Efficacy and Safety of Tisagenlecleucel in Patients with Relapsed/Refractory Follicular Lymphoma: A Real-World Analysis from the Center for Blood and Marrow Transplant Research (CIBMTR) Registry

Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR)-T-cell therapy approved for the treatment of patients (pts) with relapsed/refractory (r/r) follicular lymphoma (FL) who have received ≥2 lines of prior therapy. In the initial report of the ELARA study, responses to tisagenlecleucel were high (overall response rate [ORR], 86.2%; complete response rate [CRR], 69.1%) and toxicity was mild (cytokine release syndrome [CRS], 48.5% any grade, no grade ≥3; immune effector cell-associated neurotoxicity syndrome [ICANS], 4.1% any grade, 1% grade ≥3). However, there are limited data regarding outcomes of r/r FL pts treated with commercial tisagenlecleucel. In this study, carried out by Dr. Daniel J. Landsburg et al, the authors present the first real-world data from the CIBMTR registry of pts with r/r FL treated with tisagenlecleucel in the US.

Data were collected as a part of a noninterventional, prospective, longitudinal study using the CIBMTR registry. All pts received commercial tisagenlecleucel in the US after the FDA approval date of May 27, 2022. Efficacy outcomes included ORR, CRR, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Key safety outcomes included incidence and severity of adverse events (AEs), including CRS, ICANS, and cytopenias.

As of March 5, 2024, 92 pts had received tisagenlecleucel (infused set). Median age at infusion was 66.1 years (range: 36.4-83.4). All pts had a reported Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Seventy-five pts (81.5%) had a medical comorbidity, including diabetes (23.9%), pulmonary disease (20.7%), cardiac disease (16.3%), and renal disease (1.1%). Median number of prior therapies was 4 (range: 1-10); 20.7% of pts had primary refractory disease. Fludarabine + cyclophosphamide (68.5%) and bendamustine (23.9%) were the most common lymphodepleting chemotherapy regimens.

Among patients with ≥100 days’ follow-up evaluable for safety and efficacy (n=64), median follow-up was 6.7 months (range: 2.7-16.9). ORR was 90.6% (95% CI: 80.7-96.5) and CRR was 76.6%. Median DOR, PFS, and OS were not reached. Three- and 6-month PFS estimates were 87.4% (95% CI: 76.3-93.5) and 77.8% (95% CI: 64.6-86.5), respectively. Three- and 6-month OS estimates were 100% and 94.1% (95% CI: 82.7-98.1), respectively.

Within 100 days of infusion, CRS, ICANS, and clinically significant infections were experienced by 62.5%, 20.3%, and 20.3% of pts, respectively. No cases of grade ≥3 CRS were reported. Median time to CRS onset was 2.0 days (range: 1.0-5.0). Twenty-eight of 40 pts who experienced CRS (70%) received treatment; all but one received tocilizumab to manage CRS (96.4%). Grade 3 and 4 ICANS were each experienced by 1 pt (1.6%). Median time to ICANS onset was 5.0 days (range: 1.0-7.0). All pts who experienced ICANS received treatment; corticosteroids were used to manage ICANS in 10 pts (76.9%). Six prolonged cytopenias (persisting >30 days) were reported: thrombocytopenia (n=5) and neutropenia (n=1); recovery at 3 months was experienced by 60% and 100% of pts, respectively. Two pts reported subsequent neoplasms (basal cell skin malignancy and squamous cell skin malignancy). Five deaths occurred >30 days post infusion: 4 due to disease progression, 1 due to acute respiratory distress syndrome (ARDS).

In the first analysis of patients with r/r FL captured in the CIBMTR registry, pts treated with tisagenlecleucel experienced ORR and CRR similar to ELARA despite the high rate of comorbidities (81.5%) and a median of 4 prior therapies. Although numerically higher rates of any grade CRS and ICANS were reported, rates of grade ≥3 CRS and ICANS were similar to pts treated on ELARA. Early estimates of PFS and OS are encouraging. Additional exploratory analyses will be performed to identify predictors of efficacy and safety outcomes.

