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Background: The objective of this study is to assess the concordance and added value of combined comparative genomic hybridization plus single-nucleotide polymorphism microarray (CGH/SNP) analyses in pediatric acute lymphoblastic leukemia (ALL) risk stratification compared to conventional cytogenetic methods., Procedure: This is a retrospective study that included patients aged 1-18 years diagnosed with de novo ALL at Sainte-Justine Hospital between 2016 and 2021. Results from conventional cytogenetic and molecular analyses were collected and compared to those of CGH/SNP., Results: A total of 135 ALL patients were included. Sample failures or non-diagnostic analyses occurred in 17.8% cases with G-banding karyotypes versus 1.5% cases with CGH/SNP. The mean turnaround time for results was significantly faster for CGH/SNP than karyotype with 5.8 versus 10.7 days, respectively. The comparison of ploidy assessment by CGH/SNP and G-banding karyotype showed strong concordance (r = .82, p < .001, r 2  = .68). Furthermore, G-banding karyotype did not detect additional clinically relevant aberrations that were missed by the combined analysis of CGH/SNP and fluorescence in situ hybridization. The most common gene alterations detected by CGH/SNP were deletions involving CDKN2A (35.8%), ETV6 (31.3%), CDKN2B (28.4%), PAX5 (20.1%), IKZF1 (12.7%), and copy-neutral loss of heterozygosity (CN-LOH) of 9p (9.0%). Among these, only ETV6 deletion was found to have a significant prognostic impact with superior event-free survival in both univariate and multivariate analyses (adjusted hazard ratio 0.08, 95% confidence interval: 0.01-0.50, p = .02)., Conclusion: CGH/SNP provided faster, reliable, and highly concordant results than those obtained by conventional cytogenetics. CGH/SNP identified recurrent gene deletions in pediatric ALL, of which ETV6 deletion conferred a favorable prognosis., (© 2024 Wiley Periodicals LLC.)

