Effect of Autograft CD34+ Dose on Outcome in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplant for Central Nervous System Tumors.

Consolidation with autologous hematopoietic stem cell transplantation (HSCT) has improved survival for patients with central nervous system tumors (CNSTs). The impact of the autologous graft CD34+ dose on patient outcomes is unknown. We wanted to analyze the relationship between CD34+ dose, total nucleated cell (TNC) dose, and clinical outcomes, including overall survival (OS), progression-free survival (PFS), relapse, non-relapse mortality (NRM), endothelial-injury complications (EIC), and time to neutrophil engraftment in children undergoing autologous HSCT for CNSTs. A retrospective analysis of the CIBMTR database was performed. Children aged <10 years who underwent autologous HSCT between 2008 to 2018 for an indication of CNST were included. An optimal cut point was identified for patient age, CD34+ cell dose, and TNC, using the maximum likelihood method and PFS as an endpoint. Univariable analysis for PFS, OS, and relapse was described using the Kaplan-Meier estimator. Cox models were fitted for PFS and OS outcomes. Cause-specific hazards models were fitted for relapse and NRM. One hundred fifteen patients met the inclusion criteria. A statistically significant association was identified between autograft CD34+ content and clinical outcomes. Children receiving >3.6×106/kg CD34+ cells experienced superior PFS (p = .04) and OS (p = .04) compared to children receiving ≤3.6 × 106/kg. Relapse rates were lower in patients receiving >3.6 × 106/kg CD34+ cells (p = .05). Higher CD34+ doses were not associated with increased NRM (p = .59). Stratification of CD34+ dose by quartile did not reveal any statistically significant differences between quartiles for 3-year PFS (p = .66), OS (p = .29), risk of relapse (p = .57), or EIC (p = .87). There were no significant differences in patient outcomes based on TNC, and those receiving a TNC >4.4 × 108/kg did not experience superior PFS (p = .26), superior OS (p = .14), reduced risk of relapse (p = .37), or reduced NRM (p = .25). Children with medulloblastoma had superior PFS (p < .001), OS (p = .01), and relapse rates (p = .001) compared to those with other CNS tumor types. Median time to neutrophil engraftment was 10 days versus 12 days in the highest and lowest infused CD34+ quartiles, respectively. For children undergoing autologous HSCT for CNSTs, increasing CD34+ cell dose was associated with significantly improved OS and PFS, and lower relapse rates, without increased NRM or EICs.

Treatment outcomes of high-dose chemotherapy plus stem cell rescue in high-risk neuroblastoma patients in Thailand.

BACKGROUND: In 2013, the Thai Pediatric Oncology Group (ThaiPOG) introduced a national protocol in which high-dose chemotherapy plus stem cell rescue is performed without immunotherapy. METHODS: This study aimed to elucidate the outcomes of high-risk neuroblastoma (HR-NB) patients treated with the ThaiPOG protocol. This retrospective cohort review included 48 patients (30 males, 18 females) with a median age of 3 years (range, 8 months to 18 years) who were treated at 5 ThaiPOG treatment centers in Thailand in 2000-2018. RESULTS: Eight of the 48 patients showed MYCN amplification. Twenty-three patients (48%) received 131I-meta-iodobenzylguanidine prior to high-dose chemotherapy and stem cell rescue. The majority of patients achieved a complete or very good response prior to consolidation treatment. The 5-year overall survival (OS) and event-free survival (EFS) rates were 45.1% and 40.4%, respectively. Patients aged >2 years had a nonsignificantly higher mortality risk (hazard ratio [HR], 2.66; 95% confidence interval [CI], 0.92-7.68; P=0.07). The MYCN amplification group had lower OS and EFS rates than the MYCN nonamplification group, but the difference was not statistically significant (45% OS and 37.5% EFS vs. 33.3% OS and 16.6% EFS; P=0.67 and P=0.67, respectively). Cis-retinoic acid treatment for 12 months was a strong prognostic factor that could reduce mortality rates among HR-NB patients (HR, 0.27; 95% CI, 0.09-0.785; P=0.01). CONCLUSION: High-dose chemotherapy plus stem cell rescue followed by cis-retinoic acid for 12 months was well tolerated and could improve the survival rates of patients with HR-NB.

A Pharmacokinetic Study of Native E.coli Asparaginase for Acute Lymphoblastic Leukemia Treated with ThaiPOG Protocol.

