1. Clinical Focus: Management of Transfusional Iron Overload in Patients With Sickle Cell Anemia, Thalassemia, and Myelodysplastic Syndromes Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC This program is supported by an educational grant from

2. clinicaloptions.com/oncology Clinical Focus Faculty Rami Komrokji, MD Associate Professor of Oncologic Services Department of Oncologic Services University of South Florida Clinical Director Malignant Hematology H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida

3. clinicaloptions.com/oncology Clinical Focus Disclosure of Conflicts of Interest  Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.  The faculty and CCO staff reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity.

4. clinicaloptions.com/oncology Clinical Focus Disclosures Rami Komrokji, MD, has no significant financial relationships to disclose. The following PIM clinical content reviewers, Linda Graham, RN, BSN, BA; Jan Hixon, RN, BSN, MA; Trace Hutchison, PharmD; Julia Kirkwood, RN, BSN; and Jan Schultz, RN, MSN, CCMEP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

5. clinicaloptions.com/oncology Clinical Focus Overview: Transfusional Iron Overload 1. Brittenham GM. N Engl J Med. 2011;364:146-156.  Red blood cell transfusions are commonly used to relieve anemia due to thalassemia, sickle cell disease, myelodysplastic syndromes, and other congenital and acquired refractory anemias  Lack of iron excretion mechanisms leads to accumulation of iron in liver, heart and endocrine organs (anterior pituitary, pancreatic β cells)  Increases iron-induced liver disease, endocrine disorders, cardiomyopathy, liver cirrhosis  Techniques to monitor for iron overload –Serum ferritin, liver biopsy, MRI, number of transfusions

6. clinicaloptions.com/oncology Clinical Focus 2. Malcovati L, et. al. J Clin Oncol. 2005;23:7594-7603. Transfusion Dependency in MDS  Transfusion-dependent patients had a significantly shorter OS than transfusion-independent patients (HR: 2.16; P <.001) Cumulative Proportion Surviving 0 0.5 0.7 1.0 0.3 Survival Time (Mos) 080140 0.9 0.8 0.6 0.4 0.2 0.1 120100604020 *Excludes isolated 5q-. Good IPSS Risk* Intermediate IPSS Risk Transfusion independent Transfusion dependent Cumulative Proportion Surviving 0 0.5 0.7 1.0 0.3 Survival Time (Mos) 080140 0.9 0.8 0.6 0.4 0.2 0.1 120100604020 Transfusion independent Transfusion dependent

7. clinicaloptions.com/oncology Clinical Focus Survival and Risk of AML in MDS Patients Stratified by Serum Ferritin Levels  Development of transfusional iron overload is a significant independent prognostic factor for overall survival and evolution to AML 3. Sanz G, et al. 2008 ASH. Abstract 640. Probability 0 0.4 1.0 0.6 5 0.8 0.2 Yrs From Diagnosis 0101520 Ferritin < 1000 μg/L Ferritin ≥ 1000 μg/L P <.0001 OSTime Without AML Probability 0 0.4 1.0 0.6 5 0.8 0.2 Yrs From Diagnosis 0101520 P <.0001

8. clinicaloptions.com/oncology Clinical Focus Risk of Cardiac Events in MDS Patients With Multiple Transfusions  513 new cases of MDS from January - March 2003 in the US Medicare SAF5% claims database −SAF5%, standard analytic file comprised of randomly selected, 5% sample of all Medicare beneficiaries  During a 3-yr follow-up, cardiac events were more common in transfused vs nontransfused MDS patients (P <.001) and in MDS patients vs individuals without MDS (P <.001) Cardiac Events (%) 0 MDS Nontransfused (n = 307) 40 20 Overall Medicare SAF5% population (N = 1,379,185) 82.4 80 60 MDS Transfused (n = 205) 67.1 54.5 100 5. Goldberg SL, et al. J Clin Oncol. 2010;28:2847-2852.

9. clinicaloptions.com/oncology Clinical Focus Risk of Diabetes in MDS Patients With Multiple Transfusions  Development of diabetes was more common in transfused than in nontransfused MDS patients and overall SAF5% Medicare population during a 3-yr follow-up * For comparison of transfused and nontransfused MDS patients. Developed Diabetes (%) 0 30 50 40 MDS Patients (n = 513) 20 10 Overall Medicare SAF5% population (N = 1,379,185) 40.0 33.1 P <.0001 Developed Diabetes (%) 0 30 50 40 MDS Transfused (n = 205) 20 10 P =.02* Overall Medicare SAF5% population (N = 1,379,185) MDS Non- transfused (n = 307) 6. Goldberg SL, et al. J Clin Oncol. 2010;28:2847-2852. 33.1 37.1 44.4

