Indications for Successful Iron Overload Treatment and Monitoring: Other Anaemias

1
Indications for Successful Iron Overload
Treatment and Monitoring Other Anaemias
Adlette Inati, MDHead, Division of Paediatric
Haematology-OncologyMedical Director, Children's
Center for Cancer and Blood DiseasesRafik Hariri
University Hospital Beirut, Lebanon 
2
Diamond-Blackfan Anaemia

• A rare red cell aplasia commonly associated with
  physical anomalies and rarely with cancer
  predisposition1,2
• Diagnosis based on clinical grounds, presence of
  hypoproductive normocytic or macrocytic anaemia,
  elevated erythrocyte ADA activity, and mutations
  of small (RPS19, RPS24, and RPS17) and large
  (Rpl35) ribosomal subunit genes1-5
• Treatment corticosteroids, blood transfusion,
  and bone marrow transplantation1,2,6,7

1. Halperin DS, Freedman MH. Am J Pediatr Hematol
Oncol. 198911380-394. 2. DBAR registry of NA.
www.dbar.org. 3. Draptchinskaia N, et al. Nat
Genet. 199921169-175. 4. Choesmel V, et al. Hum
Mol Genet. 2008171253-1263. 5. Farrar JE, et
al. Blood. 20081121582-1592. 6. Ball SE, et al.
Br J Haematol. 199694645-653. 7. Willig TN, et
al. Pediatr Res. 199946553-561.
3
Fanconis Anaemia

• An autosomal recessive bone marrow failure
  syndrome associated with physical anomalies and a
  risk for malignancy1,2
• Diagnosis Based on clinical background, presence
  of chromosomal breaks and radial chromosomes and
  Fanconis anaemia genes (13 identified so far)2
• Therapy Supportive, androgens, stem cell
  transplantation, and treatment of malignancies2
• Median survival 38 years and can be
  extraordinarily variable3

1. Kutler DI, et al. Blood. 20031011249-1256.
2. Fanconi Anemia Research Fund. About Fanconi
anemia. 2007. http//www.fanconi.org/aboutfa/FA.h
tm. 3. Janov AJ, et al. Medicine. 19967577-78.
4
Sideroblastic Anaemia

• A heterogeneous group of disorders characterized
  by microcytic hypochromic anaemia and ringed
  sideroblasts in the bone marrow1
• 3 forms hereditary, acquired, and idiopathic1
• Reported mutations erythroid-specific
  5-aminolevulinate synthase (ALAS2) gene, ABC7
  transporter gene, SLC19A2 gene, and PUS1 gene1,2
• Diagnosis based on the presence of hypochromic
  microcytic anaemia, increased serum transferrin
  saturation, transferrin and serum ferritin
  levels, decreased free erythrocyte protoporphyrin
  level (in X-linked forms), ringed sideroblasts at
  the late, nondividing erythroblast stage
  (diagnostic hallmark), and increased iron in bone
  marrow macrophages2
• Therapy vitamin B6 (pyridoxine) replacement,
  removal of the offending agent, red blood cell
  transfusions and chelation, treatment of
  malignancies1

1. Iron Disorders Institute. Sideroblastic
anemia. Available at http//www.irondisorders.org
/Disorders/Sideroblastic.asp 2. Camaschella C. Br
J Haematol. 200814327-38. 3. Bottomley S.
Clinical aspects, diagnosis, and treatment of the
sideroblastic anemias. May 2007. Clinical
aspects, diagnosis, and treatment of the
sideroblastic anemias. In UpToDate, Rose BD, ed,
UpToDate, Waltham, MA, 2007.
5
Congenital Dyserythropoietic Anaemia

• A rare group of macrocytic anaemias characterized
  by ineffective erythropoiesis, dysplastic
  erythroblast changes, and substantial iron
  overload (even in nontransfused patients)1
• Other manifestations splenomegaly,
  cholelithiasis, and skeletal anomalies1,2
• Diagnosis based on presence of haemolytic
  anaemia, low reticulocytes, binucleated
  normoblasts on a blood smear, nuclear
  abnormalities in erythroid precursors
  (pathognomonic)1-3, mutations in the CDAN I gene
  (for type 14-6) and in GATA-1 gene3
• Therapy splenectomy (for type II), interferon a
  (for type I), red cell transfusion, and iron
  chelation for those with iron overload1,2,7

