Predicting relapsed/refractory disease in childhood hemophagocytic lymphohistiocytosis based on clinical features at diagnosis: A 13-year single-institute retrospective study in Thailand.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. Relapsed/refractory disease is the main cause of death. This study aims to determine the prognostic indicators for relapsed/refractory disease in childhood HLH (R/R HLH). Infants and children under 18 years of age who were diagnosed with HLH according to HLH-2004 criteria, MAS-HLH criteria for rheumatologic diseases, or H-score undergoing treatment in Chiang Mai University hospital between 2010 and 2022 were included. Demographic data, clinical characteristics, and laboratory parameters were retrospectively reviewed. Out of 86 childhood HLH cases, 30 patients (34.9%) experienced R/R HLH. All patients with primary HLH developed R/R HLH. The most common form of secondary HLH was infection-associated hemophagocytic syndrome (IAHS), comprising 43 cases. Of these, 37.2% had relapsed or refractory disease. Univariable analysis identified several potential risk factors for R/R HLH, including younger age, severe disease status, higher HLH-2004 criteria scores, higher H-scores, overt DIC, higher pSOFA scores, and increased levels of aspartate aminotransferase, total bilirubin, and direct bilirubin. Multivariable logistic regression analysis revealed that a pSOFA score of ≥ 8 and age < 3 years were independent risk factors for R/R HLH, with adjusted odds ratios of 6.35 (95% confidence interval [CI], 1.18-34.19; P = 0.032) and 3.62 (95% CI, 1.04-12.63; P = 0.044), respectively. Children with HLH who have a pSOFA score of ≥ 8, or are younger than 3 years, are at a higher risk of relapsed or refractory disease. Further evaluation of management strategies in this context is warranted.

Rotational Thromboelastometry and Clot Waveform Analysis as Point-of-Care Tests for Diagnosis of Disseminated Intravascular Coagulation in Critically Ill Children in Thailand.

OBJECTIVES: This study aimed to determine the test performances of rotational thromboelastometry (ROTEM) and activated partial thromboplastin time-based clot waveform analysis (aPTT-CWA) compared with the International Society on Thrombosis and Hemostasis disseminated intravascular coagulation (ISTH-DIC) score for diagnosis of overt disseminated intravascular coagulation (ODIC) in critically ill children. Prognostic indicators of DIC complications were also evaluated. DESIGN: A prospective cross-sectional observational study was conducted. ROTEM and aPTT-CWA were assessed alongside standard parameters based on the ISTH-DIC score and natural anticoagulants. Both conventional and global hemostatic tests were repeated on days 3-5 for nonovert DIC. SETTING: PICU of the Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. SUBJECTS: Infants and children who were admitted to PICU with underlying diseases predisposed to DIC, such as sepsis, malignancy, major surgery, trauma, or severe illness, were included in the study between July 1, 2021, and November 30, 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-four children were enrolled in this study. The prevalence of ODIC was 20.3%. Regarding ROTEM parameters, using EXTEM clot formation time (CFT) cutoff of greater than 102 seconds provided sensitivity and specificity of 90.9% and 80.9%, respectively, for diagnosing ODIC, with the area under the curve (AUC) of 0.86. In the case of aPTT-CWA performance, no biphasic waveform was observed, whereas both maximum coagulation acceleration (Min2) of less than 0.35%/s 2 and maximum coagulation deceleration of less than 0.25%/s 2 demonstrated identical sensitivities of 76.9% and specificities of 79.6%. Combining two global hemostatic tests significantly improved the diagnostic performance (INTEM CFT + EXTEM CFT + Min2 AUC 0.92 [95% CI, 0.80-1.00] vs. EXTEM CFT AUC 0.86 [95% CI, 0.75-0.96], p = 0.034). Bleeding was the most common consequence. In multivariable logistic regression analysis, Min2 of less than 0.36%/s 2 was an independent risk factor for bleeding complications, with an adjusted odds ratio of 15.08 (95% CI, 1.08-211.15, p = 0.044). CONCLUSIONS: ROTEM and aPTT-CWA were valuable diagnostic tools in critically ill children who might require point-of-care tests. Min2 showed significant clinical implications for predicting bleeding events in this population.

