CLINICAL OUTCOMES OF PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA TREATED WITH TISAGENLECLEUCEL: PHASE 2 ELARA 3-YEAR FOLLOW-UP

Tisagenlecleucel is approved in the United States and Europe for adults with relapsed/refractory follicular lymphoma (r/r FL) after ≥2 lines of prior therapy. The primary analysis of the Phase II ELARA trial (median follow-up: 17 months; NCT03568461) reported high response rates and a favorable safety profile in heavily pretreated patients with r/r FL.
The aim of this analyses conducted by Martin Dreyling et al. is to report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after a median follow-up of more than 3 years.
Eligible patients with r/r FL (grades 1-3A) previously treated with ≥2 lines of systemic therapy (including an anti-CD20 monoclonal antibody [mAb] and alkylating agent) received a single tisagenlecleucel infusion (0.6- 6×108 CAR+ viable T cells). Bridging therapy was permitted. Baseline clinical characteristics and circulating blood naive T cells were correlated with clinical response. Cellular kinetics were assessed using quantitative polymerase chain reaction.
As of March 29, 2023, 97 patients were infused and had a median follow-up of 41 months (range, 34.2-49.7). At baseline, 68% of patients were double refractory to anti-CD20 mAb and alkylating agent, 65% had bulky disease (>7 cm or 3 lesions >3 cm), and 63% had progression of disease within 2 years of frontline systemic therapy (POD24). Comorbidities included cardiac disorders (9%), diabetes (9%), and renal insufficiency (5%). Among 94 patients evaluable for efficacy, best overall response (BOR) of complete response (CR) rate by independent review committee assessment was 68% (95% CI, 57.7%-77.3%) and overall response rate (CR + partial response) was 86% (95% CI, 77.5%-92.4%). Median progression-free survival (PFS) was 37 months; 36- month PFS was 53% in all patients and 69% in patients with a BOR of CR. In the POD24 subgroup, 36-month PFS was 50% (n=61) compared with 59% for patients without POD24 (n=33) (Figure). CAR transgene persistence was observed for up to 1290 days. Patients without POD24 had higher median in vivo CAR expansion and longer persistence than patients with POD24.
Median duration of response (DOR) was not reached; 64% of responding patients had ongoing response at the time of the 36-month analysis. Among patients with a BOR of CR, 73% had an ongoing response at the time of the 36-month analysis. High baseline levels of circulating CD8+ naive T cells (>2.14% of total T cells) were associated with prolonged PFS and DOR. Median overall survival (OS) and median time to next treatment were not reached. The OS rate at 36 months was 82%, and probability of starting a new treatment at 36 months was 35%. In the POD24 subgroup, 36- month OS rate was 83% compared with 81% in patients without POD24 (Figure). No new safety signals were reported. The most common grade ≥3 adverse events (AEs) were neutropenia (43%) and anemia (19%). The most common serious AEs were cytokine release syndrome (20% [Lee grading]), pneumonia (11%), and febrile neutropenia (8%). To date 18 patients have died during the study (progressive disease, n=8; AE, n=9; euthanasia, n=1).
Patients with r/r FL maintained a high rate of durable responses more than 3 years after tisagenlecleucel infusion, including patients in high-risk subgroups such as POD24. Tisagenlecleucel’s safety profile remains favorable with no new safety signals during extended follow-up. Correlative analyses suggest higher baseline levels of CD8+ naive T cells (>2.14%) are associated with improved long-term clinical outcomes.

LONG-TERM DURABLE RESPONSES IN PATIENTS WITH R/R ALL, DLBCL, AND FL TREATED WITH TISAGENLECLEUCEL AND ITS ASSOCIATION WITH PERSISTENCE OF CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS

Monitoring of CAR transgene levels in peripheral blood after tisagenlecleucel (tisa-cel) infusion provides information on expansion and persistence of CAR T-cells. In adult patients (pts) with DLBCL and FL, CAR T-cells expansion was similar among responders and non-responders. However, higher expansion was observed responding pediatric and young adult pts with ALL.
This analysis aimed to delineate the impact of CAR persistence and B-cell aplasia on duration of remission (DOR) using long-term follow-up data from tisa-cel treated pts.

Transgene levels in blood, measured by qPCR, were available from pivotal phase II/III studies in pts with r/r ALL (ELIANA [N=79], ENSIGN [N=64], NCT03123939 [N=69], NCT01626495 [N=60]), r/r DLBCL (JULIET [N=115]), and r/r FL (ELARA [N=97]), along with the long-term follow-up study (NCT02445222). The loss of persistence of CAR T-cells (Tloss) was defined as the time when transgene levels first dropped below 50 transgene copies/µg DNA (approximates to lower limit of quantification [LLOQ] of the assay) after maximal expansion. The impact of Tloss duration and time of the last quantifiable level (Tlast) on DOR/relapse was investigated. The impact of time to B-cell recovery (>1% CD19+ B-cells/WBCs or >3% CD19+ B-cells/lymphocytes for ALL, and 80-616 cells/µL for DLBCL and FL), on DOR/relapse was also examined.

Long-term CAR persistence in tisa-cel treated pts has been observed for up to 9, 6, and 2.5 years for ALL, DLBCL, and FL pts, respectively, reflecting differing length of follow up based on initiation of trials in respective indications. Pts who lost transgene ≤6 months (mo) or between 6-12 mo had shorter DOR relative to pts with persistent transgene (Figure, ALL pts). In ALL, the median Tloss was 27.4, 18.2, 9.7, and 18.0 mo for ongoing complete response (CR) >12 mo, CR pts between 6-12 mo, relapsed pts 12 mo, respectively.
However, of the pts who lost transgene ≤6 mo, some pts maintained durable responses for ≥12 mo — ALL: 29%; DLBCL: 15%; FL: 50%. Among ALL relapsed pts, majority (17/26, 65%) of the pts with Tloss <6 mo showed B-cell recovery; however, 6 pts had Tloss at <6 mo as well as B-cell recovery but maintained response for ≥12 mo. In ALL, NGS MRD ≤6 mo to 1 year post infusion may be a more reliable predictor of potential relapse than B-cell recovery (Pulsipher et al., 2022). The median time to B-cell recovery was 266 days in pts who relapsed/censored ≤12 mo but was not reached for pts with ongoing response at 12 mo. On the contrary, B-cell recovery seems to have no association with relapse in DLBCL or FL pts. Of ALL pts with CAR persistence, longer DOR observed in pts (with <50% blasts) at any time prior to infusion of tisa-cel vs pts with ≥50% blasts, reflecting more resistant high risk ALL at study entry or greater potential for stochastic loss of CD19 in pts with the higher disease burden.

Long-term sustained remission was observed in tisagenlecleucel-treated pts in the pivotal trials. The analyses show a positive association between CAR persistence and durable clinical responses across indications. However, some pts maintained durable responses despite early loss of transgene and/or early B-cell recovery (<6 mo post infusion; Myers et al., 2021). In DLBCL and FL, the transgene levels in blood may not represent the levels at target sites including lymph nodes. Furthermore, Tlast and Tloss are dependent on the duration of follow up and LLOQ.
Further research is needed to identify potential factors or patient characteristics that result in durable responses despite early transgene loss.