Are Fludarabine Based Regimens Still Adequate for Relapsed/Refractory Follicular Lymphoma? An 18-Year Single-Center Experience

Research Article

Ann Hematol Oncol. 2015; 2(8): 1059.

Are Fludarabine Based Regimens Still Adequate for Relapsed/Refractory Follicular Lymphoma? An 18-Year Single-Center Experience

Moita F¹*, Esteves S², Klose T², Koehler M¹ and Silva MG¹

¹Department of Hematology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Portugal

²Clinical Research Unit, Instituto Português de Oncologia de Lisboa Francisco Gentil, Portugal

*Corresponding author: Moita F, Department of Hematology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Rua Professor Lima Basto 1099-023 Lisboa, Portugal

Received: September 24, 2015; Accepted: November 10, 2015; Published: November 12, 2015


There are no standard treatment recommendations in relapsed/refractory Follicular Lymphoma (R/R FL). Fludarabine, an effective but toxic agent, has been commonly used, but trials focusing on the risk-benefit balance in this setting are lacking and novel agents are available.

We conducted a single-center cohort study to evaluate the toxicity profile and supportive care needs of fludarabine-based regimens (FBR) administered in the first or second relapse. We retrospectively evaluated 116 R/R FL patients. Of these, 78 (67%) received FBR and 38 (33%), who were analyzed as an internal reference, received alkylating-based regimens (non-FBR). Similar disease control was obtained with both treatments. Treatment-related toxicities were high in FBR (74%) and non-FBR patients (68%). Growth factor use, transfusion requirements, short-term admissions to emergency room and prolonged hospitalization for toxicity were similar in FBR and non-FBR patients, but the latter were older and had different co-morbidities.

FBR patients over 60 years had higher incidences of grade ≥2 infections (46% vs. 18%; p=0.008). These regimens lead to prolonged hematological recovery, compromising subsequent treatments. With a median follow up of approximately 5 years, secondary malignancies were reported in 14% of patients.

High FBR toxicity and the availability of effective novel agents raise concerns about its adequacy in R/R FL setting. Therapeutic choices require a careful balance between efficacy, toxicity, cost and feasibility of subsequent therapies.

Keywords: Follicular lymphoma; Relapse; Therapy; Fludarabine; Toxicity


R/R FL: Relapsed/refractory Follicular Lymphoma; FBR: Fludarabine-Based Regimens; non-FBR: Alkylating-Based Regimens; FL: Follicular Lymphoma; CLL: Chronic Lymphocytic Leukemia; R-FM: Rituximab, Fludarabine and Mitoxantrona; R-CHOP: Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone; R-FC: Rituximab, Fludarabine and Cyclophosphamide; TRT: Treatment–Related Toxicities; TTNT: Time to Next Treatment; PFS: Progression-Free Survival; OS: Overall Survival; HSCT: Hematopoietic Stem Cell Transplant; ORR: Overall Response Rate; CR: Complete Remission


Follicular lymphoma (FL), a common indolent non-Hodgkin lymphoma subtype [1], is characterized by high response rates to first line treatment, but almost universal relapses and progressively shorter subsequent remissions. Immunochemotherapy is standard for the treatment of advanced, high tumor burden cases [2]. While survival improved with the addition of the anti-CD20 monoclonal antibody rituximab to the clinical armamentarium [3-5], no chemotherapy regimen proved to be significantly superior to others in prospective, randomized studies [6,7].

FBR have been used for the past three decades in the treatment of indolent lymphomas. Their efficacy is well documented but their use has been hampered by frequent adverse events. The toxicity profile is mainly due to myelosuppression and lymphodepletion, with frequent, severe and unusual infections that can limit therapeutic benefits in elderly and fragile patients. A high incidence of second neoplasms was also reported [6,8,9].

In chronic lymphocytic leukemia (CLL) [10,11] and mantle cell lymphoma [5,12] the results of prospective clinical trials lead to precise recommendations on the use of fludarabine. In contrast, in relapsed FL, where this drug has been commonly used, there are no standard treatment recommendations. Trials focusing on the riskbenefit balance of FBR in this setting are lacking but a high incidence of hematological toxicity has been documented [13,14].

