Suzanne Koussa

Efficacy and tolerability of peginterferon alpha-2a with or without ribavirin in thalassaemia major patients with chronic hepatitis C virus infection

Thalassaemia patients with genotype 1 or 4 chronic hepatitis C virus (HCV) infection were randomised to receive peginterferon alpha‐2a 180 mg/week ribavirin for 48 weeks. Primary efficacy variable was sustained viral response (SVR) at 72 weeks. Thirty‐two patients were evaluated; 20 enrolled. Baseline characteristics were comparable. SVR occurred in four of 12 and five of eight patients in the monotherapy and combination groups (30% and 62·5%; P = 0·19), respectively. Undetectable RNA at 12 weeks and age <18 years were associated with improved SVR (P < 0·05). Transfusion requirements rose by 34% in the combination arm (P = 0·08). Peginterferon/ribavirin was effective in thalassaemics with HCV and moderate iron overload.

Comparison between deferoxamine and deferiprone (L1) in iron‐loaded thalassemia patients

Abstract: Introduction: Iron‐chelating therapy with deferoxamine in patients with thalassemia major has dramatically improved the prognosis of this disease. However, the limitations of this treatment have stimulated the design of alternative orally active iron chelators. Objective: To compare the effectiveness and safety of, and compliance with, oral deferiprone (L1), and deferoxamine, in thalassemia major patients. Methods: All patients were followed up in one center in Lebanon. Sixteen patients were on L1 (75 mg/kg/d), and 40 patients on subcutaneous deferoxamine (20–50 mg/kg/d). Serum ferritin level, urinary iron excretion (UIE) and side effects were monitored over a two year period. Results: Patients on L1 had an initial serum ferritin concentration of 3663±566 µg/l (mean±SEM), that dropped to 2599±314 at 6 months (p<0.02; paired t‐test), and stabilised at that level over the 24 months follow up. Patients on deferoxamine had an initial mean serum ferritin concentration of 3480±417 (NS compared to the L1 group), which dropped gradually to 3143±417 (p<0.05) and 2819±292 (p<0.02) at 6 and 24 months, respectively. The most common adverse reactions associated with L1 were arthralgia and nausea, but they did not necessitate stopping the drug. Conclusion: L1 had comparable efficacy as deferoxamine with minimal side effects and better compliance. Provided long term side effects are not encountered, L1 seems to be a valuable alternative iron chelator for patients unable or unwilling to use deferoxamine effectively.

β-Globin gene cluster haplotypes and HbF levels are not the only modulators of sickle cell disease in Lebanon

Abstract: Sickle cell disease (SCD) is an inherited autosomal recessive disorder of the β‐globin chain. Despite the fact that all subjects with SCD have the same single base pair mutation, the severity of the clinical and hematological manifestations is extremely variable. This study examined for the first time in Lebanon the correlation between the clinical manifestation of SCD and the β‐globin gene haplotypes. The haplotypes of 50 patients diagnosed with SCD were determined using polymerase chain reaction amplification of fragments containing nine polymorphic restriction sites around and within the ε–Gγ–Aγ–ψβ–δ–β‐globin gene complex. Most reported haplotypes were found in our population with the Benin haplotype as the most prevalent one. When the patients were divided according to their HbF levels into three groups (Group A: HbF < 5%, Group B: HbF between 5 and 15%, and Group C: HbF > 15%), surprisingly, the highest levels of HbF were associated with the most severe clinical cases. Our findings suggest that fetal hemoglobin levels are important but not the only parameters that affect the severity of the disease. In addition, the high levels of HbF in patients with CAR haplotypes did not seem to ameliorate the severity of symptoms, suggesting that genetic factors other than haplotypes are the major determinants of increased HbF levels in Lebanon.

Risk factors for pulmonary hypertension in patients with β thalassemia intermedia

BACKGROUND Pulmonary hypertension (PHT) is a common yet poorly understood complication of β thalassemia intermedia (TI). METHODS We herein evaluated risk factors for PHT in TI, through comparing 64 TI patients with evidence of PHT by symptomatology and echocardiography (Group I) to age- and sex-matched TI patients without PHT (Group II). Retrieved data included demographics, laboratory parameters, clinical characteristics, and received treatments that may influence PHT development; and reflected the period prior to PHT occurrence in Group I. RESULTS The mean age of Group I patients at development of PHT was 37.3±10.6years; with 44% being males. Among studied parameters, Group I patients were more likely to be splenectomized (4.9-times), transfusion-naive (3.5-times); hydroxyurea-naive (2.6-times), or iron chelation-naive (2.3-times); and have nucleated red blood cell count ≥300×10(6)/l (2.59-times) or a previous history of thromboembolic events (3.69-times). CONCLUSION TI patients who eventually develop PHT may be identified early on by being splenectomized, having high nucleated red blood cell counts and a previous history of thromboembolism. Prospective clinical trials that evaluate the efficacy, safety, and cost effectiveness of transfusion, iron chelation, and hydroxyurea therapy in preventing PHT in TI are invited.

