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The phase 3 FLAIR trial compared MRD-guided ibrutinib–venetoclax (I+V) to ibrutinib (I) alone and FCR in previously untreated chronic lymphocytic leukemia (CLL). I+V achieved undetectable minimal residual disease (MRD) in bone marrow at 2 years in 66.2% of patients, versus 0% with I and 48.3% with FCR. At 5 years, PFS was 93.9% with I+V, 79.0% with I, and 58.1% with FCR; OS was 95.9%, 90.5%, and 86.5%, respectively. These data suggest that MRD-guided I+V not only deepens remissions but also translates to superior long-term outcomes—this could be a real game-changer for our frontline CLL management, especially for those with unmutated immunoglobulin heavy chain variable (IGHV).

Triple therapy for CLL, AVO, is highly active and has very high MRD-negative rates compared to other studies using Ven+Obi or BTKi therapy alone. The battle between indefinite BTKi therapy vs more intense combination therapy will continue as we don’t know if one paradigm is better from a bigger picture.

This study was done with and without obinutuzumab, both arms beat obinutuzumab and chlorambucil. There were more deaths in the obinutuzumab arm even though it was superior because of COVID, so it is immunosuppressive.

Ibrutinib delays disease progression for asymptomatic patients but has no overall survival (OS) benefit; hence, still watch and wait in those patients.