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., Competing Interests: Theodore W. LaetschStock and Other Ownership Interests: Advanced MicrobubblesConsulting or Advisory Role: Novartis, Bayer, Cellectis, Aptitude Health, Clinical Education Alliance, Deciphera, Jumo Health, Massive Bio, Med Learning Group, Medscape, Physicans' Education Resource, Y-mAbs Therapeutics, AI Therapeutics, Jazz Pharmaceuticals, GentiBio, Menarini, Pyramid BiosciencesResearch Funding: Pfizer (Inst), Novartis (Inst), Bayer (Inst), AbbVie (Inst), Amgen (Inst), Atara Biotherapeutics (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), Epizyme (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Jubilant Pharmaceuticals (Inst), Novella Clinical (Inst), Servier (Inst), Foundation Medicine (Inst), Merck Sharp & Dohme (Inst), Turning Point Therapeutics (Inst) Shannon L. MaudeConsulting or Advisory Role: Novartis, KiteResearch Funding: Novartis (Inst), Wugen, Inc (Inst)Patents, Royalties, Other Intellectual Property: PCT/US2017/044425: Combination Therapies of Car and PD-1 InhibitorsTravel, Accommodations, Expenses: Novartis Susana RivesHonoraria: Novartis, Kite/Gilead, Celgene/Bristol Myers Squibb, Shire/ServierConsulting or Advisory Role: Servier, Amgen, Novartis, Kite/Gilead, Shire/Servier, Celgene/Bristol Myers Squibb, Cellectis, Jazz PharmaceuticalsSpeakers' Bureau: NovartisResearch Funding: Novartis (Inst)Travel, Accommodations, Expenses: Novartis, Shire/Servier, Cellectis, Jazz Pharmaceuticals Hidefumi HiramatsuHonoraria: Novar PharmaConsulting or Advisory Role: Novartis Henrique BittencourtConsulting or Advisory Role: Novartis Canada Pharmaceuticals Inc, Jazz PharmaceuticalsSpeakers' Bureau: Novartis Oncology Canada Peter BaderHonoraria: Medac (Inst), Riemser (Inst), Neovii (Inst)Consulting or Advisory Role: Novartis (Inst), Amgen (Inst), Miltenyi (Inst), Servier (Inst)Speakers' Bureau: Novartis (Inst), Amgen (Inst), Riemser (Inst), Medac (Inst), Miltenyi (Inst), Servier (Inst)Research Funding: Medac (Inst), Neovii (Inst), Riemser (Inst)Patents, Royalties, Other Intellectual Property: Patent on MSC licensend to Medac André BaruchelLeadership: DBV Technologies, lysogen, Medday Pharmaceuticals, Ascendis PharmaStock and Other Ownership Interests: DBV Technologies, Ascendis PharmaHonoraria: Novartis, Kite, a Gilead company, AstraZenecaConsulting or Advisory Role: Jazz Pharmaceuticals, Novartis, Servier, CelgeneResearch Funding: Jazz Pharmaceuticals (Inst), Servier (Inst)Travel, Accommodations, Expenses: Jazz Pharmaceuticals, Sanofi, Servier Michael BoyerHonoraria: NovartisEmployment: Thunder BiotechLeadership: Thunder Biotech Barbara De MoerlooseConsulting or Advisory Role: NovartisUncompensated Relationships: Novartis (Inst), Gilead Sciences (Inst), Articulate Science, Jazz Pharmaceuticals Muna QayedHonoraria: Novartis, Vertex, Medexus, Jazz Pharmaceuticals, MesoblastConsulting or Advisory Role: NovartisTravel, Accommodations, Expenses: Novartis Jochen BuechnerHonoraria: Novartis, Pfizer, KiteConsulting or Advisory Role: Novartis, Janssen (Inst), Amgen (Inst)Speakers' Bureau: Novartis Michael A. PulsipherThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Honoraria: Novartis, MesoblastConsulting or Advisory Role: Novartis, Medexus Pharmaceuticals, Equillium, Gentibio, Vertex, Bluebird BioResearch Funding: Adaptive Biotechnologies, Miltenyi Biotec Gary Douglas MyersHonoraria: NovartisConsulting or Advisory Role: NovartisSpeakers' Bureau: NovartisResearch Funding: Novartis (Inst) Heather E. StefanskiConsulting or Advisory Role: NovartisSpeakers' Bureau: Novartis Paul L. MartinConsulting or Advisory Role: Neovii Biotech GmbH, Genentech, Enlivex Therapeutics, and PharmacyclicsResearch Funding: Novartis (Inst), Bluebird Bio (Inst), AbGenomics (Inst) Eneida NemecekConsulting or Advisory Role: Novartis, Medexus, Atara Bio Christina PetersHonoraria: Neovii, Jazz Pharmaceuticals, NovartisConsulting or Advisory Role: Amgen, Neovii, NovartisSpeakers' Bureau: Medac, Riemser, AmgenResearch Funding: Medac (Inst), Neovii (Inst), Riemser (Inst), Jazz Pharmaceuticals (Inst), Amgen (Inst)Travel, Accommodations, Expenses: Neovii, Jazz Pharmaceuticals, Novartis Seong Lin KhawHonoraria: Novartis Kara L. DavisHonoraria: NovartisResearch Funding: Jazz Pharmaceuticals Joerg KruegerEmployment: JanssenConsulting or Advisory Role: Novartis, Kite/Gilead, SOBIOther Relationship: Canadian Agency for Drugs and Technologies in Health (CADTH) Adriana BalduzziSpeakers' Bureau: Novartis, Amgen, MedacTravel, Accommodations, Expenses: Novartis, Medac, Neovii Nicolas BoisselHonoraria: Amgen, ARIAD/Incyte, Novartis, Servier, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, Celgene, Sanofi, PfizerConsulting or Advisory Role: Amgen, Novartis, Servier, PfizerResearch Funding: Amgen, Novartis, Bristol Myers Squibb, Jazz PharmaceuticalsExpert Testimony: Amgen Ranjan TiwariEmployment: Novartis Darragh O’DonovanEmployment: Novartis Ireland LtdStock and Other Ownership Interests: Novartis Stephan A. GruppHonoraria: TCR2 Therapeutics, Eureka Therapeutics, CellectisConsulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Janssen, Cellular Biomedicine Group, Roche, Adaptimmune, Alimera Sciences, Cabaletta Bio, CRISPR Therapeutics/VertexResearch Funding: Novartis (Inst), Kite/Gilead (Inst), Servier (Inst), Jazz Pharmaceuticals (Inst), Vertex (Inst)Patents, Royalties, Other Intellectual Property: UPenn Toxicity management patent (Inst)Expert Testimony: Juno TherapeuticsNo other potential conflicts of interest were reported.

