Moderate- to vigorous-intensity physical activities for hemophilia A patients during low-dose pharmacokinetic-guided extended half-life factor VIII prophylaxis.

BACKGROUND: Low-dose pharmacokinetic (PK)-guided extended half-life (EHL) factor VIII (FVIII) prophylaxis can reduce the bleeding risk in hemophilia A (HA) patients. An increase in physical activities for promoting musculoskeletal health may enhance the benefits of prophylactic therapy. OBJECTIVES: To determine the clinical impact of moderate- to vigorous-intensity physical activities in HA patients during low-dose PK-guided EHL FVIII prophylaxis. PATIENTS/METHODS: This prospective study enrolled patients with moderate/severe HA (baseline FVIII levels ≤ 5 IU/dL) who had received low-dose PK-guided EHL FVIII prophylaxis for ≥ 6 months. An individualized exercise protocol was introduced to each participant, targeting a 65% increase in the maximum predicted heart rate for ≥ 150 min/week, while continuing low-dose PK-guided EHL FVIII prophylaxis for 6 months. Before and after implementing the intervention, annualized bleeding rates (ABR), annualized joint bleeding rates (AJBR), Hemophilia Joint Health Scores (HJHS), skeletal muscle mass, hemophilia-specific quality-of-life (QoL) scores and annualized FVIII consumption were compared. RESULTS: Of 13 participants (mean age ± standard deviation [SD]: 20.1 ± 6.8 years), ABR, AJBR, and HJHS were significantly reduced (mean differences [MD] ± SD: -5.7 ± 2.6 bleeds/year, -4.2 ± 2.6 joint bleeds/year, and -4.3 ± 3.2 marks, respectively; P < 0.05) after applying the 6-month exercise protocol. Skeletal muscle mass and QoL scores had also improved (P = 0.001), while FVIII usage had decreased (MD ± SD: -129.1 ± 208.7 IU/kg/year; P < 0.05). CONCLUSIONS: The combination of moderate- to vigorous-intensity physical activities with low-dose PK-guided EHL FVIII prophylaxis improves bleeding prevention, musculoskeletal status and QoL in patients with moderate/severe HA. By minimizing FVIII consumption, this strategy helps optimize hemophilia care in countries with budget constraints. CLINICALTRIALS: gov NCT05728528.

Haemophilia care in Asia: Learning from clinical practice in some Asian countries.

BACKGROUND: The healthcare systems in Asia vary greatly due to the socio-economic and cultural diversities which impact haemophilia management. METHODS: An advisory board meeting was conducted with experts in haemophilia care from Asia to understand the heterogeneity in clinical practices and care provision in the region. FINDINGS: The overall prevalence of haemophilia in Asia ranges between 3 and 8.58/100,000 patients. Haemophilia A was more prevalent as compared to haemophilia B with a ratio of around 5:1. There is under-diagnosis in the region due to lack of diagnosis, registries and/or lack of appropriate facilities in suburban areas. Most patients are referred to the haematologists by their families or primary care physicians, while some are identified during bleeding episodes. Genetic testing faces obstacles like resource constraints, services available at limited centres and unwillingness of patients to participate. Prophylaxis is offered for people with haemophilia (PWH) with a severe bleeding phenotype. Recombinant factors are approved in most countries across the region and are the preferred therapy. The challenges highlighted for not receiving a high standard of care include patients' reluctance to use an intravenous treatment, poor patient compliance due to frequency of infusions, budget constraints and lack of funding, insurance, availability and accessibility of factor concentrates. Prevalence of neutralizing antibodies ranged from 5% to 20% in the region. Use of immune tolerance induction and bypassing agents to treat inhibitors depends on their cost and availability. CONCLUSION: Haemophilia care in Asia has evolved to a great extent. However, some challenges remain for which a strategic approach along with multi-stakeholder involvement are needed.

Cost and effectiveness comparison of sirolimus versus standard treatment in Kasabach-Merritt phenomenon: a real-world evidence study in Thailand.

