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Haematologica. 2019 Nov;104(11):2249-2257. doi: 10.3324/haematol.2018.204891. Epub 2019 Mar 19.

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 three years of rituximab maintenance.

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Hematology, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid
Hematology, Hospital Ramon y Cajal, Madrid.
Hematology, Hospital Miguel Servet, Zaragoza.
Hematology, Hospital Universitario Dr Peset, Valencia.
Hematology, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona.
Hematology, Hospital Universitario de Getafe, Madrid.
Hematology, Hospital de Jerez de la Frontera, Jerez.
Fundación Hospital de Alcorcón, Madrid.
Hospital Universitario Marqués de Valdecilla, Servicio de Hematologia, Santander.
Department of Hematology, Hospital Doce de Octubre, Madrid.
Hematology, Hospital Morales Meseguer, Murcia.
Hematology, CHU Juan Canalejo, A Coruña.
Hematology, Hospital Txagorritxu, Vitoria.
Hematology, Hospital Francesc Borja, Valencia.
Hematology, Hospital La Paz, Madrid.
Hematology, Hospital San Pedro de Alcantara, Caceres.
Hematology, Hospital Universitario La Fe, Valencia.
Hematology, Hospital Universitario Puerta del Mar, Cadiz.
Hematology, Hospital de Sagunto, Valencia.
Hematology, Hospital Madrid Norte Sanchinarro, Madrid.
Hematology, Hospital General Castellon, Castellon.
Hematology, Hospital Regional Universitario de Málaga, Málaga.
Hematology, Hospital Clínico Universitario San Carlos, Madrid.
Hematology, Hospital General de Móstoles, Madrid.
Roche Farma, S.A., Madrid.
Hematology, Hospital Universitario Príncipe Asturias, Madrid.
Hematology, University Hospital of Salamanca-IBSAL, CIBERONC, USAL-CSIC, CIC-IBMCC, Salamanca.
Hematology, Consorcio Hospital General Universitario, Valencia.
Hematology, Hospital Universitario de Getafe, Madrid, Spain.


It has been postulated that monitoring measurable residual disease (MRD) could be used as a surrogate marker of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients after treatment with immunochemotherapy regimens. In this study, we analyzed the outcome of 84 patients at 3 years of follow-up after first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) induction followed by 36 months of rituximab maintenance thearpy. MRD 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 (BM) MRD analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36 months of maintenance therapy. Thirty-seven patients (44%) did not have detectable residual disease in the BM prior to maintenance therapy. Interestingly, 29 patients with detectable residual disease in the BM after induction no longer had detectable disease in the BM following maintenance therapy. After a median followup of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either undetectable or detectable residual disease in the BM, who had achieved a complete response at the time of starting maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated vs unmutated OS: 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 BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic controls, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early undetectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL 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 n. 2007-002733-36 and Identifier: NCT00545714.

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