Showing papers by "Raffaella Origa published in 2017"

New film‐coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower‐risk MDS: Results of the randomized, Phase II ECLIPSE study

Abstract: Once-daily deferasirox dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater patient adherence, satisfaction, and quality of life. However, barriers still exist to optimal adherence, including gastrointestinal tolerability and palatability, leading to development of a new film-coated tablet (FCT) formulation that can be swallowed with a light meal, without the need to disperse into a suspension prior to consumption. The randomized, open-label, phase II ECLIPSE study evaluated the safety of deferasirox DT and FCT formulations over 24 weeks in chelation-naive or pre-treated patients aged ≥10 years, with transfusion-dependent thalassemia or IPSS-R very-low-, low-, or intermediate-risk myelodysplastic syndromes. One hundred seventy-three patients were randomized 1:1 to DT (n = 86) or FCT (n = 87). Adverse events (overall), consistent with the known deferasirox safety profile, were reported in similar proportions of patients for each formulation (DT 89.5%; FCT 89.7%), with a lower frequency of severe events observed in patients receiving FCT (19.5% vs. 25.6% DT). Laboratory parameters (serum creatinine, creatinine clearance, alanine aminotransferase, aspartate aminotransferase and urine protein/creatinine ratio) generally remained stable throughout the study. Patient-reported outcomes showed greater adherence and satisfaction, better palatability and fewer concerns with FCT than DT. Treatment compliance by pill count was higher with FCT (92.9%) than with DT (85.3%). This analysis suggests deferasirox FCT offers an improved formulation with enhanced patient satisfaction, which may improve adherence, thereby reducing frequency and severity of iron overload-related complications.

Long-term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment.

Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia remains a challenge. We reported a single-centre case-control study of a large cohort of 516 children and adult patients treated with HSCT or blood transfusion support and iron chelation therapy; 258 patients (median age 12, range 1-45) underwent sibling (67%) or unrelated (33%) HSCT; 97 patients were adults (age ≥ 16 years). The median follow-up after HSCT was 11 years (range 1-30). The conditioning regimen was busulfan (80.6%) or treosulfan-based (19.4%). A cohort of 258 age-sex matched conventionally treated (CT) patients was randomly selected. In transplanted patients the 30-year overall survival (OS) and thalassemia-free survival (TFS) were 82.6 ± 2.7% and 77.8 ± 2.9%, compared to the OS of 85.3 ± 2.7% in CT patients (P = NS); The incidence of grade II-IV acute and chronic graft versus host disease (GvHD) was 23.6% and 12.9% respectively. The probability of rejection was 6.9%. Transplant-related mortality (TRM) (13.8%) was similar to the probability of dying of cardiovascular events in CT patients (12.2%). High-risk Pesaro score (class 3) was associated with lower OS (OR = 1.99, 95% C.I.=1.31-3.03) and TFS (OR = 1.54, 95% C.I.=1.12-2.12). In adult patients, the 23-years OS and TFS after HSCT were 70 ± 5% and 67.3 ± 5%, compared to 71.2 ± 5% of OS in CT (P = NS). Finally, treosulfan was associated with lower risk of acute GvHD (P = .004; OR = 0.28, 95% C.I.=0.12-0.67). In conclusion, the 30-year survival rate of ex-thalassemia patients after HSCT was similar to that expected in CT thalassemia patients, with the vast majority of HSCT survivors cured from thalassemia.

