Adjuvant immune checkpoint inhibitor therapy may benefit pediatric patients with stage III melanoma and sentinel lymph node positivity: a case series.

Melanoma is the most common skin cancer in children. While the current literature establishes treatment protocols for adult-type melanoma, very few pediatric-specific studies exist, and children are often excluded from melanoma clinical trials2. We report a case series of 23 pediatric patients aged 2-20 years old diagnosed with melanoma at the University of Rochester Medical Center between 1/1/2011 and 1/1/2022. 9/23 patients were Stage III; all patients underwent wide local excision and 9 received adjuvant therapies. 2/23 (8.7%) patients had recurrence of their malignancy after therapy while 21/23 (91.3%) remained without disease progression; 1 patient died from unknown cause, but the rest are alive and currently without disease. All patients whose initial therapy included nivolumab in addition to wide local excision did not have recurrence or progression of their disease. This case series highlights trends in the presentation, treatment, and outcomes of pediatric melanoma; however, additional multi-center studies are needed to establish the clinical utility of such features in pediatric melanoma.

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium.

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. INTERPRETATION: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. FUNDING: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.

Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT.

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 µg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 µg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 µg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.

Association of crystalloid fluid infusion with intravascular hemolysis and organ dysfunction in hematopoietic stem cell transplant patients.

Endothelial cell activation and injury is common after hematopoietic stem cell transplant (HSCT) and is associated with many post-transplant complications. An underexplored mechanism of endothelial cell damage in this population is the infusion of normal saline (NS, 0.9 % sodium chloride) and other crystalloids, as NS use is associated with adverse outcomes in other patient populations. We hypothesized that the infusion of unbalanced crystalloids during HSCT may lead to changes in biomarkers commonly associated with red blood cell (RBC) hemolysis in patients before and after infusion, and that markers of endothelial and end-organ damage during admission may be associated with markers of hemolysis and total crystalloid use. Samples were collected from 97 patients. From pre-fluid infusion to post-fluid infusion, mean haptoglobin decreased (11.7 ug/ml vs 8.4 ug/ml; p < 0.0001), hemopexin decreased (549 vs 512 µg/ml; p = 0.005), and red cell distribution width (RDW) decreased (15.7 vs 15.6; p = 0.0009). During admission (mean 19.4 days, SD 9.9), all markers of tissue and organ damage, including mean creatinine, lactate dehydrogenase (LDH), blood urea nitrogen (BUN), total bilirubin, AST, and ALT, increased from admission to peak levels (p < 0.0001). On linear regression, fluid volume (ml/kg) of crystalloid infusion positively predicted post-fluid infusion cell-free hemoglobin (r(96) = 0.34, p < 0.0001), free heme (r(96) = 0.36, p < 0.0001), and peak LDH during admission (r(75) = 0.23, p = 0.041), and negatively predicted post-fluid infusion hemopexin (r(96) = - 0.34, p < 0.0001). Unbalanced crystalloids may contribute to hemolysis and endothelial damage in HSCT patients. Alternatives such as buffered crystalloid solutions (PlasmaLyte, Lactated Ringer's) may be worth investigating in this population.

Multi-institution analysis of tumor mutational burden and outcomes in pediatric central nervous system tumor patients.

