Efficacy and safety of the combination of rituximab, fludarabine, and mitoxantrone for rituximab‐naive, recurrent/refractory follicular non‐Hodgkin lymphoma with high tumor burden

Abstract

BACKGROUND: This phase 2 trial was undertaken to evaluate the efficacy and safety of rituximab combined with intravenous fludarabine and mitoxantrone (R-FM) for patients with recurrent/refractory follicular lymphoma who had high tumor burden according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. METHODS: Fifty patients were enrolled who had received a maximum of 2 previous regimens, including 1 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/CHOP-like regimen but no previous exposure to rituximab, fludarabine, or mitoxantrone. At baseline, 58% of patients had bulky disease (lesion >7cm), 56% had high-risk Follicular Lymphoma International Prognostic Index (FLIPI) scores (range, 3-5), and 22% were refractory. Treatment consisted of 4 courses of R-FM (rituximab 375 mg/m 2 intravenously on Day 1, fludarabine 25 mg/m 2 intravenously on Days 2 through 4, and mitoxantrone 10 mg/m 2 intravenously on Day 2, recycling at Day 28) and consolidation with 2 courses of fludarabine and mitoxantrone (the same regimen without rituximab). RESULTS: The best response (84% overall response rate including 68% complete response/complete response unconfirmed) was achieved after 4 courses of R-FM. Response rates were high regardless of age, refractoriness to last previous therapy, and FLIPI score. After a median follow-up of 4 years, the 3-year progression-free survival rate was 47%, the event-free survival rate was 41%, and the 3-year overall survival rate was 66%. Grade !3 neutropenia and infections were the most common toxicities and occurred in 72% and 14% of patients, respectively. CONCLUSIONS: Cytoreduction with 4 courses of R-FM was safe and highly efficient in patients with recurrent/refractory follicular lymphoma who had high tumor burden; however, better consolidation than FM is needed to further improve outcome. Cancer 2010;116:4299-308.

Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response

“…High clinical efficacy was observed with the R-FM induction regimen with 100% overall response rate (ORR) and high CR rates (66%). 5,6 The study cohort was too small to observe the inferior OS recently reported by several study groups. [21][22][23] Previous data on rituximab PK in follicular lymphoma were mainly generated during monotherapy.…”

“…[2][3][4] Fludarabine-mitoxantrone combinations have shown strong debulking activity as initial therapy followed by rituximab maintenance. 5,6 While rituximab maintenance with a standard dose of 375 mg/m 2 prolongs clinical remissions, administration schedules still vary: 3-monthly infusions for two years and 2-monthly infusions for one or two years are those most frequently used. 4,7 Some pharmacokinetic data for rituximab have been reported for induction treatment.…”

Chemotherapy and treatment algorithms for follicular lymphoma: a look at all options

“…In a Phase II study conducted by Morschhauser et al, 50 patients with refractory/relapsed HTB FL received R-FM and showed a 3-yr PFS of 47% and 3-yr OS of 66%; 72% of patients presented neutropenia G3 which was complicated in 14% of these by an infection. Secondary tumors were observed in three patients (two cutaneous tumors and one case of chronic lymphocytic leukemia), but no case of secondary myelodysplasia was recorded [82].…”

“…The ORR was of 84% (uCR/CR 68%), achieving the best response at the end of fourth course of R-FM. After a median follow-up of 4 years, 56% of patients relapsed or died, with a median PFS and event-free survival of 33 and 26 months, respectively [82]. Other regimens cited above are also to be considered in second relapse, as bendamustine, mitoxantrone or platinum-containing regimens, as gemcitabine with oxaliplatin (Gem/Ox regimen).…”

Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial

“…Adverse prognostic factors in FL include a high (≥3) FL International Prognostic Index (FLIPI) score, representing patients aged >60 years, and/or with stage III–IV disease, anemia, >4 involved nodal areas, and/or elevated lactate dehydrogenase (LDH) [7,10,11], which has been validated in the first-line setting [11] and shown to have prognostic value at first relapse [10]. In addition, another indicator of poor prognosis is a high tumor burden by modified Groupe d’Etude des Lymphomas Folliculaires (GELF) criteria [12], which includes involvement of ≥3 nodal sites of ≥3 cm diameter, any nodal/extranodal tumor mass of ≥7 cm diameter, splenomegaly, pleural effusion or peritoneal ascites, leukocytes <1.0 x 10 9 /L, or platelets <100 x 10 9 /L [12,13]. …”