BACKGROUND: Asparaginase is one of the essential chemotherapies used to treat acute lymphoblastic leukemia (ALL). Asparaginase antibody production may cause a subtherapeutic level and result in an inferior outcome. The aim of this study was to prove the efficacy of current native E.coli asparaginase-based protocol. Moreover, does subtherapeutic result appeared in small group of the trial?. METHODS: A prospective study of asparaginase activity among patients who received native E.coli asparaginase 10,000 IU/m2 intramuscularly according to The Thai Pediatric Oncology Group (ThaiPOG) protocol was done. The plasma asparaginase activity was measured by the coupled enzymatic reaction. Pharmacokinetic data including peak activity (Cmax), time to maximum concentration (Tmax), area under the curve (AUC0-48h) being elucidated. RESULTS: Eight patients (five males and three females), median age 9.5 years, were enrolled. The median asparaginase activity of seven cases who were eligible for calculation reached Tmax within 24 hours (range 6-48 hours) with mean±SD of Cmax 3.60±0.34 (range 3.02-4.11) IU/ml. Mean±SD of AUC0-48h is 143.23±36.94 IU.h/mL (range 71.07 - 180.12 IU.h/mL). The post-48-hour activity showed a mean±SD of 3.19±0.24 IU/ml (range 2.77-3.51 IU/ml) which implied an adequacy of activity over 48 hours and proper for the 12-day period. One relapsed ALL patient showed an extremely low AUC of asparaginase activity which coincided with urticaria after asparaginase injection. Subsequently, the asparaginase antibody was demonstrated in this patient. CONCLUSION: Native E. coli asparaginase-based protocol provides a compelling pharmacokinetic effect. Asparaginase activity and/or antibody testing is recommended for all cases especially in a relapsed patient, history of high accumulative dose of asparaginase or suspected allergic reaction. Patients with low asparaginase activity or allergy may benefit from switching to an alternative form of asparaginase to maintain treatment efficacy.

Prenatal Diagnosis Leads to Early Diagnosis of Transfusion-Dependent Thalassemia and Better Growth Outcomes.

Thalassemia is the most common hematological transfusion-dependent disease in Thailand. Even though prenatal diagnosis (PND) can detect the condition, many new cases are diagnosed in pediatric practice. This study assessed the clinical outcome of patients with thalassemia who did PND. One hundred and six participants (53 female, 50%), with a median age of 8.5 years (Interquartile range [IQR] 8.00), were enrolled in the study. Twenty-one participants (19.8%) were prenatally diagnosed with thalassemia, with a median age of 8 years (IQR 9.00), 16 were diagnosed with transfusion-dependence thalassemia (TDT), and 5 participants were diagnosed with non-TDT. Another 80.2% did not prenatally diagnose, with a median age of 9 years (IQR 8.00). The PND group found early diagnosis compared with a non-PND group, at a median age of 6 months versus 15 months. There was a significant early diagnosis (P < .001). Furthermore, the participants' height for age z-score was significantly superior in the PND group (P = .018). Even though the result of PND was abnormal, the parents still willing to continue with the pregnancy. The reason was they wanted to have a child. However, their child may require lifelong transfusion therapy.

A Study to Assess and Improve Adherence to Iron Chelation Therapy in Transfusion-Dependent Thalassemia Patients.

Transfusion-dependent thalassemia (TDT) patients require regular blood transfusions. The unavoidable consequence is iron overload. Iron chelation therapy is the mainstay of treatment, of which the favorable outcome depends mainly on adherence level. The aim of this study was to assess adherence to iron chelation therapy of TDT patients. A cross-sectional cohort of TDT patients were evaluated on their adherence to chelation therapy using the Thai version of Morisky Medication Adherence Scales (MMAS-8). A total of 70 patients (38 males, 32 females), with a median age of 10 years, were enrolled in the study. Sixteen patients (22.9%) and 54 patients (77.1%) were classified as high and medium-low adherence level groups. The raised serum ferritin value for 6 months previous to enrollment in the high adherence level group is lower than the medium-low adherence level group (276.4 vs. 413.0 ng/mL, p = 0.034, respectively). Factors impacted high adherence to iron chelation including younger age (p = 0.015) and deferasirox (DFX) administration (p = 0.025). The body weight and height in both groups were not statistically different. The most common obstacle to adherence was forgetfulness. The Thai version of MMAS-8 is a practical tool for evaluating adherence to chelation therapy in TDT patients. High adherence level of patients correlates with more controlled serum ferritin level. The younger age and once-daily dose chelation therapy are associated with better adherence.

The Pattern of Microorganisms and Drug Susceptibility in Pediatric Oncologic Patients with Febrile Neutropenia.

