1. Iron & Iron Overload Saturday, October 29, 2016
Cyrus C. Hsia, HBSc, MD, FRCPC
Associate Professor of Medicine,
Schulich School of Medicine and Dentistry, Western University
Associate Medical Director, Blood Transfusion Laboratory
London Health Sciences Centre

2. Welcome
Welcome to London, Ontario
Oct 29, 2016 C. Hsia

3. Objectives
At the conclusion of this presentation the participant will be able to:
1. Understand the importance of iron in the body
2. Review the toxicity of iron to organs as a result of chronic red blood cell transfusions
3. Review the Iron Overload management in conditions such as myelodysplastic syndrome (MDS)
Oct 29, 2016 C. Hsia

4. Disclosures
Relevant conflicts of interest for current presentation in the last 3 years:
Participated as a consultant in advisory boards for Celgene, Novartis, Amgen, & Jansen
Received speakers honoraria from Celgene, Novartis, Amgen, & Jansen
Liberal use of images from the internet for illustration and teaching purposes
Oct 29, 2016 C. Hsia

5. Some Basics
To iron or not to iron…
Oct 29, 2016 C. Hsia

6. CBC
The complete blood count

7. CBC
The complete blood count

8. Blood
What is blood made of?

9. RBC Red blood cells (RBC)
Hemoglobin molecules are essential.. They carry oxygen in the red blood cells.
Each heme ring contains an iron atom
Feb 29, 2016 C. Hsia

10. Iron
Iron is essential for hemoglobin
Feb 29, 2016 C. Hsia

11. Too Little Iron Clinical Features of Iron Deficiency Anemia
Anemia in general
Fatigue (tired), shortness of breath, chest pain, palpitations, generally feel weak
Specific to iron deficiency anemia
Sore tongue, difficulty swallowing, brittle or spoon shaped nails, and cravings for ice or dirt
                                   
Oct 29, 2016 C. Hsia

12. Too Little Iron
Oct 29, 2016 C. Hsia

13. Is More Iron Better?
Oct 29, 2016 C. Hsia

14. Too Much Iron!
Oct 29, 2016 C. Hsia

15. Basic Physiology
Iron Metabolism & Regulation
Oct 29, 2016 C. Hsia

16. Iron Absorption and Metabolism
The typical daily diet contains 10–20 mg of iron. Only about 10% of dietary iron is absorbed (1–2 mg/day).
Iron homeostasis is closely regulated via intestinal absorption.
Iron is mainly absorbed in the duodenum and upper jejunum.
Most absorbed iron is used in bone marrow for erythropoiesis.
Once iron is absorbed, there is no physiologic mechanism for excretion of excess iron from the body other than blood loss (i.e., pregnancy, menstruation or other bleeding.)
Most absorbed iron is transported in the bloodstream bound to the glycoprotein transferrin. Transferrin binds only two iron atoms.
Normally, 20–45% of transferrin binding sites are filled (measured as percent transferrin saturation [TS]).
Reference:
Normal Iron Absorption and Storage.
Normal Iron Absorption and Storage.
Oct 29, 2016 C. Hsia

17. Dietary Iron
Average North American diet provides mg iron in 2 forms – heme and non-heme iron
Heme iron from meat and fish
Non-heme iron vegetables and fortified cereal
Oct 29, 2016 C. Hsia

18. Dietary Iron
Average North American diet provides mg iron in 2 forms – heme and non-heme iron
Heme iron from meat and fish
Non-heme iron vegetables and fortified cereal
Absorption in the small intestines (~1-2mg)
Daily dietary requirements
1-2 mg usually sufficient
Increased requirements for – pregnancy, menstruation, breastfeeding
Oct 29, 2016 C. Hsia

19. Iron Absorption and Metabolism
Because we cannot control how much iron is excreted, the balance of iron of depends on how much iron goes into the body.
The typical daily diet contains 10–20 mg of iron. Only about 10% of dietary iron is absorbed (1–2 mg/day).
Iron homeostasis is closely regulated via intestinal absorption.
Iron is mainly absorbed in the duodenum and upper jejunum.
Most absorbed iron is used in bone marrow for erythropoiesis.
Once iron is absorbed, there is no physiologic mechanism for excretion of excess iron from the body other than blood loss (i.e., pregnancy, menstruation or other bleeding.)
Most absorbed iron is transported in the bloodstream bound to the glycoprotein transferrin. Transferrin binds only two iron atoms.
Normally, 20–45% of transferrin binding sites are filled (measured as percent transferrin saturation [TS]).
Reference:
Normal Iron Absorption and Storage.
Normal Iron Absorption and Storage.
Oct 29, 2016 C. Hsia

