Search

Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Purpose Malnutrition is a significant issue for pediatric patients with cancer. We sought to evaluate the effectiveness and complication rate of percutaneous endoscopic gastrostomy (PEG) placement in pediatric oncology patients. Methods A retrospective chart review was performed on 49 pediatric oncology patients undergoing PEG placement at Johns Hopkins All Children's Hospital between 2000 and 2016. Demographic and clinical characteristics, complications, absolute neutrophil count at time of PEG placement and at time of complications, length of stay, and mortality were identified. Weight-for-age Z-scores were evaluated at time of- and six months post-PEG placement. Results The overall mean weight-for-age Z-score improved by 0.73 (p

Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-tumor antibiotic conjugate with proven efficacy in pediatric and adult patients with CD33+ acute myeloid leukemia. Adverse effects commonly associated with GO include hyperbilirubinemia, elevated transaminases, and sinusoidal obstruction syndrome. Cardiotoxicity has not been a commonly described adverse event. We describe two pediatric patients with relapsed/refractory acute myeloid leukemia who received fractionated GO monotherapy and subsequently developed severe acute left ventricular dysfunction. Both patients achieved remission, recovered cardiac function with medical therapy, and tolerated subsequent stem cell transplantation.

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Clinical data surrounding cGVHD therapies in younger children are limited and critically needed. Primary endpoints were to determine the recommended pediatric equivalent dose (RPED) and assess pharmacokinetics (PK) and safety. Secondary endpoints included overall response rate (ORR; comprising complete response and partial response) according to the 2014 National Institutes of Health criteria at 24 weeks, overall survival, and duration of response (DOR). Here we present the primary results from the open-label, multicenter, international phase 1/2 iMAGINE study (PCYC-1146-IM), which evaluated the PK, safety, and efficacy of ibrutinib in patients age ≥1 to22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe cGVHD. Patients age12 years received once-daily ibrutinib starting at 120 mg/m

Mutations in the CBL gene were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to patients with other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found that this disease is highly diverse in presentation and overall outcome. Moreover, we discovered somatically acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish patients with somatic CBL mutations from those with germline CBL mutations, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among patients with germline CBL mutations. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.

Key Points 3D organoid T-cell differentiation from a few hundred peripheral blood CD34+ cells was successfully achieved. 3D organoid T-cell differentiation could help physicians distinguish intrinsic from extrinsic defects underlying a clinical SCID phenotype.

Juvenile myelomonocytic leukemia (JMML) typically requires allogeneic hematopoietic cell transplantation with full donor chimerism for cure. Certain genetic subtypes, including JMML due to germline mutations in CBL, can have a more indolent course. We describe a young male patient with CBL-related JMML who experienced primary graft failure after allogeneic hematopoietic cell transplantation. Despite autologous recovery, the resulting hematopoietic tissue did not harbor the original homozygous CBL mutations, due to reversion of prior loss of heterozygosity of the 11q chromosomal region. The patient remains disease free without further leukemia-directed therapy.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients

BACKGROUND Previous studies have explored posthematopoietic cell transplant (HCT) outcomes by race in adults; however, pediatric data addressing this topic are scarce. PROCEDURE This retrospective registry study included 238 White (W) and 57 Black (B) children with hematologic malignancies (HM) receiving first allogeneic HCT between 2010 and 2019 at one of the five Florida pediatric HCT centers. RESULTS We found no differences between W and B children in transplant characteristics, other than donor type. There was a significant difference in use of human leukocyte antigen (HLA)-mismatched donors (HLA-MMD) (53% W, 71% B, p = .01). When comparing HLA-MMD use to fully HLA-matched donors, B had relative risk (RR) of 1.47 (95% CI 0.7-3) of receiving a mismatched unrelated donor (MMUD), RR of 2.34 (95% CI 1.2-4.4) of receiving a mismatched related donor (MMRD), and RR of 1.9 (95% CI 0.99-3.6) of receiving a mismatched cord blood donor (MMCBD) HCT, respectively. There was no significant difference in the incidence of aGVHD (48% W, 35% B), p = .1, or cGVHD (19% W, 28% B, p = .1), or primary cause of death. Overall 24-month survival was 61% (95% CI 55%-68%) for W, and 60% (95% CI 48-75) for B children, log-rank p = .7. While HLA matching improved survival in W children, the number of B children receiving HLA-matched HCT was too small to identify the impact of HLA matching on survival. CONCLUSIONS In this contemporary cohort of children with HM, we found that B children were more likely to receive HLA-MMD transplants, but this did not adversely affect survival or GVHD rates.

