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, Tcd 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, Tcd 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 þ 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 o1% 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.

Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia

“…Interestingly, MRD re-growth kinetics was predictive not only for PFS but also for OS, as described by ourselves and others ( Figures 2B and C). 17,18 Altogether, these results were very similar to those described in CLL patients treated with FCR iv formulation as front-line therapy.…”

Recombinant Human IL-15 Trans-Presentation by B Leukemic Cells from Chronic Lymphocytic Leukemia Induces Autologous NK Cell Proliferation Leading to Improved Anti-CD20 Immunotherapy

“…GA101 is able to increase both direct and effector cell-mediated cytotoxicity (22) and shows higher activity than does RTX in B leukemic cell depletion (23,24). Despite a low E:T ratio in patient samples, NK cells are the main effectors of RTX-mediated ADCC of CLL cells (21,25). Moga et al (26,27) demonstrated that rhIL-15 promotes NK cell cytotoxic function from healthy donors against lymphoma cell lines or primary CLL cells.…”

“…Despite the clear therapeutic benefits of RTX in B cell malignancies (16), relapses occur frequently following treatment. In vivo, anti-CD20 Abs induce potent target cell lysis through complement-dependent cytotoxicity (17)(18)(19) and primarily Ab-dependent cellular cytotoxicity (ADCC) (17,(19)(20)(21). ADCC relies on the ability of CD16 + effectors, such as NK cells, to bind Abs via the FcgRIIIa region.…”

Progressive Multifocal Leukoencephalopathy After Allogeneic Bone Marrow Transplantation for Acute Myeloid Leukemia

“…Prolonged CD4+ lymphopenia has been observed after fludarabine-based regimens for chronic lymphocytic leukemia. 33,34 Therefore, the use of a purine analogue (pentostatin) for the treatment of steroid-refractory GVHD may have contributed to the sustained depression of CD4+ T cells, even after all immunosuppression had been completely tapered off for almost 6 months. In Case 2, it is probable that ATG was a significant contributor to the patient's prolonged T-cell lymphopenia, a well-described phenomenon in the solid organ transplant literature.…”