Irene Motta

Elevated liver iron concentration is a marker of increased morbidity in patients with β thalassemia intermedia

Background Patients with β thalassemia intermedia can have substantial iron overload, irrespectively of their transfusion status, secondary to increased intestinal iron absorption. This study evaluates whether iron overload in patients with β thalassemia intermedia is associated with morbidity. Design and Methods This was a cross-sectional study of 168 patients with β thalassemia intermedia treated at two centers in Lebanon and Italy. Data on demographics, splenectomy status, transfusion status, and presence of co-morbidities were retrieved. Laboratory values of serum ferritin, fetal and total hemoglobin levels, as well as platelet and nucleated red blood cell counts were also obtained. Iron burden was determined directly by measuring liver iron concentration using magnetic resonance imaging. Patients were subdivided according to transfusion and splenectomy status into groups with phenotypes of different severity. Results The mean age of the patients was 35.2±12.6 years and 42.9% of them were male. The mean liver iron concentration was 8.4±6.7 mg Fe/g dry weight. On multivariate logistic regression analysis, after adjusting for age, gender, splenectomy status, transfusion status, and laboratory indices, an increase in 1 mg Fe/g dry weight liver iron concentration was independently and significantly associated with higher odds of thrombosis, pulmonary hypertension, hypothyroidism, osteoporosis, and hypogonadism. A liver iron concentration of at least 7 and at least 6 mg Fe/g dry weight were the best thresholds for discriminating the presence and absence of vascular and endocrine/bone morbidities, respectively (area under the receiver-operating characteristic curve: 0.72, P<0.001). Elevated liver iron concentration was associated with an increased rate of morbidity in patients with phenotypes of all severity, with a steeper increase in the rate of vascular morbidity being attributed to aging, and an earlier appearance of endocrine and bone disease. Conclusions Elevated liver iron concentration in patients with β thalassemia intermedia is a marker of increased vascular, endocrine, and bone disease.

Redefining thalassemia as a hypercoagulable state.

As the life expectancy of β‐thalassemia patients has markedly improved over the last decade, several new complications are being recognized. The presence of a high incidence of thromboembolic events, mainly in thalassemia intermedia patients, has led to the identification of a hypercoagulable state in thalassemia. In this review, the molecular and cellular mechanisms leading to hypercoagulability in thalassemia are highlighted, and the current clinical experience is summarized. Recommendations for thrombosis prophylaxis are also discussed.

Longitudinal changes in serum ferritin levels correlate with measures of hepatic stiffness in transfusion-independent patients with β-thalassemia intermedia.

Despite evidence of considerable iron overload in transfusion-independent patients with β-thalassemia intermedia, data on hepatic outcomes remain scarce. We analyzed data from a cohort of 42 β-thalassemia intermedia adults followed for four years (median age 38years), and evaluated the association between longitudinal changes in serum ferritin levels and transient elastography values, a measure of hepatic stiffness predictive of fibrosis. We observed a significant increase in both serum ferritin levels (+81.2 [μg/l]/year) and transient elastography values in non-chelated patients (n=28) (+0.3kPa/year), with two patients worsening their fibrosis stage. Chelated patients (n=14) had a significant decrease in both measures (-42.0 [μg/l]/year and -0.9kPa/year, respectively), with two patients improving their fibrosis stage. There was a strong correlation between the rate of change in serum ferritin level and the rate of change in transient elastography value (R(2): 0.836, p<0.001) noted in both non-chelated and chelated patients. An association between iron overload status and hepatic disease merits further evaluation in this subset of transfusion-independent patients.

Investigational drugs in phase I and phase II clinical trials for thalassemia

ABSTRACT Introduction: Regular transfusion and iron chelation are the current treatment of severe forms of thalassemia. As a consequence of this demanding supportive treatment, there are several unmet therapeutic needs. Due to a deeper understanding in the pathophysiology of thalassemia, new therapeutic strategies have been developed that are now in pre-clinical and clinical trials. Areas covered: Activin receptor ligand traps (luspatercept and sotatercept), drugs targeting ineffective erythropoiesis, showed encouraging results in Phase I and II clinical trials. A phase III clinical trial is currently ongoing. Ruxolitinib, a Jak2 inhibitor, has been tested to limit stress erythropoiesis in a phase II clinical trial. In addition, improvement in iron chelation has been developed. Moreover, several trials of gene therapy are currently active in different countries with different lentiviral vectors. Expert opinion: The most promising molecules are the activin receptor ligand traps. Together with gene therapy these could be an alternative to bone marrow transplant, aiming towards a curative strategy. The main limit to gene therapy seems to be the conditioning regimen, thus an in vivo gene therapy would be more suitable. At pre-clinical level gene editing is showing extremely encouraging results.

A multicentre observational study for early diagnosis of Gaucher disease in patients with Splenomegaly and/or Thrombocytopenia.

