A phase 2 study of concurrent fludarabine and rituximab for the treatment of marginal zone lymphomas

Abstract

Summary The marginal zone lymphomas (MZLs) are a recently defined group of related diseases that probably arise from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric mucosa‐associated lymphoid tissue (MALT) lymphoma has been largely limited to retrospective case series. This prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas enrolled 26 patients, 14 with nodal MZL, eight with MALT lymphomas and four with splenic MZL; 81% were receiving initial systemic therapy. Only 58% [95% confidence interval (CI) 37–77%] of patients completed the planned six cycles, due to significant haematological, infectious and allergic toxicity. Four late toxic deaths occurred due to infections [15% (95% CI 4·3–35%)], two related to delayed bone marrow aplasia and two related to myelodysplastic syndrome. Nonetheless, the overall response rate was 85% (95% CI 65–96%), with 54% complete responses. The progression‐free survival at 3·1 years of follow‐up is 79·5% (95% CI 63–96%). We conclude that, although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of MZLs, the significant haematological and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study MZLs as a separate entity.

Fludarabine, cyclophosphamide, and rituximab in patients with advanced, untreated, indolent B‐cell nonfollicular lymphomas

“…In this study, we did not observe the consistent rate of fatal infectious events that was reported in the LL02 trial, 22 in which such infections occurred mainly in patients aged >65 years who had splenic MZL; for this reason, we excluded these 2 categories of patients from our study. A previous phase 2 study by Brown et al 40 indicated that the combination of rituximab and fludarabine in MZL, although it had high efficacy, was associated with significant hematologic and infectious toxicity both during and after therapy. The excellent efficacy/safety ratio in our study may be explained in part by our exclusion of older patients from the study population.…”

Clinical and biological diversity of splenic marginal zone lymphoma

“…It appears that fludarabine has a greater activity than the other purine analogs. Excellent responses to single-agent rituximab or in combination with fludarabine or fludarabine and cyclophosphamide or cladribine have been documented [19,20,[39][40][41]. It is unknown whether chemotherapy plus rituximab is a better option than single-agent rituximab.…”

“…It is unknown whether chemotherapy plus rituximab is a better option than single-agent rituximab. Potential side effects of the purine analogs need to be taken into account, particularly in the elderly population or in patients with comorbidities [40]. Nevertheless, these schedules should be considered as front line in patients without bulky spleens and who require treatment.…”

Recognizing nodal marginal zone lymphoma: recent advances and pitfalls. A systematic review

“…100 Although treatment with fludarabine and rituximab was highly effective, it came with significant toxicity that had not been observed in other lymphoma types to that extent.…”

“…9,[14][15][16][17][18] A phase II study in 26 patients with marginal zone lymphomas, mostly NMZLs, illustrated that treatment regimens in other low-grade B-cell lymphomas cannot be simply applied to MZL. 100 Although treatment with fludarabine and rituximab was highly effective, it came with significant toxicity that had not been observed in other lymphoma types to that extent.…”