Predictive factors for L-asparaginase hypersensitivity in pediatric acute lymphoblastic leukemia.

BACKGROUND: L-Asparaginase is a crucial component of acute lymphoblastic leukemia (ALL) treatment. However, hypersensitivity is a common adverse event. This study aimed to identify risk factors for L-asparaginase hypersensitivity in childhood ALL. METHODS: Children treated for ALL at Chiang Mai University Hospital, Thailand, between 2005 and 2020 were included. Demographic data, clinical characteristics, and factors related to L-asparaginase were retrospectively reviewed. RESULTS: L-Asparaginase hypersensitivity was observed in 24 of 216 children with ALL (11.1%). All patients received native L-asparaginase intramuscularly, and events occurred exclusively during the post-induction phase without concurrent corticosteroid use. Univariable analysis showed that relapsed ALL, higher accumulated doses, increased exposure days, and longer interval between drug administrations were potential risk factors. In multivariable logistic regression analysis, interruption of L-asparaginase administration for ≥ 52 weeks and exposure duration of ≥ 15 days were independent risk factors, with adjusted odds ratio of 16.481 (95% CI 3.248-83.617, p = 0.001) and 4.919 (95% CI 1.138-21.263, p = 0.033), respectively. CONCLUSIONS: Children with ALL who require re-exposure to L-asparaginase after 52-week interruption or who have received L-asparaginase for ≥ 15 exposure days are at risk of developing L-asparaginase hypersensitivity. Further management strategies in this setting should be evaluated.

Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis.

Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, ten of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male sex (P=0.03) and age <18 years (P=0.04) were associated with HLH, corresponding to the inverse correlation between age and HLH-2004 score (r=-0.40; P=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02). Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively. Patients with male sex and/or germline HAVCR2 mutations showed an increased risk of developing HLH. Younger patients tended to manifest with HLH, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.

Treatment modalities of ALK-positive relapsed/refractory inflammatory myofibroblastic tumor of the brain and lungs in 7-year-old girl: case-based reviews.

PURPOSE: Inflammatory myofibroblastic tumor (IMT) belongs to mesenchymal neoplasm of intermediate malignancy in WHO classification. Primary CNS disease or CNS metastases (CNS-IMT) occur in minority. We describe a case of relapsed/refractory IMT of lungs with multiple brain metastases in young child who achieved long-term complete response after alectinib. This systematic review also summarizes treatment modalities and outcome of children and adolescent with CNS-IMT. METHODS: PRISMA 2020 guideline was applied to select an article from PubMed, Scopus, and Cochrane databases without time limits. This review focused on children and adolescent 0-24 years of age with CNS-IMT or inflammatory pseudotumor (CNS-IPT). The clinical characteristics and treatment outcome were explored. RESULTS: A total of 51 patients in 49 publications were identified. Median age of patients with CNS-IMT/IPT was 15-year-old and 60.8% were male. The most common location of tumor was cerebral cortex (54.9%). Complete resection of CNS-IMT/IPT was performed in 27 cases with 100% complete response and 18.5% recurrence. Nearly half of patients who received partial resection without adjuvant therapy experienced progressive disease, while the contrast group totally achieved partial response. Overall responses in 7 patients treating with ALK inhibitors were 57.1% durable complete response and 42.9% transient partial response. CONCLUSION: First-line treatment of CNS-IMT/IPT is complete resection. Patients who received partial tumor removal might have benefit from adjuvant therapy. ALK inhibitors reveal a promising result in unresectable CNS-IMT/IPT. Our case has shown a success in treating relapsed and refractory CNS-IMT as well as the primary site using 2nd-generation ALK inhibitor.

Warburg effect mimicking inborn errors of metabolism in childhood hematologic malignancies: A case-based systematic review.