The conventional treatment of Kasabach-Merritt Phenomenon (KMP) consists of corticosteroids with vincristine/vinblastine or others. The aim of the study is to compare the first-year direct costs and effectiveness between sirolimus and conventional treatment. A retrospective case-control study of KMP patients was conducted at a mean age of 9 months (1 day to 12 years) between 2000 and 2022 from four tertiary centers in Thailand. The direct costs, hematologic and clinical complete response (HCR, CCR), hospitalization, length of stay, and complications were compared. Of 29 patients, 13 underwent sirolimus (four upfront and nine were refractory to the conventional). The first-year total cost had no statistically significant difference between sirolimus VS conventional treatment (8,852.63 VS 9,083.56 USD: p value: 0.94). The therapeutics achievement was the same in both HCR (244.75 VS 168.94 days; p value: 0.60) and CCR (419.77 VS 399.87 days; p value: 0.90). The subgroup analysis of the first-line sirolimus (n = 4) compared with the conventional (n = 25) showed a more reduced total cost (4,907.84 VS 9,664.05 USD; p value: 0.26) rendered net total cost of -4,756.21 USD per patient (cost saving). A more significant contrast of therapeutic achievement by reduction of both HCR (11.67 VS 224.20 days; p value: 0.36) and CCR (38.50 VS 470.88 days; p value: 0.04) was shown. The sirolimus had no difference in hospitalization, length of stay, and complications. Even though, it was unable to identify significant differences in cost-effectiveness. Sirolimus is suitable for all patients who have diagnosis of KMP either for rescue therapy or first-line treatment.

Genetic variations of type 2 and type 3 von Willebrand diseases in Thailand.

AIMS: Von Willebrand disease (VWD) is an inherited haemostatic disorder with a wide range of bleeding phenotypes based on von Willebrand factor (VWF) levels. Multiple assays including VWF gene analysis are employed to correctly diagnose VWD and its subtypes. However, data on VWF mutations among Southeast Asian populations are lacking. We, therefore, aimed to explore genetic variations in Thai patients with type 2 and type 3 VWD by whole exome sequencing (WES). METHODS: In this multicentre study, Thai patients with type 2 and type 3 VWD, according to the definitions and VWF levels recommended by the international guidelines, were recruited. WES was performed using DNA extracted from peripheral blood in all cases. The novel variants were verified by Sanger sequencing. RESULTS: Fifteen patients (73% females; median age at diagnosis 3.0 years) with type 2 (n=12) and type 3 VWD (n=3) from 14 families were enrolled. All patients harboured at least one VWF variant. Six missense (p.Arg1374Cys, p.Arg1374His, p.Arg1399Cys, p.Arg1597Trp, p.Ser1613Pro, p.Pro1648Arg) and one splice-site (c.3379+1G>A) variants in the VWF gene were formerly described. Notably, six VWF variants, including three missense (p.Met814Ile, p.Trp856Cys, p.Pro2032Leu), one deletion (c.2251delG) and two splice-site (c.7729+4A>C, c.8115+2delT) mutations were novelly identified. Compound heterozygosity contributed to type 2 and type 3 VWD phenotypes in two and one patients, respectively. CONCLUSIONS: Type 2 and type 3 VWD in Thailand demonstrate the mutational variations among VWF exons/introns with several unique variants. The WES-based approach potentially provides helpful information to verify VWD diagnosis and facilitate genetic counselling in clinical practice.

National strategic advocacy to manage patients with inherited bleeding disorders in low and lower-middle income countries.

INTRODUCTION: Inherited bleeding disorders (IBDs) including hemophilia, von Willebrand disease, platelet disorders, mucocutaneous bleeding disorders and coagulation factor deficiencies are rarely found and under-recognized in low and lower-middle-income countries. Some patients succumbed to serious bleeding without diagnosis and treatment during childhood. AREA COVERED: Diagnosis, management, and prevention should be integrated into the existing health care system. Although some countries have not implemented appropriate health care infrastructure, an initiative plan should be set up by cooperation of experienced experts and health care providers. Identification of patients with IBDs should be started in the antenatal setting to search for females at risk of carrier state. The investigations include bleeding assessment, mixing venous clotting time, coagulogram, coagulation factor assay and mutation detection. Genotypic analysis is helpful for confirming the definite diagnosis, carrier detection as well as prenatal diagnosis for females at risk of bearing an offspring with severe bleeding manifestations. Management involves replacement therapy ranging from blood component to virus-inactivated factor concentrate. Appropriate research is an essential backbone for improving patients' care. EXPERT OPINION: Effective national strategic advocacy to manage patients with IBDs requires intensive collaboration among policy makers, health care providers, patients, and family members.

