Systematic Literature Review of the Clinical Efficacy and Safety of Treatments in the Relapsed/Refractory Setting for Patients with Follicular Lymphoma or Marginal Zone Lymphoma

Introduction

The objective of this study was to assess the efficacy and safety of current and emerging treatments in patients with follicular lymphoma (FL) or marginal zone lymphoma (MZL) who experienced relapse or refractory disease after ≥ 1 treatment.

Methods

We performed a systematic literature review to identify all publicly available randomized controlled trials (RCTs) and nonrandomized (NR) prospective interventional studies in the relapsed/refractory (R/R) setting for FL or MZL patients in EMBASE®, MEDLINE®, and the Cochrane Central Register of Controlled Clinical Trials on March 3, 2017. Additionally, four conference proceedings from 2015 and 2016 (the American Society of Hematology, European Hematology Association, European Society for Medical Oncology, and American Society of Clinical Oncology) were searched to present an up-to-date overview. For safety outcomes we extracted grade 3/4 adverse events (AE). Relevant interventions included rituximab (R), idelalisib, lenalidomide (LEN) ± R, ofatumumab (OFA), obinutuzumab (O), bortezomib (V) ± R, bendamustine (B) ± R, VBR, ibrutinib (IBRU) ± chemoimmunotherapy, brentuximab vedotin, fludarabine (F) + R, O ± B, CHOP ± R, and autologous stem cell transplantation (ASCT). Other interventions which were searched for but not identified are seen in Table 1.

Results

We screened 3255 abstracts and 126 full papers. Ten RCTs and 23 NR prospective interventional studies were selected for inclusion. In total, 29 studies reported results on chemo-based interventions (nine RCTs and 20 NR prospective interventional studies), and limited ASCT data were reported (one RCT and 3 NR prospective interventional studies). The majority of included studies reported largely FL populations with only two studies being conducted specifically in MZL. There was a considerable amount of heterogeneity across the included studies; factors contributing to this included study design, stage of disease, refractory versus relapsed population, and the median number of prior treatments. In the majority of studies patients had stage III/IV disease. Several studies reported the median number of prior treatments with large variation among the ranges presented. Population age varied, with the median age ranging from 46 to 68.5 years. The most common intervention received was R, either as monotherapy or in combination with chemotherapy.

The highest objective response rate was reported for FL/MZL patients treated with B (100%) while the lowest was reported for FL/MZL patients treated with OFA (10%). Median PFS for included studies is summarized in Table 1. Four RCTs provided significant PFS hazard ratios (HRs). Two ASCT studies reported median PFS ranging from 2.4 years (ASCT + interferon [INF]) to 83 months (ASCT + R + INF). In total, 12 studies presented duration of response (DOR) data with one study resulting in a significant DOR HR.

Overall survival (OS) data were poorly reported, with only eight studies reporting any OS data. In three of eight studies that intended to report OS, median OS had not been reached.

Safety and health-related quality of life (HRQoL) data were not consistently reported in the included studies. The most commonly reported grade 3/4 AE was neutropenia (12 studies) with an incidence ranging from 1.4% (R) to 54.7% (R-CHOP). Fatigue was also reported in nine studies with an incidence ranging from 1% (V + R) to 13% (LEN + R). Other AEs reported were anemia, diarrhea, infection, infusion-related reaction, nausea, pneumonia, sepsis, thrombocytopenia, and vomiting. Only one study presented HRQoL data (EORTC QLQ-C30).

Conclusion

This literature review provides a robust overview of response and PFS for treatments of R/R FL/MZL; however, heterogeneity in study design and patient population, as well as a general lack of reporting of OS data, make it challenging to identify an optimal treatment regimen in this setting. HRQoL data were not commonly reported despite the important role patient QoL plays in treatment selection. Additional randomized clinical trials, a more consistent approach to the reporting of clinical end points, and continued monitoring of OS data in this population may address some of these data gaps and unmet needs for patients with R/R FL/MZL.

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