IGHV mutational status and outcome for patients with chronic lymphocytic leukemia upon treatment: a Danish nationwide population-based study

Patients with chronic lymphocytic leukemia and immunoglobulin heavy-chain variable region gene unmutated status have inferior survival from time of treatment in clinical studies. We assessed real-world outcomes based on mutational status and treatment regimen in a nationwide population-based cohort, comprising all 4135 patients from the Danish chronic lymphocytic leukemia registry diagnosed between 2008 and 2017. In total, 850 patients with known mutational status received treatment: 42% of patients received intensive chemoimmunotherapy treatment consisting of fludarabine, cyclophosphamide plus rituximab, or bendamustine plus rituximab; 27% received chlorambucil in combination with anti-CD20 antibodies or as monotherapy, and 31% received other, less common, treatments. No difference in overall survival from time of first treatment according to mutational status was observed, while treatment-free survival from start of first treatment was inferior for unmutated patients. The median treatment-free survival was 2.5 years for patients treated with chlorambucil plus anti-CD20, and 1 year for chlorambucil monotherapy. The 3-year treatment-free survival for fludarabine, cyclophosphamide plus rituximab-, and bendamustine plus rituximab-treated patients was 90% and 91% for mutated, and 76% and 53% for unmutated patients respectively, and the 3-year overall survival was similar for the two regimens (86-88%). Thus, it appears that patients progressing after intensive chemoimmunotherapy as first line therapy can be rescued by subsequent treatment, without jeopardizing long overall survival, in the real-world setting. Intensive chemoimmunotherapy remains a legitimate option alongside targeted agents, and part of a personalized treatment landscape in chronic lymphocytic leukemia, while improved supportive care and treatment options are warranted for unfit patients.