Estimating the impact of improved management of haemophilia a on clinical outcomes and healthcare utilisation and costs.

OBJECTIVE: Haemophilia A (HA) is associated with high clinical and healthcare burden. We developed an Excel-based model comparing current practice to improved management in severe HA patients currently managed on demand (OD). Outcomes included short- and long-term bleed events. Expected annual bleeds were estimated based on locally-derived OD annualised bleed rate (ABR), adjusted by relative prophylaxis-related ABRs (published literature). The objective of our study was to explore the impact of improving HA prophylaxis in target countries with limited published data (Algeria, Argentina, Chile, India, Malaysia, Mexico, Taiwan and Thailand). Bleed-related healthcare resource use (HCRU) and costs were estimated as a function of bleed type, with inputs obtained from local expert estimates. Clotting factor concentrates (CFC) consumption related to treatment and prophylaxis was estimated based on locally relevant dosing. CFC costs were not included. RESULTS: When 20% of OD patients were switched to prophylaxis, projected reduction in bleeds was estimated between 3% (Taiwan) through 14% (Algeria and India); projected reductions in hospitalisations ranged from 3% (Taiwan) through 15% (India). Projected HCRU-related annual cost savings were estimated at USD 0.45 m (Algeria), 0.77 m (Argentina), 0.28 m (Chile), 0.13 m (India), 0.29 m (Malaysia), 2.79 m (Mexico), 0.15 m (Taiwan) and 0.78 m (Thailand). Net change in annual CFC consumption ranged from a 0.05% reduction (Thailand) to an overall 5.4% increase (Algeria). Our model provides a flexible framework to estimate the clinical and cost offsets of improved prophylaxis. Modest increase in CFC consumption may be an acceptable offset for improvements in health and healthcare capacity in resource constrained economies.

The long-term efficacy and safety of nilotinib in pediatric patients with CML: a 5-year update of the DIALOG study.

The efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.

Immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients with severe hemophilia A: interim results from a phase 3, prospective, multicenter, open-label study.

AIM: To determine the immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients (PUPs) with severe hemophilia A (HA). METHODS: This prospective, phase 3 study (NCT02615691) was conducted in PUPs, or patients with ≤2 exposure days (EDs) prior to screening, aged <6 years with severe HA. The primary endpoint was incidence of factor VIII (FVIII) inhibitor development. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing FVIII inhibitors or had developed a confirmed inhibitor at any time. RESULTS: Of the enrolled patients, 59/80 (73.8%) received ≥1 dose of rurioctocog alfa pegol; 54 received prophylaxis, and 35 on-demand treatment. Incidence of inhibitor development was 0.19 (10/52). Total annualized bleeding rate (95% CIs) was 3.2 (2.0-5.0) for patients receiving prophylaxis and 3.2 (1.6-6.3) for on-demand treatment. Hemostatic efficacy of most bleedings was rated as 'excellent' or 'good' after 24 hours (122/131 [93.1%]) and at resolution (161/170 [94.7%]). Five patients received ≥1 dose of rurioctocog alfa pegol for immune tolerance induction (ITI) and 1 patient was defined as having ITI success. Thirteen patients experienced 14 treatment-related adverse events, including 10 cases of FVIII inhibitor development. CONCLUSION: This is the first prospective study of rurioctocog alfa pegol for the treatment of PUPs with severe HA. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02615691).

Practices and challenges for hemophilia management under resource constraints in Thailand.