BACKGROUND Bone marrow graft cell content impacts engraftment potential after allogeneic hematopoietic cell transplantation (alloHCT). Surrogates, such as intraoperative total nucleated cell count (ioTNC), are of unclear utility in predicting final graft characteristics. In addition, demographic and clinical factors may influence graft cellular profile and recipient engraftment. PROCEDURE We retrospectively reviewed marrow harvests at our institution performed between 2009 and 2019. During this time, an ioTNC was measured after 50% of the projected final graft volume was collected. Regression models were used to assess associations between ioTNC (cells/µL) and final graft CD34+ (cells/mL), and between graft and donor characteristics and final graft CD34+ (cells/mL). RESULTS Fifty-three marrow harvests and donor-recipient pairs were analyzed. Median (range) donor and recipient ages were 13 (0.7-28) years and 9 (0.2-21) years, respectively. The median ratio of donor/recipient weight was 1.225 kg (range 0.31-7.13). Median total volume of harvested marrow was 15.3 mL/kg (range 4.3-20.4) of donor weight and 19.4 mL/kg (range 4.7-87.4) of recipient weight. Median ioTNC was 20 930/µL (range 6600-44310) or 2.1 × 109 /mL, corresponding to median predicted final graft TNC of 3.59 × 108 /kg recipient weight (range 1.28-19.42 × 108 ). Simple linear regression between ioTNC and CD34+ cells/mL resulted in an R2 of 0.42. Least absolute shrinkage and selection operator (LASSO) regression produced a moderately predictive model consisting of ioTNC, donor age, and donor weight (adjusted R2 = 0.7) of final graft CD34+ cells/mL. CONCLUSIONS ioTNC and certain donor characteristics correlate moderately well with marrow product CD34+ cells/mL, potentially informing donor selection and marrow procurement strategies.

Allogeneic hematopoietic cell transplantation (alloHCT) using haploidentical donors (haploHCT) with post-transplantation cyclophosphamide (PTCy) for augmented graft-versus-host disease (GVHD) prophylaxis has emerged as a robust platform to expand donor options with acceptable levels of GVHD and graft failure. The mechanism by which PTCy mitigates GVHD risk is partly explained by preferential cytotoxicity based on aldehyde dehydrogenase levels and up-regulation of regulatory T cells, but is incompletely understood. Myeloid-derived suppressor cells are important mediators of T-cell function and are up-regulated by cyclophosphamide exposure. We hypothesized that this cell type may play a role in GVHD protection in children undergoing haploHCT/PTCy. We prospectively collected samples in the first month after alloHCT from children undergoing standard of care (SOC) alloHCT with matched donors and tacrolimus-based GVHD prophylaxis (N = 11) and PTCy recipients (N = 11). MDSC recovery was compared using flow cytometry, and MDSC suppressive function was assessed at the peak of MDSC quantitative recovery post-alloHCT. Groups were well matched for conditioning regimen and stem cell source. PTCy recipients exhibited more robust MDSC recovery, particularly polymorphonuclear-MDSCs than SOC recipients, with preservation of T-cell suppressive function. This corresponded to significantly lower incidence of Grade II to IV acute GVHD (9.1% versus 27.3%) and moderate/severe chronic GVHD (0% versus 27.3%) in PTCy recipients. Patients who developed GVHD had decreased MDSC-mediated T-cell suppression, as well as higher levels of IL-10, a cytokine closely linked to GVHD biology. Overall, these findings provide support for the role of MDSCs in mediating GVHD protection after PTCy-based haploHCT. © 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