OBJECTIVE: The study aimed to describe the pattern of causative microorganisms, drug susceptibility, risk factors of antibiotic-resistant bacterial infection, and clinical impact of these organisms on pediatric oncology patients with febrile neutropenia. METHODS: A retrospective descriptive study of oncologic patients aged less than 15 years who were diagnosed with febrile neutropenia in King Chulalongkorn Memorial Hospital was conducted between January 2013 to December 2017. Characteristics and clinical outcomes of febrile neutropenia episodes, causative pathogens, and their antibiotic susceptibilities were recorded. RESULT: This study included 267 patients with 563 febrile neutropenia episodes. The median (range) age was 5.1 years (1 month-15 years). The most common underlying disease was acute lymphoblastic leukemia (42.7%). Of 563 febrile episodes, there were 192 (34.1%) with microbiologically documented infection. Among these 192 episodes of microbiologically documented infection, there were 214 causative pathogens: 154 bacteria (72%), 32 viruses (15%), 27 fungus (12.6%), and 1 Mycobacterium tuberculosis (0.4%). Gram-negative bacteria (48.6%) accounted for most of the causative pathogens. Twenty-three percent of them were multidrug resistant, and 18% were carbapenem resistant. Among Gram-positive bacterial infection which accounted for 23.4% of all specimens, the proportion of MRSA was 20%. The 2-week mortality rate was 3.7%. Drug-resistant Gram-negative bacterial infection caused significant adverse events and mortality compared to nonresistant bacterial infection (p < 0.05). CONCLUSION: There is high rate of drug-resistant organism infection in pediatric oncology patients in a tertiary-care center in Thailand. Infection with drug-resistant Gram-negative bacterial infection was associated with significant morbidity and mortality. Continuous surveillance for the pattern of drug-resistant infections is crucial.

Predictive Factors of Severe Adverse Events in Pediatric Oncologic Patients with Febrile Neutropenia.

OBJECTIVES: Febrile neutropenia (FN) is severe and potentially life-threatening in oncologic patients. The objective of this study is to define the factors associated with severe adverse outcomes of pediatric FN. METHODS: A retrospective and prospective descriptive study performed in pediatric patients diagnosed with FN at King Chulalongkorn Memorial Hospital from January 2013 to December 2017. Severe adverse events defined as the presence in one of these following oxygen therapies, mechanical ventilator, shock, admission to ICU, renal dysfunction, and liver dysfunction. RESULTS: The study included 267 patients with 563 febrile neutropenia episodes. The median (range) age was 5.1 years (1 month-15 year). Among 563 febrile neutropenia episodes, 115 episodes (20%) developed severe adverse events. The FN patients were classified into low and high-risk groups, 91% of patients with severe adverse events and all 21 patients who died were in high risk group. The overall mortality rate was 3.1%. Factors associated with severe adverse events were fungal infection (aOR 6.51, 95%CI 2.29-18.56), central venous catheter insertion (aOR 4.28, 95% CI 2.51-7.29), CPG defined high risk (aOR 3.35, 95%CI 1.56-7.17), viral infection (aOR 2.72, 95%CI 1.05-7.06), lower respiratory tract infection (aOR 2.52, 95%CI 1.09-5.82) and treatment not according to CPG (aOR 2.47, 95% CI 1.51-4.03). CONCLUSIONS: Fungal and viral infection, central venous catheter insertion, lower respiratory tract infection, CPG defined high risk and treatment not according to CPG were associated factors of increased risk for severe adverse events. Our current institutional CPG for FN in children was applicable and improved clinical outcomes for this group of patients. 
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Vitamin D deficiency is not associated with graft versus host disease after hematopoietic stem cell transplantation: A meta-analysis.

OBJECTIVE: Vitamin D status plays an important role in immunoregulation, and a deficiency is believed to be related to Graft Versus Host Disease (GVHD) in patients after hematopoietic stem cell transplantation (HSCT). We aim to study the association between vitamin D deficiency and GVHD after HSCT. METHODS: A literature search was conducted utilizing MEDLINE, EMBASE, and The Cochrane Library Database from inception to July 2019. Eligible studies were required to1 be clinical trials or observational studies (cohort, case-control, or cross-sectional studies);2 provide data to calculate the odds ratios (OR) of GVHD in HSCT patients with vitamin D deficiency. Two reviewers independently extracted the data and assessed the risk of bias. Pooled odds ratios (OR) with 95% confidence interval (CI) were estimated using random-effects meta-analysis through the Comprehensive Meta-Analysis 3.3 software. RESULTS: In total, 8 observational studies consisting of 1335 HSCT patients were enrolled in this systematic review. Overall, there was no significant association between vitamin D deficiency and acute GVHD (OR = 1.06, 95% CI 0.74-1.53, P > 0.05). There was no significant association between vitamin D deficiency and chronic GVHD (OR = 1.75, 95% CI 0.72-4.26, P > 0.05). Funnel plots and Egger regression asymmetry test were performed and showed no publication bias. CONCLUSION: There is not a statistically significant association between vitamin D deficiency and neither acute nor chronic GVHD.