1. Wickramasinghe SN. Curr Opin Hematol.
2000771-78. 2. Iolascon A, et al. Blood.
2001981258-1260. 3. Mehaffey MG, et al. Blood.
2001982681-2688. 4. Dgany O, et al. Am J Genet.
2002711467-1474. 5. Goede JS, et al. Ann
Hematol. 200685591-595. 6. Wickramasinghe SN,
Wood WG. Br J Haematol. 2005131431-446. 7.
Heimpel H. Ann Hematol. 200483613-621.
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Dyskeratosis Congenita

• A rare bone marrow failure syndrome characterized
  by abnormal skin pigmentation, nail dystrophy,
  and oral leukoplakia1-5
• Other manifestations pulmonary abnormalities,
  cellular immunodeficiency, and cancer
  predisposition1-5
• Inheritance X-linked (most common and most
  severe), autosomal dominant, and autosomal
  recessive1
• Diagnosis must be considered in any child or
  adult with bone marrow failure, acute myelogenous
  leukaemia or myelodysplastic syndrome, skin and
  oral changes, negative mitomycin C and
  diepoxybutane tests1-5, and TERC and DKC1
  genes1,2
• Therapy transfusions, androgens, growth factors,
  and stem cell transplantation1
• Principal cause (71) of early mortality
  attributed to bone marrow failure3

1. Dokal I. Br J Haematol. 2000110768-779. 2.
Knight S, et al. Br J Haematol. 1998103990-996.
3. Sílvia Pimenta de Carvalho et al. An bras
Dermatol. Rio de Janeiro, 78579-586, set./out.
2003. 4. Drachtman RA, Alter BP. Dermatol
Clin.19951333-39. 5. Kraemer KH. In Freedberg
IM, et al, eds. Fitzpatricks Dermatology in
General Medicine. McGraw-Hill 1999.
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Iron Overload in Other Anaemias

• An inevitable consequence of chronic red cell
  transfusion therapy regardless of the underlying
  cause of anaemia
• Can be seen even in patients who have not been
  transfused and may be local or systemic
• Local mitochondrial iron overload is present in
  all sideroblastic anaemias, whereas systemic iron
  overload occurs only in forms due to primary or
  secondary ALAS2 deficiency
• Renders affected patients at increased risk for
  developing co-morbidities with a resultant
  negative impact on survival
• Requires effective chelation therapy
• No guidelines exist for managing iron overload in
  nonthalassaemics and specifically rare anaemias,
  and treatment is based on experience in
  thalassaemia

Camaschella C. Br J Haematol. 200814327-38.
8
Transfusion Therapy Results in Iron Overload

• Iron overload can occur after 1020 transfusions
• 1 blood unit contains 200 mg iron
• Iron chelation therapy should be considered when
  a patient has received approximately 20 units
  (about 100 mL/kg) of pRBCs or when serum ferritin
  is gt1000 µg/L

Transfusional iron intake volume of packed RBCs
(mL) x 1.08 Volume of packed RBCs (mL) volume
of blood (mL) x haematocrit () Example 285 mL
blood transfused x 65 haematocrit 185 mL RBCs
x 1.08 mg iron/mL RBCs 200 mg iron
Porter JB. Br J Haematol. 2001115239-252.
Cappellini MD, et al. Blood. 20061073455-3462.
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Iron Overload Monitoring

• Many tools are available for assessing iron
  overload, and combining these tools allows more
  accurate assessment
• Serial ferritin measuresmost practical
• Liver iron concentration (biopsy/MRI/SQUID)
• Cardiac iron load by MRI

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The Challenge of Iron ChelationA Question of
Balance

• Uncoordinated iron
• Free-radical generation
• Organ damage
• Growth failure
• Organ failure
• Cardiac death

• Uncoordinated chelator
• Inhibition of metalloenzymes
• Neurotoxicity
• Growth failure
• Bone marrow toxicity

