High-Disease Burden Pre-Tisagenlecleucel Has Negative Effect on Survival in B-ALL

Targeted Therapies in OncologyJanuary 2023
Volume 11
Issue 17
Pages: 69

Treatment with tisagenlecleucel in patients with relapsed/refractory B-cell acute lymphoblastic leukemia led to a 79% morphologic complete response rate.

An intent-to-treat analysis of 200 children, adolescents, and young adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) revealed a 79% morphologic complete response (CR) rate (95% CI, 72%-84%).1 Of those, 185 patients received an infusion of tisagenlecleucel (tisa-cel; Kymriah) and were evaluated for survival and toxicity. Investigators reported an 85% CR (95% CI, 79%-89%), a 12-month overall survival (OS) rate of 72%, and an event-free survival (EFS) rate of 50% after 335 days of median follow-up for the infusion group.

Among 134 patients infused who had detectable disease at the evaluation pre-tisagenlecleucel, the CR rate was 81% (n = 108; 95% CI, 73%-86%). Of infused patients achieving morphologic CR, minimal residual disease (MRD) testing by flow cytometry was available for 98% (n = 153), with 97% (n = 148) achieving MRD-negative CR.

The objective of the study was to establish outcomes in a real-world setting and understand the variables affecting post chimeric antigen receptor (CAR) outcomes. Investigators formed a national consortium comprising 15 pediatric centers delivering standard-of-care tisagenlecleucel. Patients with R/R B-ALL who underwent leukapheresis were included in an intent-to-treat response analysis. The investigators measured the relationship between baseline characteristics and clinical outcomes.

The response rate on day 28 after administration of tisagenlecleucel was measured by bone marrow and peripheral blood morphology, and minimal residual disease was measured by flow cytometry. Secondary objectives included analysis of OS and EFS at 6 and 12 months post tisagenlecleucel administration. Exploratory end points measured risk factors for response and survival, including baseline age at diagnosis, sex, cytogenetics, prior therapy lines, prior hematopoietic stem cell transplant (HSCT), and prior CD19-directed therapy.

Patients’ median age at infusion was 12 years (range, 0-26), with 13 patients younger than 3 years at the time of infusion and 6 patients older than 21 years at the time of diagnosis. Of the 185 patients infused, thirty patients (16%) were treated for up-front refractory disease, and 83% were treated for relapsed disease. Patients underwent 3 prior lines of therapy (range, 1-10) with a median duration of 33 months (range, 3-171) between diagnosis and infusion.

Univariate and multivariate analyses associate high-disease burden (≥ 5% bone marrow lymphoblasts) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS).


Investigators reported that median OS was not reached. Among 184 patients who received the infusion, 6-month OS was 85% and 12-month OS was 72%. EFS at 6 months was 62% and at 12 months it was 50%. Thirty-seven percent of patients who responded had a relapse, and the median time from infusion to relapse was 101 days (range, 30-645).

Among patients who achieved a CR, 28% (41 of 156) underwent post-CAR HSCT. Twenty patients underwent HSCT while in remission post tisagenlecleucel without intervening relapse.


Turning to safety, among the 183 patients who were treated with tisagenlecleucel, 63% and 21%, respectively, had overall and grade 3 or greater cytokine release syndrome (CRS), with 1 CRS-attributed death. Median onset time for CRS was 5 days (range, 0-14) with a median duration of 4 days (range, 1-42).

Overall and grade 3 or greater neurotoxicity were reported in 21% and 7% of patients, respectively. Onset of neurotoxicity was 6 days (range, 3-25) post tisagenlecleucel, and the median duration was 5 days (range, 1-203). For the overall cohort, 82% had CAR-related hospital admissions before day 28 with 14.5 median inpatient days (range, 1-75), and 31% were admitted to a pediatric intensive care unit for a median duration of 6 days (range, 1-33).

Regarding neutropenic events, 67% (118 of 175) were grade 4, with a median duration among 94 evaluable patients with neutropenia of 14 days (range, 1-76). Tumor lysis syndrome was observed in 7% of patients, and 40% (73 of 181) experienced at least 1 infectious complication post infusion (median onset 68 days, range, 1-559).


The FDA approved tisagenlecleucel based on fi ndings from the phase 2 ELIANA trial (NCT02435849),2 in which investigators reported an 81% CR in 75 children, adolescents, and young adults who received an infusion. In that trial, the 12-month OS and EFS rates were 76% and 50%, respectively.

The approval indication did not require a threshold disease burden, but in the current analysis, 48% of patients who received an infusion had low burden disease, defined as lower than 5% bone marrow lymphoblasts.

The investigators noted that disease burden in ELIANA was assessed at enrollment and may have shifted during manufacturing of the CAR product. Researchers suggest that the current analysis looked at a cohort with an overall lower-disease burden than ELIANA. The investigators concluded that patients preinfusion with tisagenlecleucel are affected negatively by high-disease burden with inferior OS and EFS rates, and increased toxicity was reported.

1. Schultz LM, Baggo C, Prabhu S, et al. Disease burden affects outcomes in pediatric and young adult B-cell lymphoblastic leukemia after commercial tisagenlecleucel: a pediatric real-world chimeric antigen receptor consortium report. J Clin Oncol. 2022;40(9):945-955. doi:10.1200/JCO.20.03585
2. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. News release. Accessed December 11, 2022. https://bit.ly/3hk4Hq7
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