20. Iron in MDS
Myelodysplastic Syndromes
Oct 29, 2016 C. Hsia

21. Myelodysplastic Syndromes
Definition
Myelodysplastic syndromes (MDS) form a group of clonal hematopoietic stem cell malignancies characterized by ineffective hematopoiesis in one or more cell lineages, associated peripheral cytopenias, and risk of transformation to acute myeloid leukemia
Sloand EM. Myelodysplastic syndromes: introduction. Semin Hematolo. 2008;45:1-2. Valent P, Horny HP, Bennett JM, et al. Leuk Res 2007;31:72-36.
Oct 29, 2016 C. Hsia

22. Dr. Robert Barr and the Ford Pinto
Oct 29, 2016 C. Hsia

23. Myelodysplastic Syndromes
In other words..
MDS is a group of blood and bone marrow disorders (cancers) where the blood cells are made with defects and don’t survive as long as it should.
This leads to low blood counts in 1 or more of the blood cells.
It is NOT leukemia, but can be considered pre-leukemic.
It is NOT 1 disease and behaves differently in different people.
Oct 29, 2016 C. Hsia

24. Impact of MDS Patient Society
Poor quality of life - time and commitment to transfusions
Complications of Iron Overload
Cardiorespiratory symptoms
Hospitalizations for cardiac complications, infections, bleeding, increased risk of leukemic transformation
Increased risk of shorter survival
Society
Transfusion burden
Hospitalizations for cardiac complications, infections, complications of iron overload, bleeding, leukemia
Oct 29, 2016 C. Hsia

25. Management for MDS patients
The mainstay of management is supportive
Transfusions, antibiotics
No specific transfusion threshold, rather patient dependent based on level of hemoglobin associated with symptoms of anemia
Steensma DP and Bennett JM. The Myelodysplastic Syndromes: Diagnosis and Treatment. Mayo Clin Proc. 2006;81(1):
Oct 29, 2016 C. Hsia

26. Too much Iron
Iron overload affect on organs
Oct 29, 2016 C. Hsia

27. Why do MDS patients develop too much iron?
Each unit of packed RBC (red blood cell) contains about 250mg of iron!
2 units = 500mg
10 units = 2500mg
20 units = 5000mg
Recall that the daily amount of iron lost in the body is only 1- 2mg and the total body iron is mg.
Steensma DP and Bennett JM. The Myelodysplastic Syndromes: Diagnosis and Treatment. Mayo Clin Proc. 2006;81(1):
Oct 29, 2016 C. Hsia

28. Free Iron: The Essence of Iron Overload
Saturation of transferrin due to
Frequent blood transfusions, and
Ineffective erythropoiesis leading to increased iron absorption
Subsequent formation of NTBI in plasma
Uncontrolled iron loading of organs
Pituitary
Parathyroid
Thyroid
Heart
Liver
Pancreas
Gonads
Normal: no NTBI produced
Iron overload
100% Fe
Transferrin saturation %
30%
“Free” Iron
NTBI – non-transferrin-bound iron
Oct 29, 2016 C. Hsia
As presented by R. Wells at CCMDS 2012, Montreal. 28

29. Mitochondria Inefficient energy metabolism
Fe3+
Fe2+
NTBI
LCI O2
H2O2
O2-
OH.
ROI
ROS
Mitochondria Inefficient energy metabolism
Apoptosis
Senescence
Lipid Membrane damage
Cell lysis
Protein
Altered signaling
Proliferation
Fibrosis
DNA
Mutagenesis
Cellular Targets of Labile Iron
TfR
DMT
DMT-Divalent metal transporter
TfR-Transferrin receptor
ROI-reactive oxygen intermediates
ROS-reactive oxygen species
Regulated
Unregulated
Holotransferrin
As presented by R. Wells at CCMDS 2012, Montreal.
Oct 29, 2016 C. Hsia