Too much iron
Too much chelator
Graphic courtesy of Dr. J. Porter.
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Overview of Iron Chelators
Property Desferrioxamine1 Deferiprone2 Deferasirox3
Route SC IV (812 h, 5 d/w) Oral 3 times daily Oral once daily
Half-life 2030 min 34 h 816 h
Excretion Urinary, faecal Urinary Faecal
Adverse effects Local reactions, ophthalmologic, auditory, growth retardation, allergic Gastrointestinal disturbances, agranulocytosis/neutropaenia, arthralgia, elevated liver enzymes Gastrointestinal disturbances, rash, mild nonprogressive creatinine increase, ophthalmologic, auditory, elevated liver enzymes
Status Licensed Not licensed in USA/Canada Licensed in USA and Europe
Indications Treatment of chronic iron overload due to transfusion-dependent anaemias Thalassaemia Treatment of chronic iron overload due to transfusion-dependent anaemias
1. Desferrioxamine PI. Novartis Pharma Stein
AG. Stein, Switzerland Nov. 2007. 2. Deferiprone
Ferriprox Summary of Product Characteristics
PI. Apotex Europe LTD. 1999. 3. Deferasirox
PI. Novartis Europharm LT. West Sussex, UK.
Aug. 2006.
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Management of Iron Overload

• To date, management of transfusional iron
  overload and improved survival have been achieved
  with parenteral desferrioxamine
• Around 1/3 to 1/2 of patients are not compliant
  with desferrioxamine therapy, largely because of
  the discomfort and demanding nature of the
  regimen
• In 2005, the FDA approved deferasirox, an oral
  tridentate chelator, for the treatment of chronic
  overload due to transfusional hemosiderosis
• Deferasirox has been studied in gt700 adult and
  paediatric patients who had transfusion-related
  iron overload and underlying thalassaemia, sickle
  cell anaemia, and other anaemias

Stumpf JL. Am J Health Syst Pharm.
200764606-616. 
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Retrospective Nationwide Survey of Japanese
Patients with Transfusion-Dependent
Myelodysplastic Syndrome and Aplastic
AnaemiaJapanese National Research Group on
Idiopathic Bone Marrow Failure Syndromes

• Investigated relationships between iron overload,
  chelation practices, and morbidity/mortality in
  292 patients with MDS, AA, pure red cell aplasia,
  myelofibrosis, and other conditions
• MDS and AA accounted for about 80 of the
  underlying diseases
• MDS 52.1
• AA 30.8
• PRCA 5.1
• MF 4.5

Abbreviations AA, aplastic anaemia MDS,
myelodysplastic syndrome MF, myelofibrosis
PRCA, pure red cell aplasia. Takatoku M, et al.
Eur J Haematol. 200778487-494.
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Retrospective Nationwide Survey of Japanese
Patients with Transfusion-Dependent
Myelodysplastic Syndrome and Aplastic Anaemia

• 43 of patients received desferrioxamine therapy
  but only 8.6 received daily/continuous
  desferrioxamine
• Abnormal cardiac and liver function observed in
  21.9 (14/64) and 84.6 (11/13) of all patients
  assessed
• 75 deaths (25.7) reported, with cardiac and
  liver failure noted in 24.0 and 6.7 of cases,
  respectively, and ferritin levels gt1000 ng/mL in
  97 of deaths

Takatoku M, et al. Eur J Haematol.
200778487-494.
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Average Changes in Laboratory Values During the
Period of Transfusion Dependence in Patients
Receiving Desferrioxamine Treatment
Parameter Intermittent (once/1.9 wk) Concurrent with Transfusion Daily/Continuous
Serum ferritina,b (ng/mL) 2222.8 (n 36) 2204.8 (n 19) -1135.2 (n 9)
SGOTa,c (mU/mL) 28.0 (n 53) 40.0 (n 30) -9.2 (n 10)
SGPT (mU/mL) 28.6 (n 53) 10.3 (n 30) -28.8 (n 10)
FBS (mg/dL) 31.2 (n 31) 8.2 (n 12) -4.8 (n 5)
a Intermittent vs continuous, P lt.05.b
Continuous vs concurrent, P lt.01.c Continuous vs
concurrent, P lt.05.
Daily continuous chelation with desferrioxamine
resulted in improved serum ferritin, liver
enzymes, and fasting blood sugar
Abbreviations SGOT, serum glutamic oxaldacetic
mansaminase SGPT, serum glutamic pyruvic
transaminase FBS fasting blood
sugar Reprinted from Takatoku M. Eur J Haematol.
200778487-497, with permission from John Wiley
Sons.
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Study 0108Phase II Single-Arm Trial
?-Thalassaemia and Other Anaemias

