Results of a Phase II Multicenter Study of Immunochemotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) for Symptomatic Waldenstrom’s Macroglobulinemia

Background: In Waldenstrom’s Macroglobulinemia (WM) the combination of Fludarabine (F) + Cyclophosphamide (C) induces response rates of 85% and 55–89% in previously untreated and relapsed/refractory pts, respectively. Rituximab (R) monotherapy is active and well tolerated in WM and there is evidence that R in association with chemotherapy may improve the quality of responses. Few studies with a small number of pts demonstrated the feasibility of FCR regimen in WM with responses ranging from 79% to 90%.

Methods: in February 2005 we started a multicenter, two-stage design, phase II study on the effectiveness, tolerability and safety of FCR in symptomatic WM pts previously untreated or relapsed/refractory to one line of chemotherapy. Pts previously treated with FC combination or monoclonal antibodies were excluded. Treatment consisted of: R 375 mg/sqm d1, F 25 mg/sqm and C 250 mg/sqm iv d 2–4 every 4 weeks. Accrual of the planned 43 pts ended on March 2008. The first assessment of the disease, including bone marrow (BM) evaluation, was performed after the third FCR course. Pts with progressive disease (PD) were considered as failure, responding pts or those with SD went on to receive up to 3 further courses.

Results: 18 females and 25 males, median age 65 yrs, were enrolled. Median time from diagnosis to FCR was 25.5 mos; 65% of pts were in first line treatment, 7% and 28% in relapsed and refractory disease, respectively. According to the International Scoring System for WM (ISSWM) 39.5% of pts were low risk, 51.2% intermediate and 9.3% high risk. As of August 10, 2008 analysis has been performed on 40 pts; final evaluation will be available in October 2008, since 3 pts completed treatment but response data are pending. A median of 6 courses (range 2–6) have been administered; 65% of pts received the planned 6 cycles. Reasons for not completing the 6 courses were: 1 PD, 1 hemolytic anemia, 1 hypersensitivity reaction to R, 8 severe neutropenia, 3 pneumonia. Thirty-six pts (90%) received ≥ 4 courses of therapy and have been considered valuable for response. As the protocol was designed before 2006, response criteria did not include MR and were categorized as follows: 14% CR, 69% PR, 14% SD, 3% PD (according to the updated criteria: 14% CR, 69% PR, 6% MR, 8% SD, 3% PD). Nine of the 25 patients in PR could be considered as in “near CR” as they fulfilled criteria for CR except for the persistence of a positive immunofixation. None of the patient and disease variables (age, sex, light chain, disease status, Hb, PLT and Ig level, % BM infiltration, b2m, albumin, creatinine, ISSWM) was significant for the achievement of a response. A comparison was performed between responses achieved after the third course and after the end of treatment. We observed that there was a significant improvement of responses (p=0.015) at last response assessment (5 CR+ 25 PR+ 5 SD+ 1 PD vs 2 CR+ 20 PR + 13 SD + 1 non evaluated after the third FCR course). Extrahematological toxicity was manageable and mostly limited to grade 1 and 2. An episode of grade 3 asthenia was reported. Twenty-one pts developed Rituximab-related reactions, grade 2 maximum, limited to the first or second infusion. In one case FCR treatment was interrupted because of grade 3 cutaneous hypersensitivity. Neutropenia occurring in 60% of courses was the main haematological toxicity, which caused the interruption of planned treatment in 20% of pts. Thirty-five percent of pts developed long lasting episodes of neutropenia (median duration 5 mos, range 3–15) mostly after 6 FCR courses (range 3–6). None of the clinical and disease characteristics analysed were statistically predictive of neutropenia development. Three episodes of pneumonia and 2 of FUO requiring hospitalization were observed during neutropenia. During follow-up we observed a late improvement of responses, as 3 further PR converted to CR (after a median of 10 mos), and 1 SD to PR (after 10 mos). Median DFS and OS have not been reached after a median follow-up of 15.1 and 20.4 mos, respectively.

Conclusion: FCR produced a high ORR with good quality of responses, which improved over time. We registered, however, high incidence of neutropenia with long lasting neutropenic episodes limiting the administration of the planned therapeutic program. According to the analysis of our population it seems reasonable to reduce to four the number of planned FCR courses, administering, if required, Rituximab as consolidation/maintenance to avoid myelotoxicity.