Long Term Toxicity and Follow-up of Waldenstrom´s Macroglobulinemia Patients after Salvage Treatment with Fludarabine Cyclophosphamide Rituximab or Bendamustine and Rituximab
Authors: Tedeschi Alessandra , Picardi Paola , Goldaniga Maria Cecilia , Margiotta Casaluci Gloria , Benevolo Giulia , Ferrero Simone , Varettoni Marzia , Baratè Claudia , Gini Guido , Visco Carlo , Motta Marina , Belsito Petrizzi Valeria , Zaja Francesco , Ravelli Erica , Gentile Massimo , Frustaci Anna Maria , Orsucci Lorella , Morra Enrica , Gaidano Gianluca , Cairoli Roberto 
Published: October 2019

Abstract
Introduction
Fludarabine, cyclophosphamide and rituximab (FCR) and bendmaustine rituximab (BR) combinations have both been evaluated as salvage regimens in Waldenstrom's Macroglobulinemia. FCR exerts good quality of responses but there are some concerns regarding its use mainly for tardive myelosuppression and long term toxicity. BR showed to be effective with an excellent short term toxic profile but in literature there are no data on long term follow-up and toxicity. The aim of this study was to evaluate long term outcome and long term toxicity of patients treated with FCR and BR.
Patients and Methods
We analyzed 87 relapsed and refractory Waldenstrom's Macroglobuklinemia patients enrolled in two retrospective Italian multicenter studies in which FCR or BR were administered as salvage regimens. Patients treated with both bendamustine and fludarabine were excluded from the study. For each treatment group we compared: clinical and disease characteristics, Progression free survival (PFS) defined as progression or death for any cause from the beginning of salvage treatment; Event free survival (EFS) defined as progression or development of major infection, solid tumor, secondary MDS/AML, DLBCL, or death due to any cause.
Results
Of the 87 patients, 37 had received FCR and 50 BR. The two groups of patients did not differ in sex, median age, median number of prior treatments, previous therapy with alkylating agents, disease status, median IgM level, presence of adenopathies and/or splenomegaly at CT performed before salvage treatment. The significant differences between the two groups were: higher number of patients >70 years in the BR group (P=0.01) and lower number of patients previously treated with monoclonal antibody in the FCR population (P<0.005). Patients in both groups received a median of 6 courses. Although during treatment a higher rate of hematological toxicity was observed among patients receiving FCR, a similar number of patients discontinued treatment before the intended 6th course (15/37 after FCR, 19/50 after BR, P=0.81). No difference in terms of overall response rate (ORR 30/37 after FCR, 40/50 after BR P= 0.9) and major responses was observed. Median observation time for FCR and BR was 49 and 29 months (P=0.001) respectively. Median time to disease progression was not reached in both groups. Median PFS has been reached in both groups and resulted of 69 months with FCR versus 35 months with BR (P=0.09). When considering only responding patients median PFS after FCR resulted 93 months, not reached after BR. At 48 months the 88% patients treated with FCR were free from progression versus 51% with BR (P< 0.01) and this was significant also when considering only responding patients (90% versus 52%). Event free survival did not differ between FCR and BR when considering the whole population, median 49 m versus 35 m (P=0.19), or only responding patients 54 m versus 35 m (P=0.08). A significant higher proportion of patients in the FCR group developed a solid tumor or MDS/AML 12/37 versus 4/50 (P=0.004).
Conclusions
FCR and BR as salvage regimens led to similar outcome in terms of PFS and EFS. Considering that FCR in respect to BR exerts long lasting responses the main issue remains its long term toxicity profile. The future challenge will be to assess the long term effect of the new targeted agents.

Disclosures
Ferrero: Mundipharma: Other: Speakers Honoraria; Celgene: Other: Speakers Honoraria.