BACKGROUND: Type B lactic acidosis and hypoglycemia can occur in various pediatric conditions. In young children with a history of fasting preceding these metabolic derangements, inborn errors of metabolism should be primarily considered. However, the Warburg effect, a rare metabolic complication, can also manifest in children with hematologic malignancies. Only a few reports of this condition in children have been published in the literature. AIM: To identify the clinical course, treatment strategies, and outcomes of childhood hematologic malignancies with type B lactic acidosis. METHODS: We performed a comprehensive search of the PubMed, Scopus, and Cochrane databases without any time restriction but limited to English language articles. The databases were last accessed on July 1st, 2023. RESULTS: A total of 20 publications were included in the analysis, all of which were case reports or case series. No higher quality evidence was available. Among children with hematologic malignancies and Warburg effect, there were 14 cases of acute lymphoblastic leukemia and 6 cases of non-Hodgkin's lymphoma including our illustrative case. Lactic acidosis occurred in 55% of newly diagnosed cases and 45% of relapsed cases. The mean age was 10.3 ± 4.5 years, and 80% of cases were male. The mean serum lactate was 16.9 ± 12.6 mmol/L, and 43.8% of the cases had concomitant hypoglycemia. Lactic acidosis initially subsided in 80% of patients receiving chemotherapy compared to 60% in the contrast group. The mortality rate of newly diagnosed cases was 45.5%, while the relapsed cases represented a 100% mortality rate. All 8 patients reported before 2001 died from disease-related complications. However, patients described in reports published between 2003 and 2023 had a 54.5% rate of complete remission. CONCLUSION: This complication has historically led to fatal outcome; however, patients who received chemotherapy showed a more favorable response. Therefore, it is crucial to promptly initiate specific treatment in this context.

Coinherited Hemoglobin H/Constant Spring Disease and Heterozygous Hemoglobin Tak Causing Severe Hemolytic Anemia in a Thai Boy.

Hemoglobin (Hb) H/Constant Spring disease is a common nondeletional Hb H disease, typically causing a more severe phenotype than the deletional Hb H disease counterpart. Hb Tak, resulting from a dinucleotide insertion (+AC) at codon 146 of beta-globin gene, has an increased oxygen affinity and usually presents with polycythemia. We studied a case of a 4-year-old Thai boy with a severe, early-onset anemia. To our knowledge, he is the first reported patient with Hb H/Constant Spring disease and heterozygous Hb Tak. Trio-whole-exome sequencing does not identify other genetic variants that may contribute to the severity of anemia. The observation suggests that coinherited Hb H/Constant Spring and heterozygous Hb Tak lead to severe hemolytic anemia.

Wilms tumor with dilated cardiomyopathy: A case report.

BACKGROUND: Wilms tumor is the most common renal malignancy in childhood. It occurs primarily between the ages of 2 and 5 years. The usual manifestations are abdominal mass, hypertension, and hematuria. The case presented here had an unusual presentation, with dilated cardiomyopathy and hypertension secondary to the Wilms tumor. CASE SUMMARY: A 3-year-old boy presented with a 5-d history of irritability, poor appetite, and respiratory distress. His presenting clinical symptoms were dyspnea, tachycardia, hypertension, and a palpable abdominal mass at the left upper quadrant. His troponin T and pro-B-type natriuretic peptide levels were elevated. Echocardiography demonstrated a dilated hypokinetic left ventricle with an ejection fraction of 29%, and a suspected left renal mass. Computed tomography scan revealed a left renal mass and multiple lung nodules. The definitive diagnosis of Wilms tumor was confirmed histologically. The patient was administered neoadjuvant chemotherapy and underwent radical nephrectomy. After surgery, radiotherapy was administered, and the adjuvant chemotherapy was continued. The blood pressure and left ventricular function normalized after the treatments. CONCLUSION: Abdominal mass, dilated cardiomyopathy and hypertension can indicate Wilms tumor in pediatric patients. Chemotherapy and tumor removal achieve successful treatment.