BACKGROUND: Pediatric central nervous system (CNS) tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision-making. METHODS: We conducted a retrospective analysis of pediatric patients (age <21) diagnosed with a primary CNS tumor at four upstate New York hospitals from 2008 to 2021. Clinical and histopathologic data were identified from each patient, including genomic analysis of somatic mutations and tumor mutational burden (TMB) where available. These variables were each compared with overall survival using Cox regression analyses. Multivariable analysis was conducted to identify patient characteristics that may independently predict survival. RESULTS: We identified 119 patients. Common tumor types included low-grade glioma (N = 51), high-grade glioma (N = 29), and medulloblastoma (N = 11). Common driver mutations included TP53 inactivation (N = 16), BRAF-KIAA1549 fusion (N = 16), FGFR1 amplification (N = 12), BRAF V600E mutation (N = 12), NF1 loss (N = 12), and H3F3A K28M mutation (N = 6). Median TMB was one mutation/megabase (mut/Mb, range = 0-132). Overall survival was 79.9%. Variables associated with poorer survival on univariable analysis were higher TMB (p = .002, HR 4.97), high-grade tumors (p = .009, HR 84.3), and high-grade glioma histology (p = .021, HR 3.14). Multivariable analyses further identified TMB (p = .011, HR 4.46) and high-grade histology (p = .015, HR 5.28) as independently predictive of worse survival. Tumor progression was more common in high-TMB (N = 15, 44%) than in low-TMB tumors (N = 19, 35%). CONCLUSIONS: High TMB is correlated with higher rates of progression and death as compared to low-TMB tumors. These findings may help identify patients who may benefit from alternative treatments, such as immunotherapies.

The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions.

BACKGROUND: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. OBJECTIVE: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. METHODS: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. RESULTS: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). CONCLUSIONS: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

Allogeneic Bone Marrow Transplant as a Cure for Refractory T-Cell Large Granular Lymphocytic Leukemia in an Adolescent.

T-cell large granular lymphocytic (T-LGL) leukemia is a rare, typically indolent neoplasm with a median age of onset above 60 years. Pathogenesis involves clonal T-cell expansion, and nearly all reported pediatric cases have been associated with concurrent autoimmune disease. Immunosuppressive therapy often mitigates sequelae, but definitive cure is not routinely achieved. Here we present an otherwise healthy 13-year-old with T-LGL leukemia refractory to all standard treatments. Our patient ultimately underwent allogeneic bone marrow transplant (BMT) and is now stable in remission 3 years post-BMT. BMT may offer a viable definitive cure for refractory T-LGL leukemia in very young patients.

Adolescent and young adult (AYA) versus pediatric patients with acute leukemia have a significantly increased risk of acute GVHD following unrelated donor (URD) stem cell transplantation (SCT): the Children's Oncology Group experience.

Adolescent and young adult (AYA) patients with acute leukemia (AL) have inferior outcomes in comparison to younger patients, and are more likely to develop acute and chronic GVHD than younger children following HLA matched sibling donor stem cell transplant (SCT). We compared the incidence of grade II-IV acute GVHD, chronic GVHD, and survival in AYA (age 13-21 years) to younger children (age 2-12 years) who received an unrelated donor SCT for acute leukemia on Children's Oncology Group trials between 2004-2017. One hundred and eighty-eight children and young adults ages 2-21 years underwent URD SCT. Sixty-three percent were aged 2-12 and 37% were age 13-21. Older age was a risk factor for grade II-IV acute GVHD in multivariate analysis with a hazard ratio (HR) of 1.95 [95% confidence interval (CI) 1.23-3.10], but not for chronic GVHD, HR 1.25 [95% CI 0.57-2.71]. Younger patients relapsed more often (34.5 ± 4.4% vs. 22.8 ± 4.0%, p = 0.032), but their Event-Free Survival (42.6 ± 4.7% vs. 51.8 ± 6.1%, p = 0.18) and Overall Survival at 5 years (48.5 ± 4.9% vs. 51.5 ± 6.4%, p = 0.56) were not different than AYA patients. AYA patients who receive an URD SCT for acute leukemia are significantly more likely to develop grade II-IV acute GVHD, though survival is similar.

Successful Bone Marrow Transplantation With Intensive Post-transplant Intrathecal Chemotherapy for CNS Relapsed AML in 2 Infants.

