other blood cancers, including chronic myeloid leukemia and acute lymphoblastic leukemia. Until these FLAIR trial results, MRD assessment had not been shown to improve therapy for CLL patients with CLL,” Dr. Hillmen added.

“The results of FLAIR are the first proof that individualizing duration of therapy to each patient’s response leads to excellent outcomes, and since the vast majority of patients achieve undetectable MRD, we would anticipate very prolonged treatment-free remissions.”

Any conflicts of interest declared by the authors can be found in the original abstract.

Reference

Hillmen P, Cairns D, Bloor AJC, et al. Ibrutinib plus venetoclax with MRD-directed duration of treatment is superior to FCR and is a new standard of care for previously untreated CLL: report of the phase III UK NCRI FLAIR study. Abstract 631. Presented at the 65th American Society of Hematology Annual Meeting and Exposition; December 10, 2023; San Diego, California.

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