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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.) [ABSTRACT FROM AUTHOR]

Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse., Methods: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel., Results: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion., Conclusions: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports., Competing Interests: Competing interests: JEL has received research and/or clinical trial support from Incyte, Kamada, Mesoblast, and Biogen and has participated in consulting, study steering committees, or scientific/clinical advisory boards for Novartis, bluebird bio, Incyte, Ironwood, Mesoblast, Omeros, Oncoimmune, Talaris, and X4 Pharmaceuticals. SAG has received research and/or clinical trial support from Novartis, Servier, and Kite and has participated in consulting, study steering committees, or scientific/clinical advisory boards for Novartis, Cellectis, Adaptimmune, Eureka, TCR2, Juno, GlaxoSmithKline, Vertex, Cure Genetics, Humanigen, and Roche. MAP has participated in steering committees for the ENSIGN and ELIANA trials for Novartis, advisory boards, and educational activities for Novartis. ACD is a current employee of bluebird bio; bluebird bio has had no support or oversight of this research or manuscript. SR has received clinical trial support from Novartis, Servier, and Celgene and has participated in consulting, study steering committees, or scientific/clinical advisory boards for Novartis, Servier, Celgene, Cellectis, Kite/Bristol-Myers Squibb, JazzPharma, and Amgen. GDM has received payment and honoraria as a consultant to Novartis Pharma and for serving on the speaker’s bureau for Kymriah. KJA has participated in a speaker bureau and received travel accommodations and expenses from Novartis. MRV has participated in advisory boards for Novartis, Fate Therapeutics, and B-Mogen and has stock options from Fate Therapeutics and B-Mogen. JB has participated in study steering committees, advisory boards, and educational activities for Novartis, and advisory boards for Kite and Janssen. TWL has consulted for Novartis, Cellectis, Loxo Oncology, Eli Lilly, and Bayer; has received research funding from Novartis, Pfizer, and Bayer; and is currently affiliated with the Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA and the Division of Oncology, Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. HB has participated in consulting for Novartis and Jazz Pharmaceuticals and his department has received financial reimbursement for participation in tisagenlecleucel trials for Novartis. AB has received research and/or clinical trial support from Novartis, Servier, and Kite and participated in consulting, study steering committees, or scientific/clinical advisory boards for Novartis, Servier, Celgene, Jazz Pharma, AstraZeneca, Janssen, and Amgen. MWB has participated in advisory boards for Novartis and Thunder Biotech. BDM has received a travel grant from Jazz Pharma; her department has received financial reimbursement and compensation for participation in CTL019 trials for Novartis, and consulting for Novartis. MQ has received support for service on clinical advisory boards for Novartis and Bristol-Myers Squibb. SMD has received research support from Alexion Pharmaceuticals and served in a consulting role for Novartis. CLP has received support for service on clinical advisory board for Novartis.TAD has no conflicts to declare. PB has received institutional research grants from medac, Riemser, and Neovii and institutional compensation for advisory activity and speakers bureau from Miltenyi, Amgen, Novartis, Servier, medac, and Riemser. KS has no conflicts to declare. PAW was an employee of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. RM has no conflicts to declare. LY is an employee of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. ML is an employee of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. LKE is an employee of Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. CHJ has received research support from Novartis and Tmunity Therapeutics. SLM has received clinical trial support from Novartis and has served in a consulting role, on advisory boards, or on study steering committees for Novartis, Kite, and Wugen., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

T-cell Prolymphocytic Leukemia (T-PLL) is a rare entity, and to date has never been reported in children. Here, we describe the first pediatric case of T-PLL in a 16-year old male and review his clinical course through treatment. He underwent therapy with alemtuzumab and pentostatin, which was successful in inducing initial remission. He then underwent an allogeneic matched sibling stem cell transplant following a myeloablative conditioning regimen and remains disease-free 1.5 years after diagnosis., (© 2014 Wiley Periodicals, Inc.)

Drug resistance remains a major obstacle to successful cancer treatment. A database of drug-associated gene expression profiles was screened for molecules whose profile overlapped with a gene expression signature of glucocorticoid (GC) sensitivity/resistance in acute lymphoblastic leukemia (ALL) cells. The screen indicated that the mTOR inhibitor rapamycin profile matched the signature of GC sensitivity. We tested the hypothesis that rapamycin would induce GC sensitivity in lymphoid malignancy cells and found that it sensitized to GC-induced apoptosis via modulation of antiapoptotic MCL1. These data indicate that MCL1 is an important regulator of GC-induced apoptosis and that the combination of rapamycin and glucocorticoids has potential utility in lymphoid malignancies. Furthermore, this approach represents a strategy for identification of promising combination therapies for cancer.