The epidemiology of infant acute lymphoblastic leukemia (ALL), hypodiploid ALL, and mixed-phenotype acute leukemia (MPAL) in Canada is unknown. The main objective was to describe the prevalence, prognostic factors, and outcomes of three rare and high-risk ALL subtypes in Canada. This is a retrospective study using the Cancer in Young People-Canada (CYP-C) database. Event-free survival (EFS) and overall survival (OS) were described by the Kaplan-Meier method and compared using the log-rank test. Among 2626 children aged 0-14 years diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) between 2001 and 2018, 227 (8.6%) patients were identified to be infant ALL ( n  = 139), hypodiploid ALL ( n  = 43), or MPAL ( n  = 45). The 5-year EFS/OS was significantly worse in the infant ALL subgroup compared to that of hypodiploid ALL and MPAL. For the entire cohort, presenting White blood cells (WBCs) ≥50 × 10 9 /L was independently associated with worse EFS/OS.

Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) patients suffer risk of chemotherapy-associated toxicities and poor outcomes. We evaluated tisagenlecleucel in 16 patients with DS-ALL in two phase 2 trials (ELIANA [NCT02435849], ENSIGN [NCT02228096]) and a phase 3b, managed access protocol (B2001X [NCT03123939]). Patients were 5-22 years old, had a median of two prior lines of therapy (range, 1-4), and four (25%) had prior stem cell transplants. Fourteen of 16 patients (88%) achieved complete remission (CR) or CR with incomplete blood count recovery (CRi); 12 of 14 (86%) with CR/CRi were minimal residual disease-negative. With a median follow-up of 13.2 months (range, 0.5-49.3 months), six patients (43%) relapsed after CR (three, CD19-negative; three, unknown) between 80-721 days post-infusion. Ongoing remissions in nine patients ranged from 6-48 months. Any-grade and grade 3/4 AEs occurred in 16 and 14 patients, respectively; 44% experienced grade 3/4 cytokine release syndrome and 13% experienced grade 3/4 neurological events. Grade 3/4 prolonged cytopenias occurred in 44% of patients. No grade 3/4 infections were observed. Tisagenlecleucel expansion and long-term persistence were consistent with previous reports. Comparable to ALL patients without DS, tisagenlecleucel produced high remission rates, manageable side-effects, and promising long-term outcomes in pediatric/young adult patients with DS-ALL., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The molecular hallmark of childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA sequencing (RNA-seq) is a powerful next-generation sequencing technology that can simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multicenter phase 3 clinical trial for children with newly diagnosed ALL. The Dana-Farber Cancer Institute ALL Consortium Protocol 16-001 enrolled 173 patients with ALL who consented to optional studies and had samples available for RNA-seq. RNA-seq identified at least 1 alteration in 157 patients (91%). Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-cell ALL (B-ALL) subgroups: high hyperdiploid (n = 36), ETV6-RUNX1/-like (n = 31), TCF3-PBX1 (n = 7), KMT2A-rearranged (KMT2A-R; n = 5), intrachromosomal amplification of chromosome 21 (iAMP21) (n = 1), hypodiploid (n = 1), Philadelphia chromosome (Ph)-positive/Ph-like (n = 16), DUX4-R (n = 11), PAX5 alterations (PAX5 alt; n = 11), PAX5 P80R (n = 1), ZNF384-R (n = 4), NUTM1-R (n = 1), MEF2D-R (n = 1), and others (n = 10). RNA-seq identified 141 nonsynonymous mutations in 93 patients (54%); the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Philadelphia chromosome-like gene signature prediction, results were concordant in 74 patients (94%). In conclusion, RNA-seq identified several clinically relevant genetic alterations not detected by conventional methods, which supports the integration of this technology into front-line pediatric ALL trials. This trial was registered at www.clinicaltrials.gov as #NCT03020030., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction : Despite the significant survival improvement in childhood acutelymphoblastic leukemia (ALL), 15-20% of patients continue to relapse; outcomes following relapse remain suboptimal and have room for further improvement. Advances in genomics have shed new insights on the biology of ALL, led to the discovery of novel genomically defined ALL subtypes, refined prognostic significance and revealed new therapeutic vulnerabilities. Areas covered : In this review, the authors provide an overview of the genomic landscape of childhood ALL and highlight recent advances in molecular-based and antibody-based pharmacological approaches in the treatment of childhood ALL, from emerging preclinical evidence to published results of completed clinical trials. Expert opinion : Molecularly targeted therapies and immunotherapies have expanded the horizons of ALL therapy and represent promising therapeutic avenues for high-risk and relapsed/refractory ALL. These novel therapies are now moving into frontline ALL therapy and may define new treatment paradigms that aim to further improve survival and reduce chemotherapy-related toxicities in the management of pediatric ALL.

