Second‐line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study

Follicular lymphoma (FL) is the second most common lymphoma, and by virtue of its chronicity, may be the most prevalent and most treated lymphoma in the United States (Morton et al, 2006). The National LymphoCare Study (NLCS, ClinicalTrials.gov identifier, NCT00097565) is a prospective cohort study of disease presentation, treatment patterns and clinical outcomes that recruited consecutive patients diagnosed with FL between March 2004 and March 2007 in participating sites in the United States. The NLCS prospectively collected quarterly observations regarding disease characteristics, subsequent therapies and observed responses. Patterns of initial management in this cohort were reported previously (Friedberg et al, 2009). The current report describes patterns of subsequent active treatment and outcomes. “First-line treatment” refers to the first active treatment (Rx1), and “second-line treatment” refers to the second active treatment (Rx2), regardless of whether a relapse was recorded after first treatment. Maintenance therapy was not considered a distinct active treatment. Time to Rx2 was defined as the number of days from initiation of Rx1 to initiation of Rx2. Response/progression was determined by the local treating investigator. Patients progressing within 24 months of Rx1 were classified as early progressors (Casulo et al, 2015). Rituximab-refractory patients were identified from those who received rituximab monotherapy (R-mono) or rituximab plus chemotherapy (R-chemo) with or without rituximab maintenance therapy as Rx1. Patients with progressive disease (PD) within 6 months of completing rituximab-containing Rx1 or following rituximab maintenance therapy were considered rituximab-refractory. After a median follow-up of 8 years (range: 0 02–10 34), 2429/2652 patients had received Rx1. Of those, 889 (37%) had received Rx2, 438 (18%) had received a third active treatment (Rx3), and 229 (9%) and 123 (5%) had received four and five active treatments, respectively (Fig 1). Overall, 1465 (53%) patients remained in active follow-up at study closure; 23% had died and 24% were lost to followup, withdrew or discontinued for other reasons. The distribution of treatment choices for Rx1 to Rx5 is shown in Table I. The median time from initiation of Rx1 to Rx2 (n = 889) was 16 months (range: 0 1–112). Of patients who received Rx2, 62% did so within the first 24 months (Fig S1). The distribution of treatment choices for Rx1 is notably different than for Rx2, with a substantial increase in the use of R-mono, a mild increase in chemotherapy without rituximab, and a substantial drop in patients receiving chemoimmunotherapy for Rx2 compared with Rx1. Rituximab remained a treatment component (alone or with chemotherapy) in 70% of patients receiving Rx2. Of the patients receiving R-mono for Rx1, 44% continued to use R-mono for Rx2, while 34% switched to R-chemo. Of the patients receiving R-chemo for Rx1, 41% also used R-chemo for Rx2, 26% switched to R-mono and 33% to other therapy. The rate of anthracycline use was only 18% for Rx2, and 28% of patients remained anthracycline-na€ıve after five active treatments. Bendamustine was unavailable in the United States during the time of patient enrolment and was used in 9/2429 patients for Rx1, 50/889 for Rx2 and 56/438 for Rx3. The participation rate in a clinical trial for Rx2 remained low at 5%; 22% of patients who participated in a clinical trial for Rx2 had also participated in a clinical trial for Rx1. Overall, 341 patients were classified as early progressors. The distribution of Rx2 choices was notably similar between early progressors and others who received Rx2, with early progressors only slightly less likely to receive R-mono (30% vs. 36%) or investigational therapy (4 4% vs. 6 5%), and slightly more likely to receive any anthracycline (18% vs. 13%) or radioimmunotherapy (6 8% vs. 4 0%). Remarkably, although more frequently than others (1 1%), only 3 5% of early progressors received Rx2 strategies that included bone marrow transplant (BMT). Among patients who had received ≥5 treatments, use of radioimmunotherapy in the relapse/progression setting (n = 77) outpaced BMT (n = 53). Of 237 rituximab-refractory patients who received Rx2, 77 and 160 had received Rx1 of R-mono (217 rituximab-refractory patients) and R-chemo (486 rituximab-refractory patients), respectively. Among rituximab-refractory patients, 62% received rituximab-containing Rx2, including 22% who received R-mono; compared with 36% of patients receiving R-mono in the non-refractory cohort. Other Rx2 choices among rituximab-refractory patients included chemotherapy alone (13%), radioimmunotherapy (9%), radiation therapy (7%) and BMT (5%). Correspondence