The Safety of Chelators for Iron Overload in Sickle Cell Disease: A Brief Systematic Review

Sickle cell disease is a group of disorders that affects hemoglobin due to a mutation of the hemoglobin beta gene on chromosome 11. Patients have atypical hemoglobin molecules called hemoglobin S, which distort erythro-cytes into a “sickle-shape”. Typical symptoms of disease include periodic ep-isodes of pain, repeated infections, and anemia. This disorder is abundant in sub-Saharan African countries, the Mediterranean region, and also appears in some southern provinces in Turkey. Because of the high concentration of hemoglobin S in patients, a high risk of chronic anemia and vaso-occlusive events, such as stroke may deteriorate suddenly. In these conditions, trans-fusion of blood, especially erythrocytes, can be life-saving. However, chronic blood transfusions may lead to iron overload in patients. Erythrocyte trans-fusion is associated with a higher risk in most patients with sickle cell disease than in the general population. Therefore, chelation therapy has become an important component of the transfusion program to prevent complica-tions of iron accumulation in organs such as liver and heart. In this study, we sought to conduct a systematic review to assess the safety of iron chelat-ing agents used by patients with iron overload mainly due to necessary blood transfusion regime. Our evaluation revealed that in general iron chelation therapy, either deferasirox, deferoxamine or deferiprone, remains the most effective and safest available method to treat iron overload in sickle cell dis-ease. Furthermore, current reports do not reflect any significant safety con-cerns against the use of available chelators.

Kaynakça

Williams TN, Weatherall DJ. World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med 2012; 2(9): a011692.

Piel FB, Tatem AJ, Huang Z, et al. Global migration and the changing distribution of sickle haemoglobin: a quantitative study of temporal trends between 1960 and 2000. Lancet Glob Heal 2014; 2(2): e80-9.

Piel FB, Hay SI, Gupta S, et al. Global burden of sickle cell anaemia in children under five, 2010–2050: Modelling based on demographics, excess mortality, and interventions. PLoS Med 2013; 10(7): e1001484.

Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol 2000; 151(9): 839-45.

Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Prim 2018; 4: 18010.

Redding-Lallinger R, Knoll C. Sickle cell disease--patho-physiology and treatment. Curr Probl Pediatr Adolesc Health Care.2006; 36(10): 346-76.

Chirico EN, Pialoux V. Role of oxidative stress in the patho-genesis of sickle cell disease. IUBMB Life 2012; 64(1): 72–80.

Aslan M, Ryan TM, Adler B, et al. Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. Proc Natl Acad Sci 2001; 98(26): 15215–20.

Voskou S, Aslan M, Fanis P, et al. Oxidative stress in β-thalas-saemia and sickle cell disease. Redox Biol 2015; 6: 226–39.

Oztas Y, Durukan I, Unal S, et al. Plasma protein oxidation is correlated positively with plasma iron levels and negatively with hemolysate zinc levels in sickle-cell anemia patients. Int J Lab Hematol 2012; 34(2): 129–35.

Lobitz S, Telfer P, Cela E, et al. Newborn screening for sickle cell disease in Europe: recommendations from a Pan-European Consensus Conference. Br J Haematol 2018;183(4) : 648–60.

Kapoor S, Little JA, Pecker LH. Advances in the Treatment of Sickle Cell Disease. Mayo Clin Proc 2018; 93(12): 1810–24.

Gluckman E. Allogeneic transplantation strategies in-cluding haploidentical transplantation in sickle cell disease. Hematology Am Soc Hematol Educ Program 2013; 2013: 370-6.

Mulaku M, Opiyo N, Karumbi J, et al. Evidence review of hydroxyurea for the prevention of sickle cell complications in low-income countries. Arch Dis Child 2013; 98(11): 908-14.

Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med 2018; 379(3): 226–35.

Niihara Y, Zerez CR, Akiyama DS, et al. Oral L-glutamine therapy for sickle cell anemia: I. subjective clinical improvement and favorable change in red cell NAD redox potential. Am J Hematol 1998; 58(2): 117-21.

Porter J, Garbowski M. Consequences and management of iron overload in sickle cell disease. Hematology Am Soc Hematol Educ Program 2013; 2013: 447-56.

DeBaun MR, Vichinsky EP (Section Eds: Schrier SL, Mahoney DH, Jr; Deputy Eds: Tirnauer JS, Vichinsky EP, Schrier SL). Red blood cell transfusion in sickle cell disease. https://www.upto-date.com/contents/red-blood-cell-transfusion-in-sickle-cell-disease (accessed May 2019).[19] Thein SL, Howard J. How I treat the older adult with sickle cell disease. Blood 2018; 132(17): 1750–60.