30. How to assess
How to assess for iron overload
Oct 29, 2016 C. Hsia

31. Methods to Assess Iron Overload
Blood tests
Serum ferritin
Transferrin saturation
Liver iron concentration (LIC)
Liver biopsy
Hepatic magnetic resonance imaging (MRI); FerriScan®
Superconducting quantum interference device (SQUID)
Cardiac iron concentration
Cardiac MRI
Serum ferritin and transferrin saturation are blood tests.
Oct 29, 2016 C. Hsia

32. Mild-to-moderate iron overload
Serum Ferritin
Pros
Cons
Inexpensive and easily measured
Allows for frequent monitoring
Positive correlation with morbidity and mortality
Indirect measurement of iron burden
Requires serial measurements and/or combination with other indicators of iron overload
Levels are influenced by many factors, including infection and inflammation
Assessment of serum ferritin levels is a relatively easy and practical way to indirectly assess body iron levels. It simply requires a blood sample and the use of a commercially available kit. Kits include:
The Ferritin Blood Test ELISA kit (Calbiotech, Spring Valley, CA, USA)
The Ferritin Enzyme Immunoassay Test Kit (Biocheck, Inc., Foster City, CA, USA)
The Ferritin ELISA Kit (IBL Immuno-Biological Laboratories, Minneapolis, MN, USA)
Spectro Ferritin (Ramco Laboratories, Inc., Stafford, TX, USA).
Normal
Mild-to-moderate iron overload
Severe iron overload
< 300 μg/L
> 1,000-< 2,500 μg/L
> 2,500 μg/L
Oct 29, 2016 C. Hsia

33. Transferrin Saturation
May be useful as a complement to serum ferritin for the diagnosis of iron overload
Normal levels of transferrin saturation: 20% to 50%
Transferrin saturation > 50% is indicative of an iron-overload
Limitations2,3
Not useful for monitoring long-term trends in iron burden
Unable to detect iron overload caused primarily by the reticuloendothelial system
Not as reliable as LIC in estimating total body iron stores
Transferrin saturation reflects the ratio of serum iron to total iron-binding capacity. This value tells you how much of the transferrin that is available to bind iron serum is actually bound to iron (e.g. 30% means that 30% of free iron is being carried by transferrin). When the capacity of transferrin is exceeded, non-transferrin-bound iron (NTBI) is produced.
TS is calculated from the ratio of serum or plasma iron concentration and TIBC. Alternatively, unbound iron-binding capacity (UIBC) can be measured and TS calculated from this parameter
TIBC, total iron-binding capacity; UIBC, unbound iron-binding capacity; LIC, liver iron concentration
Mazza J. Manual of clinical hematology. Philadelphia: Lippincott Williams & Wilkins, 2002;129.
Gattermann N, et al. Hematol Oncol Clin North Am. 2005;19 Suppl 1:18-25.
Santini V, et al. Leuk Res. 2010;34:
Oct 29, 2016 C. Hsia

34. Transfusion History and Surrogate Markers
Number of units of transfused blood
No prospectively validated threshold has been established
Published recommendations, based on expert opinion, suggest a threshold of 25 to 50 units
Should not be the sole index of iron burden in MDS
Some patients (i.e., RARS) have elevated serum ferritin levels regardless of transfusion history and may benefit from initiation of iron chelation before an arbitrary number-of-units threshold has been reached
Serum ferritin levels
In the literature, experts have recommended a threshold ranging from 1000 to 2500 g/L
May be affected by inflammation
Interpretation of ferritin measurements in the context of fasting transferrin saturation is strongly recommended
Iron chelation should not be started unless transferrin saturation exceeds >0.5 (50%)
Reference:
Wells RA, Leber B, Buckstein R, Lipton JH, Hasegawa W, Grewal K, Yee K, Olney HJ, Larratt L, Vickars L, Tinmouth A. Iron overload in myelodysplastic syndromes: a Canadian consensus guideline. Leuk Res Sep;32(9):
Wells RA, et al. Leuk Res Sep;32(9):
Oct 29, 2016 C. Hsia

