Fludarabine, Mitoxantrone and Rituximab in Relapsed or Primary Failing Advanced Follicular Non-Hodgkin's Lymphoma

Follicular non Hodgkin's lymphoma's (FL), as defined by the Revised European American Lymphoma Classification (REAL) Classification, are usually characterized by a slowly progressive clinical course, a transient control by standard chemotherapeutic regimen and a pattern of repeated relapses until ultimately progressive and fatal disease.

Standard first line treatment for advanced FL consists of alkylating-based (CVP) or anthracycline containing regimen in association to interferon alpha (CHVP+IFN) chemotherapy. Others approaches have been developed mostly as secondary therapy including purine analogs alone or in combination with alkylators or mitoxantrone, high dose therapy with autologous peripheral stem cell transplantation and, more recently, treatment with the unconjugated chimeric anti-CD20 antibody (rituximab) to target the CD20 antigen highly expressed on follicular lymphoma cells. None of these strategies does appear to give a definitive survival advantage. Thus, in patients with FL, the design of novel combination programs is a major challenge.

Combination of fludarabine and mitoxantrone in low grade, predominantly Follicular NHL: results of phase II studies in relapsed or refractory patients Fludarabine is expected to potentiate other agents through inhibition of DNA polymerase alpha and DNA ligase and its consequent interference with the DNA repair process. The addition of mitoxantrone increases the cytotoxic effect of fludarabine in vitro. McLaughlin et al developed a combination of fludarabine, mitoxantrone and dexamethasone (FND), which was very effective in 51 patients with recurrent low-grade lymphoma (including 65% FL), with an overall response rate of 94% (47% complete response (CR) rate. The median duration of response in this phase II study was 21 months for CR patients but only 9 months for partial responders (PR) patients. The median survival and failure-free survival times from the time of entry onto the FND study were 34 and 14 months, respectively. Most major responses were evident after two to four courses of chemotherapy. The need for continuation of therapy beyond attainment of remission is suggested by early relapses among patients who had early discontinuation of therapy. The predominant toxic effects were myelosuppression and infections: neutropenia < 500/µl in 20 % of courses, thrombopenia < 50000/µl in 8 % of courses and infections in 12 % of courses. Non-hematological toxicity was modest.

FND appears to be comparable to, and less toxic than the combination of etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP), one of the most effective regimens available for patients with relapsed indolent lymphoma. Others studies have confirmed the significant efficacy and moderate toxicity profile of this combination as salvage therapy in low grade, predominantly follicular lymphoma.

Moreover, the omission of corticosteroids reduces the risk of opportunistic infections, while the activity of the combination against indolent lymphoma is maintained.

Preliminary data from rituximab studies alone or in combination with chemotherapy in relapsed or refractory low grade NHL In vitro, rituximab mediates complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) and apoptosis. However, the mechanism of in vivo anti-lymphoma effect remains largely unknown. Rituximab received approval for recurrent follicular lymphoma based on response rates of about 50% including 6% complete responses and duration of responses, which compare favorably to that of all other single agents including fludarabine and 2-CdA (15-19). Median time to progression for responders is around 13 months. Toxicity of rituximab is low and easily manageable. An 8 doses schedule did not show to confer a significant advantage in term of response rate and duration of response over the four doses schedule.

Rituximab has been shown to sensitize drug-resistant lymphoma cell lines to killing by cytotoxic drugs including fludarabine.

Thus, we may hypothesize that the combination of rituximab, fludarabine and mitoxantrone might lead to synergistic / additive induction of apoptosis through different pathways in lymphoma B-cells which maintain an indolent growth pattern.

This approach may provide a means to achieve longer progression free survival in relapsed or refractory patients with FL.

We opted for a four induction cycles of rituximab, fludarabine and mitoxantrone since:

1. Four cycles of a combination of fludarabine and mitoxantrone are generally sufficient to assess response,
2. the 4 doses schedule of rituximab which has been the most studied is efficient 3) The omission of dexamethasone does not appear to impair ORR and Duration Response (DR) of a combination of fludarabine and novantrone . Recycling will start on day 28.

Subsequently responding patients according the International criteria Working group will have 2 more cycle of a combination of fludarabine and mitoxantrone but no rituximab.