FPBCC was formed in 2018 by five pediatric transplant programs in Florida. One of the key objectives of the consortium is to provide outcome analyses by combining HCT data from all the participating centers in order to identify areas for improvement. In this first FPBCC landscape report we describe the patient and transplant characteristics of pediatric patients undergoing first allo and auto HCT between 2014 and 2016 in Florida. The source of data was eDBtC of the CIBMTR. Over the span of 3 years, a total of 230 pediatric patients underwent allo-HCT and 104 underwent auto-HCT at the participating centers. The most significant predictor of survival in allo-HCT recipients with malignant disorders was the degree of HLA- match, while in the recipients of allo-HCT with non-malignant disorders the predictors of survival included age, donor relationship and degree of HLA match. Our analyses identified the need to improve reporting of primary cause of death and improve on donor selection process given that the degree of HLA match remains the most important predictor of survival. This first FPBCC-wide review describes the trends in pediatric HCT activity between 2014 and 2016 among the participating centers in Florida and confirms feasibility of using eDBtC data platform and collaborative approach in order to identify areas for improvement in outcomes.

PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study’s objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1− and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

BACKGROUND The optimal conditioning regimen for alloHCT in children with myeloid malignancies remains undefined. PROCEDURE We performed a retrospective review of children undergoing alloHCT for AML and MDS over a 10-year period (2008-2018) at our institution, comparing the outcomes of recipients of either a myeloablative busulfan- or reduced toxicity mel/thio-based conditioning regimen. RESULTS A total of 49 patients underwent alloHCT for AML/MDS (mel/thio, N = 21; busulfan, N = 28). Mel/thio recipients were selected due to pretransplant comorbidities. Recipients of mel/thio were more likely to have t-AML, and less likely to have MRD

Hemophagocytic lymphohistiocytosis (HLH), a rare but life-threatening condition characterized by uncontrolled inflammation, is increasingly recognized in adults. The management of adult onset HLH is challenging, in part due to gaps in current state of knowledge on etiology, clinical presentation, diagnosis, and management. HLH secondary to triggers such as infections, autoimmune disorders, and malignancy are more commonly seen in adults although cases of familial form have also been reported. Underlying conditions such as sepsis, or malignancy could pose as major confounders while applying universal diagnostic criteria, and therefore could lead to delay in diagnosis. Despite advent of newer therapeutic agents, outcomes of adults continue to remain poor. Future efforts need to be orchestrated to develop evidence-based tailored therapies to improve outcomes of this under recognized heterogeneous entity.