35. Iron Chelation Therapy
Does removing the excess iron improve anything?
Oct 29, 2016 C. Hsia

36. Iron Chelation Therapy and Survival in MDS
1.00
Median survival 120 mos with
standard/high chelation vs
69 mos with low-dose chelation
0.75 ( P
< .0001)
Survival Distribution Function
0.50
Standard/high chelation
0.25
Low chelation
Rose et al. evaluated 170 MDS patients (all risk categories) who required transfusions for the first time in a prospective survey performed by the GroupeFrançais des Myélodysplasies (GFM). The patients, who were referred for RBC transfusions at 18 GFM centers during a 1-month period in 2005, were followed for 2 years with assessment of RBC transfusions, use and type of iron chelation, and complications.
76 patients (46%) received standard-dose chelation using deferoxamine by continuous (8-hour) subcutaneous (SC) infusion 40 mg/kg per day 3 to 5 days per week, deferiprone (30 to 75
mg/kg per day), deferiprone plus deferoxamine SC, or deferasirox (20 to 30 mg/kg per day) or low-dose chelation regimen of deferoxamine SC (2 to 3 g per week) or deferoxamine intravenously (50 to 100 mg/kg after reach RBC transfusion). The median survival for patients receiving chelation therapy was 115 months vs 51
months for non chelated patients (P < .0001). Furthermore, median survival for patients receiving standard dose chelation therapy was 120 months compared with 69 months for patients receiving low-dose chelation therapy
In summary, standard chelation produced significantly better survival benefit than low-dose chelation. Multivariate analysis revealed that good level of chelation dramatically improved chance for prolonged survival (HR = .215; P = .0002). Higher IPSS risk was associated with decreased survival (HR = 3.888; P = .0030).
Reference:
List AF. Iron overload in myelodysplastic syndromes: diagnosis and management. Cancer Control Jan;17 Suppl:2-8.
No chelation
0.00 50
100
150
200
250
Diagnosis to Death Time (Mos)
List AF. Cancer Control. 2010;17:1-7.
Oct 29, 2016 C. Hsia

37. Impact of Iron Chelation Therapy on Overall Survival
The difference in median survival (74 vs. 49 months, respectively; p = 0.002) supports the idea that iron
chelation therapy is beneficial for MDS patients.
This was a retrospective matched-pair analysis drawing on the data base of the Düsseldorf MDS registry. It included 94 patients on long-term chelation therapy and 94 matched patients without it. All patients had iron overload, defined as serum ferritin (SF) above 1000 ng/ml or a history of multiple transfusions and SF ≥ 500 ng/ml. Median SF was 1954 ng/ml in chelated and 875 ng/ml in non-chelated patients.
Median survival was 74 months in patients receiving iron chelation therapy and 49 months in the supportive care group. Cumulative risk of AML transformation in the iron chelation vs. supportive care group was 10% and 12% two years after diagnosis, and 19% and 18% five years after diagnosis, respectively (p = 0.73).
Neukirchen J, Fox F, et al. Improved survival in MDS patients receiving iron chelation therapy - a matched pair analysis of 188 patients from the Düsseldorf MDS registry. Leuk Res Aug;36(8):
N=188
Neukirchen J, et al. Leuk Res Aug;36(8): .
Oct 29, 2016 C. Hsia

38. Evidence in Support of the Beneficial Effects of Deferoxamine
Treatment
Assessment of efficacy
Findings
178 MDS
(18 who
received ICT)
DFO SC g/day
Over 12 h infusion 5 days /week
Ferritin levels
Causes of death
Overall survival
Median ferritin pre ICT was 4215g/l and 2659g/l post ICT
Ferritin increased in non ICT patients over time
IPSS score (p < 0.008) and ICT (p = 0.02) were the only factors independently predictive of OS
Median survival at 160 months for patients with low and Int-1 IPSS:
Not reached for those receiving ICT
40 months for non ICT patients
This was a retrospective review of 178 pts seen at St.Paul’s Hospital in Vancouver, Canada, from January 1981 to April 2006, with a bone marrow diagnosis of MDS. Clinical data were collected from the practice database, the Iron Chelation Program of British Columbia database, and by chart review.
The study demonstrated a significant improvement in OS in pts with MDS receiving iron chelation therapy.
Reference:
Leitch HA, et al. Improved Survival in Patients with Myelodysplastic Syndrome (MDS) Receiving Iron Chelation Therapy. Blood 2006;108 [Abstract 249].
ICT, iron chelation therapy
Leitch HA, et al. Blood 2006;108 [Abstract 249].
Oct 29, 2016 C. Hsia

