The superiority of total body irradiation (TBI)-based vs chemotherapy conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with acute lymphoblastic leukemia (ALL) has been established in the international, prospective phase-3 FORUM study, randomizing 417 patients aged 4-18 years in complete remission (CR), who received allo-HSCT from HLA-matched sibling or unrelated donors. Because of the unavailability of TBI in some regions and to accommodate individual contraindications, this study reports the prespecified comparison of outcomes of patients receiving busulfan (BU)- or treosulfan (TREO)-based regimens from 2013 to 2018. Overall, 180 and 128 patients received BU/thiotepa (THIO)/fludarabine (FLU) or TREO/THIO/FLU, respectively. Data were analyzed as of February 2023, with a median follow-up of 4.2 years (range, 0.3-9.1). 3-year overall survival was 0.71 (BU, 95% confidence interval [0.64-0.77]) and 0.72 (TREO, [0.63-0.79]) and 3-year event-free survival was 0.60 (BU, [0.53-0.67]) and 0.55 (TREO, [0.46-0.63]). The 3-year cumulative incidence of relapse (BU, 0.31 [0.25-0.38]; TREO, 0.36 [0.27-0.44]); and nonrelapse mortality (BU, 0.08 [0.05-0.13]; TREO, 0.09 [0.05-0.15]) were comparable. One case of fatal veno-occlusive disease occurred in each group. No significant differences in acute and chronic graft-versus-host disease (GVHD) or 3-year GVHD-free and relapse-free survival (BU, 0.48 [0.41-0.55]; TREO, 0.45 [0.37-0.54]) were recorded. Outcomes for patients in first and second CR were similar irrespective of the regimen. In conclusion, BU/THIO/FLU or TREO/THIO/FLU regimens can be an alternative to TBI for patients with ALL aged >4 years with contraindications or lack of access to TBI. This trial was registered at www.ClinicalTrials.gov as #NCT01949129.
- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma * therapy mortality MeSH
- Busulfan * analogs & derivatives therapeutic use MeSH
- Child MeSH
- Transplantation, Homologous MeSH
- Humans MeSH
- Adolescent MeSH
- Graft vs Host Disease * etiology MeSH
- Child, Preschool MeSH
- Transplantation Conditioning * methods MeSH
- Hematopoietic Stem Cell Transplantation * adverse effects MeSH
- Vidarabine analogs & derivatives therapeutic use administration & dosage MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of 2 TBI-free conditioning regimens in children aged <4 years with ALL. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children received transplantation and were observed for ≥6 months (median follow-up: 3 years). The 3-year OS was 0.63 (95% confidence interval [95% CI], 0.52-0.72) and 0.76 (95% CI, 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (P = .075), respectively. Three-year EFS was 0.52 (95% CI, 0.41-0.61) and 0.51 (95% CI, 0.39-0.62), respectively (P = .794). Cumulative incidence of nonrelapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI, 0.02-0.12) vs 0.03 (95% CI: <0.01-0.09) (P = .406) and 0.42 (95% CI, 0.31-0.52) vs 0.45 (95% CI, 0.34-0.56) (P = .920), respectively. Grade >1 acute graft-versus-host disease (GVHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% of those receiving Flu/Thio/Treo (P = .049), whereas grade 3/4 occurred in 10% and 9%, respectively (P = .813). The 3-year incidence of chronic GVHD was 0.07 (95% CI, 0.03-0.13) vs 0.05 (95% CI, 0.02-0.11), respectively (P = .518). In conclusion, both chemotherapeutic conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure. This trial was registered at www.clinicaltrials.gov as #NCT01949129.
- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma * etiology MeSH
- Busulfan * analogs & derivatives MeSH
- Child MeSH
- Humans MeSH
- Graft vs Host Disease * etiology MeSH
- Child, Preschool MeSH
- Transplantation Conditioning adverse effects MeSH
- Recurrence MeSH
- Thiotepa therapeutic use MeSH
- Hematopoietic Stem Cell Transplantation * adverse effects MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Child, Preschool MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Research Support, Non-U.S. Gov't MeSH
Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.
- MeSH
- Ki-67 Antigen metabolism MeSH
- Cell Differentiation * genetics MeSH
- Cell Lineage MeSH
- Histone Demethylases MeSH
- Humans MeSH
- Medulloblastoma * classification genetics pathology MeSH
- Metencephalon * embryology pathology MeSH
- Cerebellum embryology pathology MeSH
- Mutation MeSH
- Cerebellar Neoplasms * classification genetics pathology MeSH
- Hedgehog Proteins metabolism MeSH
- T-Box Domain Proteins metabolism MeSH
- Repressor Proteins MeSH
- Muscle Proteins MeSH
- Otx Transcription Factors deficiency genetics MeSH
- Core Binding Factor alpha Subunits genetics MeSH
- Transcription Factors MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.
- MeSH
- Anemia, Aplastic * therapy MeSH
- Anemia, Diamond-Blackfan * therapy MeSH
- Child MeSH
- Bone Marrow MeSH
- Humans MeSH
- Retrospective Studies MeSH
- Hematopoietic Stem Cell Transplantation * MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
PURPOSE: Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). RESULTS: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology therapy MeSH
- Busulfan administration & dosage analogs & derivatives MeSH
- Whole-Body Irradiation mortality MeSH
- Chemoradiotherapy mortality MeSH
- Child MeSH
- Etoposide administration & dosage MeSH
- Equivalence Trials as Topic MeSH
- Humans MeSH
- International Agencies MeSH
- Survival Rate MeSH
- Adolescent MeSH
- Follow-Up Studies MeSH
- Child, Preschool MeSH
- Prognosis MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Thiotepa administration & dosage MeSH
- Vidarabine administration & dosage analogs & derivatives MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.
- Publication type
- Journal Article MeSH
BACKGROUND: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. METHODS: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. RESULTS: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. CONCLUSIONS: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.
- MeSH
- Cisplatin adverse effects MeSH
- Child MeSH
- Pharmacogenomic Testing MeSH
- Pharmacogenomic Variants * MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Association Studies MeSH
- Risk Assessment MeSH
- Polymorphism, Single Nucleotide * MeSH
- Carboplatin adverse effects MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Neoplasms drug therapy MeSH
- Infant, Newborn MeSH
- Ototoxicity MeSH
- Hearing Loss, Sensorineural chemically induced genetics physiopathology MeSH
- Child, Preschool MeSH
- Cancer Survivors * MeSH
- Prospective Studies MeSH
- Antineoplastic Agents adverse effects MeSH
- Cross-Sectional Studies MeSH
- Retrospective Studies MeSH
- Risk Factors MeSH
- Hearing drug effects MeSH
- Organic Cation Transporter 2 genetics MeSH
- Age of Onset MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Europe MeSH
Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.
- Publication type
- Journal Article MeSH
