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Indications for Successful Iron Overload Treatment and Monitoring: Myelodysplastic Syndromes Norbert Gattermann, MD, PhD Professor Department of Haematology, Oncology Heinrich-Heine-University Dusseldorf, Germany MDS—Treatment Options Low risk Prognostic group High risk ´ Best supportive care, including iron chelation Growth factors Immunosuppressive treatment Differentiation induction Farnesyltransferase inhibitors Arsenic trioxide Thalidomide/lenalidomide Epigenetic treatment (eg. 5-aza cytidine, 5-aza2'-deoxycytidine) Low-dose chemotherapy Intensive chemotherapy Allogeneic stem cell transplantation Anaemia in Patients with MDS • ~80% of patients with MDS have a haemoglobin <10 g/dL at diagnosis • The majority become transfusion-dependent Sanz GF, et al. Blood. 1989;74:395. 200–250 mg iron Ineffective Erythropoiesis in MDS Duodenum Unrestrained intestinal iron absorption Suppressed hepcidin expression in the liver Increased GDF15 in the serum Liver Normal daily iron uptake ~ 1 mg Other cells in the body Urine, faeces, nails, hair, skin Erythroblasts Ineffective erythropoiesis Courtesy of Dr. N. Gattermann. Daily losses ~ 1 mg Transferrin Haemoglobin (1.7–2.4 g) Macrophages (0.5–1.5 g) Blood losses (eg, menstrual) MDS—Serum Ferritin at Diagnosis 8000 7794 Serum Ferritin (ng/mL) 6980 6000 5000 4176 3839 4000 3526 2000 2500 2284 1980 1800 1500 1290 2555 2283 2000 1749 2980 2690 1830 1590 2000 2500 2136 2000 1309 0 RA Data on file: Düsseldorf MDS Registry. Courtesy of Dr. U. Germing. RARS RAEB RAEB-T CMML (n = 650) Transfusion Requirements • Moderate transfusion requirement 2 units/month 24 units/year ~ 100 units/4 years • High transfusion requirement 4 units/month 48 units/year ~ 100 units/2 years • 100 units: ≥ 20 g iron • Normal body iron: 3–4 g Survival Disadvantage for Transfusion-Dependent MDS Patients Cazzola M, et al. N Engl J Med. 2005;352:536. Transfusion Dependency—A Risk Factor Independent of Cytogenetic Risk Group Not transfusion dependent 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 20 40 60 80 100 120 Intermediate 0 20 40 60 80 100 120 Months *Only isolated del 5q. Malcovati L, et al. J Clin Oncol. 2005;23:7594. Cumulative Proportion Surviving Favourable* Cumulative Proportion Surviving Cumulative Proportion Surviving Transfusion dependent Poor 0 20 40 60 80 100 120 Complications of Iron Overload Heart Heart failure, arrhythmias Liver Fibrosis, cirrhosis, cancer Endocrine tissues Diabetes mellitus Clinical Consequences of Acquired Transfusional Iron Overload in Adults 15 Nonthalassaemic Patients All with anaemias requiring transfusions Iron loading present <4 years in 14 patients Liver biopsy in 10 patients contained 7–25 times normal amount of iron; focal portal fibrosis typical All patients had glucose intolerance with significantly reduced insulin output Pituitary ACTH reserve limited in 10 of 12 patients; that of gonadotropin in 5 of 13 Schaefer AI, et al. N Engl J Med. 1981;304:319. Cardiac Consequences of Acquired Transfusional Iron Overload in Adults 15 Nonthalassaemic Patients • Noninvasive cardiac studies demonstrated left ventricular dysfunction in the most heavily transfused patients and frequently showed supraventricular arrhythmias • Clinical heart failure and ventricular arrhythmias occurred only in the presence of coronary artery disease • It is difficult to separate the relative contributions of myocardial iron deposition and chronic anaemia in the development of functional abnormalities in patients with transfusion-dependent anaemia Schaefer AI, et al. N Engl J Med. 1981;304:319. Contributing Factors to Cardiac Disease in Chronically Transfused Patients with MDS Age Coronary artery disease Chronic anaemia Myocardial iron deposition? Patients with Cardiac Iron (%) Relation of Cardiac Iron Deposits to Amount of Blood Transfused 100 90 131 transfused adult patients • 101 leukaemias • 30 other anaemias 80 70 60 50 40 30 20 10 0 0–25 26–50 51–75 76–100 101–200 201–300 Units of Blood Transfused Buja LM, Roberts WC. Am J Med. 1971;51:209. Iron in the Heart Aetiology and Clinical Significance • Grossly