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Epidemiology and Disease Pathophysiology:

Other Anaemias

Ali T. Taher, MD

Professor

Department of Internal Medicine

American University of Beirut Medical Center

Beirut, Lebanon

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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

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DBA-UK, the UK Diamond Blackfan Anaemia Support Group. 2007. Available at:http://www.diamondblackfan.org.uk

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

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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.

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).

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Diamond Blackfan Anaemia Physical 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.

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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.

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Diamond Blackfan Anaemia Treatment

• 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.

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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

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

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Alter, BP. In: Nathan DG, et al (eds). Hematology of Infancy and Childhood. W.B. Saunders; Philadelphia, 2003.

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

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Anomaly Frequency %

Skin — hypopigmented or hyperpigmented areas; large freckles, café-au-lait spots

55%

Short stature, delicate features 51%

Upper limbs — absent of hypoplastic thumb, supernumerary, bifid, clinodactyly

43%

Gonads — hypogenitalia, undescended/absent testes, bicornuate uterus 30%

Head — microcephaly, bird face, flat forehead, Sprengel's deformity of neck

26%

Eyes — micro-ophthalmia, ptosis, epicanthal folds, strabismus 23%

Kidney — abnormal, ectopic, or hypoplastic kidney, hydronephrosis 21%

Ears — hearing 9%

Developmental delay 11%

Alter BP, Young NS. In: Nathan DG, Orkin SH (eds). Hematology of Infancy and Childhood. W.B. Saunders; Philadelphia, 1998.

Fanconi’s AnaemiaCommon physical anomalies in children with Fanconi’s Anaemia

Reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with permission from Elsevier.

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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

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Fanconi’s Anaemia Carrier 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

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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.

Fanconi’s Anaemia Treatment

• 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.

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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.

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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

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Different Forms of Sideroblastic AnaemiaHereditary

X-linked

X-linked with ataxia

Autosomal

Sporadic congenital

Associated with thiamine-responsive megaloblastic anaemia (Rogers syndrome)

Associated with mitochondrial cytopathy (Pearson syndrome)

Associated with mitochondrial myopathy and lactic acidosis

Acquired idiopathic

Pure sideroblastic anaemia

Refractory anaemia with ring sideroblasts (RARS)

Reversible

Alcoholism

Drugs (isoniazid, chloramphenicol)

Copper deficiency (zinc toxicity)

Hypothermia

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.

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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

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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.comReproduced 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.

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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)

Sideroblastic AnaemiaDiagnosis

Bottomley S. Clinical aspects, diagnosis, and treatment of the sideroblastic anaemias. May 2007.Available at: http://patients.uptodate.comReproduced 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.

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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

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Iron Disorders Institute. Sideroblastic anemia. Available at: http://www.irondisorders.org/Disorders/Sideroblastic.asp Accessed October 23, 2007.

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

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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

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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.

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

24Heimpel H, et al. Blood. 2003;102:4576.

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

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Graphic reprinted from Hoffbrand V, Pettit JE. Atlas of Clinical Hematology. 3rd ed. Mosby; 2000, with permission from Elsevier.

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.

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1. Marks PW and Mitus AJ. Am J Hematol. 1996;51:55.2. Wickramasinghe SN, Wood WG. Br J Haematol. 2005;131:431.

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

27Marks PW; Mitus AJ. SOAm J Hematol. 1996;51:55.

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.

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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

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

Study 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

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

Disease Number of Patients

-thalassaemia 1

Thalassaemia intermedia 1

Fanconi's anaemia 1

Chronic autoimmune haemolytic anaemia 1

Congenital dyserythropoietic anaemia 1

Pyruvate kinase deficiency 2

Myelofibrosis 3

Pure red cell aplasia 3

Aplastic anaemia 4

Congenital sideroblastic anaemia 5

Unknown/other 9

Diamond Blackfan anaemia 26

MDS 47

Thalassaemia 84

31Porter J, et al. Blood. 2004;104:abstr 3193.

Other anaemias, eg, DBA, MDS (n = 80)β-thalassaemia (n = 83)

Deferasirox Dose (mg/kg/d)

10 20 305-4000

-3000

-2000

-1000

0

1000

2000

3000

4000

5000 Serum ferritin

Mea

n ±

SD

Ch

ang

e in

S

seru

m F

erri

tin

(μ

g/L

)

Deferasirox Dose (mg/kg/d)

10 20 305

Mea

n ±

SD

Ch

ang

e in

LIC

(m

g F

e/g

dw

)

-20

-15

-10

-5

0

5

10

15

LIC

Deferasirox is Effective Across a Range of Transfusion-Dependent Anaemias

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Features Diamond Blackfan

Fanconi’s Anaemia

Sideroblastic Anaemia

Congenital Dyserythropoietic

Anaemia

Pathophysiology Red cell aplasia Inherited anaemia leading to bone marrow failure

Enzyme disorder 3 forms have been described

Prevalence/incidence

5–10 per 1 million births

Unknown ? < 1 per 100,000 births

Mutation 25% of affected children have gene

defect called RPS19

FA genes (A, B, C, D1 (BRCA2), D2, E, F, G, I, J, L, M, and

NCarrier frequency

estimated between 1/600 and 1/100

Hereditary, acquired due to

prolonged exposure to toxins

or idiopathicX-linked recessive

Codanin-1 associated with CDA-I

Age of presentation 2 months 3–12 years of age 5 years

Treatment Bone marrow transplantation

Bone marrow transplantation

Androgens

Pyridoxine B6 blood transfusion

Symptomatic and includes blood transfusion

Complications Transfusional haemosiderosis

Transfusional haemosiderosisMyelodysplasia

Transfusional haemosiderosis

Leukaemia Myelodysplasia

Transfusional haemosiderosis

Summary*

*Sources as in previous slides.