Epidemiology and Disease Pathophysiology: Other Anaemias

1. Epidemiology and Disease Pathophysiology: Other Anaemias Ali T. Taher, MD Professor Department of Internal Medicine American University of Beirut Medical Center Beirut, Lebanon

2. Rare Anemias • Types • Diamond Blackfan anaemia • Fanconi’s anaemia • Sideroblastic anaemia • Congenital dyserythropoietic anaemia • Epidemiology • Incidence, prevalence, epidemiologic data • Differentiation • Diagnosis • Clinical manifestations • Complications • Prognosis and management • Factors contributing to iron overload in these populations

3. Diamond Blackfan Anaemia • Diamond Blackfan anaemia (DBA) is a blood condition resulting from a failure within the bone marrow • The hallmark of this rare anaemia is the inability to produce red blood cells • The majority of DBA cases are diagnosed between 4 months–2 years of age • This extremely rare condition affects 600–700 individuals worldwide DBA-UK, the UK Diamond Blackfan Anaemia Support Group. 2007. Available at:http://www.diamondblackfan.org.uk

4. Diamond Blackfan Anaemia • Exact pathogenic mechanisms have not been elucidated; however, DBA seems to be characterized by a fault in 1 of the early steps of red blood cell production.1 • 25% of affected children have gene defect called small ribosomal protein 19 (RPS 19)2 • Condition is named for 2 doctors who first documented cases in the 1930s1 • Dr. Louis Diamond (founder of the Haematology/Oncology branch at Children's Hospital in Boston, USA) • Dr. Kenneth D. Blackfan (Chief of the Paediatric Department). 1. DBA-UK, the UK Diamond Blackfan Anaemia Support Group. 2007. Available at:http://www.diamondblackfan.org.uk 2. Draptchinskaia N et al. Nat Genet. 1999 Feb;21:169.

5. Diamond Blackfan AnaemiaPhysical Examination 30%–50% of patients with DBA have associated congenital abnormalities • Craniofacial abnormalities • Neck anomalies • Thumb abnormalities • Genitourinary malformations • Pre- and postnatal growth failure Halperin DS; Freedman MH. Am J Pediatr Hematol Oncol. 1989;11:380.Reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with permission from Elsevier.

6. Diamond Blackfan Anaemia • Children are reported to have typical facies with tow-colored hair, snub nose, wide set eyes, thick upper lip and an intelligent expression, although facies with different appearances have been reported in other children1 • Physical anomalies are more common in males2 • Growth retardation occurs in 30% of affected patients2 • Often associated with other congenital abnormalities and the need for ongoing therapy 1. Freedman MH. In: Hoffman R, et al (eds). Hematology: Basic Principles and Practice. Philadelphia, PA: Churchill Livingstone, 2005. 2. Ball SE, et al. Br J Haematol. 1996;94:645. Reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with permission from Elsevier.

7. Diamond Blackfan AnaemiaTreatment • The mainstays of therapy of DBA are corticosteroids and blood transfusion1 • However, 1 study reported remissions in 22% of patients2 • Transfusion therapy is the mainstay of treatment for patients in whom steroid therapy is ineffective or in whom corticosteroid toxicity is prohibitive2 • Bone marrow transplantation has been employed with success in steroid refractory patients2 • Prognosis is dependent on transfusion dependence and subsequent complications of iron overload2 1. Freedman MH. In: Hoffman R, et al (eds). Hematology: Basic Principles and Practice. Philadelphia, PA: Churchill Livingstone, 2005. 2. Willig TN, et al. Pediatr Res. 1999;46:553.

8. Fanconi’s Anaemia • Fanconi’s anaemia (FA) represents 1 of the inherited anaemias that leads to bone marrow failure; these are also known as aplastic anaemias1 • Recessive disorder2 • A child whose parents both carry a mutation in the same FA gene has a 25% chance of inheriting the defective gene from both parents, causing him or her to have FA • At least 13 FA genes have been identified: A, B, C, D1 (BRCA2), D2, E, F, G, I, J, L, M, and N2 • Mutations in these genes account for almost all cases of Fanconi’s anaemia 1. Alter, BP. In: Nathan DG, et al (eds). Hematology of Infancy and Childhood. W.B. Saunders; Philadelphia 2003. 2. Fanconi Anemia Research Fund. About Fanconi anemia. 2007. Available at: http://www.fanconi.org/aboutfa/AboutFAHead.htm

9. Fanconi’s Anaemia • Clinical manifestations • Most children with FA are diagnosed between 6 to 9 years of age; the median age for boys is 6.5 years and for girls is 8 years • Approximately 4% of cases are recognized between birth and 1 year of age and 9% diagnosed after 16 years of age Alter, BP. In: Nathan DG, et al (eds). Hematology of Infancy and Childhood. W.B. Saunders; Philadelphia, 2003.

