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Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children's Oncology Group cellular therapy-based trials advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T-cell depletion is used, and the depth of remission as measured by next-generation sequencing-based minimal residual disease assessment pretransplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease., (© 2023 Wiley Periodicals LLC.)

Background: Recent data show survival after matched unrelated donor (MUD) bone marrow transplantation (BMT) is similar to matched sibling procedures for young patients with severe aplastic anemia (SAA). Donor delays, risk of transplant-related mortality (TRM), and concern about chronic graft versus host disease raise questions about whether MUD BMT or immune suppression therapy (IST) should be preferred initial therapy for young patients lacking matched sibling donors., Procedure: We performed a pilot trial to assess the feasibility of randomizing patients under age 26 with newly diagnosed SAA to receive IST versus MUD BMT. Primary aims assessed the acceptability of randomization and timing of BMT. Secondary aims measured toxicities, response, and survival., Results: Sixty-seven patients with possible SAA were screened at nine centers. Of 57 with confirmed SAA, 23 underwent randomization and received therapy with a median follow-up of 18 months. Of 12 randomized to BMT, 10 started BMT as initial therapy at a median of 36 days after randomization. One BMT recipient experienced secondary graft failure, requiring a second procedure. Six of 11 randomized to IST responded, whereas five with refractory disease underwent successful salvage BMT. One patient achieving complete response relapsed after discontinuation of immune suppression and died of infection after salvage BMT., Conclusions: This feasibility study showed that a high percentage of patients underwent randomization and received up-front MUD BMT. Our study lays the groundwork for a larger randomized trial that will define best initial therapy for young patients with SAA who have an available MUD., (© 2020 Wiley Periodicals, Inc.)

A pediatric patient diagnosed initially with B-lymphoblastic leukemia (B-ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T-cell (CAR-T) therapy and hematopoietic stem cell transplant. A TCF3-ZNF384 fusion was identified at diagnosis, persisted through B-ALL relapse, and was also present in the AML relapse cell population. ZNF384-rearrangements define a molecular subtype of B-ALL characterized by a pro-B-cell immunophenotype; furthermore, ZNF384-rearrangements are prevalent in mixed-phenotype acute leukemias. Lineage switch following CAR-T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion., (© 2018 Wiley Periodicals, Inc.)

We report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. Seventy-eight percent of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease-free survival (DFS) was 24% at a median of 3 years. Post-transplant leukemic relapse was more frequent than expected for children with DS-ALL (54%) than for non-DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS-ALL., (© 2014 Wiley Periodicals, Inc.)

The role of SCT in pediatric oncology has continued to evolve with the introduction of new therapeutic agents and immunological insights into cancer. COG has focused its efforts on the study of hematopoietic stem cell transplantation in the treatment of pediatric malignancies in several major multi-institutional Phase II and Phase III studies. These studies include addressing the impact of allogenicity in ALL (ASCT0431), and establishing autologous stem cell transplant as the standard of care in neuroblastoma. Reducing transplant-associated toxicity was addressed in the ASCT0521 study, where the TNFα inhibitor etanercept was tested for the treatment of idiopathic pneumonia syndrome. Impact of cell dose was explored in the single versus tandem umbilical cord blood study CTN-0501, in close collaboration with the BMT-CTN., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Granulocyte colony stimulating factor (G-CSF) is used for collection of hematopoietic cells in most adult and a smaller but significant percentage of pediatric normal donor harvests. Short and long-term risks of G-CSF administration and leukopheresis are not well understood in the pediatric population., Procedure: Literature review including observations from the IBMTR, NMDP, EBMT, German Donor Registry, and the authors' work., Results: G-CSF causes temporary discomfort in a minority of younger donors. Rare serious side effects of G-CSF have yet to be reported in children. To date, an increase in hematological malignancies after short-term G-CSF use has not been detected in adult donors and no cases have been reported in children. Reported complications of leukopheresis in children are rare and minor, but donors <20 kg may be exposed to allogeneic blood products. Pediatric aged donors vary widely in their ability to assent or consent to the risks of a donation procedure. There are key regulations and ethical imperitives, which must be addressed in deciding which donation procedures are appropriate for minors., Conclusions: While short term administration of G-CSF and leukopheresis appear to be safe and effective procedures when used to assist in collection of a hematopoietic cell graft from a normal pediatric donor, institutions adding or substituting one or both of these procedures for standard marrow donation must decide whether the donor should be considered a research subject, and if so, whether the new procedures are a minor increase over minimal risk. Because these procedures are being performed on and off study at many pediatric centers, a comprehensive study addressing donor safety could help clarify risks of rare adverse events.

Preliminary studies indicate that G-CSF-primed marrow harvesting may result in a graft with increased mononuclear cells collected, increased CD34(+) stem and progenitor cell dose and a potential for more rapid engraftment. Increased cell dose plus other potential positive effects of G-CSF priming have resulted in improved survival in non-randomized preliminary studies. These benefits may be available without the increased risk of chronic graft versus host disease (GVHD) that is experienced with allogeneic peripheral blood stem cell (PBSC) transplant. A phase III Children's Oncology Group (COG)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) trial comparing G-CSF-primed marrow to standard marrow has been proposed. This document reviews background studies of G-CSF-primed marrow and addresses benefits and risks of G-CSF administration to normal pediatric donors. We conclude that the approach is promising and warrants further study. Risks of G-CSF to the donor are minimal and benefits to both donor and recipient may occur.

Background: Long-term survival of pediatric patients with chronic myelogenous leukemia (CML) receiving myeloablative hematopoietic stem cell transplantation from fully-matched related and unrelated donors has been reported between 60 and 75%, but is associated with significant morbidity. Imatinib mesylate (STI-571, Gleevec) and reduced intensity conditioning stem cell transplantation (RIC) are two promising new tools that offer potential for decreasing therapy associated morbidity for patients with CML., Results: Large trials have shown significant responses in chronic phase patients treated with imatinib and reasonable but short-lived responses in advanced phase CML. Data from adult studies is beginning to define populations likely to progress or have prolonged responses to imatinib, and some adult treatment paradigms are moving toward reserving transplantation until patients are at risk of failure with imatinib. Early trials of RIC transplantation in CML show decreased transplant related morbidity with efficacy similar to conventional transplantation, but the approach has yet to be verified in phase III studies. Data in pediatric patients with imatinib and RIC transplantation is limited., Conclusions: Studies with imatinib are underway in pediatrics, but whether pediatric dosing schemes will lead to outcomes similar to adults is unknown. Because HLA-matched myeloablative transplantation offers a high rate of cure in the pediatric population, clinical studies assessing the role of imatinib mesylate and RIC transplantation should be planned carefully in order to avoid sub-optimal outcomes., (Copyright 2004 Wiley-Liss, Inc.)