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Iron Overload and Iron Chelation: the Inside Story

Iron Overload and Iron Chelation: the Inside Story

Iron Overload and : The Inside Story

Jerry L. Spivak, MD Professor of Medicine and Oncology Johns Hopkins University School of Medicine Baltimore, Maryland

[email protected] Iron as a Prosthetic Group

• transport - ,

• proliferation - Ribonucleotide reductase

• Electron transport - Flavoproteins

• Respiratory enzymes -

• Oxidases - Catalase

• Reductases - Cytochromes Body Iron Stores (♂)

Hemoglobin 2.5 gm

Myoglobin/ and nonheme 0.4 gm enzymes

Ferritin/ 1.0 gm(2/1ratio)

Transferrin 0.005 gm

There is no normal mechanism for iron excretion above physiologic losses “Tales From the Crypt” Iron Absorption and the Mucosal Iron Block Stomach Sugars, Duodenum pHamino acids pH and Fe++ Heme-Fe Fe +++ Dctyd (ferri-reductase) Heme-Fe Mature DMT1 HCP-1

Ferritin Fe++ Fe+++ Mitochondria FPN () Other processes

Plasma Enterocyte precursor Enterocyte precursor () (Macrophage) Noniron-loaded Iron-loaded FPN () Ferritin/Fe++ Fe+++ Fe++ Hepcidin Other cells Iron Balance in Adults

Gastrointestinal Absorption 1-2 mg/day

Storage Iron Functional iron cells and 18 mg Plasma transferrin 4 mg Red cell hemoglobin 1000 mg Myoglobin Cytochromes 2500 mg

Physiologic daily iron loss 1-2 mg/day Natural Modifiers of Iron Absorption

Iron Absorption Inhibitors

Spinach ,whole grains such as buckwheat and amaranth, other vegetables such as chard and rhubarb, as well as beans and nuts, all contain significant levels of oxalic acid, which binds with iron, inhibiting its absorption. Soy beans contain phytic acid, which also bind iron. Tea and coffee contain tannins, which block iron absorption. Clay and heavy metals also inhibit iron absorption.

Iron Absorption Enhancers

•/fish/poultry •Vitamin C-rich fruits: oranges, cantaloupe, strawberries, grapefruit •Vegetables: broccoli, brussel sprouts, tomato, tomato juice, potato, green & red peppers •White wine Iron Turnover in the of Chronic

Gastrointestinal Absorption <1 mg/day

Hepcidin

Storage Iron Hepcidin Functional iron Liver cells and Plasma transferrin Bone marrow RES 2 mg Red cell hemoglobin 1500 mg Myoglobin Cytochromes 2000 mg

Physiologic daily iron loss 1 mg/day Hepcidin Regulation*

*IL-6 and LPS also activate hepcidin expression

Semin Liver Dis 31:280, 2011 Preservation of the MCHC at the Expense of the MCV

Blood 20: 173, 1962 Iron Regulatory

•HFE • Senses cellular iron uptake • Tfr-2 • Senses cellular iron uptake • No anemia • Upregulates Hepcidin (with Tfr-2 (HJV) and HFE)

• Hepcidin • Downregulates • DMT1 • Imports GI iron Iron overload • Ferroportin (FPN) • Exports intracellular iron to Tf anemia • Tfr-1 • Receptor for Tf-bound iron • Hephaestin and • Iron oxidases (cellular and ceruloplasmin circulating) Essential Factors in and the Effect of Cancer, or Infection • Intensity of the stimulus • Erythropoietin production is suppressed by cytokines and iron overload

• Functional capacity of the • Erythroid progenitor cell bone marrow proliferation is suppressed by cytokines and erythropoietin lack

• Iron is sequestered and its • Available nutrients absorption is inhibited by hepcidin

• Red cell survival • Red cell survival is reduced and loss is increased due to diagnostic testing Role of Iron Sequestration in the Anemia of Chronic Disease

• There is no impairment of utilization of absorbed iron

• There is no impairment of plasma transferrin iron uptake by erythroid cells

• Reduced expression and decreased iron utilization are primarily consequences of EPO deficiency

• Iron cannot correct the anemia of chronic disease in the absence of

• Pharmacologic concentrations of EPO can correct the anemia of chronic disease but not iron deficiency anemia

• Correction of the anemia of chronic disease with EPO can occur without a change in the iron abnormalities

• Correction of the anemia of chronic disease with EPO is associated with mobilization of iron stores and sometimes iron deficiency Hypoxic Regulation of Erythropoietin Production