The unique needs of adolescent and young adult (AYA) oncology patients have been identified through research and well described in the literature.1–4 Defined as individuals aged 15–39 years, these patients benefit from age-appropriate multidisciplinary care with attention to psychosocial, fertility, financial, and physical effects of cancer, from diagnosis through survivorship. These are termed the pillars of AYA care. With the goal of improving outcomes for the 72,000 AYA patients diagnosed with cancer every year in the United States, AYA programs are being developed. Organizations such as Teen Cancer America (TCA, www.teencanceramerica.org) and Critical Mass (criticalmass.org) provide advocacy, collaboration, and resources for personnel, as well as physical space for AYA patients at major medical centers. Early reports of successful programs have been mitigated more recently by recognition of real barriers to successful program development, prompting an ongoing national dialogue. This article seeks to examine our institution's model and offer solutions to overcome real and perceived barriers to optimal AYA oncology care. Specifically, we examine our institution's model that involves a pediatric oncologist AYA champion employed within an adult cancer center, which we term the Immersive Model. This differs from other models that typically separate pediatric and adult oncology by building and department or medical group. Traditionally, AYA programs have been created to bridge the gap between pediatric and adult centers, often using acute lymphoblastic leukemia (ALL) care as a model. Pediatric oncologists would expand the age of patients seen upward, to provide direct care or participate in tumor boards with adult medicine colleagues. There is a data-driven consensus in the pediatric oncology community that so-called pediatric-inspired regimens improve outcomes for AYA patients compared with standard adult approaches for ALL and a perception that the medical oncology world has been slow to universally adopt these regimens with variation in levels of adoption across centers.5–8 Controversy regarding the optimal treatment for ALL continues at many centers, causing AYA program growth to be hindered. Moffitt Cancer Center (MCC) is a National Cancer Institute-designated Comprehensive Cancer Center based in Tampa, Florida that is uniquely organized by multidisciplinary disease teams rather than the more traditional model of departments of medicine, surgery, and other specialties. Thus, it is common for physicians to report to chairs with different, medical, or surgical, for example, board certifications and training than their own. The AYA program at MCC is led by a pediatric oncologist who reports directly to the chair of the Sarcoma Program, who is a surgical oncologist. MCC does not have a pediatric oncology practice and does not routinely care for patients under 15 years of age, although disease-specific expertise may be provided on a case-by-case basis, with administrative approval. MCC sees ∼16,000 new patients each year, with over 1500 of these new patients ranging from 15 to 39 years of age. This means that 100–125 unique AYA patients visit MCC each day, and 10% of inpatient beds are occupied by AYA patients. This volume prompted an administrative decision to contribute hospital resources to AYA patients, with coordinator support. Clinically, the Immersive Model began at MCC with a pediatric oncologist from All Children's Hospital providing care to sarcoma patients up to 40 years of age with select diagnoses. The program continues to collaborate with Johns Hopkins All Children's Hospital in a variety of ways, including several ongoing research collaborations and multiple physicians with clinical privileges at both facilities. Other groups, bringing broad and necessary expertise, began participating in the program (Fig. 1). MCC has grown to a multidisciplinary AYA Committee that is structured with five subcommittees that focus on: fertility, research, patient education, social events, and psychosocial issues. The entire group meets monthly in an open forum to share communication and discuss opportunities, provide updates on new and ongoing committee initiatives, and review factors that facilitate and obstruct local AYA care. Open in a separate window FIG. 1. AYA Program Organizational Chart: The AYA program incorporates many disciplines and areas of expertise together across traditional cancer center departments. AYA, adolescent and young adult.

Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy indicated in the USA for treatment of patients up to 25 years (y) of age with B-cell ALL that is refractory or in second or later relapse. Overall response rate was 82% with 24 months' (mo) follow-up in the registrational ELIANA trial [Grupp et al. Blood 2018]; pooled data from ELIANA and ENSIGN revealed similar outcomes upon stratification by age ( Methods: This noninterventional prospective study used data from the CIBMTR registry and included patients aged ≤25y with R/R ALL. Eligible patients received commercial tisagenlecleucel after August 30, 2017, in the USA or Canada. Age-specific analyses were conducted in patients aged Results: As of October 30, 2020, data from 451 patients were collected, all of whom received tisagenlecleucel. The median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25-34). Patients aged ≥18y appeared to have greater disease burden at baseline than those aged In the efficacy set (median follow-up 21.5mo; range 11.9-37.2; N=322), BOR of CR was 87.3% (95% CI 83.1-90.7); MRD status was available for 150 patients, of whom 98.7% were MRD negative. Median DOR was 23.9mo (95% CI 12.3-not estimable [NE]), median EFS was 14.0mo (9.8-24.8) and median RFS was 23.9mo (13.0-NE); 12mo EFS and RFS were 54.3% and 62.3%, respectively. For OS, the median was not reached. Efficacy outcomes were generally similar across age groups (Table 1). In the safety set (median follow-up 20.0mo; range 2.6-37.2; N=400), most AEs of interest occurred within 100 days of infusion. Any-grade CRS was observed in 58.0% of patients; Grade ≥3 in 17.8%. Treatment for CRS included tocilizumab (n=113; 28.3% of all patients) and corticosteroids (n=31; 7.8%). Neurotoxicity was observed in 27.3% of patients; Grade ≥3 in 10.0%. Treatment for neurotoxicity included tocilizumab (n=17; 4.3% of all patients) and corticosteroids (n=28; 7.0%). During the reporting period, 82 (20.5%) patients died; the most common cause of death was recurrence/persistence/progression of primary disease. CRS and chimeric antigen receptor (CAR)-T cell-related encephalopathy syndrome were the primary cause of death in 2 patients and 1 patient, respectively. Overall, safety data were similar across age groups, although more patients aged ≥18y experienced any-grade CRS or neurotoxicity and were subsequently treated (Table 1). Conclusions: Updated registry data for pediatric and young adult patients with R/R ALL treated with tisagenlecleucel revealed that patients aged ≥18y had a greater disease burden and were more heavily pre-treated at baseline than patients aged Figure 1 Figure 1. Disclosures Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Margossian: Cue Biopharma, Inc.: Current Employment; Novartis: Other: Ad hoc Advisory Boards. Nikiforow: Kite/Gilead: Other: Ad hoc advisory boards; Novartis: Other: Ad hoc advisory boards; Iovance: Other: Ad hoc advisory boards; GlaxoSmithKline (GSK): Other: Ad hoc advisory boards. Martin: Novartis: Other: Local PI for clinical trial; Bluebird Bio: Other: Local PI for clinical trial. Rouce: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Pfizer: Consultancy. Tiwari: Novartis Healthcare private limited: Current Employment. Redondo: Novartis: Current Employment. Willert: Novartis: Current Employment. Agarwal: Novartis Pharmaceutical Corporation: Current Employment, Current holder of individual stocks in a privately-held company. Pasquini: Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Kite, Vertex, and Servier: Research Funding; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding.

BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.