Hypertransfusion: A Successful Method of Treatment in Thalassemia Intermedia Patients With Spinal Cord Compression Secondary to Extramedullary Hematopoiesis

Summary of Background Data. Extramedullary hematopoiesis is a common compensatory phenomenon to chronic hemolytic anemias including thalassemia. Several sites can be involved including the liver, the spleen, the lymph nodes, and other less common locations. Spinal cord compression may result in the rare cases wherein the hematopoietic develops intraspinally. Treatment of such conditions still is controversial. Objective. This article reviews the literature and reports two cases of thalassemia intermedia involving patients who presented with neurologic symptoms after acute spinal cord compression secondary to extramedullary hematopoiesis. Methods. The diagnosis was established by magnetic resonance imaging. Hypertransfusion therapy was used as our first-line treatment method. Results. Complete neurologic recovery was achieved. Improvement in the neurologic status started as soon as the first week of treatment. Conclusions. Clinical awareness is important for early diagnosis and prevention of irreversible neurologic complications in such cases. Magnetic resonance imaging is the radiologic method of choice for diagnosing extramedullary hematopoietic masses and for delineating the extent of spinal cord involvement. Hypertransfusion seems to be a promising treatment method that should be recommended as a first-line approach or as an adjuvant therapy to other methods.

Health-related quality of life in adults with transfusion-independent thalassaemia intermedia compared to regularly transfused thalassaemia major: new insights

Background: In patients with β thalassaemia intermedia (TI), the milder anaemia and transfusion independence imply better health‐related quality of life (HR‐QoL). However, the unbalanced pathophysiology of the disease allows for several serious clinical complications to manifest, which may have a negative impact on HR‐QoL. Methods: This was a cross‐sectional study on adult patients with transfusion‐ and iron chelation‐independent TI and β thalassaemia major (TM) attending the Chronic Care Center, Hazmieh, Lebanon. A total of 80 patients agreed to participate in the study [32 TI (median age 24 yr) and 48 TM (median age 23 yr)]. The RAND SF‐36 survey was used to assess HR‐QoL. Data on patient demographics, clinical complications and socioeconomic status were collected. Results: Patients with TI and TM were comparable with age and gender, but patients with TM had a significantly longer median duration with a known thalassaemia diagnosis. Patients with TI had a higher proportion of multiple complications. Socioeconomic parameters were comparable, except for patients with TI being more commonly married. The mean Total, Physical Health and Mental Health Scores were significantly lower in patients with TI compared to TM, indicating poorer HR‐QoL. There was a statistically significant positive correlation between the duration with a known thalassaemia diagnosis and a higher Mental Health Score (rs = 0.73, P = 0.020). The mean Physical Health Score was significantly lower in patients with multiple clinical complications compared to patients with single or no complications (P = 0.012). Associations remained independently significant at multivariate analysis. Conclusion: Patients with transfusion‐independent TI have lower HR‐QoL compared to TM patients. At a comparable age, the shorter duration since diagnosis and the multiplicity of complications may explain these findings.

Brain magnetic resonance angiography in splenectomized adults with β-thalassemia intermedia.

Background: Hypercoagulability and venous thromboembolism are common in patients with β‐thalassemia intermedia (TI), especially in the splenectomized adult. Although arterial involvement is not commonly reported, we have recently observed a high prevalence (60%) of silent brain infarction on brain MRI in 30 splenectomized adults with TI. The pathophysiology of these white matter lesions remains unknown. Methods: In this prospective work, we evaluated magnetic resonance angiography (MRA) scans of the same cohort of 30 patients. Data collected were the presence or absence of vascular lesions, their locations, and severity. Correlations between MRA abnormality and patients/disease characteristics were evaluated. Comparisons between MRA and previous MRI findings were made. Results: Of 29 evaluable patients, 8 (27.6%) had evidence of arterial stenosis on MRA. The majority of lesions had mild narrowing and mostly involved the internal carotid artery. Five patients (17.2%) had evidence of aneurysms. Low total hemoglobin and high non‐transferrin‐bound iron levels independently characterized patients with evidence of stenosis on MRA. Among the 18 patients with silent brain infarction on MRI, three had evidence of stenosis on MRA with only one patient having lesions that could explain the silent infarcts. Conclusions: Cerebral vasculopathy is common in splenectomized adults with TI. However, large‐vessel disease does not explain the occurrence of silent brain infarction. The combined use of MRA and MRI better identifies splenectomized TI adults with neuroimaging abnormalities.