N Engl J Med 348:1282, 2003 Effect ofIron on Administration

Serum Epo (mU/ml) 1000 1200 1400 1600 200 400 600 800 0 2024681 12 10 8 6 4 2 0 –2 Fe Rx Time (days) theSerumErythropoietin Level Hb, g/dL sEpo, mU/mL Blood 91:2139, 1998 8 9 10 5 6 7

Hgb, g/dL Br J Haematol 94:288, 1996 Hepcidin Expression is Subordinate to Tissue

Increased storage iron

J Clin Invest 110:1042, 2002

Serum Immunoreactive Erythropoietin in Iron Deficiency Anemia

100

80

60 P <.005 40 sEPO (mU/ml) 20

0 9.5–9.9 10.0–10.4 10.5–10.9 11.0–11.4

Hgb (g/dL) Transfusion According to the Hemoglobin Level in MDS Hemoglobin gm %

Time (months)

B J Haematol 94:288, 1996 – Bypassing a Natural Barrier Body Iron Homeostasis

• After intake, iron is normally sequestered in complexes: – Serum transferrin • Iron transport in blood/extracellular fluid • Capacity can be exceeded resulting in Nontransferrin-Bound Iron (NTBI) – NTBI is the most toxic form of iron

– Ferritin • Binds intracellular iron • High levels in the serum reflect iron overload but can be affected by NASH, inflammation (Still’s disease and cancer) infection (hematophagocytosis, ) • A < 45 % with a high serum ferritin (>400 ng/mL) is characteristic of inflammation or , not iron overload, where the transferrin saturation is always > 50 % and often > 95 % Iron excess as a Toxin

Increased transferrin saturation (>50 %) leads to deposition of iron in nonerythroid tissues such as the , liver and leading to: Congestive Hepatic fibrosis mellitus and other endocrinopathies Increased susceptibility to infection

Increased transferrin saturation leads to the accumulation of nontransferrin-bound iron (NBTI), labile or bound to other proteins, and free formation.

(Fenton reaction)

The generation of free hydroxyl radicals causes tissue damage through oxidative reactions with proteins, lipids and nuclei acids. Potential Mechanisms for Iron-induced Cellular Injury

Int J Hematol 76:219, 2002 Measures of Body Iron Content

• • Diurnal variation, affected by diet inflammation and infection • Serum transferrin • Affected by nutrition, liver disease, inflammation, infection and FPN and ceruloplasmin • Serum ferritin • An acute phase reactant, specific only if low. Correlation with LIC = 0.63

• Liver • Defines iron storage site and liver . May not correlate with cardiac iron burden • Liver iron by MRI • May not correlate with cardiac iron status • Cardiac MRI (T2*) • Correlates with cardiac function

• Bone marrow aspirate • Considered the “gold standard” but is invasive and not always technically adequate Serum Ferritin: Disadvantages LIC Predicts Total Body Iron Liver MRI Correlation With Biopsy Correlation between Plasma Ferritin (Pl Fer) and Hepatic Iron Concentration

LIC

Pl Fer

Months of R = 0.63 Brit J Haematol 89:880, 1995

Am J Hematol 42:81, 1993 Causes of Extreme Hyperferritinemia (>1500 µg/L)

World J Gastroenterol 12:5866, 2006 BBA 1763:700, 2006 Hereditary (HFE) Hemochromatosis • An autosomal recessive disorder due to a C282Y and rarely an H63D mutation in Northern Europeans (0.3-1.2 % prevalence) with variable • Serum ferritin is elevated in 84 % of men and 65 % of female C282Y homozygotes • Serum ferritin is > 1000 µg in 37 % of men and 3% of female C282Y homozygotes • If baseline ferritin is < 1000 µg , < 50 % of men and 20 % of females exceeded 1000 µg after 12 years • If baseline ferritin is < 1000 µg at age 55, < 15 % progressed to > 1000 µg in 12 years • Iron overload was present in 28 % of men and 1 % of women at age 65. • Iron overload with C282Y/H63D is rare without other risk factors such as liver disease • C282Y homozygosity doubles the colon cancer risk in everyone and the breast cancer risk in women’ • H63D homozygosity triples the hereditary nonpolyposis colon cancer risk • Environmental cofactors are alcohol, hepatic steatosis and • Non-citrus fruits are protective • An elevated transferrin saturation (> 45 %) is the earliest clue • Phlebotomy should start if the ferritin is if there is evidence of iron overload to achieve a ferritin of 50 µg • is indicated for a ferritin >1000 µg and abnormal liver function Major Complications of Iron Overload •