39. Hematologic Improvement in MDS with Deferasirox
Reference N
IPSS Risk
RBC Response
Neutrophil Response
Platelet Response
Median time to response
Cilloni D et al 2011* 57
Low/Int-1
45.6% NR
3 months
List A et al 2012*
173
52**
77***
15%
22%
169 days
(range, 84 to 382 days)
Gattermann N et al. 2010
247 50
100
21.5%
(53/247)
(11/50)
13%
(13/100)
113 days
Nolte F et al, 2012
11%
Angelucci E et al. 2012
152
Transfusion independence in 12%
References:
Cilloni D, et al. ASH Annual Meeting Abstract 611;
List AF, et al. J Clin Oncol 2012; 30(17):2134-9;
Gattermann N, et al. ASH Annual Meeting Abstract 2912;
Nolte Fet al. Ann Hematol 2013; 92(2): ;
Angelucci E, et al. ASH Annual Meeting Abstract 425.
*RBC, platelet, and neutrophil responses are assessed according to IWG 2006 criteria
**Met the neutrophil inclusion criteria
*** Met the platelet inclusion criteria
IPSS, International Prognostic Scoring System; RBC, red blood cell; NR, not reported; IWG, International Working Group.
1. Cilloni D, et al. ASH Annual Meeting Abstract 611; 2. List AF, et al. J Clin Oncol 2012; 30(17):2134-9; 3.Gattermann N, et al. ASH Annual Meeting Abstract 2912; 4. Nolte Fet al. Ann Hematol 2013; 92(2): ; 5. Angelucci E, et al. ASH Annual Meeting Abstract 425.
Oct 29, 2016 C. Hsia

40. Characteristics of Currently Available Iron Chelators in Canada
Guidelines for the Clinical Care of Patients with Thalassemia in Canada
Oct 29, 2016 C. Hsia

41. Characteristics of Currently Available Iron Chelators in Canada
Deferoxamine
Deferiprone
Deferasirox
Route of administration
Subcutaneous or intravenous
Oral
Plasma half-life
Short (20 min)
Moderate (2 hrs)
Long (8-16 hrs)
Primary route of
iron excretion
Urine and stool
Urine
Stool
Recommended dosage (mg/kg/day)
30-60
10 -40
Delivery
s.c.or i.v.
(8-12 hours)
5-7 days/week
Oral, 3 times daily
Oral, once daily
Charge of iron (III) complex (hydrophilic
or lipophilic)
Charged
Hydrophilic
Uncharged
Lipophilic
Guidelines for the Clinical Care of Patients with Thalassemia in Canada
Oct 29, 2016 C. Hsia

42. Canadian Panel Recommendations: Patient Selection for Iron Chelation Therapy
Iron chelation should be considered for transfusion-dependent MDS patients with a good prognosis (Low or Int-1 IPSS score or WHO classification of RA,RARS, or 5q-syndrome) as well as a higher IPSS score (Int-2 or High) who have:
Serum ferritin>1000 g/L, or
Who are candidates for allogeneic stem cell transplantation, or
Have a life expectancy >1 year
Iron chelation should be initiated when transfusion-dependent patients:
Have evidence of iron-related organ damage, or
Have serum ferritin >1000 g/L and fasting transferrin saturation >0.5, irrespective of the number of units of blood transfused
Wells RA, et al. Leuk Res. 2008;32(9):

43. Other Recommendations for Management of Iron Overload in MDS Patients
Characteristics
NCCN
MDS Foundation
Transfusion status
Received > 20 RBC
transfusions;
Continuing transfusions
Transfusion dependent,
requiring 2 U/mo for >1 y
Serum ferritin concentration
> 2500 g/L
> 1000 g/L
MDS risk category
IPSS: low or intermediate-1
IPSS: low or intermediate-1;
WHO: RA, RARS, and 5q-
Patient profile
Candidate for allograft
Candidate for allograft;
need to preserve organ function;
Life expectancy >1 y without comorbidities limiting progress
References :
GATTERMANN, N. « Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload », Int J Hematol., 2008, 88(1):24-29.
BENNETT, J. M., MDS FOUNDATION’S WORKING GROUP ON TRANSFUSIONAL IRON OVERLOAD. « Consensus statement on iron overload in myelodysplastic syndromes », Am J Hematol., 2008, 83(11):
Gattermann, N. Int J Hematol. 2008;88(1):24-29.
Bennett JM, et al. Am J Hematol. 2008;83(11):

