Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Clinical and Treatment History of Patients with Partial DiGeorge Syndrome and Autoimmune Cytopenia at Multiple Centers.

BACKGROUND: Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation. OBJECTIVES: Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC. METHODS: Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation. RESULTS: Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19hiCD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators. CONCLUSIONS: AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens.

SOCS1 Haploinsufficiency Presenting as Severe Enthesitis, Bone Marrow Hypocellularity, and Refractory Thrombocytopenia in a Pediatric Patient with Subsequent Response to JAK Inhibition.

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient's peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype.

Newborn tandem mass spectroscopy screening for adenosine deaminase deficiency.

BACKGROUND: Newborn screening (NBS) by means of T cell receptor excision circles (TREC) is now universal in the United States, Puerto Rico, and the Navajo Nation as a strategy to identify severe combined immunodeficiency (SCID) in newborns. Owing to the characteristics of adenosine deaminase (ADA) deficiency, a small but important number of cases can be missed by this screening. OBJECTIVE: To evaluate the results of the first year statewide NBS for ADA by means of dried blood spot NBS. METHODS: On October 7, 2019, the state of Michigan began screening newborn dried blood spots for ADA deficiency by means of the Neobase-2 tandem mass spectroscopy (TMS) kit. We report 1 known case of ADA deficiency in the 18 months before screening. We then reviewed the results of the first 2 years of TMS ADA screening in Michigan. RESULTS: There was 1 patient with ADA deficiency known to our centers in the 18 months before initiation of TMS ADA screening; this patient died of complications of their disease. In the first 2 years of TMS ADA NBS, 206,321 infants were screened, and 2 patients had positive ADA screen results. Both patients had ADA deficiency confirmed through biochemical and genetic testing. One patient identified also had a positive TREC screen and was confirmed to have ADA-SCID. CONCLUSION: In our first 2 years, TMS NBS for ADA deficiency identified 2 patients with ADA deficiency at negligible cost, including 1 patient who would not have been identified by TREC NBS. This report provides initial evidence of the value of specific NBS for ADA deficiency.

Histiocytic Neoplasms, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

Adjustments to pharmacologic therapies for hemophagocytic lymphohistiocytosis while on extracorporeal support.

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysregulatory syndrome characterized by severe inflammation and end-organ damage. Due to significant organ dysfunction, patients often require extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). In this report, we describe consideration for adjusting treatment in the context of extracorporeal organ support. We describe agents commonly used and dosing adjustments made in light of extracorporeal organ support. We report six cases that illustrate the feasibility of initiating standard HLH therapies in patients requiring these modalities.

Line Associated Thrombosis in Pediatric Patients With NF-κB Pathway Variants.

Our report explores the complex role that nuclear factor-kappa B (NF-κB) plays in thrombosis formation, inflammation, and immunity; while additionally demonstrating that patients with NF-κB pathway pathogenic variants appear to carry a substantial thrombotic risk, particularly when secondary thrombotic risk factors are present. We propose that prophylactic anticoagulation should be strongly considered in such patients during high-risk situations and provide additional hematologic management strategies for those with NF-κB pathway alterations. We hope our work also calls to attention the potential need for a broader assessment of venous thromboembolism risk in patients with immune dysregulation to better delineate which patient populations may benefit from anticoagulation prophylaxis.

Somatic mutations and clonal hematopoiesis in congenital neutropenia.

Severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS) are congenital neutropenia syndromes with a high rate of leukemic transformation. Hematopoietic stressors may contribute to leukemic transformation by increasing the mutation rate in hematopoietic stem/progenitor cells (HSPCs) and/or by promoting clonal hematopoiesis. We sequenced the exome of individual hematopoietic colonies derived from 13 patients with congenital neutropenia to measure total mutation burden and performed error-corrected sequencing on a panel of 46 genes on 80 patients with congenital neutropenia to assess for clonal hematopoiesis. An average of 3.6 ± 1.2 somatic mutations per exome was identified in HSPCs from patients with SCN compared with 3.9 ± 0.4 for healthy controls (P = NS). Clonal hematopoiesis due to mutations in TP53 was present in 48% (13/27) of patients with SDS but was not seen in healthy controls (0/17, P < .001) or patients with SCN (0/40, P < .001). Our SDS cohort was young (median age 6.3 years), and many of the patients had multiple TP53 mutations. Conversely, clonal hematopoiesis due to mutations of CSF3R was present in patients with SCN but was not detected in healthy controls or patients with SDS. These data show that hematopoietic stress, including granulocyte colony-stimulating factor, do not increase the mutation burden in HSPCs in congenital neutropenia. Rather, distinct hematopoietic stressors result in the selective expansion of HSPCs carrying specific gene mutations. In particular, in SDS there is enormous selective pressure to expand TP53-mutated HSPCs, suggesting that acquisition of TP53 mutations is an early, likely initiating event, in the transformation to myelodysplastic syndrome/acute myeloid leukemia in patients with SDS.

L-leucine improves anemia and growth in patients with transfusion-dependent Diamond-Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond-Blackfan Anemia Registry.