• Hepatic fibrosis (reversible with phlebotomy)

• Hepatocellular cancer

• Diabetes mellitus

•

•

•

•

• Pituitary-adrenal axis impairment

• Increased susceptibility to infection (MDS)

• Increased risk of leukemic transformation (MDS)

• Impaired survival post BMT Terminal Heart Failure due to Cardiac Iron Overload

Circulation 30: 698,1964 Cardiac Disease is the Major Cause of Death in β-

Lancet 334:27, 1989 Correlation Between NTBI and Transferrin Saturation

Am J Hematol 84:29, 2009

Survival in MDS According to Diagnosis (WHO criteria)

J Clin Onc 23:7594, 2005 Survival of MDS patients by transfusion dependence (N = 467)

Overall survival Leukaemia-free survival (HR = 1.91; p < 0.001) (HR = 1.84; p = 0.001)

1.0 Transfusion independent 1.0 Transfusion independent 0.9 Transfusion dependent 0.9 Transfusion dependent 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 Cumulative proportion surviving Cumulative proportion surviving Cumulative proportion 0.0 0.0 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180 Survival time (months) Survival time (months)

HR = hazard ratio. Malcovati L, et al. J Clin Oncol. 2005;23:7594-603. Survival of MDS patients by severity of transfusion requirement

Overall survival Leukaemia-free survival (HR = 1.36; p < 0.001) (HR = 1.40; p < 0.001)

0 U pRBC/4 weeks 0 U pRBC/4 weeks 1.0 1 U pRBC/4 weeks 1.0 1 U pRBC/4 weeks 2 U pRBC/4 weeks 2 U pRBC/4 weeks 3 U pRBC/4 weeks 3 U pRBC/4 weeks 0.8 0.8 4 U pRBC/4 weeks 4 U pRBC/4 weeks

0.6 0.6

0.4 0.4 Cumulative survival 0.2 Cumulative survival 0.2

0.0 0.0 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180 Survival time (months) Survival time (months) pRBC = packed red blood cells. Malcovati L, et al. Haematologica. 2006;91:1588-90. Overall survival of transfusion-dependent patients by serum ferritin level

RA/RARS/5q− RCMD/RCMD-RS (HR = 1.42; p < 0.001) (HR = 1.33; p = 0.07)

Serum ferritin Serum ferritin 1.0 1.0 1,000 µg/L 1,000 µg/L 0.9 1,500 µg/L 0.9 1,500 µg/L 0.8 2,000 µg/L 0.8 2,000 µg/L 0.7 2,500 µg/L 0.7 2,500 µg/L 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 Cumulative proportion surviving Cumulative proportion Cumulative proportion surviving 0.0 0.0 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180 Survival time (months) Survival time (months) RA = refractory anaemia; RARS = RA with ringed sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia; RCMD-RS = RCMD with ringed sideroblasts.. Malcovati L, et al. Haematologica. 2006;91:1588-90. Impact of Pretransplant Serum Ferritin on Outcome in MDS Patients

Blood 109:4586, 2007 Prevalence of comorbidities in transfusion- dependent MDS

100 With transfusion (n = 205) Without transfusion (n = 307) 82.4 81.0

67.1 62.9 55.7 50 44.4 40.4 37.1 Patients (%)

14.6 6.2 1.0 0.7 0 Cardiac Diabetes Dyspnoea Hepatic Infectious Fungal events 2003–2005 2003–2005 events complications infection 2003–2005 2003–2005 2003–2005 2003–2005

Transfused MDS patients have a higher prevalence of cardiac events, diabetes mellitus, dyspnoea, and hepatic and infectious than non-transfused MDS patients

Goldberg SL, et al. J Clin Oncol. 2010;28:2847-52. Probability of non-leukemic death in transfusion dependent MDS patients

100 N = 467 p = 0.01

75

51 50

31 Percentage 25 88 2 0 Cardiac Infection Haemorrhage Hepatic Other failure cirrhosis

Malcovati L, et al. J Clin Oncol. 2005;23:7594-603 Current Guidelines for Iron Chelation in MDS Patients Organization Transfusion Serum Ferritin Life Expectancy/ Status (ng/mL) MDS Risk Score (units of blood)

Italian > 50 units – > 6 months Society UK Hematology ≥ 25 units – Low/ Int-1 Society NCCN > 20-30 units > 2500 Low/Int-1 SCT MDS Foundation ≥ 24 units > 1000 > 1year

Austrian Transfusion- > 2000 or organ 2years/SCT/ Hematology dependent damage Chemotherapy Society Canadian Transfusion- > 1000 or organ Low/Int-1/SCT Hematology dependent damage Int-2 if > 1year life Society expectancy Japanese > 40 units * > 1000 > 1 year Hematology Society Iron Promotes the Growth of Candida

Blood 34:441, 1969 Correlation Between Hepcidin and Ferritin in MDS Subtypes

PLoS One 6:e23109, 2011 What about higher risk MDS and AML progression?