44. Canadian Panel Recommendations: Choice of Chelating Agent*
Once the decision has been made to initiate iron chelation therapy, either DFO or DSX may be used
DFO 20–50 mg/kg/day by subcutaneous or intravenous infusion over 12–15 h or by BID SC bolus injections 5 days/week
DSX 20–30 mg/kg PO QD
Baseline investigations prior to the initiation of chelation therapy
Ophthalmological examination (slit lamp, retinal and corneal assessments)
Audiometry
Complete blood count
Creatinine (for DSX)
As auditory disturbances (high-frequency hearing loss, decreased hearing) have been reported with chelating agents, auditory testing is recommended before the initiation of treatment and thereafter at regular intervals.
Chelating agents also cause chelation of metals such as iron, copper, zinc, cobalt and nickel in the retina. These metals are essential for normal retinal function.
Ocular disturbances (lens opacities, early cataracts, maculopathies) have been reported with chelating agents. Thus, ophthalmic testing (including fundoscopy) is recommended before the start of the treatment and thereafter at regular intervals.
Reference:
Exjade, Product Monograph. Novartis Pharmaceuticals Canada Inc.February 11, 2015.
*Recommendations were written before deferiprone was approved in Canada
DFO, Deferoxamine; DFX, Deferasirox
Wells RA, et al. Leuk Res. 2008;32(9):

45. EAP requirements in Ontario
EAP Reimbursement Criteria Updated April 30, 2014
Oct 29, 2016 C. Hsia

46. Deferasirox: Therapy Initiation and Monitoring
Calculate dose (according to rate of transfusions:
<1u/month: 20 mg/kg/d
2u/month, 30 mg/kg/d
>2u/month, 40 mg/kg/d
Start at either 250 mg/day or 500 mg/day
Increase dose by 250 mg/day or 500mg/day each week after assessment of tolerability, until calculated dose is reached or until intolerable side effects occur
In aces of intolerable side effects, continue with to highest tolerated dose level for ongoing treatment

47. Proposed Response Criteria for the Therapy of Iron Overload
Complete Response (CR)
Decrease of serum ferritin to < 2000 ng/mL and decrease at least by 500 ng/mL
(e.g. from 2300 ng/mL to 1600 ng/mL)
Minor Response (MiR)
Decrease of serum ferritin to < 2000 ng mL, but less than by 500 ng/mL
(e.g. from 2300 ng/mL to 1900 ng/mL)
Stable Iron Load (SIL)
Ferritin constantly elevated but < 4000 ng/mL
No Response (NR)
Further increase of ferritin (by at least 500 ng/mL or ferritin constantly > 4000 ng/mL)
Iron overload in myelodysplastic syndromes (MDS) - diagnosis, management, and response criteria: a proposal of the Austrian MDS platform.
Valent P, et al. Eur J Clin Invest. 2008;38(3):

48. Canadian Panel Recommendations: Routine Follow-up of and Dose Adjustments
Clinic visit once monthly for 3 months, then quarterly (once every 3 months)
Ferritin, TSH/T3/T4, LFTs, creatinine, glucose q3monthly (CBC and creatinine weekly for four weeks after initiation of DSX therapy and after any dose increase)
Urinalysis (for proteinuria) monthly for DSX
Annual audiometry and ophthalmological assessments
2D echo, if abnormal at baseline or if clinically indicated
Dosage adjustments
Reduce dose of iron chelation therapy when ferritin falls below 2000 g/L
Discontinue iron chelation therapy when ferritin <1000 g/L
For DSX, follow product monograph if creatinine is elevated
Wells RA, et al. Leuk Res. 2008;32(9):

49. Summary
Iron is essential in the production and function of hemoglobin and red blood cells.
Too little iron (iron deficiency anemia) and too much iron (iron overload) can be detrimental
Number of RBC transfusions and iron overload are important yet often neglected issues in MDS management that appear to be negative predictors of survival
Iron chelation therapy should be considered in the management of MDS patients with iron overload due to frequent transfusions
Oct 29, 2016 C. Hsia

