Addition of Fresh Frozen Plasma to Rituximab Induces a Major Clinical and Laboratory Response in Patients with Refractory Advanced CLL.
Authors: Klepfish Abraham , Schattner Amichay , Kotsianidis Ioannis , Rachmilewitz E.A. 
Published: April 2020

Abstract
Background
Rituximab (RTX) is a chimeric IgG1 monoclonal antibody that specifically targets the CD20 surface antigen uniquely present on B lymphocytes. It is effective in patients with indolent B cell malignancies, but the response of patients with CLL is inferior [Hillmen P. Semin Oncol. 2004] We report three patients with advanced Fludarabine-resistant CLL, two of them resistant also to RTX, successfully treated by combining fresh frozen plasma (FFP) with standard-dose single-agent Rituximab.
Patients
The patients’ characteristics prior to the treatment are summarized (Table 1). All three of them had the disease for more than 10 years and were heavily pretreated.
Patients characteristics prior to the FFP-RTX treatment Gender/Age Disease duration (yr) No of previous treatments B Symptoms Lymph count/mcl Hb(g/dl) /Plt/mcl LN / Spleen Other F/59 12 3 + RTX + 448,000 9.0 / 40,000 Massive / 20cm Bed ridden, diarrhea, colon involvement M/79 16 3 − 234,000 9.7 / 75,000 ≤ 1.5cm / 22cm Resp. Infections M/70 11 3 + RTX − 169,000 6.4 / 13,000 Massive / Normal Resp. Infections
Treatment
Treatment consisted of 2 units of FFP followed with standard-dose RTX as a single agent: 375 mg/m2 in most cycles, repeated every 4–8 weeks.
Results
Toxicity was minimal and well-tolerated. Patient 2, known to be allergic to Allopurinol, developed a moderate tumor lysis syndrome, resolved with standard treatment. Disease-related parameters after treatment and survival duration are summarized in table 2. A major improvement of clinical signs and symptoms, along with a significant reduction of lymphoid masses and splenomegaly and correction of anemia and thrombocytopenia without inducing neutropenia has been achieved in all the patients. The response was durable. Patient 1 died of Escherichia coli sepsis 4 months after the last cycle.
Patients characteristics after FFP-RTX treatment No of cycles B symptoms Lymph/mcl Hb(gm) / Plt/mcl LN / Spleen Other Overall survival (mo) 4 - 38,200 11.1 / 92,000 −50% / 17cm Ambulatory, diarrhea resolved 7 5 - 900 13.0 / 128,000 NL / 15cm Asymptomatic 8+ 2 - 3,200 9.9 / 123,000 −50% / 13cm Asymptomatic 3+
Comment
Complement-dependent cell lysis, apoptosis, and antibody-dependent cellular cytotoxicity were suggested as the major mechanisms mediating the cytoreductive effect of RTX. A rapid and dramatic clinical and laboratory response to standard-dose Rituximab was achieved following the addition of FFP in three CLL patients with advanced disease and very high WBC counts, proven to be refractory to alkylating agents and Fludarabine, and in patients 1 and 3 also to RTX. The mechanism of this phenomenon is still under investigation. It is possible, that providing FFP-derived complement is the factor, that initiated the response by correcting qualitative and quantitative abnormalities of the complement system, previously reported in CLL patients with advanced disease [Schlesinger M. et al. Leukemia.1996], thus enhancing complement-dependent cell lysis by Rituximab. If confirmed in larger series of patients, adding FFP to Rituximab may provide a useful therapeutic option in patients with advanced CLL resistant to immuno-chemotherapy.