Efficacy and Side Effects of Deferiprone (L1) in Thalassemia Patients Not Compliant with Desferrioxamine

We report our experience with deferiprone (L1) (DFP) in 17 thalassemic patients, followed up in one center in Lebanon, who were initially on desferrioxamine and then shifted to DFP at a dose of 50–75 mg/kg/day as the sole chelator during 1-year follow-up. All 17 patients were compliant with therapy and there was no change in physical examination over the study period. Eight patients (47.1%) were positive for hepatitis C virus (HCV) antibodies. Urinary iron excretion was 21.8 ± 14 mg/24 h (mean ± SD) 1 week after starting DFP and dropped 12 months later to 13 ± 7.4 mg/24 h (p = 0.009, paired t test). The initial serum ferritin level was 3,863 ± 2,344 μg/l which dropped to 3,179 ± 2,075 at 12 months after starting therapy (p = 0.07). HCV-negative patients as a group exhibited a significant decrease in serum ferritin after 6 and 12 months of DFP therapy (3,942 ± 2,739 vs. 2,341 ± 1,179 and 2,681 ± 1,519 μg/l; p < 0.03 and p < 0.05, respectively). The most frequent side effects were joint pain, stiffness or swelling in 6 patients (35.3%), and nausea in 7 patients (41.2%), but these were well tolerated and did not require stopping treatment.

Survival and Complications of Beta-Thalassemia in Lebanon

β-Thalassemia major is a debilitating disease with a considerable incidence in Lebanon (around 2–3% carriership). The present article describes our experience to this day with 214 patients, emphasizing the survival of β-thalassemia major and development of complications among patients with different parameters. Fifteen deaths were reported. The most common cause of death was heart failure (60%). Patients with a ferritin level of 3,000 ng/ml showed better survival than those with a level >3,000 ng/ml (p < 0.006). In addition, patients with a ferritin level of 1,500 ng/ml showed less complication-free survival than those with a level >1,500 ng/ml (p < 0.024). High level of ferritin (1,500 ng/ml) is associated with increased risk of heart failure. Overall and complication-free survival were statistically different among patients classified according to birth cohort or ferritin level. The Chronic Care Center, a multidisciplinary center located in the suburbs of Beirut, led to an increase in complication-free as well as overall survival. Although patients are being diagnosed earlier and chelation therapy is being initiated at an earlier age, complications due to iron overload still persist. The introduction of new oral iron chelators and better iron overload quantitation methods will most likely modify this picture, and a follow-up study will examine their impact.

A randomized phase I/II trial of HQK-1001, an oral fetal globin gene inducer, in β-thalassaemia intermedia and HbE/β-thalassaemia

β‐thalassaemia intermedia (BTI) syndromes cause haemolytic anaemia, ineffective erythropoiesis, and widespread complications. Higher fetal globin expression within genotypes reduces globin imbalance and ameliorates anaemia. Sodium 2,2 dimethylbutyrate (HQK‐1001), an orally bioavailable short‐chain fatty acid derivative, induces γ‐globin expression experimentally and is well‐tolerated in normal subjects. Accordingly, a randomized, blinded, placebo‐controlled, Phase I/II trial was performed in 21 adult BTI patients (14 with HbE/β0 thalassaemia and seven with β+/β0 thalassaemia intermedia, to determine effective doses for fetal globin induction, safety, and tolerability. HQK‐1001 or placebo were administered once daily for 8 weeks at four dose levels (10, 20, 30, or 40 mg/kg per day), and subjects were monitored for laboratory and clinical events. Pharmacokinetic profiles demonstrated a t1/2 of 10–12 h. Adverse events with HQK‐1001 treatment were not significantly different from placebo treatment. The 20 mg/kg treatment doses increased median HbF above baseline levels by 6·6% and 4·4 g/l (P < 0·01) in 8/9 subjects; total haemoglobin (Hb) increased by a mean of 11 g/l in 4/9 subjects. These findings identified a safe oral therapeutic which induces fetal globin in BTI. Further investigation of HQK‐1001 with longer dosing to definitively evaluate its haematological potential appears warranted.