50. So Where Do You Want to Be?
Oct 29, 2016 C. Hsia

51. Bone marrow factory - The future
Any Questions?
Oct 29, 2016 C. Hsia

52. References ASH Education Book 2005 – 2015
World Health Organization Classification of Tumours. Pathology & Genetics: Tumours of Haematopoietic and Lymphoid Tissues. Edited by Elaine S. Jaffe, Nacy Lee Harris, Harald Stein, James W. Vardiman. IARC Press Lyon 2001.
Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. British Journal of Haematology. 1982; 51:
Harris NL, Jaffe ES, Diebold J, et al. World Health Organization Classification of Neoplastic Diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting – Airlie House, Virginia, November J Clin Oncol. 1999;17:
Greenberg P, Cox C, LeBeau MM, et al. International Scoring System for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:
Greenberg PL, Sun Z, Miller KB, Bennett JM, Tallman MS, Dewald G, Paietta E, van der Jagt R, Houston J, Thomas ML, Cella D, Rowe JM. Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996). Blood Sep 17;114(12): PMID:
Steensma DP and Bennett JM. The Myelodysplastic Syndromes: Diagnosis and Treatment. Mayo Clin Proc. 2006;81(1):
Komrokji RS and Bennett JM. Evolving classifications of the myelodysplastic syndromes. Current Opinion in Hematology. 2007;14:
Hellström-Lindberg E, Ahlgren T, Beguin Y, et al. Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Blood Jul 1;92(1):68-75.
Malcovati L. Prognostic Factors and Life Expectancy in Myelodysplastic Syndromes Classified According to WHO Criteria: A Basis for Clinical Decision Making. J Clin Oncol 2005;23:
Garcia-Manero G. Standard-of-care Approaches for Myelodysplastic Syndromes. JCO 2009 Education Book pp
Garcia-Manero G. Demethylating agents in myeloid malignancies. Current Opinion in Oncology. 2008;20:
Fenaux P, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. Lancet Oncol 2009;10:
Silverman LR, et al. Randomized Controlled Trial of Azacitidine in patients with Myelodysplastic Syndrome: A Study of the Cancer and Leukemia Group B. JCO 20:
Stresemann C and Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 2008;123:8-13.
Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med Nov 5;361(19): PMID:
Oct 29, 2016 C. Hsia

53. Acknowledgements
Select slides taken from Dr. Richard Wells’ presentation – The Silent Disease: Management of Iron Overload in Daily Practice
Oct 29, 2016 C. Hsia

54. Appendices
Oct 29, 2016 C. Hsia

55. Assessment of Iron Overload and Common Adverse Events of Chelators
Observation
Frequency
IOL assessment
AE monitoring
Iron intake rate
Each transfusion ✓
Chelation dose and frequency
3 monthly
Renal functiona
As frequently as required
Liver function
Sequential serum ferritin, transferrin saturationb
GTT, thyroid, calcium metabolism (BMD)c
Yearly in adults
Liver iron (T2* MRI)d
At baseline, where feasible; and, subsequently, as clinically indicated
Cardiac function (echo, MRI, ECG)
At baseline, then as clinically indicated
Cardiac iron (T2* MRI)
For patients receiving > 50 units RBC prior to ICT, or with CHF or arrythmias
Slit lamp examination, audiometrye
Yearly
Ocular and auditory disturbances have been reported when deferoxamine mesylate was administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. The ocular disturbances include blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory abnormalities reported have been tinnitus and hearing loss including high frequency sensorineural hearing loss. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment.
Reference:
Desferal, Product Monograph, Novartis Pharmaceuticals Canada Inc. November 2, 2011
aCreatinine should be measured at least every two weeks with each dose increase until stable. bTransferrin saturation > 80% may indicate the presence of oxidative stress. cBased on early/suggestive data in transfusion-dependent hemoglobinopathies. dHepatic IOL is underestimated in up to 25% of patients. eOcular & audiological side effects have been reported at low ferritin levels.
Leitch HA. How I treat iron overload in MDS and why. Canadian Perspectives in Clinical Hematology