BACKGROUND: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, short stature, congenital anomalies, and cancer predisposition. Most cases are due to mutations in genes encoding ribosomal proteins (RP) leading to RP haploinsufficiency. Effective treatments for the anemia of DBA include chronic red cell transfusions, long-term corticosteroid therapy, or hematopoietic stem cell transplantation. In a small patient series and in animal models, there have been hematologic responses to L-leucine with amelioration of anemia. The study objectives of this clinical trial were to determine feasibility, safety, and efficacy of L-leucine in transfusion-dependent patients with DBA. PROCEDURE: Patients ≥2 years of age received L-leucine 700 mg/m2 orally three times daily for nine months to determine a hematologic response and any improvement in growth (NCT01362595). RESULTS: This multicenter, phase I/II study enrolled 55 subjects; 43 were evaluable. There were 21 males; the median age at enrollment was 10.4 years (range, 2.5-46.1 years). No significant adverse events were attributable to L-leucine. Two subjects had a complete erythroid response and five had a partial response. Nine of 25, and 11 of 25, subjects experienced a positive weight and height percentile change, respectively, at the end of therapy. CONCLUSIONS: L-leucine is safe, resulted in an erythroid response in 16% of subjects with DBA, and led to an increase in weight and linear growth velocity in 36% and 44% of evaluable subjects, respectively. Further studies will be critical to understand the role of L-leucine in the management of patients with DBA.

Neutropenia Is an Underrecognized Finding in Pediatric Primary Immunodeficiency Diseases: An Analysis of the United States Immunodeficiency Network Registry.

BACKGROUND: The frequency of neutropenia in pediatric primary immunodeficiency disorders (PIDDs) is unknown and potentially underappreciated. Our study aimed to determine the overall frequency and severity of neutropenia in children diagnosed with a PIDD entered in the United States Immunodeficiency Network (USIDNET) patient registry. PROCEDURE: Neutropenia data and demographic/clinical information from 1145 patients younger than 21 years of age was obtained from the USIDNET registry. RESULTS: Neutropenia is more common in PIDD patients entered within the USIDNET registry than previously appreciated. There was a >10% occurrence rate of neutropenia in all broad primary immunodeficiency categories as well as in nearly all individual PIDDs. Neutropenia frequency was greater in African American pediatric PIDD patients than in white or Asian patients. The degree of neutropenia did not associate with mortality in pediatric patients with a PIDD. CONCLUSION: Although our study did not assess the frequency of PIDD in patients presenting with neutropenia, the possibility of a primary immune disorder should be considered in patients with idiopathic neutropenia.

Provider Perceptions of Quality of Life, Neurocognition, Physical Well-being, and Psychosocial Health in Patients with Primary Immunodeficiency/Immune Dysregulation Conditions.

PURPOSE: Both pediatric and adult patients with a primary immunodeficiency/immune dysregulation (PID/PIDR) diagnosis report inferior quality of life (QOL) and patient-reported outcomes (PROs) as compared with their healthy peers. Recognition of the negative impact on QOL and PROs provides an opportunity for clinicians to intervene with supportive measures. However, provider perceptions of PID/PIDR patients' quality of life, physical well-being, psychosocial health and neurocognition, and access to supportive resources have yet to be systematically evaluated. METHODS: We report specialty providers' perception of the QOL and psychosocial and physical well-being of their pediatric and adult patients with PID/PIDR through the utilization of an online survey assessing QOL and the impact of disease or its associated treatment on their physical well-being, mental health, social relationships, neurocognition, and work/school performance. RESULTS: Clinicians trended towards believing adult PID/PIDR patients had worse overall QOL than children with PID/PIDR. Providers additionally identified their adult patients' QOL to be more deleteriously affected by co-morbidities than their pediatric patients. Clinicians distinguished anxiety and social relationships as the psychosocial aspects most often affected by a complex immunological diagnosis in all patients. Of physical health considerations, energy, rather than mobility or pain, was perceived to be more negatively influenced by PID/PIDR in both adult and pediatric patients. CONCLUSIONS: Knowledge of these clinician perceptions can affect communication of findings with patients, as well as ongoing management, and thus, it is important to understand these fully to improve healthcare delivery to, and clinical management of, these patients.

Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study.

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.

Fetal Hydrops Secondary to in utero Pancytopenia.

Nonimmune hydrops remains a challenge in the prenatal setting with many cases not having a clear etiology determined prior to birth. We present an unusual case of one fetus of a dichorionic twin pair presenting at 24 weeks' gestation with hydrops and fetal pancytopenia with complete absence of white cells of unknown etiology, as revealed by cordocentesis. Serial red blood cell transfusions resulted in resolution of hydrops and continuation of the pregnancy until 35 weeks' gestation. Pancytopenia was noted throughout gestation and persisted in the newborn period. Moreover, the T-cell receptor excision circle (TREC) assay, a newborn screening test for severe T-cell deficiency, was abnormal at birth. Further evaluation revealed detectable TRECs and normal response to lymphocyte mitogens indicating some preserved thymic and lymphocyte function. The affected child had spontaneous resolution of the pancytopenia, including her severe T-cell deficiency, by 10 weeks of life. There has been no recurrence as of 24 months of age. The self-resolving nature of the pancytopenia is an important feature of this case of nonimmune hydrops. The abnormal TREC assay at birth in the affected infant may help explain the discordant prenatal findings.

