Michael Pulsipher, MD
Tisagenlecleucel (Kymriah), the first FDA-approved CAR T-cell therapy, induced a complete remission (CR) with complete or incomplete hematologic recovery in 83% of pediatric, adolescent, and young adult patients with acute lymphoblastic lymphoma (ALL).
The updated data from the pivotal ELIANA trial were presented at the 2017 SOHO Annual Meeting. Tisagenlecleucel (formerly CTL019) treatment led to a CR with complete hematologic recovery in almost two-thirds of patients. All patients who attained CRs also met criteria for minimal residual disease (MRD)–negative status.
“The primary efficacy analysis was consistent with the interim analysis where the primary endpoint was met,” said Michael Pulsipher, MD, a pediatric hematologist at Children’s Hospital of Los Angeles and the University of Southern California.
The ELIANA study was the first-ever global multicenter trial of CAR T-cell therapy. Trial was conducted at 25 sites in North America, Europe, and the Asia-Pacific region. Tisagenlecleucel for the trial was produced at Novartis’s manufacturing site in the United States. Personnel at participating sites underwent training in tisagenlecleucel-specific logistics and patient management, said Pulsipher.
The study population included patients ages 3 to 21 years with B-cell ALL and bone marrow with ≥5% lymphoblasts. The interim efficacy analysis showed an overall response rate of 82%.
The data presented at SOHO included 68 patients treated with tisagenlecleucel, 63 of whom were evaluable for response (≥3 months of follow-up or discontinuation). The primary endpoint was overall remission (CR with complete or incomplete hematologic recovery) within 3 months and maintained for at least 4 weeks, as assessed by an independent review committee.
Before CAR T-cell infusion, all patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide. CAR T-cell therapy consisted of a single weight-adjusted (≤50 kg versus >50 kg) infusion of tisagenlecleucel.
A total of 107 patients were screened by investigators, and enrolled 88 for the trial. Infusion is pending for 4 patients, and 16 others discontinued before infusion (7 because of manufacturing or release issues and 9 because of death or adverse events [AEs]). Of 68 infused patients, 49 remained in follow-up. The 19 discontinuations consisted of 7 deaths, lack of efficacy and initiation of new therapy for ALL while still in CR (5 each), and patient/guardian decision in 2 cases.
The median age was 12 for the 68 infused patients. The patients had received a median of 3 prior lines of therapy for ALL (range, 1-8), and 59% of the patients had a prior stem-cell transplant. Disease status was refractory in 21% and relapsed in 79%. The patients had a median morphologic blast count in marrow of 73%, high-risk genetic lesions in 29% of cases, and Down syndrome in 9%.
The overall response rate of 83% included CRs with complete hematologic recovery in 63% of patients and CRs with incomplete recovery in 19%. Additionally, 83% of patients met the secondary endpoint: CR (with or without complete recovery) within 3 months with MRD-negative bone marrow.
Among all infused patients, the relapse-free survival rate was 75% at 6 months and 64% at 9 and 12 months. Overall survival (OS) was 89% at 6 months and 79% at 9 and 12 months. Median OS was 16.6 months.
Grade 3/4 AE frequency decreased with increasing time from tisagenlecleucel infusion. The overall incidence of grade 3/4 AEs was 85%, including 82% within the first 8 weeks, decreasing to 39% beyond 8 weeks. The proportion of events considered to be treatment related were 72% overall, 71% during the first 8 weeks, and 14% after 8 weeks.
“The majority of adverse events occurred in the first 8 weeks after tisagenlecleucel infusion,” said Pulsipher.
The most common AEs were cytokine release syndrome (CRS, 78% all grades, 48% grade 3/4), fever (40%, 15%), decreased appetite (37%, 15%), febrile neutropenia (37%, 37%), hypotension (31%, 22%), elevated AST (28%, 16%), hypokalemia (24%, 15%), and hypoxia (24%, 18%).
In addition to CRS, AEs of special interest included cytopenias not resolved by day 28 (37% overall, 33% grade 3/4), infections (43%, 27%), neurologic events (44%, 15%), and tumor lysis syndrome (4%, 4%).
Two patients died within 30 days of infusion, 1 of progressive ALL and 1 because of cerebral hemorrhage. No patient died of refractory CRS, and no cerebral edema was reported.
Patient quality of life improved from baseline to 3 months by 2 different assessment instruments.
Pulsipher M, Buechner J, Grupp SA, et al. Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): update to the interim analysis. Presented at 2017 SOHO Annual Meeting. Abstract ALL-152.