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.)

Infant acute lymphoblastic leukemias (ALL) are rare hematological malignancies occurring in children younger than 1 year of age, most frequently associated with KMT2A rearrangements (KMT2A-r). The smaller subset without KMT2A-r, which represents 20% of infant ALL cases, is poorly characterized. Here we report two cases of chemotherapy-sensitive non-KMT2A-r infant ALL. Transcriptome analyses revealed identical ACIN1-NUTM1 gene fusions in both cases, derived from cryptic chromosomal rearrangements undetected by standard cytogenetic approaches. Two isoforms of the gene fusion, joining exons 3 or 4 of ACIN1 to exon 3 of NUTM1, were identified. Both fusion transcripts contained the functional DNA-binding SAP (SAF-A/B, Acinus, and PIAS) domain of ACIN1 and most of NUTM1. The detection of the ACIN1-NUTM1 fusion by RT-PCR allowed the molecular monitoring of minimal residual disease in a clinical setting. Based on publicly available genomic datasets and literature review, we predict that NUTM1 gene fusions are recurrent events in infant ALL. As such, we propose two clinically relevant assays to screen for NUTM1 rearrangements in bone marrow cells, independent of the fusion partner: NUMT1 immunohistochemistry and NUTM1 RNA expression. In sum, our study identifies ACIN1-NUTM1 as a recurrent and possibly cryptic fusion in non-KMT2A-r infant ALL, provides clinical tools to screen for NUTM1-rearranged leukemia and contributes to the refinement of this new subgroup., (© 2019 Wiley Periodicals, Inc.)

Access to hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) primarily depends on disease-related factors but may be influenced by social and economic determinants. We included all children aged < 15 years with newly diagnosed ALL in Canada between 2001 and 2018 using the Cancer in Young People in Canada national registry. We examined factors potentially associated with the likelihood of receiving HSCT using univariate and multivariable logistic regression models. A total of 3992 patients with newly diagnosed ALL were included. Three hundred twenty-five (8.1%) received an HSCT and formed the transplant cohort. In multivariable analysis factors independently associated with an increased odds of receiving HSCT were male sex (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.05 to 1.93), initial WBC ≥ 50,000 × 10 9 /L (OR, 1.58; 95% CI, 1.09 to 2.28), mixed phenotype acute leukemia relative to B-precursor ALL (OR, 34.32; 95% CI, 16.64 to 70.79), T cell relative to B-precursor ALL (OR, 1.77; 95% CI, 1.07 to 2.91), unfavorable relative to standard cytogenetics (OR, 3.96; 95% CI, 2.56 to 6.12), and relapse before HSCT (OR, 32.77; 95%, 23.89 to 44.96). No association was found between race, neighborhood income quintile or region at diagnosis, and receipt of HSCT. Diagnosis at an HSCT treating center (OR, 1.51; 95% CI, 1.09 to 2.09) and residential distance from the ALL treating center (OR, 1.84 for ≥300 km compared with <100 km; 95% CI, 1.17 to 2.91) were associated with higher odds of receiving HSCT. In a publically funded healthcare system, children with ALL had equitable access to HSCT, which was largely governed by biologic disease-related factors. Patients diagnosed at an HSCT performing center and patients who live farthest away from their treatment center had higher odds of receiving HSCT, although the effect was small, possibly suggesting preferential referral to HSCT for some patients., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Over the past decades, survival of patients with acute lymphoblastic leukemia (ALL) has dramatically improved, but the subgroup of patients with relapsed/refractory ALL still continues to have dismal prognosis. As an emerging therapeutic approach, chimeric antigen receptor-modified T-cells (CAR-T) represent one of the few practice-changing therapies for this subgroup of patients. Originally conceived and built in Philadelphia (University of Pennsylvania), CTL019 or tisagenlecleucel, the first CAR-T approved by the US Food and Drug Administration, showed impressive results in refractory/relapsed ALL since the publication on two pediatric patients in 2013. It is in this context that we provide a review of this product in terms of manufacturing, pharmacology, toxicity, and efficacy studies. Evaluation and management of toxicities, particularly cytokine release syndrome and neurotoxicity, is recognized as an essential part of the patient treatment with broader use of IL-6 receptor inhibitor. An under-assessed aspect, the quality of life of patients entering CAR-T cells treatment, will also be reviewed. By their unique nature, CAR-T cells such as tisagenlecleucel operate in a different way than typical drugs, but also provide unique hope for B-cell malignancies., Competing Interests: Disclosure Henrique Bittencourt and Pierre Teira are consulting for Novartis Oncology. The other authors report no conflicts of interest in this work.

