Good prognosis of adult hemophagocytic lymphohistiocytosis associated with the germline HAVCR2 mutation.

Hemophagocytic lymphohistiocytosis (HLH) in adults may be idiopathic or secondary to various conditions. Recent studies identified germline hepatitis A virus-cellular receptor 2 (HAVCR2) mutations in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with HLH. The roles of this mutation in HLH, especially in idiopathic group, have never been explored. Of the 65 HLH cases, we detected germline HAVCR2Y82C mutations in nine (13.8%) cases (five SPTCL and four idiopathic HLH). Other causes of HLH were hematologic malignancies excluding SPTCL (32.3%), idiopathic HLH without HAVCR2 mutation (29.2%), infections (15.3%), and autoimmune diseases (9.2%). Germline HAVCR2 mutation was significantly associated with less anemia and better survival. This defines a distinct subgroup of HLH.

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.

Whole exome sequencing and rare variant association study to identify genetic modifiers, KLF1 mutations, and a novel double mutation in Thai patients with hemoglobin E/beta-thalassemia.

OBJECTIVES: Clinical manifestations of patients with Hemoglobin E/beta-thalassemia vary from mild to severe phenotypes despite exhibiting the same genotype. Studies have partially identified genetic modifiers. We aimed to study the association between rare variants in protein-coding regions and clinical severity in Thai patients. METHODS: From April to November 2018, a case-control study was conducted based on clinical information and DNA samples collected from Thai patients with hemoglobin E/beta-thalassemia over the age of four years. Cases were patients with severe symptoms, while patients with mild symptoms acted as controls. Whole exome sequencing and rare variant association study were used to analyze the data. RESULTS: All 338 unrelated patients were classified into 165 severe and 173 mild cases. Genotypes comprised 81.4% of hemoglobin E/beta-thalassemia, 2.7% of homozygous or compound heterozygous beta-thalassemia, and 0.3% of (뫧)0 thalassemia Hb E while 15.7% of samples were not classified as beta-thalassemia. A novel cis heterozygotes of IVS I-7 (A > T) and codon 26 (G > A) was identified. Six genes (COL4A3, DLK1, FAM186A, PZP, THPO, and TRIM51) showed the strongest associations with severity (observed p-values of <0.05; significance lost after correction for multiplicity). Among known modifiers, KLF1 variants were found in four mild patients and one severe patient. CONCLUSION: No rare variants were identified as contributors to the clinical heterogeneity of hemoglobin E/beta-thalassemia. KLF1 mutations are potential genetic modifiers. Studies to identify genetic factors are still important and helpful for predicting severity and developing targeted therapy.

Time-dependent treatment effects of metronomic chemotherapy in unfit AML patients: a secondary analysis of a randomised controlled trial.

OBJECTIVES: To examine the presence of the time-dependent effect of metronomic chemotherapy for the treatment of older patients with acute myeloid leukemia (AML) who were unfit for standard chemotherapy and to reanalyze the data using an appropriate statistical approach in the presence of non-proportional hazards, the restricted mean survival time (RMST). RESULTS: This was a secondary analysis of a multi-center, open-label, randomized controlled trial, which was conducted in seven tertiary care hospitals across Thailand. A total of 81 unfit AML patients were randomized into two treatment groups, metronomic chemotherapy and palliative treatment. The hazard ratio of metronomic chemotherapy over palliative treatment was time-dependent. At three landmark time points of 90, 180, 365 days, the restricted mean survival time differences were 13.3 (95% CI 1.9-24.7) days, 28.9 (95% CI 3.3-54.4) days, and 40.4 (95% CI - 1.3 to 82.0) days, respectively. With non-proportional hazards modeling and RMST analysis, we were able to conclude that metronomic chemotherapy is a potentially effective alternative treatment for elderly AML patients who were medically unfit for intensive chemotherapy. In the future clinical trials, non-proportional hazards should be carefully inspected and properly handled with appropriate statistical methods. Trial registration Randomized clinical trial TCTR20150918001; registration date: 15/09/2015. Retrospectively registered.

