Suporn Chuncharunee

Pulmonary arterial hypertension in previously splenectomized patients with β-thalassemic disorders

Our aim was to study the cause and describe the clinical features of pulmonary arterial hypertension (PHT) in splenectomized β-thalassemia (β-Thal) patients. Ten splenectomized β-Thal patients with systolic pulmonary artery (PA) pressure >30 mm Hg were evaluated by echocardiography, right-heart catheterization, and pulmonary angiography. Five of these patients later underwent hemodynamic studies. Echocardiography and pulmonary angiography on the 10 patients showed normal values of left ventricular systolic function and no findings of acute or chronic pulmonary embolism. Hemodynamic evaluation showed very high PA pressures associated with markedly increased pulmonary vascular resistance indices (PVRIs). Hematological evaluation of the 10 patients showed marked anemia, markedly increased numbers of nucleated red blood cells (nRBCs), and serum ferritin. Mean platelet count, plasma β2 thromboglobulin, and thrombin—antithrombin III complex levels were significantly increased. It was concluded that PHT can be found in splenectomized β-Thal patients. Features associated with PHT were female sex, hemoglobin E/β-Thal, status many years postsplenectomy, marked anemia, markedly increased nRBC count, thrombocytosis, and very high serum ferritin levels. PHT was not due to pulmonary emboli. Our findings suggested that severe PHT was due to increased PVRI from thrombotic pulmonary arteriopathy, likely from chronic low-grade hypercoagulability and platelet activation after splenectomy.

International reproducibility of single breathhold T2* MR for cardiac and liver iron assessment among five thalassemia centers.

To examine the reproducibility of the single breathhold T2* technique from different scanners, after installation of standard methodology in five international centers.

Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study

Nontransfusion-dependent thalassemia (NTDT) patients may develop iron overload and its associated complications despite receiving only occasional or no transfusions. The present 1-year, randomized, double-blind, placebo-controlled THALASSA (Assessment of Exjade in Nontransfusion-Dependent Thalassemia) trial assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients. A total of 166 patients were randomized in a 2:1:2:1 ratio to starting doses of 5 or 10 mg/kg/d of deferasirox or placebo. The means ± SD of the actual deferasirox doses received over the duration of the study in the 5 and 10 mg/kg/d starting dose cohorts were 5.7 ± 1.4 and 11.5 ± 2.9 mg/kg/d, respectively. At 1 year, the liver iron concentration (LIC) decreased significantly compared with placebo (least-squares mean [LSM] ± SEM, -2.33 ± 0.7 mg Fe/g dry weight [dw], P = .001, and -4.18 ± 0.69 mg Fe/g dw, P < .001) for the 5 and 10 mg/kg/d deferasirox groups, respectively (baseline values [means ± SD], 13.11 ± 7.29 and 14.56 ± 7.92 mg Fe/g dw, respectively). Similarly, serum ferritin decreased significantly compared with placebo by LSM -235 and -337 ng/mL for the deferasirox 5 and 10 mg/kg/d groups, respectively (P < .001). In the placebo patients, LIC and serum ferritin increased from baseline by 0.38 mg Fe/g dw and 115 ng/mL (LSM), respectively. The most common drug-related adverse events were nausea (n = 11; 6.6%), rash (n = 8; 4.8%), and diarrhea (n = 6; 3.6%). This is the first randomized study showing that iron chelation with deferasirox significantly reduces iron overload in NTDT patients with a frequency of overall adverse events similar to placebo.

A scoring system for the classification of β-thalassemia/Hb E disease severity

β‐Thalassemia intermediate patients show a remarkable clinical heterogeneity. We examined the phenotypic diversity of 950 β‐thalassemia/Hb E patients in an attempt to construct a system for classifying disease severity. A novel scoring system based on six independent parameters, hemoglobin level, age at disease presentation, age at receiving first blood transfusion, requirement for transfusion, spleen size, and growth and development, was able to separate patients into three distinctive severity categories: mild, moderate, and severe courses. This system, therefore, can increase the accuracy of studies of genotype–phenotype interactions and facilitate decisions for appropriate patient management. Am. J. Hematol. 2008.

In vivo Platelet Activation and Hyperaggregation in Hemoglobin E/β-Thalassemia: A Consequence of Splenectomy

Patients with hemoglobin E/β-thalassemia (E/β-Thal) who have undergone splenectomy are prone to thrombosis in the small pulmonary arteries.To study the role of platelets in this situation, we assayed plasma β2-thromboglobulin (βTG) and performed whole blood platelet aggregation analysis of 30 E/β-Thal patients, half of whom had undergone splenectomy.We compared results with those obtained with 15 healthy control subjects. Plasma βTG levels in splenectomy patients were significantly higher than in control subjects and patients who had not undergone splenectomy, and platelets in splenectomy patients exhibited hyperaggregation in response to adenosine diphosphate, thrombin, and ristocetin. Levels of plasma thrombin-antithrombin III complex were also significantly higher. This finding is likely due to an increased number of erythrocytes with exposed phosphatidylserines, an effect that has been associated with splenectomy. The increased presence of thrombin in the blood may well be the cause of platelet hyperactivity, which was evident only in the asplenic patients. Platelet hyperactivity very likely plays a pathogenetic role in the thrombosis of small pulmonary arteries that occurs in E/β-Thal patients who have undergone splenectomy.

Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia

Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non‐transfusion‐dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade® in non‐transfusion‐dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron‐overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).

Treatment outcome of thalidomide based regimens in newly diagnosed and relapsed/refractory non-transplant multiple myeloma patients: a single center experience from Thailand.

BackgroundThalidomide based regimen is an effective and well tolerated therapy in multiple myeloma (MM) patients, however, there were a small number of studies written about the results of thalidomide therapy in non-transplant MM patients. We therefore conducted a retrospective study of 42 consecutive patients with newly diagnosed and relapsed/refractory MM treated with thalidomide- based induction regimens followed by thalidomide maintenance therapy.ResultsInduction regimens with thalidomide and dexamethasone, and the oral combination of melphalan, prednisolone and thalidomide were administrated in 22 and 16 patients, respectively. The remaining 4 patients received other thalidomide- containing regimens. Twenty-nine patients received thalidomide as a salvage regimen. Twenty-three out of 26 patients achieving complete remission (CR) and very good partial remission (VGPR) received thalidomide maintenance. Of the 41 evaluable patients, median time of treatment was 21 months (3- 45 months), ORR was 92.7% with a 63.4% CR/VGPR. With a median follow up of 23 months, 3-year- PFS and 3-year-OS were 58.6 and 72.6%, respectively. Median time to progression was 42 months. While 3-year-PFS and 3-year-OS in non-transplant patients receiving thalidomide maintenance therapy were 67 and 80%, respectively.ConclusionsProlonged thalidomide therapy enhanced survival rate and less frequently developed serious toxicity in non-transplant multiple myeloma patients.

Approaching low liver iron burden in chelated patients with non-transfusion-dependent thalassemia: the safety profile of deferasirox

Patients with non‐transfusion‐dependent thalassemia (NTDT) often develop iron overload and related complications, and may require iron chelation. However, the risk of over‐chelation emerges as patients reach low, near‐normal body iron levels and dose adjustments may be needed. In the THALASSA study, the threshold for chelation interruption was LIC <3 mg Fe/g dw (LIC<3); 24 patients receiving deferasirox for up to 2 yr reached this target. A post hoc analysis was performed to characterize the safety profile of deferasirox as these patients approached LIC<3.

Deferasirox demonstrates a dose-dependent reduction in liver iron concentration and consistent efficacy across subgroups of non-transfusion-dependent thalassemia patients

The 1‐year THALASSA study enrolled 166 patients with various non‐transfusion‐dependent thalassemia (NTDT) syndromes, degrees of iron burden and patient characteristics, and demonstrated the overall efficacy and safety of deferasirox in reducing liver iron concentration (LIC) in these patients. Here, reduction in LIC with deferasirox 5 and 10 mg/kg/day starting dose groups is shown to be consistent across the following patient subgroups—baseline LIC/serum ferritin, age, gender, race, splenectomy (yes/no), and underlying NTDT syndrome (β‐thalassemia intermedia, HbE/β‐thalassemia or α‐thalassemia). These analyses also evaluated deferasirox dosing strategies for patients with NTDT. Greater reductions in LIC were achieved in patients dose‐escalated at Week 24 from deferasirox 10 mg/kg/day starting dose to 20 mg/kg/day. Patients who received an average actual dose of deferasirox >12.5–≤17.5 mg/kg/day achieved a greater LIC decrease compared with the ≥7.5–≤12.5 mg/kg/day and >0–<7.5 mg/kg/day subgroups, demonstrating a dose–response efficacy. LIC reduction across patient subgroups was generally consistent with the primary efficacy analysis with a similar safety profile. Am. J. Hematol. 88:503–506, 2013.

Activation of mononuclear phagocytes and its relationship to asplenia and phosphatidylserine exposing red blood cells in hemoglobin E/β-thalassemia patients.

Aged or abnormal red blood cells with exposed phosphatidylserine (PSRBCs) are cleared from the circulation by splenic macrophages. In asplenic patients, other mononuclear phagocytic cells in tissues and in circulation may function in this capacity. To better understand these changes and the relationship among splenic status, PS-RBCs, blood monocytes, and serum tumor necrosis factor (TNF-α), a product of mononuclear phagocyte activation, patients with hemoglobin E/β-thalassemia (E/β-Thal) were studied. Whole blood of 20 nonsplenectomized, 20 splenectomized E/β-Thal patients, and 20 healthy subjects was assayed for PS-RBCs; for monocytes, activated monocytes, and monocyte response to lipopolysaccharide stimulation; and serum was assayed for TNF-α. Asplenic E/β-Thal patients had significantly increased (P < 0.05) amounts of PS-RBCs, monocytes, activated monocytes, and levels of serum TNF-α. The amount of PS-RBCs correlated with levels of serum TNF-α, but the amount of activated monocytes did not correlate with either the amount of PS-RBCs or levels of serum TNF-α. Monocyte response to lipopolysaccharide stimulation in asplenic patients was not as efficient as in the other patients or in normals (77 vs. 404, and 304 folds increment, respectively). The results suggest that splenectomy in E/β-Thal patients led to an increased amount of PSRBCs and activation in the mononuclear phagocytic system.