visible cardiac iron deposits (CID) are always associated with cardiac dysfunction and usually chronic heart failure • Extensive CID occur in patients who receive >100 units of blood unless bleeding diatheses coexist • Patients with chronic anaemia and hepatic cirrhosis who receive <100 units of blood also may have extensive CID • CID initially occur in ventricular myocardium, and are usually more extensive in ventricular than atrial myocardium • CID are always more extensive in working than in conducting myocardium • Supraventricular arrhythmias correlate with the extent of CID in atrial myocardium Buja LM, Roberts WC. Am J Med. 1971;51:209. MRI Detection of Cardiac Iron Overload in MDS Patients with T2* <20 ms Proportion of MDS Patients Average No. of PRC Units Transfused Serum Ferritin (mean; ng/mL) Average Hepatic T2* (ms) Glanville J, et al.1 3/7 208 5865 1.4 Chacko J, et al.2 1/11 116 4400 1.5 Konen E, et al. 1/10 50 4250 2–3 1. Glanville J, et al. Blood. 2006;108:Abstract 1553. 2. Chacko J, et al. Br J Haematol. 2007;138:587. 3. Konen E, et al. Am J Hematol. 2007;82:1013. WHO Classification of MDS—Patients in the Düsseldorf Registry (%) % MDS Blood Bone marrow 3.7 5q– syndrome • Anaemia • Blasts <5% • Platelets normal to increased • Megakaryocytes normal to increased • Blasts <5% • No Auer rods • Isolated del(5q) 8.8 RA • Anaemia • Blasts ≤1% • Dyserythropoiesis only • Blasts <5% • Ringed sideroblasts <15% 7.8 RARS • Anaemia • Blasts ≤1% • Dyserythropoiesis only • Blasts <5% • Ringed sideroblasts <15% 31.0 RCMD • Cytopaenia of ≥2 lineages • Blasts ≤1% • Monocytes <1000/µL • >10% of cells per lineage dysplastic • No Auer rods • Blasts <5% • Ringed sideroblasts <15% 15.4 RCMD-RS • Cytopaenia of ≥2 lineages • Blasts ≤ 1% • Monocytes <1000/µL • >10% of cells per lineage dysplastic • No Auer rods • Blasts <5% • Ringed sideroblasts ≥15% 15.0 RAEB I • Cytopaenia of ≥2 lineages • PB blasts ≤5% • Monocytes <1000/µL • Uni-linear or multi-linear dysplasia • No Auer rods • Blasts 5%–9% 18.3 RAEB II • Cytopaenia of ≥2 lineages • PB blasts ≤19% • ± Auer rods • Uni-linear or multi-linear dysplasia • ± Auer rods • Blasts 10%–19% Courtesy of Dr. U. Germing. Cumulative Survival of MDS Patients According to WHO Type Cumulative Proportion Surviving Düsseldorf MDS Registry, n = 1598 P <.00005 1.0 .8 5q- syndrom .6 .4 RCMD RA RARS .2 RAEB II 0.0 0 24 RAEB I 48 72 RSCMD 96 120 144 168 Months Gattermann N. Hematol Oncol Clin North Am. 2005;19(suppl 1):S13. 192 216 240 264 288 312 336 Survival of RCMD+RSCMD Patients According to IPSS Düsseldorf MDS Registry MDS Type RA No. IPSS Score Median survival (months) 131 RARS RCMD RSCMD RAEBI RAEBII 5q- 211 41 146 420 247 200 Low 36% Int-1 50% Int-2 13% High 1% 62 36 12 7 RCMD = refractory cytopaenia with multilineage dysplasia; RSCMD = refractory sideroblastic cytopaenia with multilineage dysplasia; IPSS = International Prognostic Scoring System; RA = refractory anaemia; RARS = refractory anaemia with ringed sideroblasts; RAEB = refractory anaemia with excess blasts. Courtesy of Dr. U. Germing. Requirement for Iron Chelator Therapy in MDS Patients Crude Estimate Median survival ~ 20% of MDS patients (RA+RARS) ~ 15% of MDS patients (RCMD±RS) 5–6 years 5–6 years 36% low-risk ~ 20% of MDS patients (RCMD±RS) years Courtesy of Dr. U. Germing. 50% int-1 3 Iron overload in MDS—Consensus Meeting Nagasaki, Japan, May 11, 2005 Question Consensus How would you define the role of chelation therapy in MDS? Highly likely to be clinically important in a subgroup of patients What does chelation therapy need to achieve in MDS patients with iron overload? – Prevention of complications – Treatment of complications – Improvement of survival What are the clinical consequences of no iron chelation? Potential cardiac, hepatic, and endocrine complications In patients with MDS, when would you assess body iron stores? – At diagnosis – At regular intervals (considering transfusion rates) Gattermann N, et al. Hematol/Oncol Clin North Am. 2005;19(suppl 1):18. Iron overload in MDS—Consensus Meeting Nagasaki, Japan, May 11, 2005 Question Consensus How frequently would you monitor iron