Timing of CAR-T therapy in follicular lymphoma.

Low-grade follicular lymphoma (FL) is an indolent malignancy that is characterized by a relapsing and remitting course with multiple lines of therapy needed to control the disease over time [1]. In recent years, various therapeutic options have been approved by the US Food and Drug Administration (FDA) for the treatment of FL. Sequencing therapies to maximize the benefit and minimize the risks and side effects in FL is becoming more challenging with the expansion of the therapeutic armamentarium [2]. This is particularly an issue in the relapsed and refractory (R/R) setting where treatment options have wide ranges of efficacy and toxicity profiles [2]. Also, in some cases, asymptomatic relapses can be observed without the need for immediate therapeutic intervention. Thus, the timing and order of treatments for FL vary between individual patients. There are nine classes of therapeutic interventions that are currently available for the treatment of FL. These include antiCD20 monoclonal antibodies, chemotherapeutic agents, immunomodulatory agents, radioimmunotherapy, EZH2 inhibitors, PI3K inhibitors, high-dose chemotherapy followed by autologous stem cell rescue (ASCT), allogeneic hematopoietic cell transplantation, and anti-CD19 chimeric antigen receptor T-cells (CAR-T) therapy [2–11]. In addition, a new class of antibodies that has dual specificity (known as bispecific antibodies) is currently being evaluated [12]. The purpose of this editorial is to discuss the optimal timing for the use of available CAR-T products in R/R FL. There are two anti-CD19 CAR-T therapies with FDA approval in R/R FL after two or more lines of systemic therapy. Axicabtagene ciloleucel (Yescarta) which was approved on 5 March 2021, for the treatment of adult patients with R/R FL based on the phase 2 ZUMA-5 clinical trial. Tisagenlecleucel (Kymriah) is the second product that was approved on 27 May 2022, for the same indication based on the phase 2 ELARA clinical trial [10,11]. The ZUMA-5 clinical trial enrolled patients with FL and marginal zone lymphoma (MZL) who had received at least two lines of prior therapy, which had to include an antiCD20 monoclonal antibody combined with an alkylating agent. Patients were heavily pretreated, with a median of three prior lines of therapy. Enrolled patients were relatively young, with a median age of 60 years. Bulky disease was seen in 52% of the patients. Disease progression within 24 months of receiving initial chemoimmunotherapy (POD24) was seen in 55% of patient with FL included in the study [10]. POD24 is a strong indicator of shortened survival [13,14]. Among patients with FL, the objective response rate (ORR) was at 94%, with 80% achieving complete response (CR). The ORR and CR rates are among the highest reported to date in such a heavily pretreated population of R/R FL. The follow-up was 17.5 months, which is relatively short for a study of FL. Thus, the overall survival (OS) benefit is immature to evaluate. Median progressionfree survival (PFS) was not reached. Most of the FDAapproved therapies for FL in the third-line or later have a median PFS of approximately 1 year [4,6,7]. The ELARA clinical trial was designed to evaluate Tisagenlecleucel in adult patients with refractory or relapsed FL within 6 months after completion of two or more lines of systemic therapy or relapsed after an autologous hematopoietic stem cell transplant [11]. Arguably, the study population had a higher risk of disease compared to ZUMA-5. The median follow-up was short, 11 months. The ORR was 86% and 66% achieved a CR, which is again significantly higher compared to other available therapeutic options in this high-risk population [11]. Based on the above pivotal trials, CAR-T appears to be a very effective treatment [10,11]. Patients with high-risk disease are likely to experience significant benefit utilizing this therapeutic modality. Although the risk stratification tools at diagnosis are not very accurate in predicting patients who could benefit from such treatment modalities in the future, the disease behavior after treatment represents a more reliable predictor of outcome especially in the events of POD24, which represents a critical unmet need [13,14]. The ZUMA-5 and ELARA trials were enriched for patients with R/R FL who met the POD24 definition [10,11]. Of note, both trials included patients who previously received ASCT and those who did not [10,11]. ASCT is an effective treatment for R/R FL and since there is no data comparing CAR-T therapy to ASCT or the sequencing of thereof in R/R FL, this area remains to be investigated [8,15]. As of now, ASCT-eligible patients are likely to receive ASCT after their first relapse if POD24 and CAR-T therapy could be considered after per FDA label.