High prognostic value of measurable residual disease detection by flow cytometry in chronic lymphocytic leukemia patients treated with front-line fludarabine, cyclophosphamide, and rituximab, followed by a three-year rituximab maintenance

Monitoring measurable residual disease has been postulated to be a surrogate marker of progression free survival in chronic lymphocytic leukemia patients after treatment with immunochemotherapy regimens. In this study, we have analyzed the outcome of 84 patients at 3 years of follow up after first line treatment with fludarabine, cyclophosphamide and rituximab induction followed by 36 months of rituximab maintenance. Measurable residual disease was assessed by a quantitative four-color flow cytometry panel with a sensitivity level of 10-4. Eighty out of 84 evaluable patients (95.2%) achieved at least a partial response or better at the end of induction. After clinical evaluation, 74 patients went into rituximab maintenance and the primary endpoint was assessed in the final analysis at 3-years of follow up. Bone marrow measurable residual disease analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36-month of maintenance. Thirty-seven cases (44%) had undetectable bone marrow residual disease prior to maintenance. Interestingly, 29 patients with detectable bone marrow residual disease after induction, had undetectable bone marrow residual disease following maintenance. After a median follow-up of 6.30 years, median overall survival and progression free survival were not reached in patients with either undetectable or detectable bone marrow residual disease, who had achieved a complete response at the time of starting maintenance. Interestingly, univariate analysis showed that after rituximab maintenance overall survival was not affected by IGHV status (mutated vs unmutated overall survival: 85.7% alive at 7.2 years vs 79.6 % alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and bone marrow residual disease after 4 courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete 2 additional courses of rituximab and continue with maintenance for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full 6-cycles induction regimen. These data show that fludarabine, cyclophosphamide and rituximab followed by rituximab maintenance produce high-quality responses with less relapse and improved overall survival compared to historic controls, showing a favorable tolerability. Furthermore, attaining an early undetectable residual disease status could reduce the length of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of bone marrow measurable residual disease after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with chronic lymphocytic leukemia undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strategies. This trial is registered with EudraCT No.: 2007-002733-36 and ClinicalTrials.gov Identifier: NCT00545714