overload? At least every 3 months in patients receiving transfusion Which tools would you use to diagnose and monitor iron overload? – Serum ferritin – Transferrin saturation – Liver MRI What would you use most frequently? Serum ferritin When would you start chelation therapy? Serum ferritin >1000–2000 ng/mL considering rate of transfusions For how long would you continue chelation therapy? As long as transfusion therapy continues (as long as iron overload is clinically relevant) Iron overload in MDS—Consensus Meeting Nagasaki, Japan, May 11, 2005 Question Consensus What is the patient profile of who might benefit from the treatment of iron overload ? – Transfusion-dependent patients – Low risk MDS: IPSS low or Int-1 – WHO-type RA and RARS and 5q– Candidates for allografting – MDS patients with documented stable disease – Ferritin levels >1000–2000 ng/mL or other evidence of significant tissue iron overload – Absence of comorbidities severely limiting prognosis NCCN Guidelines Myelodysplastic Syndromes • For relatively low-risk patients with excessive iron accumulation resulting from the number of red blood cell (RBC) transfusions received, iron chelation therapy should be instituted • This treatment is used predominantly for patients with relatively lower-risk MDS, whose clinical course suggests ongoing chronic RBC transfusion need, and for those with concurrent cardiac or hepatic dysfunction • . . . generally administered for patients who have previously received 20–30 units of RBCs, for whom ongoing RBC transfusions are anticipated and for those with serum ferritin levels >2500 µg/L • Monitoring serum ferritin may be useful, aiming to decrease ferritin levels to <1000 µg/L NCCN Practice Guidelines in Oncology. V3. Myelodysplastic Syndromes. 2006. Improved Survival in Patients with MDS Receiving Iron Chelation Therapy Retrospective review of 178 patients (36 RA, 42 RARS, 28 RAEB, 16 RAEB-T or AML, 25 CMML, 31 other) 28 Ferritin ≥2000 ng/mL 22 Clinical evidence of iron overload 18 10 No-ICT Chelation therapy Median overall survival for low or int-1 IPSS Not reached at 160 mo P <.03 “Although we were not able to demonstrate a decrease in organ dysfunction in patients receiving ICT for MDS, there was a significant improvement in overall survival. These are to our knowledge the first data documenting improvement in clinical outcome in patients with MDS receiving ICT.” 40 mo (0.7–224) Leitch H, et al. Blood. 2006;108:Abstract 249. Iron Chelation Therapy Improves Survival in Regularly Transfused MDS Patients—A Prospective Analysis by the GFM Survival Distribution Function 1.00 Median Survival: 63 months (whole group) 115 vs 51 months (P <.0001) 0.75 0.50 CT 0.25 No CT 0.00 0 50 100 150 Diagnosis to Death Time (months) GFM = Groupe Francophone des Myelodysplasies. Rose C, et al. Blood. 2007;110:Abstract 249. 200 250 IPSS = low IPSS = int 1 Median: not reached vs 69 months (P <.002) Median: 115 vs 50 months (P <.003) 1.00 Survival Distribution Function Survival Distribution Function Survival–According IPSS Chelation therapy 0.75 0.50 No chelation therapy 0.25 1.00 0.75 Chelation therapy 0.50 No chelation therapy 0.25 0.00 0.00 0 50 100 150 200 Diagnosis to Death Time (months) Rose C, et al. Blood. 2007:110:Abstract 249. 250 0 20 40 60 80 100 Diagnosis to Death Time (months) 120 140 The Relative Importance of Iron Overload in MDS Morbidity Iron chelation Complications of chronic anaemia Complications of marrow failure Clinical problems in MDS Leukaemic transformation Courtesy of Dr. N. Gattermann. Problems of aging Comcomitant diseases Summary Iron overload in MDS starts before transfusion therapy is initiated. This is due to ineffective erythropoiesis The most important cause of iron overload in MDS is chronic transfusion therapy MDS patients with unfavorable prognosis usually do not survive long enough to develop the clinical consequences of iron overload MDS patients with good prognosis (RA, RARS, 5q-) should receive iron chelation therapy if transfusiondependent Besides preventing iron-related organ damage, iron chelation therapy may also improve bone marrow function in patients with MDS