Clinical Outcomes of Patients with High-Risk Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel: Phase 2 ELARA 4-Year Update

Treatment strategies for patients (pts) with relapsed/refractory follicular lymphoma (r/r FL) require consideration of prior therapies and pt-related factors to identify those who are likely to benefit from available treatment options. Tisagenlecleucel is a CAR-T cell therapy approved in the United States and Europe for adults with r/r FL after ≥2 lines of prior therapy. The primary analysis of the phase 2 ELARA trial reported high response rates and a favorable safety profile in pts with high-risk r/r FL. In this study, carried out by Catherine Thieblemont et al, the authors report 4-year follow-up of efficacy, safety, and pharmacokinetics findings.
Eligible patients with r/r FL (grades 1-3A) previously treated with ≥2 lines of systemic therapy (including an anti-CD20 monoclonal antibody 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 progression-free survival (PFS) and overall survival (OS). Cellular kinetics were determined by measurement of transgene levels by quantitative polymerase chain reaction. Minimal residual disease (MRD) levels were determined via clonoSEQ® Next Generation Sequencing assay performed at Adaptive Biotechnologies (Seattle, WA, USA): pre-infusion tissue samples were used for the clonotype identification; MRD tracking was performed in post-infusion plasma (ctDNA) samples.

As of March 27, 2024, 97 patients were infused. Ninety-four pts were evaluable for efficacy with a median follow-up of 53 months (range: 46-62). At baseline, among efficacy-evaluable pts, key pt subgroups at high-risk were identified; 72.3% of pts had FL that was refractory to ≥2 prior regimens, 66.0% had bulky disease (>7 cm or 3 lesions >3 cm), 64.9% had progression of disease within 2 years of frontline systemic therapy (POD24), 60.6% had high Follicular Lymphoma International Prognostic Index (FLIPI; ≥3), and 21.3% had high tumor burden (total metabolic tumor volume >510 mL). Median PFS was 53.3 months (95% CI: 18.2-NE) by independent review committee (IRC) among all pts; 48-mo PFS was 50.2% in all pts and 66.1% in pts with a best overall response of complete response. Among identified pt subgroups at high risk, 48-mo PFS by IRC was 45.5% (POD24), 45.5% (high FLIPI), 45.2% (bulky disease), 52.8% (double refractory), and 23.2% (high tumor burden). Median OS was not reached; 48-mo OS was 79.3% in efficacy-evaluable pts. Among identified pt subgroups at high risk, 48-mo OS was 80.8% (POD24), 73.2% (high FLIPI), 73.0% (bulky disease), 83.7% (double refractory), and 65.5% (high tumor burden). MRD data were available on 32/97 pts (33.0%); 28/32 pts (87.5%) achieved MRD negativity at any time point. MRD-negative status was achieved in 82.8% (24/29) of evaluable pts at day 28, 77.8% (14/18) at month 3, 72.7% (16/22) at month 6, and 82.4% (14/17) at month 12, respectively. CAR transgene persistence (Tlast; time to last quantifiable transgene level) was observed for up to 1680 days; median Tlast was 210 days (range: 13-1680). No new safety signals have been reported since the last data cut. Second primary malignancies (defined as any new cancer occurring post infusion regardless of tisagenlecleucel relationship) were reported in 6 (6.2%) pts and included basal cell carcinoma (n=2), squamous cell carcinoma (n=2), acute myeloid leukemia (n=1), bladder transitional cell carcinoma (n=1), Bowen’s disease (n=1), malignant melanoma (n=1), metastatic squamous cell carcinoma (n=1), and myelodysplastic syndrome (n=1). As of the data cutoff, 19 pts have died during the study: 8 due to progressive disease, 10 due to AEs (1 pt each; acute myeloid leukemia, bladder transitional cell carcinoma, cardiac arrest, CRS, encephalitis, gastrointestinal hemorrhage, infection, metastatic squamous cell carcinoma, pneumonia, sepsis), and 1 from euthanasia.