BACKGROUND: Infant acute myeloid leukemia is a rare but aggressive form of leukemia. OBSERVATION: We report 2 children who presented with hyperleukocytosis, subsequently diagnosed with infant acute myeloid leukemia, and both developed isolated central nervous system relapse while on chemotherapy. Both infants underwent successful bone marrow transplantation with myeloablative conditioning (thiotepa, busulfan, and cyclophosphamide) without radiation, followed by 12 empiric post-transplant lumbar punctures with intrathecal cytarabine. Both patients tolerated these therapies well, and are without infections, chronic graft-versus-host disease, or any post-transplant sequelae. CONCLUSION: Nonradiation-based conditioning followed by empiric central nervous system-directed intrathecal chemotherapy may be considered for high-risk infants with leukemia.

Increased early mortality after fludarabine and melphalan conditioning with peripheral blood grafts in haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide.

Due to the evolving use of haploidentical donor grafts in hematopoietic cell transplantation, there is increased need to better understand the risks and benefits of using bone marrow versus peripheral blood grafts, as well as how specific pre-transplantation conditioning regimens impact patient safety and treatment outcomes. We performed a retrospective analysis of 38 patients at two centers who underwent haploidentical hematopoietic cell transplantation using fludarabine plus melphalan-based conditioning regimens with post-transplant cyclophosphamide and peripheral blood donor grafts. We observed an unexpectedly high rate of early non-relapse mortality and severe cytokine release syndrome. The poor outcomes with 1-year overall survival of 34%, disease-free survival of 29%, and non-relapse mortality of 34% motivate us to reconsider the appropriateness of the combination of fludarabine and melphalan conditioning with T-cell replete peripheral blood grafts in the setting of haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.

Use of Communication Technology to Improve Clinical Trial Participation in Adolescents and Young Adults With Cancer: Consensus Statement From the Children's Oncology Group Adolescent and Young Adult Responsible Investigator Network.

Adolescents and young adults (AYAs; age 15-39 years) with cancer are under-represented in cancer clinical trials because of patient, provider, and institutional barriers. Health care technology is increasingly available to and highly used among AYAs and has the potential to improve cancer care delivery. The COVID-19 pandemic forced institutions to rapidly adopt novel approaches for enrollment and monitoring of patients on cancer clinical trials, many of which have the potential for improving AYA trial participation overall. This consensus statement from the Children's Oncology Group AYA Oncology Discipline Committee reviews opportunities to use technology to optimize AYA trial enrollment and study conduct, as well as considerations for widespread implementation of these practices. The use of remote patient eligibility screening, electronic informed consent, virtual tumor boards, remote study visits, and remote patient monitoring are recommended to increase AYA access to trials and decrease the burden of participation. Widespread adoption of these strategies will require new policies focusing on reimbursement for telehealth, license portability, facile communication between electronic health record systems and advanced safeguards to maintain patient privacy and security. Studies are needed to determine optimal approaches to further incorporate technology at every stage of the clinical trial process, from enrollment through study completion.

Physician risk perceptions and surveillance practices for tyrosine kinase inhibitor long-term effects in pediatric CML.

Chronic myeloid leukemia (CML) is effectively treated with long-term tyrosine kinase inhibitor (TKI) therapy, yet little is known about risks of prolonged TKI exposure in young patients, and long-term effect monitoring is not standardized. We surveyed North American pediatric oncologists (n = 119) to evaluate perceived risk of and surveillance practices for potential toxicities associated with prolonged TKI exposure in children and adolescents/young adults (AYAs) with CML. Survey domains included general and specific risk perceptions and surveillance practices for asymptomatic patients on chronic TKI therapy. We analyzed data descriptively and explored relationships between risk perceptions and surveillance. Risk perceptions varied among oncologists but were similar across six categories (thyroid, cardiac, vascular, metabolic, fertility, psychologic), with less than one-third rating each risk as moderate or high in pediatric and AYA patients. More oncologists perceived moderate or high risk of growth abnormalities in children (62% pediatric, 14% AYA) and financial toxicity in all patients (60% pediatric, 64% AYA). A greater proportion of oncologists with moderate or high perceived risk of thyroid abnormalities reported testing thyroid function compared to those with lower perceived risk; patterns for metabolic risk/lipid tests and cardiac risk/tests were similar. In summary, we found that pediatric oncologists had variable risk perceptions and surveillance practices for potential toxicities associated with prolonged TKI exposure. Standardizing surveillance would help quantify risks and refine recommendations.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.2017085 .