10. Fanconi’s AnaemiaCommon physical anomalies in children with Fanconi’s Anaemia Alter BP, Young NS. In: Nathan DG, Orkin SH (eds). Hematology of Infancy and Childhood. W.B. Saunders; Philadelphia, 1998. Reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with permission from Elsevier.

11. Fanconi’s Anaemia Testing for FA • The chromosome breakage test is regarded as the definitive test for FA • Any infant born with characteristic thumb and arm abnormalities should receive testing for FA • Regardless of whether other defects are present, all patients developing aplastic anaemia at any age should be tested for FA; this may be the only abnormality present in many patients with FA • Testing for FA prior to contemplating bone marrow transplantation for aplastic anaemia is considered essential Fanconi Anemia Research Fund. About Fanconi anemia. 2007. Available at: http://www.fanconi.org/aboutfa/AboutFAHead.htm

12. Fanconi’s AnaemiaCarrier Frequency • Worldwide, the total number of FA patients has not been reported • Researchers estimate that carrier frequency for FA ranges between 1 per 600 and 1 per 100 • Case data on more than 3000 patients is maintained at the International Fanconi Anemia Registry at The Rockefeller University in New York, NY Fanconi Anemia Research Fund. About Fanconi anemia. 2007. Available at: http://www.fanconi.org/aboutfa/AboutFAHead.htm

13. Fanconi’s AnaemiaTreatment • Androgens • For > 40 years, have been used to treat patients with FA, with ~ 50% response rate • Stimulate the production of red blood cells, and potentially platelets • Treatment may be effective for many years, but eventually most patients fail to respond • Growth factors • Acting to stimulate the production of white blood cells, G-CSF appears to be effective in the treatment of patients with FA • Bone marrow transplantation • While this is the only potentially curative treatment for FA, substantial risks are associated with this procedure; FA patients have high sensitivity to chemotherapy and radiation. Fanconi Anemia Research Fund. About Fanconi anemia. 2007. Available at: http://www.fanconi.org/aboutfa/AboutFAHead.htm. Freedman MH. In: Hoffman R, et al (eds). Hematology: Basic Principles and Practice. Philadelphia, PA; Churchill Livingstone; 2005.

14. Fanconi’s AnaemiaPrognosis and Complications • Approximately 25% of patients will develop a malignancy1 • Myelodysplastic syndromes (MDS) • Acute myelocytic leukemia (AML) • Squamous cell carcinoma of the head and neck • The presence of clonal chromosomal changes may be a risk factor for malignancy in patients with FA2 • Malignancy may be the first manifestation of FA, so the diagnosis of FA should be considered in patients presenting with cancers at an unusually young age3 1. Kutler DI, et al. Blood. 2003;101:1249. 2. Tonnies H. Blood. 2003;101:3872. 3. Alter BP, Young NS. In: Nathan DG, Orkin SH (eds). Hematology of Infancy and Childhood. WB Saunders; Philadelphia, PA; 1998.

15. Sideroblastic Anaemia • With all sideroblastic anaemias, principal clinical features are those of an indolent or progressive anaemia • Laboratory results, combined with patient history and clinical findings, usually permit accurate diagnosis of the various forms of sideroblastic anaemia • In several hereditary forms of sideroblastic anaemia, and in some patients with idiopathic acquired sideroblastic anaemia, molecular defects can be identified Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anemias. May 2007.Available at: http://patients.uptodate.com

16. Different Forms of Sideroblastic Anaemia Bottomley, SS. In: Greer JP, et al (eds). Wintrobe's Clinical Hematology. 11th Ed. Lippincott, Williams and Wilkins; Philadelphia, PA. 2004. Reprinted from Bottomley SS. Sideroblastic anemias. In: Greer JP, Foerster J, et al, eds. Wintrobe's Clinical Hematology, 11th ed. Philadelphia, Penn: Lippincott, Williams and Wilkins; 2004:1011, with permission from Lippincott, Williams and Wilkins.

