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Chronic Lymphocytic Leukemia

Immune recovery after fludarabine–cyclophosphamide–rituximab treatment in B-chronic lymphocytic leukemia: implication for maintenance immunotherapy

Abstract

Thirty B-cell chronic lymphocytic leukemia patients were treated with fludarabine–cyclophosphamide–rituximab (FCR) and immune cell counts (natural killer (NK) cells, CD4, CD8, Tγδ and monocytes) were monitored from the end of treatment (EOT) up to 36 months (M36). Moreover, nonleukemic peripheral blood lymphocyte cytotoxicity (PBL/CTC) as well as rituximab (RTX)-dependent PBL/CTC was also measured at the initiation of therapy, EOT and M12. These parameters were correlated with post-FCR monitoring of the minimal residual disease (MRD) level in blood using a four-color flow cytometry technique. FCR induced a profound and sustained depletion of all T-cell populations, Tγδ being the most affected, whereas NK cells were relatively preserved. Both basal and interleukin-2-stimulated nonleukemic PBL/CTC against MEC-2, a CLL cell line, increased during the post-FCR period. There was no correlation between immune recovery parameters and MRD progression profile, except that patients with high post-FCR CD4+ counts experienced rapid MRD progression. MRD at M12 predicts clinical relapse. The limited data show RTX-mediated LBL/CTC activity against autologous B-cell cells in individuals with <1% residual disease at M12, opening avenues for immunomodulation post-FCR with anti-CD20 antibodies. To conclude, our study suggests that MRD increase at M12 precedes disease evolution post-FCR, and should be assessed as a surrogate marker for proactive management of CLL relapse.

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Acknowledgements

We are grateful to the patients who participated in the study and their referring physicians. We also thank Pr C Récher for a critical reading of the paper. This work was supported by grants from INSERM and Association Laurette Fugain (ALF/No 07-05). We thank F Hoffmann-La Roche Ltd for providing rituximab used in our experiments. EG is the recipient of a grant from Ministère délégué à l’Enseignement supérieur et à la Recherche.

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Ysebaert, L., Gross, E., Kühlein, E. et al. Immune recovery after fludarabine–cyclophosphamide–rituximab treatment in B-chronic lymphocytic leukemia: implication for maintenance immunotherapy. Leukemia 24, 1310–1316 (2010). https://doi.org/10.1038/leu.2010.89

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