• Iron is mutagenic in hematopoietic cells and can promote progression to AML in mice1

Apoptosis •NTBI  LPI  ROS* – ROS damage X • membranes •proteins • nucleic acids Mutagenesis Genomic instability AML?

●Chelation induced apoptosis, differentiation & repressed signalling in 2-5 AML cells & cell lines in vitro & in vivo 1. Chan LSA, et al. Blood 2010;116:[abstract 122] 2. Eberhard Y, et al. Blood. 2009;114:3064-73. 3. Jiang Y, et al. Leukemia. 2005;19:1239-47. ROS = , NTBI = non-transferrin 4. Ohyashiki JH, et al. Cancer Sci. 2009;100:970-7. bound iron 5. Callens C, et al. J Exp Med. 2010;207:731-50. Currently Available Iron Chelation Agents

Deferoxamine

Usual dose (mg/kg/day) 25−60 75 20−30

Route of administration Subcutaneous or intravenous, Oral, three times daily Oral, once daily 8−12 hours, 5 days/week

Half-life 20−30 minutes 3−4 hours 8−16 hours

Route of excretion Urinary and fecal Urinary Fecal

Main adverse effects Local reactions, ocular and Gastrointestinal disturbances, Gastrointestinal disturbances, auditory abnormalities, growth agranulocytosis/neutropenia rash, mild non-progressive retardation, allergic reaction arthralgia, elevated liver enzymes increase, elevated liver enzymes

Leuk Res 31(S3):S16, 2007 ,

CHF Risk Reduction with Chelation According to EF Improvement

J Cardio Mag Res 13: 45, 2011 Effect of Deferasirox on LIC in Sickle Cell Anemia

B J Haematol 136:501, 2007 Leuk Res 34:1560, 2011 Deferasirox Normalizes LPI in MDS Patients

US03 study1 EPIC study – MDS cohort2 Patients, n 55 38 39 37 34 Pre-administration 1.2 1.2 Post-administration 1.0 p  0.00001* 1.0 mol/L) μ 0.8 0.8 SD (

0.6  0.6 Normal threshold 0.4 Threshold of normal LPI 0.4 (≤ 0.5 µmol/L) 0.2 0.2 Mean LPI Mean LPI (µmol/L)

0 0 BL 3 6 9 12 Baseline 12 28 52 Months from baseline Time (weeks) Patients with baseline LPI ≥ 0.5 μmol/L = 41%

*Comparison of baseline LPI vs each treatment time point 1. List AF, et al. Blood. 2008;112:[abstract 634]. 2. Gattermann N, et al. Leuk Res. 2010;34:1143-50. Successful Iron Chelation Improves Erythropoiesis in MDS

Br J Haematol 94:288, 1996 ERYTHROID RESPONSE DURING IRON CHELATION

Transfusion 50:1568, 2010 EPIC: reduction in serum ferritin is associated with improvement in ALT in MDS

• At 12 months, there were significant reductions in – median serum ferritin (−253 µg/L; p = 0.002) – mean ALT (−27.7 ± 37.4 U/L; p < 0.0001)

3,000 Serum ferritin ALT 70

2,500 60 Mean ALT(U/L) 50 2,000 40 1,500 30 1,000 20

500 Mean actual deferasirox dose: 10 19.2 ± 5.4 mg/kg/day Median serum ferritin (µg/L) 0 0 Baseline36912 3 6 9 12 Time (months) ALT = alanine ; EPIC = European Prospective Investigation into Cancer and Nutrition. Gattermann N, et al. Leuk Res. [Epub ahead of print 2010 May 5]. Survival is improved in MDS with Chelation

Survival in chelated versus non-chelated MDS patients with (a) transfusion requirements <3 PRBC/month and (b) transfusion requirements >3 PRBC/month.