Hemophilia is an inherited bleeding disorder caused by deficiency of a specific coagulation factor. Factor VIII deficiency is responsible for hemophilia A while factor IX deficiency is responsible for hemophilia B. As per the 2020 annual global survey by the World Federation of Hemophilia, only 1828 Thai hemophiliacs have been registered to the national healthcare system. The reason for the low number is the underdiagnosis which is a major concern in the real-world practice among Asian countries. In Thailand, most hemophiliacs are diagnosed by general practitioners, pediatricians or internists at rural hospitals and are referred to hemophilia specialists at the Hemophilia Treatment Centers (HTCs). Despite the challenges pertaining to infrastructure and cost of treatment, Thailand has progressed substantially in providing the required hemophilia care, as evidenced by an evolution in acquiring and sharing knowledge as well as collaborative efforts among multiple stakeholders over the past three decades. In this letter-to-the-editor, the authors have summarized the practices for and challenges faced with hemophilia management in Thailand.

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.

Postoperative radiotherapy timing, molecular subgroups and treatment outcomes of Thai pediatric patients with medulloblastoma.

INTRODUCTION: Medulloblastoma (MB) is the most common childhood malignant brain tumor worldwide. Recently, molecular classification was established and started to play a role in the management of MB; however, studies involving molecular defined MB in Southeast Asia have been limited. We aimed to describe, and correlate clinical characteristics and molecular subgroups with therapeutic outcomes of Thai pediatric patients with MB. MATERIALS AND METHODS: Pediatric MB patients treated at King Chulalongkorn Memorial Hospital in Thailand from 2006 to 2018 were recruited. Patients were classified by clinical characteristics into standard- and high-risk groups, which determined treatment regimen. Retrospectively, available tumor tissues were classified into 3 molecular subgroups using immunohistochemistry: 1) WNT, 2) SHH, and 3) non-WNT/non-SHH. The primary outcome was 5-year overall survival (OS). Risk factors associated with OS were analyzed using cox regression analysis. RESULTS: Fifty-three Thai pediatric patients with MB were enrolled. The median follow-up time was 60 months. The 5-year OS for all patients, and patients with standard-risk and high-risk were 74.2%, 76.3% and 71.4%, respectively. Tumor tissues of 24 patients were available, of which 23 could be molecularly classified. Two, one and 20 were in the WNT, SHH and non-WNT/non-SHH subtypes with 5-year OS of 100%, 100% and 78.9%, respectively. Using multivariate analysis, the interval of more than 8 weeks between surgery and radiotherapy was significantly correlated with a decrease in the 5-year OS. CONCLUSION: Interval between surgery and radiotherapy within 8 weeks was associated with good therapeutic outcomes among Thai pediatric patients with MB. Simplified molecular subtyping combined with clinical characteristics is practical in risk classification of patients with MB in institutes with limited resources.

Clinical outcomes of low-dose pharmacokinetic-guided extended half-life versus low-dose standard half-life factor VIII concentrate prophylaxis in haemophilia A patients.

INTRODUCTION: Despite receiving standard half-life (SHL) factor VIII (FVIII) concentrates prophylaxis, some severe haemophilia A (HA) patients still encounter spontaneous breakthrough bleeding. Individualized pharmacokinetic (PK)-guided dosing of extended half-life (EHL) FVIII concentrates may reduce their bleeding events. AIM: To compare clinical outcomes before and after switching low-dose prophylaxis using weight-based SHL FVIII to PK-guided EHL FVIII concentrates, taking into consideration of a trough FVIII activity at 1 IU/dl above natural baseline. METHODS: In this single-centre prospective cohort, Thai severe or moderate HA (FVIII activity ≤3 IU/dl) patients receiving low-dose weight-based SHL FVIII prophylaxis were enrolled. After a 3-day wash-out period, participants underwent low-dose EHL FVIII prophylaxis with PK-based adjustment (myPKFiT® ) for 6 months. The annualized bleeding rates (ABR), the annualized joint bleeding rates (AJBR), the haemophilia-specific quality-of-life (Haemo-QoL or Haemo-QoL-A) scores, the Hemophilia Joint Health Scores (HJHS) and the annualized FVIII consumption were compared between the two prophylactic periods. RESULTS: Of 15 eligible subjects (mean age 18.7 ± 6.7 years), ABR, AJBR and HJHS were significantly reduced (mean differences of -11.1 ± 4.9 bleeds/year, -10.4 ± 5.2 joint bleeds/year and -5.1 ± 1.5 marks, respectively; P < .001 for all comparisons) after switching regimen. The quality-of-life scores had also improved (P = .001). Nonetheless, FVIII consumption tended to increase despite no statistical significance (means of 1240.9 ± 531.3 SHL FVIII IU/kg/year versus 1591.7 ± 438.9 EHL FVIII IU/kg/year; P = .05). CONCLUSIONS: This is the first low-dose, PK-guided, EHL FVIII prophylaxis clinical study in Thailand. Benefits and practicability of this personalized regimen may support the implementation of regular FVIII prophylaxis in developing countries with budget constraints. CLINICALTRIALS: gov NCT05281185.