Gene Expression and Survival of Acute Lymphoblastic Leukemia Cells After Allogeneic Transplant.

BACKGROUND/AIM: This study explored the mechanisms of the allogeneic graft versus leukemia effect in acute lymphoblastic leukemia (ALL) cells by examining whether they change gene expression in the post-transplant environment containing cytokines and the immunosuppressant cyclosporine, and if such changes affect ALL cell survival. MATERIALS AND METHODS: RNASeq was used to assess leukemia global gene expression and flow cytometry to measure ALL survival in the presence of T cells, NK cells, cytokines, and cyclosporine. RESULTS: A total of 4,805 genes were differentially expressed. Gene set enrichment analysis demonstrated up-regulation of biological processes related to cytokine responses, control of viral infection, and regulation of leukocyte function including proliferation. Down-regulated genes were related to mesenchymal tissue morphogenesis. ALL cells exposed to cytokines and cyclosporine retained susceptibility to T and NK cell killing, and also exhibited increased cell death without exposure to killer cells. CONCLUSION: A significant portion of the graft versus leukemia effect may be mediated by cytokines and cyclosporine.

Off-on-off-on use of imatinib in three children with fibrodysplasia ossificans progressiva.

The compassionate use of available medications with unproven efficacy is often in conflict with their clinical evaluation in placebo-controlled clinical trials. For ultra-rare diseases where no approved treatments exist, such as fibrodysplasia ossificans progressiva (FOP), routine clinical trial enrollment for available medications may be difficult to achieve. Therefore adaptive methods of evaluation are often desirable. Off-on-off-on (O4) approaches offer an opportunity to rapidly assess the potential symptomatic efficacy and tolerability of a medication with a limited number of patients and may aid in the design of more focused clinical trials that are amenable to enrollment. Here we report three children with classic FOP who had recalcitrant flare-ups of the back and who had been treated with an O4 regimen of imatinib. In all three children, fewer flare-ups, decreased swelling and improved function with activities of daily living were reported by the parents and treating physician when the children were "on" imatinib than when they were "off" imatinib. The median time to improvement on imatinib was 2-3 weeks. The anecdotal O4 experience with imatinib reported here in three children with FOP who had recalcitrant flare-ups of the back supports the design of a brief placebo controlled trial to assess the potential efficacy of imatinib in reducing the symptoms in children with refractory flare-ups of FOP. A tool to prospectively measure and quantitate flare-up symptoms is presently being developed and validated and will be used for such a study.

Myeloablative Carboplatin and Thiotepa With Autologous Stem Cell Rescue for Nonmedulloblastoma High-risk CNS Tumors in Young Children.

Malignant central nervous system (CNS) tumors in young children have a poor prognosis and pose a therapeutic challenge. We describe 11 patients with high-risk CNS tumors (6 atypical teratoid/rhabdoid tumor, 4 nonmedulloblastoma CNS embryonal tumors, and 1 glioblastoma multiforme) who received 32 consolidation cycles of myeloablative carboplatin/thiotepa followed by autologous peripheral blood stem cell rescue. All patients underwent successful stem cell harvest without significant complications. Mean time to absolute neutrophil count ≥0.5×103/µL was 10.2±1.3 days and the mean length of hospital stay was 15.7±3.0 days. There were no regimen-related deaths. Five-year event-free survival and overall survival were 45.5±15.0% and 58.4±16.3%, respectively. Tandem carboplatin/thiotepa consolidation with autologous stem cell rescue is well-tolerated in young children with nonmedulloblastoma CNS tumors.

Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers.

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.

Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.