Efficacy and Safety of Metronomic Chemotherapy Versus Palliative Hydroxyurea in Unfit Acute Myeloid Leukemia Patients: A Multicenter, Open-Label Randomized Controlled Trial.

BACKGROUND: Management of unfit AML patients is a therapeutic challenge. Most hematologists tend to avoid aggressive treatment leaving patients with a choice of best supportive care. We hypothesized that metronomic chemotherapy could be an alternative treatment for unfit AML patients. METHODS: A multi-center randomized controlled trial was conducted in seven university-affiliated hospitals in Thailand. Unfit AML patients were recruited and followed up from December 2014 to December 2017. Patients were randomly assigned to receive either metronomic chemotherapy or palliative hydroxyurea. Overall survival rates were compared using Cox's proportional hazard survival analysis. RESULTS: A total of 81 eligible patients were randomly allocated and included for ITT analysis. The OS rate was higher in group receiving metronomic chemotherapy than in group receiving palliative treatment at 6 and 12 months with borderline significance (6 months HR 0.60; 95%CI 0.36, 1.02; p-value 0.060; 12 months: HR 0.66; 95%CI 0.41, 1.08; p-value 0.097). CONCLUSION: Metronomic chemotherapy could prolong survival time of unfit AML patients, especially in the first 12 months after diagnosis without increasing treatment-associated adverse events.

Determination of Normal HbA1C Levels in Non-Diabetic Patients with Hemoglobin E.

OBJECTIVE: Hemoglobin E (Hb E) possesses an influence on HbA1c levels. Careful interpretation of HbA1c is needed in areas with a high prevalence of Hb E, including Thailand. Therefore, the normal levels of HbA1c in non-diabetic Hb E subjects were collected and assessed. METHODS: A cross-sectional study was conducted in Hb E subjects aged 18 years and above (N=70). An oral glucose tolerance test was performed. HbA1c levels were measured with 3 assays: ion exchange HPLC, immunoassay (ImmA), and enzymatic assay (EnzA). Individuals who received regular blood transfusions and diabetic patients were excluded. RESULTS: Among 34 subjects with heterozygous Hb E (EA), the mean (±SD) HbA1c levels by HPLC, ImmA, and EnzA were 5.63±0.55%, 4.73±0.62%, and 5.29±0.37%, respectively. Among 29 subjects with homozygous Hb E (EE), the mean (±SD) HbA1c levels by HPLC, ImmA, and EnzA were 3.37±0.69%, 4.37±0.76, and 4.91±0.28%, respectively. Immunoassay and enzymatic methods seem preferable over HPLC for this population. The HbA1c level of 5.7 (99th percentile) from immunoassay is a proposed cut-off point for detecting individuals who are at an increased risk of diabetes. CONCLUSION: There are subjects with hemoglobin E whose HbA1c levels are deemed inaccurate due to the techniques used. Within this study normal HbA1c levels were determined by 3 different assays. The HbA1c level of 5.7 by immunoassay (Advia, 1600) is proposed as the cut-off point for diagnosing subjects at risk of diabetes.

Epidemiologic study of major complications in adolescent and adult patients with thalassemia in Northeastern Thailand: the E-SAAN study phase I.