KRAS Mutation in Pediatric Intracranial Germ Cell Tumors.

BACKGROUND: Intracranial germ cell tumors (IGCTs) are rare, highly curable neoplasms. KRAS is a gene in the KIT/RAS signaling pathway, and KRAS mutations have been reported in patients diagnosed with IGCTs. OBJECTIVES: To describe the clinicopathologic and molecular features of KRAS mutation and the treatment outcome of children diagnosed with IGCTs. METHODS: Patients diagnosed with IGCTs at the Department of Pediatrics, King Chulalongkorn Memorial Hospital from 2007 to 2016 were retrospectively reviewed. DNA was extracted from formalin-fixed, paraffin-embedded tissue and used for molecular study. Mutations in codons 12, 13, and 61 of the KRAS gene were detected using the cobas® KRAS mutation test and pyrosequencing. RESULTS: Eighteen patients were diagnosed with IGCTs (11 males and 7 females): nine with germinomas and nine with non-germinomatous GCTs (NGGCTs). The age range of the patients was 5-14 years (median 10.5 years). Elevated markers were revealed in approximately 25% of the patients. Four patients (two with germinomas and two with NGGCTs) had leptomeningeal involvement. All patients underwent tumor biopsy and received neoadjuvant chemotherapy. Radiotherapy was administered in 16 patients, and craniospinal radiation was administered only in patients with leptomeningeal metastasis. With a median follow-up of 26 months, overall survival was 88.9% in the patients with germinomas and 37% in the patients with NGGCTs. Mutation of the KRAS gene was detected using pyrosequencing in one patient. The mutation located at codon 61, with frequency 38.3% units, nucleotide substitution CAA > CTA, and amino acid substitution, was Q61L. The patient carrying the mutant gene was diagnosed with germinoma with cerebrospinal fluid metastasis and eventually died from treatment-related toxicity. CONCLUSION: Our study revealed the treatment outcomes of IGCTs in Thai children. The metastatic germinoma patient with KRAS codon 61 mutation had a poor outcome, supporting that Q61L has a clinical correlation with IGCTs.

Immune Response after 2 Doses of BNT162b2 mRNA COVID-19 Vaccinations in Children and Adolescents with Cancer and Hematologic Diseases.

