Download Indications for Successful Iron Overload Treatments and

Indications for Successful Iron
Overload Treatment and
Monitoring: Other Anaemias
Adlette Inati, MD
Head, Division of Paediatric Haematology-Oncology
Medical Director, Children's Center for Cancer and Blood
Diseases
Rafik Hariri University Hospital
Beirut, Lebanon
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. 1989;11:380-394. 2. DBAR registry of NA. www.dbar.org.
3. Draptchinskaia N, et al. Nat Genet. 1999;21:169-175. 4. Choesmel V, et al. Hum Mol Genet. 2008;17:1253-1263.
5. Farrar JE, et al. Blood. 2008;112:1582-1592. 6. Ball SE, et al. Br J Haematol. 1996;94:645-653. 7. Willig TN, et al.
Pediatr Res. 1999;46:553-561.
Fanconi’s 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
Fanconi’s 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. 2003;101:1249-1256. 2. Fanconi Anemia Research Fund. About Fanconi anemia. 2007.
http://www.fanconi.org/aboutfa/FA.htm. 3. Janov AJ, et al. Medicine. 1996;75:77-78.
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. 2008;143;27-38. 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.
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 α (for type I), red cell
transfusion, and iron chelation for those with iron overload1,2,7
1. Wickramasinghe SN. Curr Opin Hematol. 2000;7:71-78. 2. Iolascon A, et al. Blood. 2001;98:1258-1260. 3. Mehaffey MG,
et al. Blood. 2001;98:2681-2688. 4. Dgany O, et al. Am J Genet. 2002;71:1467-1474. 5. Goede JS, et al. Ann Hematol.
2006;85:591-595. 6. Wickramasinghe SN, Wood WG. Br J Haematol. 2005;131:431-446. 7. Heimpel H. Ann Hematol.
2004;83:613-621.
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. 2000;110:768-779. 2. Knight S, et al. Br J Haematol. 1998;103;990-996. 3. Sílvia Pimenta de
Carvalho et al. An bras Dermatol. Rio de Janeiro, 78:579-586, set./out. 2003. 4. Drachtman RA, Alter BP. Dermatol
Clin.1995;13:33-39. 5. Kraemer KH. In Freedberg IM, et al, eds. Fitzpatrick´s Dermatology in General Medicine.
McGraw-Hill; 1999.
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 comorbidities 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. 2008;143:27-38.
Transfusion Therapy Results
in Iron Overload
• Iron overload can occur after 10–20 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
>1000 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. 2001;115:239-252. Cappellini MD, et al. Blood. 2006;107:3455-3462.
Iron Overload Monitoring
Many tools are available for assessing iron
overload, and combining these tools allows more
accurate assessment
• Serial ferritin measures—most practical
• Liver iron concentration (biopsy/MRI/SQUID)
• Cardiac iron load by MRI
The Challenge of Iron Chelation
A Question of Balance
•
•
•
•
•
•
Uncoordinated iron
Free-radical generation
Organ damage
Growth failure
Organ failure
Cardiac death
Too much iron
Graphic courtesy of Dr. J. Porter.
•
•
•
•
•
Uncoordinated chelator
Inhibition of
metalloenzymes
Neurotoxicity
Growth failure
Bone marrow toxicity
Too much chelator
Overview of Iron Chelators
Property
Desferrioxamine1
Deferiprone2
Deferasirox3
Route
SC IV
(8–12 h, 5 d/w)
Oral
3 times daily
Oral
once daily
Half-life
20–30 min
3–4 h
8–16 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.
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 >700 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. 2007;64:606-616.
Retrospective Nationwide Survey of Japanese
Patients with Transfusion-Dependent
Myelodysplastic Syndrome and Aplastic Anaemia
Japanese 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. 2007;78:487-494.
Retrospective Nationwide Survey of
Japanese Patients with TransfusionDependent 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 >1000 ng/mL in 97%
of deaths
Takatoku M, et al. Eur J Haematol. 2007;78:487-494.
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
+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)
Serum ferritina,b (ng/mL)
a
Intermittent vs continuous, P <.05.
Continuous vs concurrent, P <.01.
c Continuous vs concurrent, P <.05.
b
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. 2007;78:487-497, with permission from John Wiley & Sons.
Study 0108—Phase 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 β-thalassaemia
– 99 patients with other anaemias (MDS 47, DBA 30, rare
anaemias 22)
– Aged 3–81 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. 2008;80:168-176.
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. 2008;80:168-176, with permission from John Wiley & Sons.
Relative Response of Patients with MDS and
Other Transfusion-Dependent Anaemias to
Deferasirox—1-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. 2008;80:168-176, with permission from John Wiley & Sons.
Relative Response of Patients with MDS and
Other Transfusion-Dependent Anaemias to
Deferasirox—1-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. 2008;80:168-176.
Relative Response of Patients with MDS and
Other Transfusion-Dependent Anaemias to
Deferasirox—1-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. 2008;80:168-176.
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
Conclusions
• Emerging clinical data indicate that transfusiondependent 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