INTRODUCTION: Thalassemia-related complications are one of the main factors that increase morbidity and mortality in aging patients with thalassemia. This study was aimed to report the prevalence and clinical risk factors for the complications in thalassemia. METHODS: A multi-center prospective cohort study was conducted in patients with thalassemia aged ≥10 years old. Thalassemia-related complications were heart failure, pulmonary hypertension, extramedullary hematopoiesis, endocrine disorders, infections, thrombosis and leg ulcers. The clinical parameters significantly associated with the complications were analyzed by logistic regression methods. RESULTS: The prevalence of thalassemia-related complications was 60.5% in patients with transfusion-dependent thalassemia (TDT) and 43% in patients with non-transfusion-dependent thalassemia (NTDT). Splenectomy was statistically associated with complications in both TDT and NTDT patients (adjusted odds ratio (AOR) = 7.4, p-value = 0.0001 and AOR = 2.6, p-value = 0.001). Age ≥50 years old (AOR = 2.9, p-value = 0.04) and female gender (AOR = 0.5, p-value = 0.03) were statistically associated with the complications in patients with NTDT. CONCLUSION: Nearly half of the patients in this cohort had disease-related complications. Splenectomy and advanced age were important factors for complication involvement. Early screening for the complications may reduce the morbidity and mortality in patients with thalassemia.

A Clinical Risk Score for Predicting Paraspinal Extramedullary Hematopoiesis in Patients with Thalassemia: The KKU-EMH Score.

Background: Paraspinal extramedullary hematopoiesis (EMH) is uncommon, but it is one of major complications of increased morbidity in patients with thalassemia. Objective: To develop a clinical risk score for predicting paraspinal extramedullary hematopoiesis in patients with thalassemia. Material and Method: A retrospective study was conducted in adult patients with thalassemia at Srinagarind Hospital, Khon Kaen University (KKU) and Udonthani Hospital, Thailand. Paraspinal EMH was defined as radiologic evidence of EMH foci with or without symptoms. The clinical parameters significantly associated with EMH were entered into the logistic regression model. The risk score was derived from the final model's coefficients. A receiver-operating characteristic (ROC) curve was constructed to determine the area under the ROC curve and the cut-off point. Results: The KKU-EMH score included: 1) age greater than 25 year (2 points) and 2) thalassemic facie (3 points). Using the cut-off of 5 points, the score showed good discrimination with an area under the ROC curve of 0.83 (95% CI 0.76 to 0.90). Conclusion: Advanced age and thalassemic facie are independent risk factors for paraspinal EMH in patients with thalassemia. The KKU-EMH score is a practical score. It can be used as a screening tool for paraspinal EMH in patients with ß-thalassemia.

Phenotype and Genotype in a Cohort of 312 Adult Patients with Nontransfusion-Dependent Thalassemia in Northeast Thailand.

Patients with nontransfusion-dependent thalassemia (NTDT) do not require regular blood transfusion for survival but may encounter several complications that contribute to morbidity and mortality. We report the molecular heterogeneity and hematological features of NTDT in 312 adult patients in northeast Thailand. Hemoglobin (Hb) and DNA analyses identified 177 subjects with Hb E-ß-thalassemia, 1 with homozygous ß0-thalassemia and 134 with Hb H, AEBart's and EEBart's diseases. For ß-thalassemia, 12 different mutations including both ß0- and ß+-thalassemias were detected. Coinheritance of α-thalassemia as an ameliorating factor was observed in 18 of 178 cases (10.1%) with ß-thalassemia. The α-globin gene triplicated haplotype (αααanti3.7) was observed in 1 case of Hb E-ß0-thalassemia. The presence of the -158 (Cx2192;T) Gx03B3;-XmnI polymorphism (+/+) was found to be associated with increased Hb F expression, but its frequency in the studied subjects was low. Those with α-thalassemia included 17 with deletional and 51 nondeletional Hb H, and 63 with AEBart's and 3 with EEBart's diseases. The hematological parameters of these NTDT and genotype-phenotype relationships are presented. The diverse molecular heterogeneity of NTDT underlines the importance of complete genotyping of the patient. These results should prove useful for management planning, the prediction of clinical outcome and to improve genetic counseling for NTDT patients.

A risk score for predicting pulmonary hypertension in patients with non-transfusion-dependent thalassemia in northeastern Thailand: The E-SAAN score.