Pediatric chronic graft-versus-host disease (cGvHD) contributes to poor quality of life and increased morbidity and mortality in long term survivors of hematopoietic stem cell transplant (HSCT). Given the insidious nature of cGvHD, diagnosing cGvHD in children according to the National Institutes of Health Consensus Criteria (NIH-CC) can be challenging, particularly in the early phase of disease development. Diagnostic cGvHD biomarkers could aid in diagnosis. The Applied Biomarkers of Late Effects / Pediatric Blood and Marrow Transplant Consortium (ABLE / PBMTC 1202) study was a prospective, multi-institution study at 27 pediatric HSCT centers that evaluated biomarkers of cGvHD. Detailed clinical evaluation of cGvHD, including central adjudication when necessary, occurred as per the NIH-CC. Of the 302 enrolled children, 233 were included in this diagnostic cGvHD biomarker analysis, including 43 with cGvHD and 190 non-cGVHD controls. Peripheral blood was drawn into a STRECK tube at the onset of cGvHD and before escalation of immune suppression, sent overnight to a central laboratory, and evaluated by flow cytometry. Five flow cytometric antibody panels consisting of 76 combinations of cell surface markers were used to delineate subpopulations of T, Regulatory T (Tregs, CD4+CD127LowCD25+), B, NK, and myeloid cells. We analyzed each marker in two ways. First, to control for normal post-HSCT immune reconstitution, we divided cGvHD subjects into early- (day 0-120), mid- (day 121-240), and late-onset (>day 240) and compared their marker values against non-cGVHD controls at day 100, 6-months, and 12-months, respectively, using fixed effect linear regression models. Second, we compared the marker values of all cGvHD subjects at diagnosis against the marker values of non-cGvHD controls at all three time points and used mixed effect linear regression models to account for within-subject correlations. A cellular subpopulation was considered a clinically relevant and potential diagnostic cGvHD biomarker if all 4 criteria were met: a) the effect ratio (mean marker value of cGvHD subjects over non-cGvHD controls) was ≥1.3 or ≤0.75, b) the p-value was ≤.05, c) the receiver-operating characteristic area under the curve was ≥0.60, and d) the marker was detected by both the mixed effect model and in the same direction across all measurement time points in the fixed effect models. Using these criteria, 8 cellular subpopulations arose as potential diagnostic biomarkers of pediatric cGvHD (Table). Key subsets identified in cGvHD patients included decreased proportions of naïve helper T cells (CD4+CD45RA+, PD1-CD4+CD45RA+, CCR7+CD4+CD45RA+, CD27+CD4+CD45RA+), decreased naïve and recently emigrated Tregs (CD31+CD45RA+, PD1-CD45RA+), and decreased non-cytolytic regulatory NK cells (CD56BrightCD335High, CD56BrightPerforinLow). CD4+ recent thymic emigrants (CD4+CD31+CD45RA+), markers of thymopoeisis, were also significantly decreased in cGvHD (p=0.01) but did not meet all the required biomarker criteria. Evaluation of specific subsets of pediatric cGvHD showed that CD21LowCD19+ B cells were lower in patients with pulmonary (n=12) compared to a mucocutaneous predominant phenotype (n=31) (p=0.048). Cases of progressive cGvHD (n=18), characterized by concurrent acute GvHD features (overlap syndrome), had decreased proportions of CD19 B cells, T3 transitional B cells (CD38LowCD10-) and mature naïve B cells (IgD+CD27-), decreased naïve helper T cells (CCR7+CD4+CD45RA+) and increased activated NK cells (CD56dimCD69+) (all p Using a well characterized cohort of pediatric patients with cGvHD, the ABLE / PBTMC 1202 study showed that a variety of subpopulations of naïve helper T cells, Tregs, and regulatory NK cells were associated with cGvHD. Additional B-cell markers were associated with progressive cGvHD in children. These data support alterations in thymopoeisis and decreases in regulatory T- and NK-cell populations underlying pediatric cGvHD. Future work includes the addition of non-cellular plasma markers into a clinically applicable diagnostic biomarker algorithm to aid clinicians in the accurate diagnosis of pediatric cGvHD, as well as further validation in the ABLE 2.0 / Pediatric Transplant Cellular Therapy Consortium 1901 study. Disclosures Wahlstrom: Pharmacyclics: Current Employment. Pulsipher:Mesoblast: Honoraria; Adaptive: Research Funding; Miltenyi: Honoraria, Research Funding; Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria.

IntroductionInflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.MethodsWe collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.ResultsForty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2years following allogeneic HCT.ConclusionsIn this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

Key Points Constitutional mismatch repair deficiency syndrome should be considered in children with acute leukemia and characteristic skin lesions. The high mutation burden of CMMRD-related cancers contributes to treatment resistance, necessitating individualized treatment strategies.

In the era of newborn screening (NBS) for severe combined immunodeficiency (SCID) and the possibility of gene therapy (GT), it is important to link SCID phenotype to the underlying genetic disease. In western countries, X-linked interleukin 2 receptor gamma chain (IL2RG) and adenosine deaminase (ADA) deficiency SCID are two of the most common types of SCID and can be treated by GT. As a challenge, both IL2RG and ADA genes are highly polymorphic and a gene–based diagnosis may be difficult if the variant is of unknown significance or if it is located in non-coding areas of the genes that are not routinely evaluated with exon-based genetic testing (e.g., introns, promoters, and the 5′and 3′ untranslated regions). Therefore, it is important to extend evaluation to non-coding areas of a SCID gene if the exon-based sequencing is inconclusive and there is strong suspicion that a variant in that gene is the cause for disease. Functional studies are often required in these cases to confirm a pathogenic variant. We present here two unique examples of X-linked SCID with variable immune phenotypes, where IL2R gamma chain expression was detected and no pathogenic variant was identified on initial genetic testing. Pathogenic IL2RG variants were subsequently confirmed by functional assay of gamma chain signaling and maternal X-inactivation studies. We propose that such tests can facilitate confirmation of suspected cases of X-linked SCID in newborns when initial genetic testing is inconclusive. Early identification of pathogenic IL2RG variants is especially important to ensure eligibility for gene therapy.