Gaucher disease (GD) is the most common lysosomal disorder resulting from deficient activity of the β‐glucosidase enzyme that causes accumulation of glucosylceramide in the macrophage–monocyte system. Notably, because of non‐specific symptoms and a lack of awareness, patients with GD experience long diagnostic delays. The aim of this study was to apply a diagnostic algorithm to identify GD type 1 among adults subjects referred to Italian haematology outpatient units because of splenomegaly and/or thrombocytopenia and, eventually, to estimate the prevalence of GD in this selected population. One hundred and ninety‐six subjects (61 females, 135 males; mean age 47.8 ± 18.2 years) have been enrolled in the study and tested for β‐glucosidase enzyme activity on dried blood spot (DBS). Seven of 196 patients have been diagnosed with GD, (5 females and 2 males) with mean age 31.8 ± 8.2 years, with a prevalence of 3.6% (with a prevalence of 3.6% (I95% CI 1.4–7.2; 1/28 patients) in this population. These results show that the use of an appropriate diagnostic algorithm and a simple diagnostic method, such as DBS, are important tools to facilitate the diagnosis of a rare disease even for not disease‐expert physicians.

A giant adrenal myelolipoma in a beta-thalassemia major patient: Does ineffective erythropoiesis play a role?

A 40-year-old thalassemia major (genotype b0 cod39/b1 IVSI-110) patient, regularly transfused with three units of packed red cells every three weeks with an average pre-transfusion hemoglobin level of 100 g/L, presented in 2002 with a right abdominal mass measuring 7.5 cm of maximum width found incidentally during the annual ultrasound (US) examination of the abdomen. A subsequent MRI showed radiological features suggestive for extramedullary hematopoiesis (EMH) thus the mass was periodically monitored. In 2009, because of the progressive increase in mass volume, hydroxyurea therapy was started at increasing dosage up to 15 mg/kg per day. In 2014 and 2015, a US evaluation showed a rapidly increasing volume of the abdominal mass. A computed tomography (CT) scan of the abdomen and pelvis with intravenous iodine contrast (Image 1) showed a huge well circumscribed retroperitoneal poly-lobed mass in the right abdomen measuring 19 3 15 3 25 cm, originating from the right adrenal gland and displacing the liver medially and the right kidney caudally and anteriorly; moreover, it compressed the inferior vena cava and displaced the mesenteric vessels. The mass was poorly vascularized with low contrast enhancement and marked heterogeneity, primarily due to the presence of fat tissue. At this time the radiological features were more suggestive of either an angiomyolipoma or a myelolipoma rather than EMH. Laparotomy was performed and a 3.5 kg encapsulated tumor (Image 1) attached to the right adrenal gland was removed. Gross examination showed a soft yellow to red cut surface with focal areas of hemorrhage. Extensive sampling was performed given the size of the mass and microscopic examination showed typical features of myelolipomas, with varying proportions of mature adipose tissue admixed with trilineage hematopoiesis (Image 1). A thin rim of residual adrenal tissue was present at the edge of the mass. Myelolipoma is a rare tumor that accounts for approximately the 4% of adrenal tumors. Some cases are associated with chronic hemolytic anemias or ineffective erythropoiesis, including both transfusion dependent and transfusion independent thalassemia [1–4], sickle cell anemia [5,6], and hereditary spherocytosis [7,8]. In a few cases the diagnosis of myelolipoma allowed the retrospective diagnosis of the underlying congenital anemia [5,8]. These associations suggest that the tumor is under the control of hematopoietic stimuli. It has been demonstrated that the first hematopoietic activity, known as primitive hematopoiesis, appears in the blood islands of the yolk sac. However, the first hematopoietic stem cells (HSC), defined by their capacity for long-term and multi-lineage engraftment in adult recipients, appear in the mammal embryo in the (AGM) region, and then home to the fetal liver [9,10]. We demonstrated by flow cytometry that the mass of our patient contained erythroid precursors (Image 1). Hence, residual HSC in organs derived from the AGM region in patients with ineffective erythropoiesis might be the source of the tumor mass. In our cohort of 190 patients affected by transfusion dependent thalassemia, we observed four cases of myelolipoma, three originating from the adrenal glands and one from the pelvic region. Further investigations involving a greater number of patients are needed to establish the prevalence of a tumor that might be underestimated in patients affected by diseases with chronic anemia and ineffective erythropoiesis.

Clinical Complications and Their Management

The hallmarks of thalassemias are ineffective erythropoiesis and peripheral hemolysis leading to a cascade of events responsible for several clinical complications. This pathophysiologic mechanism can be partially controlled by blood transfusions or by correction of the severity of ineffective erythropoiesis. Thalassemias include a spectrum of phenotypes. Two main groups can be clinically distinguished: transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) thalassemia. Both conditions are characterized by several clinical complications along life; some are shared, whereas some have higher prevalence in one group over the other. The authors present the most common clinical complications in TDT and NTDT and their management.