BACKGROUND: The BNT162b2 mRNA COVID-19 vaccine has been administered to children and adolescents with cancer and hematologic diseases since they are at high risk of manifesting severe symptoms if they have COVID-19 infection but the adequate immune response after vaccination in these immunocompromised patients are questionable. OBJECTIVE: To evaluate the immune response of children and adolescents with cancer and hematologic diseases after receiving 2 doses of the BNT162b2 mRNA COVID-19 vaccine. METHODS: This is a prospective cohort study of patients with cancer and hematologic disease, who aged 12- 18 years old and received 2 doses the BNT162b2 vaccines at 4 weeks apart were enrolled. Immunogenicity was determined by measuring serum anti-SARS-CoV-2 immunoglobulin antibodies directed against the receptor binding domain (RBD) of S1 domain of the spike protein (Anti S-RBD), surrogated viral neutralization test (sVNT) of SARS-CoV-2 and Delta strain. Blood samples were collected and analyzed at 4 and 12 weeks after vaccination. The seroprotective rate was defined as sVNT ≥ 68%. RESULTS: From Oct 2021 to Jan 2022, 43 children were enrolled, 21 were on-therapy and 22 were off-therapy. 25 were hematologic malignancy, 15 solid tumor and 3 hematologic diseases with immunosuppressive drugs. The GMT (95%CI) of a anti S-RBD IgG level at 4 weeks after vaccination were 56.05 (13.2,238.2) and 3633 (2689,4908) BAU/mL in on-therapy and off-therapy group, respectively, p<0.001. The sVNT (95%CI) of delta strain were 26% (5.85-73.55%) and 97.05% (96.0-97.4%) as the seroprotective level which were 33.3% in on-therapy group and 100% in off-therapy group (p<0.001). 14 children in on-therapy group need an additional dose. CONCLUSION: After complete vaccination, the seroprotective rate and antibody level in pediatric and adolescent patients with cancer and hematologic disease who receive immunosuppressive agents are quite low, compared with patients who had complete treatment. Additional dose of primary series should be offered.

Clinical and molecular characteristics of Thai patients with ELANE-related neutropaenia.

AIMS: Congenital neutropaenia is a rare inherited disorder that mainly affects neutrophils causing severe infection. Mutations in several genes have been implicated in the disease pathogenesis. The genetic defects may vary in different populations, influenced by ethnicity and geographical location. Here we describe the clinical and genotypic characteristics of seven unrelated Thai cases with congenital neutropaenia. METHODS: Seven unrelated patients with congenital neutropaenia were enrolled (5 female and 2 male) at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Clinical and laboratory data were collected. Whole exome sequencing (WES) analysis was performed in all cases. RESULTS: WES successfully identified disease-causing mutations in the ELANE gene in all cases, including two novel ones: a heterozygous 12 base pair (bp) inframe insertion (c.289_300dupCAGGTGTTCGCC; p.Q97_A100dup) and a heterozygous 18 bp inframe deletion (c.698_715delCCCCGGTGGCACAGTTTG; p.A233_F238delAPVAQF). Five other previously described ELANE mutations (p.Arg103Pro, p.Gly214Arg, p.Trp241X, p.Ser126Leu and p.Leu47Arg) were also detected. CONCLUSIONS: All Thai patients with congenital neutropaenia in this study harboured causative mutations in the ELANE gene, suggesting it the most common associated with the disease. Two novel mutations were also identified, expanding the genotypic spectrum of ELANE.

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 phase 2 study of nilotinib in pediatric patients with CML: long-term update on growth retardation and safety.

The phase 2, open-label study (DIALOG) of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) met its coprimary end points, showing sustained nilotinib efficacy in patients with newly diagnosed (ND) or imatinib/dasatinib resistant/intolerant (R/I) CML. This update assessed growth and safety profiles in patients who had completed ≥48, 28-day treatment cycles of nilotinib 230 mg/m2 twice daily, or previously discontinued the study. Height was assessed regularly and reported using standard deviation scores (SDSs) based on World Health Organization growth charts. All data were summarized descriptively (cutoff, 6 March 2019). Overall, 33 patients in the R/I cohort and 25 patients in the ND cohort received nilotinib. Each cohort showed a negative slope in height SDS over the course of the study, indicating attenuated growth rates during nilotinib treatment: overall median change from baseline in height SDS after 48 cycles was -0.54 SDS (range, - 1.6 to 0.4) and -0.91 SDS (-1.4 to -0.1) in R/I and ND cohorts, respectively. Patients in the R/I cohort were shorter at baseline than those in the ND cohort, and remained so throughout the study. The most common all-cause adverse events were increased blood bilirubin (53.4%), headache (46.6%), pyrexia (37.9%), and increased alanine transferase (36.2%). Apart from the impact on growth, the safety profile of nilotinib was generally consistent with previous reports. This study was registered on www.clinicaltrials.gov at #NCT01844765.