Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849 ), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.

Management of adverse events in young adults and children with acute B-cell lymphoblastic leukemia receiving anti-CD19 chimeric antigen receptor (CAR) T-cell therapy

“…According to the ELIANA study, 71% and 59% of pediatric B-ALL patients developed BCA at 12 and 24 months, respectively. In this review, the most frequent grade 3/4 adverse event occurring >1 year after the infusion was infection, with a prevalence of 20.4% [7]. In adults, pathogen-specific antibodies can be detected in the blood due to CD19-negative plasma cells [60].…”

“…Tisagenlecleucel (tisa-cel), a second-generation CD19-directed chimeric antigen receptor (CAR) T-cell product, is an effective and well-tolerated therapy approved by the Food and Drug Administration for use in pediatric and young adult patients with R/R B-cell ALL and in adults with R/R/diffuse large Bcell lymphoma and R/R follicular lymphoma [5]. The pivotal ELIANA clinical trials [6] along with the recently published data [7] demonstrated high long-term (median follow-up of 38.8 months) relapsefree survival and OS rates of 52% and 63%, respectively, in children with B-cell ALL.…”

CAR T-Cells for Cure in Pediatric B-ALL

“…In the two articles that accompany this editorial, 2,3 we get both a longitudinal perspective on the use of CD19 chimeric antigen receptor (CAR) T-cells to achieve durable remissions in children and young adults with B-cell acute lymphoblastic leukemia along with insights for the role of combinatorial treatment approach with the infusion of two unique CAR T-cell products in optimizing remission rates. Collectively, these efforts strongly support the critically important role for CAR T-cells in children and young adults with B-cell acute lymphoblastic leukemia in achieving a cure—while laying a foundation for what future iterations of CAR T-cell–based approaches may look like to improve upon current outcomes.…”

“…In a highly anticipated follow-up from the phase II study of tisagenlecleucel in childhood B-ALL, 4 Laetsch et al 2 expanded on their original analysis to report on long-term outcomes. With a total of 79 patients infused and a median follow-up of 38.8 months, the overall remission rate was 82% (n = 65) at 3 months—which excluded four patients with initial response at day 28 but had either interval therapy (n = 1), relapse (n = 2), or experienced nonrelapse mortality (n = 1) before 3 months.…”

“…7-9 With the desire to avoid short- and long-term toxicities associated with HSCT, avoiding HSCT is certainly understandable—but has to be balanced with risks of post-CAR T-cell relapse for which outcomes are poor. 10,11 Although there has been limited data on the role of consolidative HSCT after tisagenlecleucel, Laetsch et al 2 reported that data were available for eight of the 11 patients who underwent consolidative HSCT, all of whom remain in remission with a median of 18 months of follow-up. Wang et al 3 incorporated a planned consolidative HSCT for patients at risk for myeloid lineage switch (KMT2Ar/ZNF384r) (n = 24).…”