Background Oral mucositis (OM) occurs in up to 70-80% of children undergoing myeloablative conditioning during hematopoietic cell transplant (HCT). OM has various negative clinical sequelae; therefore, efforts to prevent this common transplant complication have important potential clinical benefits. The keratinocyte growth factor, palifermin, stimulates the proliferation of mucosal cells and may be protective against the development of OM when administered to patients receiving regimens containing total body irradiation (TBI) or alkylating agents. Methods We performed a retrospective review of children (up to age 21 years) undergoing autologous or allogeneic HCT who received palifermin in the peri-transplant period over a 5-year period (2014-2018) at our institution. Subjects were included if they received TBI (≥12 Gy) or multiple alkylating agents (including melphalan) as part of their conditioning regimen. The recommended dosing is 60 mcg/kg/day intravenously 3 days before conditioning and 3 doses post-HCT on days 0, +1, +2. We excluded children who completed the pre-transplant palifermin doses greater than 48 hours prior to initiation of the conditioning regimen and those who did not receive all 6 planned doses. The primary outcome was the incidence, severity, and duration of mucositis. Secondary outcomes included the need for supportive care measures such as parenteral nutrition (PN) and patient controlled analgesia (PCA) use. We also examined the cost associated with palifermin use. Results A total of 44 children were evaluated. Ten children were excluded due to inappropriate palifermin dosing, two were excluded for infectious complications that resulted in aborting the preparative regimen, and two had incomplete data during chart review. Thirty remaining evaluable subjects were included in the full analysis. The most common chemotherapy-only conditioning regimens were carboplatin/etoposide/melphalan (n=8) and fludarabine/melphalan/thiotepa (n=7); 12 patients received TBI. Twenty-two patients (73.3%) developed Grade 3 or 4 mucositis (Grade 3, n=17; Grade 4, n=5). The median duration of mucositis, PN use, and PCA were 15 days (IQR 10-20), 18 days (IQR 13-25), and 10.5 days (IQR 7-16), respectively. The median hospital length of stay was 33 days (IQR 27-45). When subjects who were excluded due to inappropriate dosing were included in the analysis, there were no significant changes in the primary and secondary outcome measures. The average cost of palifermin per patient is approximately $15,350, translating to $135,080 of additional overall charges annually. Conclusion Despite the use of palifermin, the incidence of severe OM was high in our pediatric population. Given concerns regarding cost and questionable efficacy, the role of palifermin in HCT supportive care remains uncertain.

Background The prognosis of children who relapse after allogeneic hematopoietic cell transplant (alloHCT) for myeloid malignancies remains poor. Procedure To describe the safety and feasibility of post-transplant azacitidine for relapse prevention, we retrospectively reviewed the charts of 18 children undergoing alloHCT for myeloid malignancies. Results There were 15 evaluable patients since three patients did not receive planned azacitidine due to early relapse or TRM. Azacitidine (32 mg/m2 /dose for 5 days, in 28-day cycles as tolerated up to 1 year post-transplant) was started at a median of 66 days post-transplant (range 42-118). Two-thirds (10/15) of patients received eight or more cycles. Five patients stopped therapy early, only one attributable to toxicity. Mild myelosuppression was the most common reason for cycle delays. Dose modifications were made in three patients. There were three relapses, two of which occurred in patients in CR2 and one in CR1, with a median follow-up of 20 months (range 12.5-28), and no TRM in patients who received azacitidine. Conclusions Post-transplant azacitidine in children is safe and feasible, with most patients successfully receiving all planned cycles. Despite the limitations of a small cohort, low relapse incidence suggests a potential benefit in disease control that warrants further investigation.