Leukemia Res 34:864, 2010 GFM: effect of iron chelation therapy on survival in lower-risk MDS patients

IPSS = Low IPSS = Int-1 Median: not reached vs 69 months Median: 115 vs 50 months (p < 0.002) (p < 0.003)

1.00 1.00

Iron chelation (n = 30) 0.75 0.75 Iron chelation (n = 23)

0.50 0.50

0.25 0.25

Survival distribution Survival distribution function No chelation (n = 29)

No chelation (n = 15) Survival distribution function 0.00 0.00 0 50 100 150 200 250 0 20 40 60 80 100 120 140 Time from diagnosis to death (months) Time from diagnosis to death (months)

Results were the same regardless of sex and age.

GFM = Groupe Francophone des Myélodysplasies. Rose C, et al. Leuk Res. [Epub ahead of print 2010 Feb 1]. NTBI elevation during allogeneic SCT

C 140 1.1 1 120 0.9 100 0.8 0.7 80

mol/L) 0.6 μ 60 0.5 0.4 NTBI ( 40 0.3 0.2 Transferrin saturation (%) Transferrin 20 0.1 0 0 −14 −70 71421 0 20 40 60 80 100 120 140 160 Time from SCT (days) Transferrin saturation (%)

C = onset of conditioning regimen. Sahlstedt L, et al. Br J Haematol. 2001;113:836-8. Iron Chelation Before SCT Improves Survival (n = 101)

1.0 1.0 1.0 SF > 1,000 SF < 1,000 IC 0.8 0.8 0.8

0.6 0.6 0.6

p = 0.000 p = 0.003 0.4 0.4 0.4 p = 0.001 Overall survival rate Overall survival Treatment-related mortality mortality rate Treatment-related 0.2 SF > 1,000 Event-free survival 0.2 SF > 1,000 0.2 SF < 1,000 SF < 1,000 IC IC 0 0 0 0 12 24 36 48 60 0 12 24 36 48 60 0 12 24 36 48 60 Months from transplantation Months from transplantation Months from transplantation

SF > 1,000 = patients with serum ferritin ≥ 1,000 µg/L at the time of SCT; SF < 1,000 = patients with serum ferritin < 1,000 µg/L at the time of SCT, without ICT; Lee JW, et al. Bone Marrow IC = patients with serum ferritin decreased to < 1,000 µg/L with ICT before SCT. Transplant. 2009;44:793-7. EPIC Study: Adverse Events with Deferasirox

Adverse event* Number (%) Diarrhoea 111 (32.6) 45 (13.2) Vomiting 26 (7.6) Abdominal pain 26 (7.6) Upper abdominal pain 25 (7.3) Rash 23 (6.7) 21 (6.2)

Total number 341 *Drug-related as assessed by the investigator.

Gattermann N, et al. Leuk Res. 2010;34:1143-50. Most Frequent Side Effects of Deferiprone Therapy in Patients

Side effect n %

Gastrointestinal symptoms (abdominal discomfort, pain, nausea, vomiting, ) 18 37.5

Granulocytopenia (neutrophils = 0.5–1.0 × 109 /L) 5 13.0

Agranulocytosis (neutrophils < 0.5 × 109 /L) 2 4.0

Elevation of liver enzymes (>3 × upper normal limits) 9 18.8

Weight gain, fluid retention 2 4.0

Hemoglobin 35: 217, 2011 Correlation of Anemia and Survival in the Elderly

JAGS 45:825, 1997 Probability of Death in MDS According to the Hemoglobin Level

Men Women

Haematologica 2011 Probability of Cardiac Death in MDS According to the Hemoglobin Level

Men Women

Haematologica 2011 Improved Overall Survival in MDS with EPO/G-CSF Therapy

EPO/G-CSF

Control

J Clin Oncol 26:3607, 2008 Summary • Iron overload is associated with impaired survival and an increased risk of leukemic transformation in MDS patients with Low or Int-1 disease

• Risk assessment based on iron stores is imperfect because of poor correlation between the transfusion burden and body iron store measurements

• Iron chelation therapy can reduce total body iron stores and NTBI

• Iron chelation is associated with improved survival as well as an improved response to bone marrow transplantation in MDS patients

• Oral chelation may be more effective than parenteral chelation in reducing intracellular cardiac iron and combining oral and parenteral chelation may be the most effective strategy

• Anemia per se contributes to iron overload and is also an important cofactor for disease morbidity in iron-overloaded MDS patients

• Current transfusion practice needs to be altered to maintain the hematocrit commensurate with continuous relief of tissue hypoxia on a gender-specific basis

• The threshold for initiating iron chelation should be based on organ dysfunction Gold is for the mistress, silver for the maid, for the craftsman cunning at his trade but iron said the Baron sitting in his hall, iron, cold iron is the master of them all.

Rudyard Kipling Which of these Individuals is Tebowing? ABC

Answer:

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