Arrhythmias in hematopoietic stem cell transplantation: A systematic review and meta-analysis.

BACKGROUND: There are controversial data regarding the relationship between hematopoietic stem cell transplantation and arrhythmias. This meta-analysis was performed to evaluate the incidence of arrhythmias in patients following hematopoietic stem cell transplantation (HSCT). METHODS: A literature search was conducted utilizing MEDLINE, EMBASE, and Cochrane Databases from inception through April 2019. Pooled incidence with 95% confidence interval (CI) were calculated using random-effects meta-analysis. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42019131833). RESULTS: Thirteen studies consisting of 10,587 patients undergoing HSCT were enrolled in this systematic review. Overall, the pooled estimated incidence of all types of arrhythmias following HSCT was 7.2% (95% CI: 4.9%-10.5%). With respect to the most common type of arrhythmia, the pooled estimated incidence of atrial fibrillation/atrial flutter (AF/AFL) within 30 days following HSCT was 4.2% (95% CI: 1.7%-9.6%). Egger's regression test demonstrated no significant publication bias in this meta-analysis of post-HSCT arrhythmia incidence. CONCLUSION: The overall estimated incidence of arrhythmias following HSCT was 7.2%. Future large scale studies are needed to further elucidate the significance and clinical impact of arrhythmias in post-HSCT patients.

Safety of paediatric percutaneous native kidney biopsy and factors predicting bleeding complications.

AIM: Data on safety of paediatric percutaneous native kidney biopsy (PNKB) using automated biopsy devices and real-time ultrasonography are lacking. The objective of this study was to evaluate the safety and to identify factors predicting bleeding complications associated with this PNKB protocol. METHODS: A total of 227 patients aged <18 years who underwent the first PNKB were analyzed. The primary outcome was bleeding complications divided into minor and major bleeding complications. Minor bleeding complications included perirenal haematoma and macroscopic haematuria. Major bleeding complications included requirement of blood transfusion, a higher level of care or vasopressors to maintain haemodynamic stability, requirement of angiographic or surgical intervention, or death. RESULTS: Perirenal haematoma occurred in 58 patients (25%) and macroscopic haematuria occurred in 46 patients (20%). Two factors were independently associated with perirenal haematoma in a multivariate model. These were male gender and weight for height Z-score <-0.5. Three patients (1.3%), all with perirenal haematoma had major bleeding complications (two required blood transfusion and one underwent surgery to repair an injured renal artery). CONCLUSIONS: The favourable safety information from our study is useful when counselling the parents and patients undergoing similar protocols. PNKB can be safely performed when precautions are taken to prevent bleeding. Selection of biopsy instruments should be tailored according to patient size.

Pregnancy in biliary atresia after kasai operation complicated by portal hypertension.

Hepatic portoenterostomy or Kasai operation has been widely accepted as the standard therapy for biliary atresia. Recently, more female patients have grown up and reached adulthood; therefore, pregnancy in women with biliary atresia is sometimes inevitable. The authors report a 17-year-old woman with biliary atresia post Kasai operation at 3 months of age. After the operation, she became jaundice-free but developed portal hypertension with abnormal liver function. She had several episodes of esophageal variceal bleeding and was treated by beta-blocker and endoscopic sclerotherapy. Since then, she was lost to follow up for nearly 2 years. She came back again with 12 weeks of gestation with no symptoms of gastrointestinal bleeding for antenatal care. At 32 weeks of gestation, she presented with severe hematemesis from variceal bleeding and had thrombocytopenia from hypersplenism. She was treated with somatostatin analogue, fluid and blood component replacement and other supportive treatments. Cesarean section was performed when she was stable at 33 weeks of gestation. After the operation, her clinical status was improved and had no other complications. Her baby experienced complications of prematurity but improved after treatment. Pregnancy may affect the natural course of portal hypertension and worsen the clinical outcome. Pregnancy should be avoided in patients with portal hypertension, however it is not contraindicated. Pregnancy in biliary atresia patients needs intensive prenatal care.