Enhancing the Action of Rituximab in Chronic Lymphocytic Leukemia by Adding Fresh Frozen Plasma

Abstract

Many patients with chronic lymphocytic leukemia (CLL) develop progressive treatment-resistant disease. Rituximab (RTX), a monoclonal antibody targeting CD20 on B lymphocytes and widely used in other indolent B-cell neoplasms is less efficacious in CLL, possibly because of associated complement deficiencies. Initial in vitro and in vivo observations support the central role of complement in rituximab-mediated loss of CD20(+) cells in CLL. In an open trial conducted in outpatient hematology clinics in Israel and Greece, we examined whether providing complement by concurrent administration of fresh frozen plasma (FFP) would enhance the effect of RTX in CLL. Five patients with severe treatment-resistant CLL were included in the trial. All had been previously treated with fludarabine, and three also failed treatment with RTX. Each patient was treated with two units of FFP followed with RTX 375 mg/m(2) as a single agent, repeated every 1-2 weeks as needed. A rapid and dramatic clinical and laboratory response was achieved in all patients. Lymphocyte counts dropped markedly followed by shrinkage of lymph nodes and spleen and improvement of the anemia and thrombocytopenia. This could be maintained over 8 months (median) with additional cycles if necessary. Treatment was well tolerated in all cases. In conclusion, adding FFP to RTX may provide a useful therapeutic option in patients with advanced CLL resistant to treatment. Further studies are needed to confirm and study the efficacy of the FFP/RTX combination in advanced CLL, establish the mechanisms, and possibly extend its use to other B-cell-dependent pathologies, such as treatment-refractory autoimmune diseases.

Mechanism of Action of Type II, Glycoengineered, Anti-CD20 Monoclonal Antibody GA101 in B-Chronic Lymphocytic Leukemia Whole Blood Assays in Comparison with Rituximab and Alemtuzumab

“…Our data are in agreement with studies suggesting complement is a limiting factor in B-CLL patients treated with rituximab (41) and that infusion of fresh-frozen plasma to patients in addition to the Ab may improve clinical response dramatically (42,43). Our data thus suggest a significant role of complement in vivo at least for the clearance of circulating neoplastic B cells by rituximab.…”

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

“…68,69 The use of fresh-frozen plasma as a source of complement in combination with rituximab has been evaluated in refractory CLL patients and resulted in a remarkable clinical response. 70,71 Other data, however, suggest that complement can be detrimental in mAb therapy. A possible negative relation of complement fixation and ADCC was shown in vitro, as incubation of rituximab with complement-active serum blocked the adhesion of NK cells via the FcgRIII (CD16).…”

Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies

“…Initiation of the complement cascade leads to both CDC and CDCC and the latter may have been lost or underappreciated in all the experiments with relatively short time frame like minutes or a few hours 76 . For example, the beneficial effects of fresh-frozen plasma therapy administrated simultaneously to rituximab in CLL patients were proposed 77 and reported 78,79 . 87 .…”