Navigating the Treatment Landscape of Advanced Follicular Lymphoma: Should You Consider a CAR, and Which Model?

Follicular lymphoma (FL), the most common of the indolent non-Hodgkin lymphomas, can be associated with heterogeneous clinical presentations and outcomes. With therapeutic advancements, most notably rituximab, the median survival of FL in the modern era is at least 18 years.¹  Despite the favorable natural history, clinical courses can be highly variable, and there is a scarcity of reliably predictive biomarkers. In the absence of robust randomized trials, navigating the vastness of single-arm phase II trials can be overwhelming, and we often share the burden of treatment selection with our co-pilot, the patient.

Outcomes following frontline chemoimmunotherapy have been favorable for most patients, with robust response rates and five- to eight-year progression-free survival (PFS) estimates.^2-5  However, among those with early relapse or progressive disease within 24 months (POD24) of frontline chemoimmunotherapy, overall survival (OS) has been poor.⁶  Similarly, nonresponse or progression within six months of rituximab informed the selection of the GADOLIN study population, which revealed favorable outcomes with obinutuzumab combined with bendamustine over bendamustine alone in relapsed/refractory (R/R) FL.⁷  In contrast, the AUGMENT study was enriched for rituximab-sensitive patients and demonstrated that the addition of lenalidomide to rituximab was superior to rituximab alone in R/R FL.⁸  In the third-line or later setting, we have seen drugs approved (idelalisib,⁹  copanlisib,¹⁰  umbralisib,¹¹  and tazemetostat¹² ) based on single-arm phase II trials, with median PFS rates of approximately 13 months or less. With all these options available and limited randomized studies to inform treatment selection, how does one define a preferred approach? We often choose based on prior therapy outcomes and toxicity profile and strike a balance between patient and provider goals. With so many options, is there a need for additional therapies that will undoubtedly make this process more burdensome?

There is an unmet need for more effective options, specifically time-limited, well-tolerated therapies (just ask any patient with R/R FL). Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the management of R/R large B-cell lymphoma and may be moving to second-line for high-risk patients.¹³  What is less clear is how to define high-risk patients with FL that warrant pursuit of CAR-T therapy over the other available options. Two recent, single-arm, multicenter phase II studies, ZUMA-5 and ELARA, explored autologous anti-CD19 CAR-Ts in R/R FL after two or more lines of therapy. Through examining the patient populations, efficacy, and safety outcomes, it may become apparent when to consider CAR-T therapy in R/R FL.

ZUMA-5 enrolled 127 patients with FL, and 124 were successfully infused with axicabtagene ciloleucel (axi-cel). No bridging except for corticosteroids was allowed per protocol, and the median time from leukapheresis to axi-cel delivery was 17 days. The median age of the patients with FL enrolled was 60 years (range, 53-67 years), with 31 percent being 65 years or older. Most patients had grade 1 to 2 FL, and 24 percent had grade 3A. All had a performance status of 0 to 1, 44 percent had high-risk FL International Prognostic Index (FLIPI), and 52 percent had high tumor burden (GELF criteria). The median number of prior lines of therapy was three (range, 2-4 lines) with nearly all (99%) having had prior chemoimmunotherapy. More than half (55%) were POD24, and 58 percent were refractory to their last therapy. With a median follow-up of 17.5 months, nearly all (94%) patients with FL responded. A total of 79 percent achieved a complete remission (CR) and 62 percent were in ongoing response. Median PFS and OS were not reached as of this first publication. Cytokine release syndrome occurred in 78 percent of patients with FL, with grade 3 or worse in 6 percent. Median time to onset was four days, and median duration was six days. One patient with bulky disease died due to multiorgan failure on day 7. Neurotoxicity occurred in 56 percent, with grade 3 or worse in 15 percent and a median time to onset of seven days and a median duration of 14 days. Among young, heavily pretreated, high-risk patients with FL, axi-cel was a highly effective, time-limited therapy that was reasonably well tolerated.

ELARA enrolled 98 patients with FL; 97 were successfully infused with tisagenlecleucel (tisa-cel) including 18 percent in the outpatient setting. The median time from enrollment to infusion was 46 days with 45 percent receiving bridging chemotherapy. Median age was 57 years (range, 49-64 years), with 25 percent of patients being 65 years or older. Fifty-eight (60%) had high-risk FLIPI and 64 percent had bulky disease. The median number of prior lines of therapy was four (range, 2-13 lines), 63 percent were POD24, and 78 percent were refractory to their last therapy. With a median follow-up of 16.6 months, 69 percent achieved CR. CR rates were comparable across subgroups except for POD24 which was lower (59% vs. 88%). Median PFS and OS were not reached. Cytokine release syndrome occurred in 49 percent, and all were grade 1 or 2 with a median time to onset and resolution of four days. Neurotoxicity occurred in 4 percent with 1 percent being grade 3 or worse. The toxicity profile of tisa-cel makes this a viable option in R/R FL.