Gregory A. Yanik

BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).

= .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.

IMPORTANCE: Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging. OBJECTIVE: To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-site, observational, consecutive case series (May 2012-October 2014) involving 102 children and young adults (mean age, 10.6 years; median age, 11.5 years, range, 0-22 years) with relapsed, refractory, or rare cancer. EXPOSURES: Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians. MAIN OUTCOMES AND MEASURES: Proportion of patients with potentially actionable findings, results of clinical actions based on integrative clinical sequencing, and estimated proportion of patients or their families at risk of future cancer. RESULTS: Of the 104 screened patients, 102 enrolled with 91 (89%) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Forty-two patients (46%) had actionable findings that changed their cancer management: 15 of 28 (54%) with hematological malignancies and 27 of 63 (43%) with solid tumors. Individualized actions were taken in 23 of the 91 (25%) based on actionable integrative clinical sequencing findings, including change in treatment for 14 patients (15%) and genetic counseling for future risk for 9 patients (10%). Nine of 91 (10%) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening. CONCLUSIONS AND RELEVANCE: In this single-center case series involving young patients with relapsed or refractory cancer, incorporation of integrative clinical sequencing data into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling for a small proportion of patients. The lack of a control group limited assessing whether better clinical outcomes resulted from this approach than outcomes that would have occurred with standard care.

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.

Dendritic cells (DCs) have been shown to be a promising adjuvant for inducing immunity to cancer. We evaluated tumor lysate-pulsed DC in a Phase I trial of pediatric patients with solid tumors. Children with relapsed solid malignancies who had failed standard therapies were eligible. The vaccine used immature DC (CD14-, CD80+, CD86+, CD83-, and HLA-DR+) generated from peripheral blood monocytes in the presence of granulocyte/monocyte colony-stimulating factor and interleukin-4. These DC were then pulsed separately with tumor cell lysates and the immunogenic protein keyhole limpet hemocyanin (KLH) for 24 h and then combined. A total of 1 x 10(6) to 1 x 10(7) DC are administered intradermally every 2 weeks for a total of three vaccinations. Fifteen patients (ages 3-17 years) were enrolled with 10 patients completing all vaccinations. Leukapheresis yields averaged 2.8 x 10(8) peripheral blood mononuclear cells (PBMC)/kg, and DC yields averaged 10.9% of starting PBMC. Patients with neuroblastoma, sarcoma, and renal malignancies were treated without obvious toxicity. Delayed-type hypersensitivity (DTH) response was detected in 7 of 10 patients for KLH and 3 of 6 patients for tumor lysates. Priming of T cells to KLH was seen in 6 of 10 patients and to tumor in 3 of 7 patients as demonstrated by specific IFN-gamma-secreting T cells in unstimulated PBMCs. Significant regression of multiple metastatic sites was seen in 1 patient. Five patients showed stable disease, including 3 who had minimal disease at time of vaccine therapy and remain free of tumor with 16-30 months follow-up. Our results demonstrate that it is feasible to generate large numbers of functional DC from pediatric patients even in those highly pretreated and with a large tumor burden. The DC can be administered in an outpatient setting without any observable toxicity. Most importantly, we have demonstrated the ability of the tumor lysate/KLH-pulsed DC to generate specific T-cell responses and to elicit regression of metastatic disease.