Ataxia Telangiectasia and Cancer Predisposition: Challenges in Management.

Immune dysregulation and predisposition to malignancies are critical comorbidities in children affected with ataxia telangiectasia. In addition, these children exhibit increased toxicity to conventional cancer therapy and dose reductions have been proposed to prevent life threatening adverse effects. These modifications to the treatment regimen may result in suboptimal outcomes for these patients. Our report of 3 children with ataxia telangiectasia and cancer highlight the immense challenges in the management of these children, underlining the need for the development of novel, biological agents with reduced acute and long-term side effects in the treatment of cancers in these children.

Making Improvements in the ED: Does ED Busyness Affect Time to Antibiotics in Febrile Pediatric Oncology Patients Presenting to the Emergency Department?

OBJECTIVES: Febrile neutropenic pediatric patients are at heightened risk for serious bacterial infections, and rapid antibiotic administration (in <60 minutes) improves survival. Our objectives were to reduce the time-to-antibiotic (TTA) administration and to evaluate the effect of overall emergency department (ED) busyness on TTA. METHODS: This study was a quality improvement initiative with retrospective chart review to reduce TTA in febrile children with underlying diagnosis of cancer or hematologic immunodeficiency who visited the pediatric ED. A multidisciplinary clinical practice guideline (CPG) was implemented to improve TTA. The CPG's main focus was delivery of antibiotics before availability of laboratory data. We collected data on TTA during baseline and intervention periods. Concurrent patient arrivals to the ED per hour served as a proxy of busyness. Time to antibiotic was compared with the number of concurrent arrivals per hour. Analyses included scatter plot and regression analysis. RESULTS: There were 253 visits from October 1, 2010 to March 30, 2012. Median TTA administration dropped from 207 to 89 minutes (P < 0.001). Eight months after completing all intervention periods, the median had dropped again to 44 minutes with 70% of patients receiving antibiotics within 60 minutes of ED arrival. There was no correlation between concurrent patient arrivals and TTA administration during the historical or intervention periods. CONCLUSIONS: Implementation of a CPG and process improvements significantly reduced median TTA administration. Total patient arrivals per hour as a proxy of ED crowding did not affect TTA administration. Our data suggest that positive improvements in clinical care can be successful despite fluctuations in ED patient volume.

Ringed sideroblasts in ß-thalassemia.

Symptomatic ß-thalassemia is one of the globally most common inherited disorders. The initial clinical presentation is variable. Although common hematological analyses are typically sufficient to diagnose the disease, sometimes the diagnosis can be more challenging. We describe a series of patients with ß-thalassemia whose diagnosis was delayed, required bone marrow examination in one affected member of each family, and revealed ringed sideroblasts, highlighting the association of this morphological finding with these disorders. Thus, in the absence of characteristic congenital sideroblastic mutations or causes of acquired sideroblastic anemia, the presence of ringed sideroblasts should raise the suspicion of ß-thalassemia.

Hospital discharges for fever and neutropenia in pediatric cancer patients: United States, 2009.

BACKGROUND: Fever and neutropenia (FN) is a common complication of pediatric cancer treatment, but hospital utilization patterns for this condition are not well described. METHODS: Data were analyzed from the Kids' Inpatient Database (KID), an all-payer US hospital database, for 2009. Pediatric FN patients were identified using: age ≤19 years, urgent or emergent admit type, non-transferred, and a combination of ICD-9-CM codes for fever and neutropenia. Sampling weights were used to permit national inferences. RESULTS: Pediatric cancer patients accounted for 1.5 % of pediatric hospital discharges in 2009 (n = 110,967), with 10.1 % of cancer-related discharges meeting FN criteria (n = 11,261). Two-fifths of FN discharges had a "short length of stay" (SLOS) of ≤3 days, which accounted for approximately $65.5 million in hospital charges. Upper respiratory infection (6.0 %) and acute otitis media (AOM) (3.7 %) were the most common infections associated with SLOS. Factors significantly associated with SLOS included living in the Midwest region (OR = 1.65, 1.22-2.24) or West region (OR 1.54, 1.11-2.14) versus Northeast, having a diagnosis of AOM (OR = 1.39, 1.03-1.87) or viral infection (OR = 1.63, 1.18-2.25) versus those without those comorbidities, and having a soft tissue sarcoma (OR = 1.47, 1.05-2.04), Hodgkin lymphoma (OR = 2.33, 1.62-3.35), or an ovarian/testicular tumor (OR = 1.76, 1.05-2.95) compared with patients without these diagnoses. CONCLUSION: FN represents a common precipitant for hospitalizations among pediatric cancer patients. SLOS admissions are rarely associated with serious infections, but contribute substantially to the burden of hospitalization for pediatric FN.