New therapeutic targets in transfusion-dependent and -independent thalassemia

β-Thalassemias are characterized by reduced production of β-globin chain, resulting in α/β-chain unbalance and precipitation of α-globin-heme complexes and determining ineffective erythropoiesis. Ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hematopoietic expansion are the disease hallmarks, and they are related to the severity of the chain unbalance. Several clinical forms of β-thalassemia, including the coinheritance of β-thalassemia with hemoglobin E resulting in hemoglobin E/β-thalassemia, have been described. Clinically, β-thalassemias can be classified as transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) according to the severity of the phenotype, which is caused by a wide spectrum of mutations in a homozygous or compound heterozygous state. Current treatment of TDT consists of regular transfusions that lead to iron overload, requiring iron chelation to prevent iron-related organ toxicity. NTDT patients do not require transfusions or only occasionally require them; however, they develop iron overload as well because of increased intestinal iron absorption caused by chronic anemia. Hematopoietic stem cell allogenic transplant is the only approved cure for β-thalassemia; however, it is still limited by clinical conditions and the availability of matched donors as well as by potential graft-versus-host disease (GVHD). Gene therapy could avoid the GVHD risk, although hematopoietic stem cells must be genetically modified ex vivo. Epigenetic manipulation and genomic editing are novel experimental approaches. An increased understanding of the pathophysiology that controls the disease process prompted us to explore alternative therapeutic approaches that address the underlying chain unbalance, ineffective erythropoiesis, and iron dysregulation. Molecules, such as JAK2 inhibitors and the activin-receptor ligand trap that target ineffective erythropoiesis, are already in clinical trials with promising results. Other agents aimed to generate iron-restricted erythropoiesis are also under experimental evaluation.

Deferasirox: an orphan drug for chronic iron overload in non-transfusion dependent thalassemia syndromes

ABSTRACT Introduction: Patients with non-transfusion dependent thalassemia (NTDT) are at a significant risk of developing iron overload due to increased iron absorption from the gastrointestinal tract, resulting in a host of comorbidities. Deferasirox, the only oral iron chelator approved for use in NTDT, has been evaluated in several prospective studies and clinical trials. Areas covered: In this review, we will summarize the studies investigating the use of deferasirox in NTDT, focusing on the two largest clinical trials available thus far. THALASSA, the first prospective, randomized and placebo-controlled trial has demonstrated significant reduction in iron burden with deferasirox treatment along with a favorable side effect profile. THETIS, an ongoing clinical trial, has confirmed the findings of THALASSA and highlighted the efficacy and safety of using higher doses of deferasirox along with an earlier dose escalation protocol. Expert opinion: Longer follow-up and continued investigations will further tailor the treatment approach to iron chelation in patients with NTDT, which will likely affect their comorbidity profile and impact their quality of life scores. Since the iron chelation treatment algorithm in NTDT relies on MRI technology, further understanding of the molecular processes governing iron overload in this population may help establish diagnostic surrogates in resource limited countries in order to guide treatment with deferasirox.

Prevalence and predictors of liver fibrosis evaluated by vibration controlled transient elastography in type 1 Gaucher disease

BACKGROUND & AIMS Long-term liver-related complications of Gaucher disease (GD) include cirrhosis, portal hypertension and hepatocellular carcinoma. Although liver fibrosis is the main determinant of adverse liver-related clinical outcomes, it has rarely been evaluated in previously published cohorts of GD patients. We aimed at: assessing the prevalence of significant liver fibrosis in a cohort of patients with type 1 GD; identifying its predictors among GD-related variables, enzyme replacement therapy (ERT) and metabolic features. METHODS 37 adult type 1 GD patients from two Italian academic referral centers were prospectively submitted to vibration controlled transient elastography (Fibroscan®); significant fibrosis was defined as liver stiffness ≥7 kPa. RESULTS Median liver stiffness was 4.6 [3-15.1] kPa and 7 patients (19%) had significant fibrosis. Significant fibrosis was associated with splenectomy (p = .046) and with scores (DS3: p = .002; SSI: p = .026) and biomarkers (ACE: p = .016; HDL cholesterol: p = .004) of GD severity. Length of ERT was significantly lower in GD patients with significant fibrosis. In the subgroup of 29 patients who were on stable ERT for at least 24 months, further to splenectomy, GD severity and non-N370S GBA1 genotypes, also diastolic blood pressure, BMI and the number of metabolic syndrome (MetS) components emerged as factors significantly associated with significant fibrosis. CONCLUSIONS Significant fibrosis is present in a remarkable proportion of adult type 1 GD patients. Splenectomy, GD severity and GBA1 genotypes are major GD-related predictors of liver fibrosis. Length of ERT is inversely correlated with liver disease in GD patients, suggesting a beneficial effect of ERT on liver fibrosis. However, GD patients on stable ERT should be monitored for metabolic complications, since MetS features may enhance liver disease progression despite optimal GD control.