Page 203 - 2021_09-Haematologica-web

Letters to the Editor
62.2% vs. 95.0%, and 18.5% vs. 95.0%, respectively. Survival was also significantly worse in non-regularly transfused patients compared to regularly transfused patients when considering mortality from cardiovascular disease (Log-rank test χ2: 4.571, P=0.033, Figure 1C) or hepatic disease (Log-rank test Chi-square: 4.989, P=0.026). Survival was comparable between splenec- tomized (n = 886) and non-splenectomized (n = 1,147) patients.
Iron chelation therapy was concomitantly used in all regularly-transfused patients and in 1,168 (67.7%) non- regularly-transfused patients, beginning at a median age of 15 years (IQR: 7-26). Survival was comparable in chelated and non-chelated patients for all-cause mortality (Log-rank test χ2: 0.717, P=0.397). Survival was also com- parable in chelated and non-chelated patients when con- sidering mortality from cardiovascular disease (Log-rank test χ2: 0.001, P=0.0969), but was significantly worse in non-chelated compared with chelated patients when considering mortality from hepatic disease (Log-rank test χ2: 11.489, P=0.001, Figure 1D).
On multivariate Cox regression analysis, including reg- ular transfusion and iron chelation as explanatory vari- ables, regular transfusion therapy was associated with a reduction of approximately 80% in the risk of all-cause mortality (hazard ratio [HR]: 0.202, 95.0%CI: 0.080- 0.509, P=0.001) and mortality from cardiovascular dis- ease (HR: 0.199, 95.0%CI: 0.046-0.869, P=0.032); while iron chelation therapy was associated with a reduction of around 73% in the risk of mortality from hepatic disease (HR: 0.277, 95.0%CI: 0.093-0.830, P=0.022).
This is the first study to provide mortality estimates in a large cohort of NTDT patients. Cardiovascular disease was the leading cause of death, but unlike in patients with TDT, this cannot be fully explained by cardiac siderosis and subsequent heart failure secondary to chronic transfusions given that the cohort is not so trans- fusion-dependent. Chronic anemia and hypercoagulabili- ty can play a considerable role in the development of vas- cular disease in NTDT (large- and micro-vessel thrombo- sis, pulmonary hypertension, peripheral and renal vascu- lar disease) with or without cardiac dysfunction. In fact, and as seen in regularly-transfused patients in this cohort, transfusions in this context may have a protective effect by halting ineffective erythropoiesis and subsequent pathogeneses; an observation made in previous cross- sectional studies.6 Improvement in hemolysis markers, nucleated red cells and cardiac index have also been reported in longitudinal studies of NTDT patients who were started on regular transfusions in adulthood.10 This also explains why iron chelation did not seem to have a role in preventing cardiovascular deaths in this cohort. Thus, a trial of chronic transfusion in patients at risk of significant morbidity may be justified but this needs to be weighed against the eventual risk of secondary siderosis and the elevated need and high cost of iron chelation therapy in a regular transfusion setting. We await data from various novel therapies targeting ineffective ery- thropoiesis and anemia in NTDT.11
Iron overload in non-regularly-transfused NTDT patients is attributed to hepcidin dysregulation and increased intestinal iron absorption.12 Observational studies indicate that hepatic siderosis is the main conse- quence, with no evidence of iron deposition in the heart (unlike in transfusional siderosis).1 Several reports have linked iron overload to hepatic fibrosis and hepatocellular carcinoma in NTDT;13-15 these were a common cause of death in this cohort, although at older ages considering they require more time to manifest. Iron chelation was
associated with a lower risk of death from hepatic dis- ease, adding further evidence to data from clinical trials showing significant decline in liver iron concentration in NTDT patients receiving iron chelation.8,9
Our work merits further evaluation in prospective birth cohorts to address missing information and loss to fol- low-up bias typical of long-term retrospective studies, a factor that can lead to an over-estimation of survival risk. The study could also include additional subsets of non- transfusion-dependent patients including hemoglobin E/β-thalassemia and α-thalassemia, and further explore the role of genotype and environment in geographical variations in outcomes.
Khaled M. Musallam,1* Angela Vitrano,2* Antonella Meloni,3 Sebastiano Addario Pollina,4 Mehran Karimi,5 Amal El- Beshlawy,6 Mahmoud Hajipour,7 Vito Di Marco,8 Saqib Hussain Ansari,9 Aldo Filosa,10 Paolo Ricchi,10 Adriana Ceci,11 Shahina Daar,12 Efthymia Vlachaki,13 Sylvia Titi Singer,14 Zaki A. Naserullah,15 Alessia Pepe,3 Salvatore Scondotto,4 Gabriella Dardanoni,4 Fedele Bonifazi,11 Vijay G. Sankaran,16 Elliott Vichinsky,14 Ali T. Taher17 and Aurelio Maggio2 International Working Group on Thalassemia (IWG-THAL)
*KMM and AV contributed equally as co-first authors.
1Thalassemia Center, Burjeel Medical City, Abu Dhabi, UAE; 2Campus of Haematology Franco and Piera Cutino, AOOR Villa Sofia-V. Cervello, Palermo, Italy; 3MRI Unit, Fondazione G. Monasterio CNR-Regione Toscana, Pisa, Italy; 4D.A.S.O.E, Regione Siciliana, Palermo, Italy; 5Haematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 6Department of Pediatric Haematology, Faculty of Medicine, Cairo University, Cairo, Egypt; 7Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 8Department of Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy; 9Department of Pediatric Haematology & Molecular Medicine, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan; 10Rare Blood Cell Disease Unit, "Cardarelli" Hospital, Naples, Italy; 11Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus, Valenzano (BA), Italy; 12Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Sultanate of Oman, Wallenberg Research Centre, Stellenbosch Institute for Advanced Study, Stellenbosch University, Stellenbosch, South Africa; 13Thalassaemia Unit, Ippokratio University Hospital, Thessaloniki, Greece;
14Division of Hematology-Oncology, Department of Pediatrics, University of California San Francisco, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA; 15Dammam Maternity
and Child Hospital, Dammam, Saudi Arabia; 16Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA and 17Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
Correspondence:
AURELIO MAGGIO - md.amaggio@gmail.com doi:10.3324/haematol.2021.278684
Received: March 1, 2021.
Accepted: April 13, 2021.
Pre-published: April 22, 2021.
Disclosures: KMM has been or is a consultant for Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics and Vifor Pharma; AM received speakers’ honoraria from Chiesi Farmaceutici S.p.A.; EV received hononaria from DEMO S.A.
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