Intention-to-treat outcomes utilising a stringent event definition in children and young people treated with tisagenlecleucel for r/r ALL through a national access scheme

Abstract

CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2-74.2%) and 46.5% (95%CI 37.6-57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1-44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3-75.8) and 55.3% (95%CI 43.6-70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival.

Fig. 1. Patient flowchart.

CR/CRi complete remission with/without haematological recovery, DoD died of disease, PD progressive disease, HSCT allogeneic haematopoietic stem cell transplantation, MRD minimal residual disease. *Patients died from procedural mortality (n = 3).

Fig. 2. Survival outcomes after tisagenlecleucel in r/r B-ALL.

Survival in the intention to treat (a) and infused (b) cohorts. OS overall survival, EFS event-free survival as per ELIANA definition, stringent EFS stringent event-free survival.

Fig. 3. Further outcomes for infused cohort (n = 125).

a Probability of remaining in B-cell aplasia. Main events are B-cell recovery or CD19 positive relapse, competing events are non-response, disease emergence other than CD19 positive and death. b Cumulative incidence of relapse. Death in remission and non-response are competing events. All documented relapses were considered, i.e. including those occurring after MRD emergence and/or other therapy following CAR T. This is because censoring further treatments received after CAR T would underestimate the true incidence of relapse after tisagenlecleucel infusion. c Cumulative incidence of relapse stratified by immunophenotype. Competing events non-response, death in remission, myeloid switch and relapse with unknown immunophenotype.

Fig. 4. Detailed outcomes after CAR T failure.

HSCT allogeneic haematopoietic stem cell transplantation, MRD minimal residual disease, TRM transplant related mortality, DoD died of disease.

Fig. 5. Survival after CAR T failure (n = 62).

a OS and EFS for the 62 responding patients that subsequently failed CAR T. b OS and (c) EFS stratified according to type of CAR T failure. MRD measurable residual disease emergence, LBCA early loss of B-cell aplasia.