17. Sideroblastic Anaemia • Anaemia generally remains stable over many years in hereditary forms of the sideroblastic anaemias resulting from X-linked or autosomal inheritance, or in association with sporadic congenital defects • In some individuals there is progression of anaemia over time, which may be in part the result of the following factors: • Prior intake of pyridoxine • Lyonization, or progressive skewing of X inactivation patterns associated with aging, in women with X-linked sideroblastic anaemia • Iron overload toxicity Bottomley, et al. Am J Hum Genet. 1998;63:A352. Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anemias. May 2007. Available at: http://patients.uptodate.com

18. Sideroblastic AnaemiaDiagnosis • Complete blood count • Erythrocyte hypochromia and microcytosis the degree of which roughly parallels the severity of the anaemia • In more anaemic patients, marked variation in RBC size and shape and occasional siderocytes are prominent • Iron studies • Increased serum transferrin saturation • Reduced transferrin • Increased serum ferritin levels • Increase in marrow reticuloendothelial iron Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anemias. May 2007.Available at: http://patients.uptodate.com Reproduced with permission from: Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anemias. In: UpToDate, Rose BD, ed, UpToDate, Waltham, MA, 2007. Copyright 2007 UpToDate, Inc. For more information visit www.uptodate.com.

19. Sideroblastic AnaemiaDiagnosis Bone marrow examination • Prominent at the late, non-dividing erythroblast stage, ring sideroblasts are considered the diagnostic hallmark of sideroblastic anaemia • There is also a significant increase of iron in bone marrow macrophages, the result of ineffective erythropoiesis (intramedullary haemolysis) Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anaemias. May 2007.Available at: http://patients.uptodate.com Reproduced with permission from: Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anemias. In: UpToDate, Rose BD, ed, UpToDate, Waltham, MA, 2007. Copyright 2007 UpToDate, Inc. For more information visit www.uptodate.com.

20. Sideroblastic AnaemiaDiagnosis • Free erythrocyte protoporphyrin (FEP) • Levels are reduced in X-linked sideroblastic anaemia, as defective ALAS2 enzymatic activity results in reduced protoporphyrin production • Molecular studies • X-linked form of hereditary sideroblastic anaemia • Mutations common in erythroid-specific 5-aminolevulinate synthase (ALAS2) gene • X-linked sideroblastic anaemia with ataxia • Mutations found in ABC7 transporter gene • Thiamine-responsive megaloblastic anaemia syndrome • Mutations in SLC19A2 gene • Mitochondrial myopathy and sideroblastic anaemia disorder • Mutations in PUS1 gene Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anemias.Available at: http://patients.uptodate.com

21. Sideroblastic AnaemiaTreatment The treatment of sideroblastic anaemia varies according to its cause • Acquired sideroblastic anaemia should be treated by the removal of the offending agent; anaemia may subsequently resolve • Underlying inflammatory conditions, such as rheumatoid arthritis, should be treated • Vitamin B6 (pyridoxine) 50–200 mg/day may reverse anaemia • Response to pyridoxine therapy has been documented in hereditary, acquired, and idiopathic anaemias • Pregnant women and nursing mothers may wish to limit pyridoxine to 100 mg/day, later resuming a higher B6 dosage • Whole red blood cell transfusion may be required in extreme cases of anaemia Iron Disorders Institute. Sideroblastic anemia. Available at: http://www.irondisorders.org/Disorders/Sideroblastic.asp Accessed October 23, 2007.

22. Sideroblastic AnaemiaPrognosis and Complications • Iron overload accompanies sideroblastic anaemia • When repeated whole red blood cell transfusion is needed to treat anaemia, it exacerbates existing iron burden • Patients will probably require chelation therapy • In patients with acquired sideroblastic anaemia, leukaemia (eg, acute granulocytic leukaemia) may develop • In the early preleukaemic stages of disease, myelodysplastic syndromes are typically observed Iron Disorders Institute. Sideroblastic anemia. Available at: http://www.irondisorders.org/Disorders/Sideroblastic.asp

23. Congenital Dyserythropoietic Anaemia (CDA) • The CDAs (types I, II, III, and IV) form a rare group of disorders that result in anaemia caused by ineffective erythropoiesis and may present in childhood1 • Loci of the genes for types I, II, and III have been identified but only 1 gene, associated with type I CDA, has thus far been identified. This gene has been termed codanin-1, and may be involved in nuclear envelope integrity2 • In one retrospective study of 98 subjects with CDA type II3 • Mean age at presentation was 5 years (range: 1 month–25 years), although the mean age at the time of correct diagnosis was 16 years (range: 4 months–65 years)3 • Anaemia and jaundice were present in 66% and 53% of subjects, respectively 1. Wickramasinghe SN. Curr Opin Hematol. 2000;7:71. 2. Dgany O, et al. Am J Hum Genet. 2002;71:1467. 3. Iolascon A. Blood. 2001;98:1258.