INTRODUCTION: Pulmonary hypertension (PH) is a major complication in patients with non-transfusion-dependent thalassemia (NTDT). The risk score was developed to be a screening test for PH risk in these patients. METHODS: A multi-center study was conducted in patients with NTDT aged ≥10 years old. PH risk was defined as tricuspid regurgitation velocity >2.9 m/s by echocardiography. The clinical parameters significantly associated with PH were entered into the logistic regression model. RESULTS: The E-SAAN score included (1) age >35 years (2.5 points), (2) time after splenectomy >5 years (2.5 points), and (3) ß-thalassemia/hemoglobin E (2 points). Using the cut-off point of 4.5 points, the score showed a good discrimination in the validating group with an area under receiver-operating characteristics curve of 0.88 (95% CI 0.8-0.95). CONCLUSION: The E-SAAN score is a simple and practical score which can be used as a screening test for PH risk in patients with NTDT.

Effect of genotype on pulmonary hypertension risk in patients with thalassemia.

INTRODUCTION: Pulmonary hypertension is one of the major complications in patients with non-transfusion-dependent thalassemia (NTDT). Patients with NTDT have distinct genetic subgroups. Therefore, the effects of different genotype groups on pulmonary hypertension risk in patients with NTDT were assessed. METHODS: A cross-sectional study was conducted in patients with NTDT aged ≥ 10 yr old at Srinagarind University Hospital and Udonthani Hospital, Thailand. Pulmonary hypertension risk was defined as peak tricuspid regurgitation velocity > 2.9 m/s by trans-thoracic echocardiography. Clinical characteristics and laboratory data that literature has indicated as risk factors for pulmonary hypertension were collected. The effect of genotype group on pulmonary hypertension risk was evaluated by using multivariate logistic regression analysis. RESULTS: Of 219 patients, pulmonary hypertension risk was found in 24 patients (10.96%). All patients were categorized into two groups according to genetic data that included: (i) ß-thalassemia (139, 63.5%), (ii) α-thalassemia and combined α and ß-thalassemia (80, 36.5%). Genotype groups were statistically and significantly associated with pulmonary hypertension risk based on the adjusted odds ratios after adjustment for other factors. Patients with ß-thalassemia had a statistically significant higher risk for pulmonary hypertension risk (odds ratio = 9.47, P = 0.036) compared to patients with α-thalassemia and patients with combined α and ß-thalassemia. CONCLUSION: The genotype group is an independent risk factor for pulmonary hypertension in patients with NTDT. Echocardiography should be routinely recommended for all patients with ß-thalassemia. Routine screening in patients with α-thalassemia and combined α and ß-thalassemia, however, may not be necessary or should focus on the older population.

Inadvertent intrathecal vincristine administration: report of a fatal case despite cerebrospinal fluid lavage and a review of the literature.

Accidental intrathecal vincristine administration results in progressive ascending radiculomyeloencephalopathy usually leading to fatal outcome. No specific therapy for intrathecal vincristine toxicity has been reported. We report a 63-year-old man with diffuse large B-cell lymphoma at the right testis who inadvertently received intrathecal vincristine. Direct CSF aspiration and irrigation was done 30 minutes after the incident. Ventriculostomy and lumbar drain was placed. Intrathecal irrigation was started at 6.5 hours using FFP-containing lactate solution and continued for 11 days. In addition, antineurotoxic and neuroprotective agents were given. His neurological symptom deteriorated slowly and he died on day 12. Among 16 reported cases undergoing lumbar drainage and/or irrigation, 56.3% can survive 30 days or more and 37.5% had survive more than 6 months. Immediate CSF drainage and early irrigation is related to good outcome (prolonged survival with no encephalopathy). In our case, his poor outcome might be due to the delayed starting of irrigation. In conclusion, the appropriate and effective management of this complication is unknown. However, emergency cerebrospinal fluid drainage and irrigation remains the principal of management.