Systematic Intention to Treat Analysis of Real-World Outcomes in Children and Young Adults Receiving Tisagenlecleucel: From Elegibility through Treatment Failure

Background Since the approval of Tisagenlecleucel for R/R B-ALL, a UK CAR T cell panel was established to ensure equity of access, assess elegibility and allocate to JACIE-FACT approved IEC centres. This framework uniquely tracks patients from allocation to infusion and after therapy failure. We report outcomes for ALL patients allocated to receive Tisagenlecleucel nationally, including on an intention to treat (ITT) basis and for those patients who fail CAR T cell therapy.

Methods All patients discussed up to the 15^th of June 2022 were included against a national panel. Retrospective data collection was on a standardised datasheet. Survival outcomes were assessed using Kaplan-Meier survival from infusion. These included overall survival (OS; interval to death from any cause) and event-free survival as defined in the ELIANA study (classic EFS; interval to death, relapse, or failure to respond by day 30, censoring patients receiving further therapy). For ITT survival, outcomes were assessed from allocation. A more comprehensive EFS measure capturing all clinically relevant events (interval to molecular or frank relapse, further therapy, death or treatment failure was analysed; stringent EFS). Data analysis was carried out in R (version 4.1.2).

Results 147 patients were screened. Five were ineligible due to CD19 disease (n=1), lymphopaenia (n=2) and GVHD(n=2). Of 142 eligible patients, 12 were not apheresed and 13 not infused, see Figure 1. The ITT cohort included 128 eligible patients, excluding patients lost to follow-up or had insufficient data provided for survival analysis.

57.8% (74) patients were male, median age at infusion was 11.3 years (IQR 6.9-16). Cytogenetic status (n=98) included high risk (n=35, 35.7%), favourable (n=25, 25.5%); and intermediate (n=39, 39.7%). Prior refractory disease was noted in 55 (42%). Median relapses were 2 (IQR 1-2) and lines of therapy was 3 (2-3 IQR). 52 patients (45.2% out of 115) additionally had prior SCT. 34 (26.6%) of patients had received blinatumomab and 13 (10.2%) inotuzumab prior to CART.

Median CART dose infused was 1.3E+06 cells/kg (IQR 3 -2.85E+06). Of 114 infused patients, 101 (88.6%) were in CR/Cri at day 30; 72 (78.3%) were MRD negative.

Overall survival (infused cohort) was 79.9% (95% CI: 72-89%) at 1y and 67.7% at 2y (95%CI: 57-80%, median OS not reached). EFS by the classic / ELIANA definition was 70.9% (95%CI: 62-81%) and 50% (95%CI: 38-67%) at 1 and 2 years respectively. Median EFS was 22 months. Stringent EFS was 45% (95%CI: 36-56%) at 1y and 37.8% (95%CI: 28-51%) at 2y, median 214 days. For the ITT cohort, OS at 1 and 2 years was 78.6% (95%CI: 71-87%) and 65.3% (95%CI:55-77%) , standard EFS 67.2% (58.2-77.5%) and 44.7% (95%CI: 32-61%) and stringent EFS 44.5% (95%CI: 36-55%) and 34.8% (95%CI: 26-47% median stringent EFS 270 days).

Of 111 infused patients, two died prior to day 30, 8 patients did not respond, 5 died of disease shortly after. Three patients had not achieved day 30 to assess response.

Of 101 responding patients, 17 had MRD relapse and went on to further therapy, a further 19 had therapy for early loss of B-cell aplasia, 11 had frank relapse of which 6 were CD19 negative. Outcomes are shown in Figure 1.

At a median follow-up of 16.5 months from infusion, 12/17 patients with loss of B Cell aplasia, 9/17 patients with MRD and 2/11 with frank relapse are alive and in MRD neg remission.

CART cell therapy was well tolerated, 91 patients (79.8%) had mainly mild CRS, 77 grade 1-2 (84.6%) and 14 grade 3-4 (15.4%). Neurotoxicity occurred in 21 patients (18.4%) (13 (62%) grade 1-2 and 7 (33.3%) grade 3-4). One patient died from severe neurotoxicity, possibly Fludarabine related. 44 (39%) received tocilizumab. Further toxicity outcomes will be presented.

Conclusion We present a unique systematic outcome analysis for paediatric and young adult patients with B-ALL allocated to receive tisagenlecleucel treatment under a national access scheme in the UK. Outcomes are based on standard OS and EFS, as well as more stringent EFS definition capturing all clinically meaningful endpoints, for both the infused and ITT cohorts. We track all patients beyond failure of therapy, observing a 50% chance of effective salvage post event (23/50 events including loss B cell aplasia, MRD or frank relapse). These data are relevant for clinicians counselling patients for CART therapy and the likelihood of survival, from the point of being eligible through outcomes after failure of CART therapy.

Roddie:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. O'Reilly:Kite Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to educational meetings, Speakers Bureau; Novartis: Honoraria, Other: travel to educational meetings. Snowden:Kiadis: Other: clinical trial IDMC membership ; Medac: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Mallinckrodt: Speakers Bureau; Gilead: Speakers Bureau; Janssen and Jazz: Speakers Bureau. Jalowiec:Kite Gilead: Honoraria. Nicholson:Amgen: Other: Travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting grant. Marks:Kite: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria. Uttenthal:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: conference sponsorship, Speakers Bureau; BMS: Other: conference sponsorship; Atara: Membership on an entity's Board of Directors or advisory committees; Kite Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference sponsorship, Speakers Bureau. Chaganti:AbbVie: Consultancy, Honoraria; Adicet Bio: Consultancy, Honoraria; Atara Biotherapeutics: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Orion Pharma: Consultancy, Honoraria; Pierre Fabre: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Amrolia:Bluebird Bio: Research Funding; Pierre Fabre: Consultancy; UCL Business: Patents & Royalties; Bluebird Bio: Research Funding; Pierre Fabre: Consultancy; Autolus: Patents & Royalties, Research Funding; ADC Therapeutics: Patents & Royalties: named inventor WO2022063853A1. Ghorashian:Novartis: Honoraria, Speakers Bureau; UCLB: Patents & Royalties.