In frontline, a randomized trial showed that rituximab, fludarabine and Mitoxantrone (R-FM) was as effective as rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). However, fludarabine use was compromised by excessive toxicity [6]. Similar results were documented in a phase 2 trial where rituximab, fludarabine and cyclophosphamide (R-FC) lead to high response rates but also excessive deaths and premature study termination [15].

Among treatment options for R/R FL, bendamustine, an alkylating agent sharing similarities with the purine-analog structure, has recently been widely adopted [2]. Its toxicity profile compares favorably with anthracycline-and fludarabine-based regimens [16] but long term results have not been published. Restricted availability in some European countries, including Portugal, limited its use as an alternative to fludarabine. Novel agents that may prove beneficial in terms of efficacy and toxicity are becoming available, although cost issues are of concern. We believe it is still relevant to characterize the risks and benefits of FBR in this setting.

Our aim was to evaluate the toxicity profile and associated supportive care of FBR regimens in the real life setting of relapsed FL, profiting from the 18-year experience of a single center where other alternatives were limited.


We conducted a single-center cohort study. Fifty percent of all patients with grade 1, 2 or 3a FL referred to our tertiary cancer center in Portugal between 1994 and 2011were randomly selected for retrospective review. Patients undergoing second or third line treatment until 2014 were included in the analysis. Patients receiving first line FBR, and relapsed patients receiving oral cyclophosphamide, chlorambucil, rituximab alone, Y90 ibritumomab tiuxetan or intensive regimens (ESHAP) were excluded.

FBR were recommended during this period for relapsed disease and included mainly FC (fludarabine 25-30 mg/m²/day, x3 days; cyclophosphamide 200-300 mg/m²/day x3 days every 28 days, 6 cycles), FMC (fludarabine 20-25 mg/m²/day x3 days; Mitoxantrone 8-10 mg/m²/day x1 day; cyclophosphamide 200-300 mg/m²/day x3 days every 28 days, 4 cycles). Rituximab 375 mg/m² was added on day 1 after 2003. Maintenance with rituximab 375 mg/m² every 8 weeks started in 2012.

According to local practice, patients not receiving FBR were treated with6 to 8 CHOP or CVP cycles ±Rituximab [6].

Growth factors were allowed at the physician’s discretion. Chemotherapy cycles were delayed or suspended according to toxicities.

The cut-off date for analysis was May 2015. Demographic and clinical variables were recorded. For internal reference, patients receiving non-FBR were also analyzed.

Relevant treatment–related toxicities (TRT) included grade 3-4 hematological events, grade ≥2 infections and allergies, and second neoplasms. The frequency and severity of side effects were recorded according to the NCI-CTCAE v4.0 [17]. Response to therapy, time to next treatment (TTNT), progression-free survival (PFS) and overall survival (OS) (calculated from the start of second or third line treatment) [18] was also evaluated. Patients undergoing consolidation with autologous or allogeneic hematopoietic stem cell transplant (HSCT) were censored for PFS at the time of transplant.

Time-to-event endpoints were analyzed by Kaplan-Meier method. Group comparisons were performed with Pearson’s Chisquared test or Fisher’s exact test for categorical variables; t-test or Wilcoxon rank sum test were used for quantitative variables. All tests were two-sided with a 5% significance level. All analyses were done using R software [19].


Patient population, treatment and effectiveness

Of 449 randomly selected patients, 116 fulfilled the inclusion criteria (Figure 1). Seventy-eight (67%) patients received FBR as second or third line while 38 (33%) received other regimens. Most patients were treated at first relapse (76% in the FBR and 87% in the non-FBR group). First line treatment was mostly CHOP or CVP (93%) with or without rituximab.

Patient characteristics are summarized in Table 1. Non-FBR patients were older at the start of second/third line treatment (p=0.022) and had a higher incidence of chronic kidney disease (p=0.010). This group additionally had longer response duration to first line therapy (median 2.3 versus 1.3 years, p=0.001). Groups were balanced for gender, other co-morbidities, FLIPI risk and response to first treatment.