We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19 - relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.

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 .).

For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n = 257, 40%) or second complete remission (CR2; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2 + (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction: During recent decades, the prognosis of childhood acute lymphoblastic leukemia (ALL) has improved dramatically, nowadays, reaching a cure rate of almost 90%. These results are due to a better management and combination of old therapies, refined risk-group stratification and emergence of minimal residual disease (MRD) combined with treatment's intensification for high-risk subgroups. However, the subgroup of patients with refractory/relapsed ALL still presents a dismal prognosis indicating necessity for innovative therapeutic approaches. Areas covered: We performed an exhaustive review of current first-line therapies for childhood ALL in the worldwide main consortia, summarized the major advances for front-line and relapse treatment and highlighted recent and promising innovative therapies with an overview of the most promising ongoing clinical trials. Expert opinion: Two major avenues marked the beginning of 21 st century. First, is the introduction of tyrosine-kinase inhibitor coupled to chemotherapy for treatment of Philadelphia positive ALL opening new treatment possibilities for the recently identified subgroup of Ph-like ALL. Second, is the breakthrough of immunotherapy, notably CAR T-cell and specific antibody-based therapy, with remarkable success observed in initial studies. This review gives an insight on current knowledge in these innovative therapeutic directions, summarizes currently ongoing clinical trials and addresses challenges these approaches are faced with.

Relapsed/refractory acute lymphoblastic leukemia (ALL) is a leading cause of death by cancer in children. Our institution has switched relapse treatment strategy to improve survival. We reviewed records of first relapse/refractory childhood ALL between 1996 and 2012. Based on length of first remission, relapse site and immunophenotype, patients were classified into two groups: standard-risk relapse (SRR) and high-risk relapse and refractory (HRRR). Before 2007, all patients were uniformly treated with the same induction as at presentation, followed by hematopoietic stem cell transplantation (HSCT). Since 2007, treatment was given according to risk of failure: SRR were mostly treated with chemotherapy; HRRR patients underwent HSCT after intensive chemotherapy, aiming reduction of pre-transplant disease burden. Sixty-four patients were included. Thirty (47%) were SRR and 34 (53%) HRRR, including 11 with refractory ALL. Five-years overall survival (OS) and event-free survival (EFS) were similar for SRR, but were significantly higher with new risk-based strategy for HRRR: 56% versus 17% (P = 0.03) for OS, and 56% vs 11% for EFS (P = 0.008), respectively. In multivariate analysis, treatment strategy was significantly associated with survival. In conclusion, change for a risk-based strategy in our institution increased survival of high-risk patients to levels similar of those of standard-risk patients., Competing Interests: The authors have declared that no competing interests exist.