Sustained remissions in CLL after frontline FCR treatment with very long-term follow-up

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) achieves durable remissions, with flattening of the progression-free survival (PFS) curve in patients with mutated IGHV gene (IGHV-M). We updated long-term follow-up results from the original 300 patient FCR study initiated at M.D. Anderson in 1999. Current median follow-up is 19.0 years. With this extended follow-up, the median PFS for patients with IGHV-M was 14.6 years vs 4.2 years for patients with unmutated IGHV (IGHV-UM). Disease progression beyond 10 years was uncommon. Sixteen of 94 (17%) patients in remission at 10 years subsequently progressed with the additional follow-up compared to our prior report in 2015. Only 4 of 45 (9%) of patients with IGHV-M progressed beyond 10 years. Excluding Richter transformation, 96 of 300 (32%) patients developed 106 other malignancies, with 19/300 (6.3%) developing therapy-related myeloid neoplasms (tMNs), which were fatal in 16/19 (84%). No pre-treatment patient characteristics predicted for risk of tMNs. In summary, FCR remains an option for patients with IGHV-M CLL, with a significant fraction achieving functional cure of CLL. A risk-benefit assessment is warranted when counseling patients, balancing potential functional cure with the risk of late relapses and serious secondary malignancies.