Treatment of hepatitis C virus infection with direct-acting antiviral drugs is safe and effective in patients with hemoglobinopathies

Abstract: Progression of liver fibrosis in patients with hemoglobinopathies is strongly related to the severity of iron overload and the presence of chronic hepatitis C virus (HCV) infection. Effective iron chelation therapy and HCV infection eradication may prevent liver complications. The European Association for the Study of the Liver guidelines recommend interferon-free regimens for the treatment of HCV infection in patients with hemoglobinopathies. However, data regarding the use of direct-acting antiviral drugs (DAAs) in this patient population are few. This observational study evaluated the safety and efficacy of therapy with DAAs in an Italian cohort of patients with hemoglobinopathies, chronic HCV infection and advanced liver fibrosis. Between March 2015 and December 2016, 139 patients received DAAs and completed 12 weeks of follow up after the end of treatment for the evaluation of sustained virological response (12SVR). The 12SVR (93.5%) was comparable with that typically observed in cirrhotic patients without hemoglobinopathies. Three patients died during the period of observation of causes unrelated to DAAs. One patient did not achieve a virological response and five (3.6%) relapsed during 12 weeks of follow-up after the end of therapy. In addition, patients showed significant reductions in serum ferritin at 12 weeks to levels similar to those observed in a control group of 39 patients with thalassemia major without HCV infection, who adhered to chelation therapy and had no overt iron overload. In conclusion, the use of DAAs appears to be safe and effective in patients with hemoglobinopathies and advanced liver disease due to HCV.

Changes in HbA2 and HbF in alpha thalassemia carriers with KLF1 mutation

Abstract: α-thalassemia carriers are common in Mediterranean regions, particularly in the Sardinian population. Their haematological phenotype is characterized by reduced MCV and/or MCH with normal or slightly reduced HbA2 levels and normal HbF. Kruppel-like factor 1 (KLF1) is a pleiotropic erythroid transcription factor that is essential for haematopoiesis. Mutations in the KLF1 gene trigger a series of benign human red blood phenotypes, such as an increase in HbA2 and HBF. Recently, it has been found that KLF1 mutations were a frequent cause of borderline HbA2 levels in a group of Sardinian subjects. Here, we found that KLF1 mutations modulate the phenotype in a cohort of α-thalassemia carriers.

EPO and hepcidin plasma concentrations in blood donors and β-thalassemia intermedia are not related to commercially tested plasma ERFE concentrations

Abstract: REFERENCES [1] Glenthøj A, Ørskov AD, Hansen JW, Hadrup SR, O’Connell C, Grønbæk K. Immune mechanisms in myelodysplastic syndrome. Int J Mol Sci. 2016;17:944. [2] Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–2405. [3] Malcovati L, Cazzola M. The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP). Hematology Am Soc Hematol Educ Program. 2015;2015:299–307. [4] Fattizzo B, Zaninoni A, Nesa F, et al. Lessons from very severe, refractory, and fatal primary autoimmune hemolytic anemias. Am J Hematol. 2015;90:E149–E151. [5] Zaninoni A, Imperiali FG, Cattaneo A, et al. Detection of erythroblast antibodies in mitogen-stimulated bone marrow cultures from patients with myelodysplastic syndromes. Transfusion. 2016;56:2037–2041. [6] Kwok B, Hall JM, Witte JS, et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood. 2015;126:2355–2361.

Hematological phenotypes in children according to the α-globin genotypes

Abstract: Limited information is available on the hematological characterization of the α-thalassemia carrier in pediatric age. The objective of this report was to evaluate the red cell indices according to the α-globin genotype in a cohort of children evaluated in Sardinia. Moreover, we verified the frequency of different α-globin genotypes in this cohort. A total of 453 subjects were investigated for hematological indices and for the most common α-globin defects present in Sardinia. Of them, 352 with HbA2 ≤ 3.2%, and no iron deficiency anemia were taken into consideration to evaluate the red cell indices according to the α-globin genotype in pediatric age. A total of 11 different α-genotypes were detected, confirming the wide heterogeneity of α-thalassemia in Sardinia. Moreover, our results showed that the hematological parameters in normal children may be conditioned by the clinically occult coinheritance of mild α-thalassemia alleles as already described in the adult population while microcytosis and hypocromia in children without iron deficiency should suggest the coexistence of two α-globin defects. We concluded that recognizing the α-globin gene mutations for a particular population with their particular red cell indices may help pediatricians to perform a correct diagnosis distinguishing among physiological and pathological types of microcytosis and hypocromia.

