Fludarabine, Cyclophosphamide and Rituximab in Waldenström’s Macroglobulinemia: An Effective Regimen Requiring a New Category of Response Criteria and a Delayed Assessment of Results
Authors: Tedeschi Alessandra , Miqueleiz Sara , Ricci Francesca , Luraschi Annalisa , Schiavone Mario , Andriani Alessandro , Petrucci Maria Teresa , Ferrara Felicetto , Morra Enrica 
Published: October 2019

Abstract
Rituximab (R) is an active and well tolerated agent in the treatment of Waldenstrom’s Macroglobulinemia (WM) whether used in untreated or in refractory/relapsed pts. Furthermore, there is evidence that the association of R with chemotherapy may improve the quality of responses. Fludarabine and Cyclophosphamide (FC) are synergistic with R in vitro in lymphoma cell lines, and the administration of the three drugs is associated with higher response rates in other lymphoprolipherative disorders. We updated our experience to define the efficacy and tolerability of FCR in symptomatic pts with WM. Patients: Nineteen pts, median age 57 y, received R 375 mg/sqm iv d 1, F 25 mg/sqm iv d 2–4, C 250 mg/sqm iv d 2–4 every 4 weeks. Anti-infective prophylaxis with cotrimoxazole and acyclovir was administered. Median time from diagnosis to FCR treatment was 46 m (range 1–156). Five pts received FCR as first line treatment while 14 pts, of whom 8 refractory, had been previously treated with a median of 2 lines of therapy (range 1–6), 5 having previous received monoclonal antibodies. Splenomegaly and lymphadenopathy were present in 32% and 36% of pts, respectively. In 42% of cases Hb was <10g/dL, in 32% serum albumin was <3,5 g/dL, and in 53% β2M >3mg/dL. IgM median level was 4015 mg/dL (range 277– 10900), being > 4000 mg/dL in 53% of pts. Three pts were HCV-RNA positive and presented with cryoglobulinemia.
Results: Pts received a median of 6 courses (range 3–6). Responses according to the IInd International Workshop on WM, updated in 2006, were categorized as follows: 15 PR (79%), 3 SD (16%), 1 PD (5%). Eight of the 15 PR pts could be considered as in “near CR”. In fact, the new response category could be justified by the achievement of complete resolution of symptoms, of adenopathy/organomegaly on CT scan, absence of malignant cells at BM immunophenotype and hystology, with only a persistence of a positive serum immunofixation (median serum MC protein of 0.3 g/dL). None of the variables considered (splenomegaly, lymphadenopathy, Hb level, serum albumin, β2M, IgM) was significantly associated with response. Ten pts showed a delayed response: 1 converted to CR after 4 m, in 9 a progressive reduction of MC is still detectable after a median follow-up of 10 m (range 4–31). Two pts underwent stem cell transplant (1 auto, 1 allo). Toxicity: Mild or moderate effects limited to the first and second R infusion, such as fever, hypotension, cutaneous rash, were seen in 5 pts (26%). None developed IgM “flare”. Neutropenia, observed in 82% of courses, was the main source of adverse effects. Two episodes of FUO and 1 clinically documented pneumonia were recorded. One pt died 3 m after the end of treatment while in PR for disseminated Aspegillosis.
Conclusion: FCR regimen proved to be active and well tolerated even in previously heavily pre-treated WM pts; the response rate obtained is in line with clinical trials using R associated with other chemotherapeutic agents. A high percentage of near CRs and a progressive improvement of the quality of response has been observed even in pts with longer follow-up. The high incidence and long lasting episodes of neutropenia did not translate in major infectious episodes.