• 1-year trial designed to evaluate the efficacy of
  deferasirox in 184 regularly transfused patients
• 85 patients with ß-thalassaemia
• 99 patients with other anaemias (MDS 47, DBA 30,
  rare anaemias 22)
• Aged 381 years
• Patients treated with deferasirox for 1 year, and
  dosage determined by baseline liver iron
  concentration assessed by liver biopsy or SQUID
• A total of 152 patients (82.6) completed 1 year
  of treatment

Porter J, et al. Eur J Haematol. 200880168-176.
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Mean Changes in LIC and Ferritin by Disease Group
and Dose
Abbreviations DBA, Diamond-Blackfan anaemia
LIC, liver iron concentration MDS,
myelodysplastic syndrome. Reprinted from Porter
J, et al. Eur J Haematol. 200880168-176, with
permission from John Wiley Sons.
18
Relative Response of Patients with MDS and Other
Transfusion-Dependent Anaemias to
Deferasirox1-Year Prospective Study Iron
Excretion Across Dose and Disease Groups
Abbreviations DBA, Diamond-Blackfan anaemia
MDS, myelodysplastic syndrome. Reprinted from
Porter J, et al. Eur J Haematol. 200880168-176,
with permission from John Wiley Sons.
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Relative Response of Patients with MDS and Other
Transfusion-Dependent Anaemias to
Deferasirox1-Year Prospective Study

• Iron-overloaded patients with myelodysplastic
  syndrome, Diamond-Blackfan anaemia, and other
  rare anaemias responded to deferasirox in a
  dose-dependent manner as did patients with
  ?-thalassaemia, with respect to both efficacy and
  safety parameters
• Deferasirox was effective and generally well
  tolerated, resulting in a clinically relevant
  reduction in overall body iron burden across a
  broad range of anaemia types
• Changes in serum ferritin and liver iron
  concentration correlated, supporting the use of
  serial serum ferritin measures for monitoring
  deferasirox therapy

Porter J, et al. Eur J Haematol. 200880168-176.
20
Relative Response of Patients with MDS and Other
Transfusion-Dependent Anaemias to
Deferasirox1-Year Prospective Study

• Patients with Diamond-Blackfan anaemia who had
  the highest average transfusional iron intake,
  showed the smallest reductions in liver iron
  concentration (LIC) while patients with
  myelodysplastic syndrome, who had the lowest mean
  iron intake, showed the largest dose-dependent
  reductions in LIC
• If the differences in transfusional iron loading
  rate are accounted for, the response to chelation
  with deferasirox is similar across the different
  types of transfusion-dependent anaemia studied
• The most common drug-related adverse events were
  mild, eg, transient gastrointestinal
  disturbances, skin rash, and mild, nonprogressive
  serum creatinine increases

Porter J, et al. Eur J Haematol. 200880168-176.
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Conclusions

• Patients with rare anaemias often require chronic
  red blood cell transfusion
• Iron overload in such patients can occur before
  transfusion therapy is initiated. This is due to
  ineffective erythropoiesis and/or increased
  gastrointestinal iron absorption
• The most important cause of iron overload in
  other anaemias remains chronic transfusion
  therapy
• Patients with rare anaemias are underscreened and
  undertreated for their iron overload

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Conclusions

• Emerging clinical data indicate that
  transfusion-dependent patients with rare anaemias
  are at risk for the consequences of iron
  overload, including progressive damage to the
  liver, heart, and endocrine organs
• Iron overloaded patients, regardless of the
  underlying disease, should receive iron chelation
  therapy as early as possible to prevent organ
  damage
• The availability of an oral iron chelator may
  improve compliance in patients noncompliant with
  the difficult desferrioxamine regimen
• Identification and registration of patients in an
  international registry and initiation of
  collaborative trials are needed in order to lay
  guidelines for transfusion and iron overload
  treatment in rare anaemias