Wood JC, Cohen AR, Pressel SL, et al. Organ iron accumu-lation in chronically transfused children with sickle cell anae-mia: baseline results from the TWiTCH trial. Br J Haematol 2016; 172(1): 12 2–3 0 .

Tavares AHJ, Benites BD, Fertrin KY. Myocardial iron over-load in sickle cell disease: A rare but potentially fatal complica-tion of transfusion. Transfus Med Rev 2019; 33(3):170-175.

Estcourt LJ, Fortin PM, Hopewell S, et al. Red blood cell transfusion to treat or prevent complications in sickle cell dis-ease: an overview of Cochrane reviews. Cochrane Database Syst Rev 2016; 2016(2). pii: CD012082.

Schrier SL, Bacon BR (Section Ed: Mentzer WC; Deputy Ed: Tirnauer JS). Iron chelators: Choice of agent, dosing, and adverse effects. https://www.uptodate.com/contents/iron-chelators-choice-of-agent-dosing-and-adverse -effects?-search=Iron%20chelators%20Choice%20of%20agent,%20dosing, %20and %20adverse%20effects&source=search_re-sult&selectedTitle=1~150&usage_type=default&display_rank=1 (accessed May 2019).

De Montalembert M, Ribeil JA, Brousse V, et al. Cardiac iron overload in chronically transfused patients with thalassemia, sickle cell anemia, or myelodysplastic syndrome. PLoS One 2 017; 12(3): e 017 2147.

Chou ST. Transfusion therapy for sickle cell disease: a bal-ancing act. Hematology Am Soc Hematol Educ Program 2013; 2013: 439 - 4 6 .

Coates TD, Wood JC. How we manage iron overload in sick-le cell patients. Br J Haematol 2017; 177(5): 703-16.

Botzenhardt S, Li N, Chan EW, et al. Safety profiles of iron chelators in young patients with haemoglobinopathies. Eur J Haematol 2017; 98(3): 198-217.

Moher D, Shamseer L, Clarke M, et al. Preferred report-ing items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4:1.

Alvarez O, Yovetich NA, Scott JP, et al. Pain and other non-neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial. Am J Hematol 2013; 88(11): 932–8.

Calvaruso G, Vitrano A, Di Maggio R, et al. Deferiprone ver-sus deferoxamine in sickle cell disease: results from a 5-year long-term Italian multi-center randomized clinical trial. Blood Cells Mol Dis 2014; 53(4): 265–71.

Goldberg SL, Giardina PJ, Chirnomas D, et al. The palatabili-ty and tolerability of deferasirox taken with different beverages or foods. Pediatr Blood Cancer 2013; 60(9):1507-12.

Antmen B, Karakaş Z, Yeşilipek MA, et al. Deferasirox in chil-dren with transfusion‐dependent thalassemia or sickle cell ane-mia: A large cohort real‐life experience from Turkey (REACH‐THEM). Eur J Haematol. 2019; 102(2): 123-30.

Vichinsky E, Torres M, Minniti CP, et al. Efficacy and safety of deferasirox compared with deferoxamine in sickle cell disease: Two-year results including pharmacokinetics and concomitant hydroxyurea. Am J Hematol 2013; 88(12): 1068–73.

Jordan LB, Vekeman F, Sengupta A, et al. Persistence and compliance of deferoxamine versus deferasirox in Medicaid patients with sickle-cell disease. J Clin Pharm Ther 2012; 37(2): 17 3 – 81.

Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet 2017; 390: 311–23.

Raghupathy R, Manwani D, Little JA. Iron overload in sickle cell disease. Adv Hematol. 2010; 2010: 272940.

Cancado R, Watman NP, Lobo C, et al. Assessment of liv-er and cardiac iron overload using MRI in patients with chron-ic anemias in Latin American countries: results from ASIMILA study. Hematology 2018; 23(9): 676–82.

Mohsin A, Hassan M. A 3-year study of deferasirox therapyn sickle cell disease patients in Basra, Southern Iraq. Niger J Clin Pract. 2018; 21(6): 735-42.

Vichinsky E, Bernaudin F, Forni GL, et al. Long-term safety and efficacy of deferasirox (Exjade®) for up to 5 years in trans-fusional iron-overloaded patients with sickle cell disease. Br J Haematol 2011; 154(3): 387–97.

Kalpatthi R, Peters B, Kane I, et al. Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease. Pediatr Blood Cancer 2010; 55(7): 1338 – 42 .

Cappellini MD, Porter J, El-Beshlawy A, et al. Tailoring iron chelation by iron intake and serum ferritin: The prospective EPIC study of deferasirox in 1744 patients with transfusion-de-pendent anemias. Haematologica 2010; 95(4): 557-66.

Kaynak Göster