24. Congenital Dyserythropoietic Anaemia In a second study of 48 patients with type II CDA • Majority of patients had splenomegaly within the first 3 decades of life • Absence of splenomegaly in an adolescent should raise doubts regarding the diagnosis • Gallstones were found in 22 of 39 patients before the age of 40 years, appearing during childhood or adolescence a small percentage of the time; cholecystectomy was performed at a median age of 26 years • In a patient with congenital haemolytic anaemia, inadequate reticulocyte response suggests this diagnosis, while the presence of binucleated normoblasts on the peripheral blood smear is noted as being highly specific Heimpel H, et al. Blood. 2003;102:4576.

25. Congenital Dyserythropoietic Anaemia • These disorders have pathognomonic cytopathologic findings consisting of nuclear abnormalities in bone marrow erythroid precursors1 • Families with variants of CDA that do not fall into the outlined types have also been reported2 • An X-linked form is caused by a mutation in the gene for GATA-1, a transcription factor that contributes to the regulation of erythropoiesis3 1. Marks PW and Mitus AJ. Am J Hematol. 1996;51:55. 2. Wickramasinghe SN, Wood WG. Br J Haematol. 2005;131:431. 3. Mehaffey M, et al. Blood. 2001;98:2681. Graphic reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with permission from Elsevier.

26. Congenital Dyserythropoietic AnaemiaTreatment Therapy depends on the type, and may include • Splenectomy (effective in type II CDA but not in type I)1 • Interferon α (effective in most patients with type I)2 • Transfusion in symptomatic patients2 1. Marks PW and Mitus AJ. Am J Hematol. 1996;51:55. 2. Wickramasinghe SN, Wood WG. Br J Haematol. 2005;131:431.

27. Congenital Dyserythropoietic AnaemiaPrognosis and Complications • Haemosiderosis, caused by multiple RBC transfusions and increased absorption of intestinal iron, is a problem for patients with all types of CDA • Iron chelation may be used in the treatment of the iron overload state in these patients. Iron therapy is almost always contraindicated in these patients because of their predisposition to develop iron overload. Marks PW; Mitus AJ. SOAm J Hematol. 1996;51:55.

28. Iron Overload in Rare Anaemias • Iron overload • Accompanies all transfusion-dependent anaemia • Repeated whole red blood cell (RBC) transfusion will contribute significantly to this existing iron burden and likely require chelation therapy • Haemosiderosis, caused by multiple RBC transfusions and increased absorption of intestinal iron, is a problem for patients with all types of transfusion-dependent anaemia • Iron chelation may be used in the treatment of the iron overload state in these patients • Iron therapy is almost always contraindicated in these patients because of their predisposition to develop iron overload

29. Study 0108—Phase II Single-Arm Trial-Thalassaemia and Other AnaemiasStudy Design • 1-year trial • 85 patients with β-thalassaemia • 99 patients with rare anaemia • Patients treated with deferasirox for 1 year • LIC assessed by liver biopsy or SQUID • Ongoing safety and serum ferritin monitoring

30. Study 0108—Phase II Single-Arm Trial-Thalassaemia and Other Anaemias

31. Deferasirox is Effective Across a Range of Transfusion-Dependent Anaemias β-thalassaemia (n = 83) Other anaemias, eg, DBA, MDS (n = 80) LIC Serum ferritin 5000 4000 15 3000 10 2000 5 Mean ± SD Change in Sserum Ferritin (μg/L) 1000 Mean ± SD Change in LIC (mg Fe/g dw) 0 0 -1000 -5 -2000 -10 -3000 -15 -4000 10 10 5 5 20 30 20 30 -20 Deferasirox Dose (mg/kg/d) Deferasirox Dose (mg/kg/d) Porter J, et al. Blood. 2004;104:abstr 3193.

32. Summary* *Sources as in previous slides.