Causes of hospital admission in children and adults with transfusion-dependent thalassemia in Sardinia, 2000-2015.

Abstract: Dear Editor, Since its opening in the 1980s, II Clinica Pediatrica at Ospedale Microcitemico BA.Cao^ in Cagliari, Italy has been the reference for all types of medical conditions occurring in thalassemia major (TM) patients of all ages from South Sardinia. Between 2000 and 2015, 276 subjects out of 642 (43%) transfused at the same hospital were admitted once or more to II Clinica Pediatrica for a total of 690 admissions. The mean age at first hospital admission was 24.3 ± 10.9 years (range 0.2–51 years). At the start of the observation period, all patients followed up at the abovementioned center were on desferrioxamine, with the exception of 21 who were on deferiprone. In December 2015, 15.2% were on desferrioxamine, 25.2% were on deferiprone, 45.4% were on deferasirox, 13.3% were on desferrioxamine plus deferiprone, and 0.8% were on desferrioxamine plus deferasirox. Over the entire period, the top five most prevalent causes of hospital admission were heart failure and/or arrhythmias, infections, mesenteric lymphadenitis in patients treated with subcutaneuous desferrioxamine, digestive tract diseases, and liver diseases. The causes of hospitalization varied according to patient age. Most children admitted between 0 and 10 years of age had a diagnosis of infection. After 30 years of age, infections were the second most common reason for hospital admission, surpassed by heart failure and arrhythmia. The age group characterized by the lowest number of hospital admissions was 10–20 years. Most patients in this group were admitted for mesenteric lymphadenitis. Finally, the analysis of hospital admissions overtime highlighted a progressive decrease in the total days of hospital admission in patients with TM (3514 days between 2000 and 2003, 857 days between 2004 and 2007, 518 days between 2008 and 2011, and 466 days between 2012 and 2015), despite the increasing number of patients transfused at the abovementioned center during the four periods (556, 566, 574 and 594, respectively). Specifically, the rate of patients diagnosed with mesenteric lymphadenitis progressively declined (p < 0.0001 between the years 2000–2003 and the two more recent four-year periods). The admissions for other infectious diseases significantly decreased after 2003 (p < 0.0001). In addition, the rate of patients admitted for heart disease showed a sharp decrease from the 2000–2003 period to the 2004–2007 period (p = 0.0009) and substantial stability afterward (Table 1) [1]. In conclusion, this report shows that the increasing use of oral chelators has deeply influenced the causes of hospital admission in TM in high-income countries. On one hand, the downsized adoption of desferrioxamine has involved a clear decrease in the number of hospital admissions for mesenteric lymphadenitis due to Yersinia enterocolitica which can use ferrioxamine for growth [2, 3]. On the other hand, the advent of chelation regimes that are more cardioprotective than the monotherapy with desferrioxamine supports the reduction of admissions for heart disease in parallel to the previously described decrease in mortality [4–6]. However, the absence of a further decline in the rate of patients admitted to the hospital with heart failure in the last four-year period calls for reflection on the always topical issue of therapeutical * Raffaella Origa raffaella.origa@unica.it; secondacasella@hotmail.com

Earlier initiation of transfusional and iron chelation therapies in recently born children with transfusion-dependent thalassemia.

Abstract: Kebede Begna , Aref Al-Kali, Michelle Elliott, James Foran, Naseema Gangat, William Hogan, Christopher Hook, Jose Leis, Mark Litzow, Ruben Mesa, Jeanne Palmer, Animesh Pardanani, Mrinal Patnaik , Candido Rivera, Lisa Sproat, Raoul Tibes, Alexandra Wolanskyj-Spinner, Ayalew Tefferi Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota Division of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida Division of Hematology/Medical Oncology, Mayo Clinic, Scottsdale, Arizona