Updated long-term follow-up from the ELARA trial continues to demonstrate robust durable responses >4 years post infusion, alongside a favorable safety profile. Correlative analyses suggest that most baseline high-risk disease characteristics (double-refractory disease, bulky disease, POD24, and high FLIPI) are not associated with inferior efficacy following tisagenlecleucel infusion in pts with r/r FL. Furthermore, high frequencies of MRD-negative status were achieved in a subset of evaluable pts.

A SWOT-Consensus for CAR-T in Follicular Lymphoma: Fine Tuning of Patient Journey and Selection

Lymphoma is the primary cause of death for FL (follicular lymphoma) patients. Continuous therapy with targeted drugs yields only short-lasting responses in relapsed/refractory (R/R) FL patients, particularly in those with a high disease burden or those who relapse within 24 months of prior therapies. CAR-T therapies were approved for R/R FL after at least two prior therapies based on the prolonged remission reported in over 40% of patients. However, the expected progression-free survival (PFS) for third-line FL patients in real-life settings is 9-10 months. Recently, bispecific antibody (BiTE) therapies have also been approved in the same setting, but indirect comparisons indicate lower PFS and deep response rates compared to CAR-T therapies. Despite current NCCN guidelines favoring CAR-T therapies for R/R FL, several hurdles limit the timely access to CAR-T for many patients, adversely affecting FL patient survival.

The present project, carried out by Dr Monia Marchetti et al, aims to define the ideal patient flow that may optimize CAR-T therapeutic yield in FL, utilizing the GRADE framework. This framework suggests developing statements based on patient-intervention-comparator-outcome (PICO) questions. A Core Panel (CP) of eight national key opinion leaders formulated three questions to identify patients who should receive CAR-T therapy in the third line, as well as those in the first- and second-line who can undergo pre-assessment to optimize the eventual process to CAR-T.

The CP selected critical outcomes for each PICO question and identified the most relevant clinical factors to select patient subgroups, facilitating personalized decision-making. A SWOT analysis was conducted: Strengths and Weaknesses included clinical benefits and undesirable outcomes related to the intervention, while Opportunities and Threats addressed the non-clinical positive and negative consequences of the intervention. Based on the SWOT analysis, Good Practice Statements (GPS), Research Statements (RS), and Remarks (RK) were elaborated and approved by the CP. An External Panel of 12 senior hematologists validated the statements based on a median Likert score of ≥7 (scale 1-9).

A national panel of 20 hematologists developed 9 Good Practice Statements (GPS), 3 Research Statements (RS), and 9 Remarks (RK).

GPS 3.1 – In order to improve survival in patients who have failed two prior lines of therapy and exhibit refractory disease and/or early relapse, CAR-T therapy is strongly recommended, irrespective of prior ASCT and FLIPI score or metabolic tumor volume at relapse.

GPS 3.2 – Patients with late relapses require careful assessment of available therapeutic options (including watchful waiting), even if the above criteria apply.

GPS 3.3 – In order to prevent lymphocytoapheresis failure, patients who have received bendamustine within the last six months should be considered for treatments alternative to CAR-T.

GPS 2.1 – Preliminary assessment of CAR-T eligibility is recommended for FL patients who are refractory to frontline therapy, experience early relapse (POD24), or exhibit a high disease burden at relapse (GELF mass criteria or metabolic tumor burden), provided they do not have significant comorbidities.

GPS 2.2 – Potential candidates for subsequent CAR-T therapy should avoid second-line treatments that might negatively impact lymphocyte collection.

GPS 2.3 – Early assessment of response is recommended in FL patients who may be potential candidates for third-line CAR-T therapy (see GPS 2.1).

GPS 1.1 – In order to timely implement possible CAR-T therapy, hematology centers are recommended to establish a specific “CAR-T pathway” starting from diagnosis in younger FL patients and those with a high disease burden (FLIPI/m7FLIPI, metabolic tumor burden).

GPS 1.2 – A CAR-T focused choice of second-line treatment is recommended for patients diagnosed at a young age, with a high disease burden, or with a suboptimal response after frontline therapy (e.g., less than VGPR).

The journey of FL patients to CAR-T can be improved and optimized by incorporating specific recommendations into clinical practice. SWOT analysis can aid in developing clinical recommendations based on both clinical evidence and non-clinical outcomes.