10. clinicaloptions.com/oncology Clinical Focus 0 50 100 150200 No ICT ICT Median Survival (Mos) 40.1 mos (0.7-224) (Not reached at 160 mos) P <.03  For patients with low and intermediate-1 MDS, ICT was associated with a significant improvement in OS 7. Leitch HA. Leuk Res. 2007;31(suppl 3):S7-S9. + Retrospective Analysis of Survival in MDS Patients Receiving Iron Chelation Therapy

11. clinicaloptions.com/oncology Clinical Focus Iron Chelation Therapy and Survival in MDS  Survey of 170 patients with MDS referred for RBC transfusion at 18 French treatment centers during 1-mo period –Assessments: hematologic data, RBC transfusion requirement, iron chelation therapy, and iron overload –Cohort survival prospectively followed  Standard iron chelation therapy –Deferoxamine 40 mg/kg/day SC for 3-5 days/wk: n = 41 –Deferiprone 30-75 mg/kg/day: n = 5 –Deferoxamine SC + deferiprone: n = 5 –Deferasirox 20-30 mg/kg/day: n = 6  Low-dose iron chelation therapy –Deferoxamine bolus 2-3 g/wk SC: n = 12 –Deferoxamine 50-100 mg/kg IV once after RBC transfusion: n = 7 8. Rose C, et al. ASH 2007. Abstract 249.

12. clinicaloptions.com/oncology Clinical Focus Iron Chelation Therapy and Survival in MDS  OS significantly improved for patients who received iron chelation therapy  Results consistent across all subgroups analyzed (IPSS low and intermediate-1, sex, age) 9. Rose C, et al. ASH 2007. Abstract 249. Median survival: 115 mos iron chelation therapy 51 mos no iron chelation therapy P <.0001 ICT No CT Diagnosis to Death Time (Mos) 050100150200250 0 0.25 0.50 0.75 1.00 Survival Distribution Function

13. clinicaloptions.com/oncology Clinical Focus Deferasirox in MDS: EPIC and US03 Studies  US03 [10,11] results –HI by IWG criteria: 8/176 (5%) –Erythroid response: 5 –Major platelet response: 1 –Combined platelet + neutrophil response: 1  Both EPIC [12,13] and US03 [11] studies required –Baseline serum ferritin ≥ 1000 ng/mL –> 20 units red blood cell transfusions  Treatment: deferasirox 10-30 mg/kg daily 10. List AF, et al. ASH 2008. Abstract 634. 11. List AF, et al. J Clin Oncol. 2012;30:2134-2139. 12. Gattermann N, et al. ASH 2008. Abstract 633. 13. Cappellini MD, et al. Haematologica. 2010;95:557-66. Mo Serum Ferritin, ng/mL EPIC (N = 341) US03 (N = 176) 027303397 323583057 622102802 920762635 1219042501

14. clinicaloptions.com/oncology Clinical Focus  Retrospective analysis of patients with lower-risk MDS (low- and int-1 risk) –Serum ferritin ≥1000 ng/mL –N = 97: n = 45 (ICT), n = 52 (BSC) –ICT included n = 10 (deferoxamine) and n = 35 (deferasirox) –Median follow-up: 86 mos  ICT in lower risk MDS patients with elevated serum ferritin ≥ 1000 ng/mL was associated with improved OS and a trend to lower AML transformation) 14. Komrokji RS, et al. ASH 2011. Abstract 2776. ICTBSC Patients, n4552 OS, mos5934  HR (95% CI; P value)0.52 (0.31-0.87;.013) Progression to AML, %15.621.2  P value.33 Iron Chelation Therapy in Patients With Low-Risk MDS

15. clinicaloptions.com/oncology Clinical Focus Screening 1 mo 4 yrs1 yr2 yrs Randomized 2:1 (Deferasirox:Placebo) 3 yrs5 yrs IA: at 50% of primary composite events (~ 3 yrs) at 75% of primary composite events (~ 4 yrs) 54% chance to stop the trial depending on IA results IA Placebo N = 210 10 mg/kg/day (1st 2 weeks) 20 mg/kg/day (weeks 2-12) Up to 40 mg/kg/day (after 12 weeks) Deferasirox N = 420 10 mg/kg/day (1st 2 wks) 20 mg/kg/day (Wks 2-12) Up to 40 mg/kg/day (after 12 wks) Expected end of study Low or int-1 risk MDS Serum ferritin > 1000 mcg/L and < 2500 mcg/L TELESTO Study

16. clinicaloptions.com/oncology Clinical Focus MDS Patients Who Are Likely to Benefit Most From Management of Iron Overload CharacteristicNCCN [16] MDS Foundation [17] Transfusion status  Received 20-30 packed RBC units  Continuing transfusions  Transfusion dependent, requiring 2 units/mo for > 1 yr Serum ferritin level  > 2500 ng/mL  1000 ng/mL MDS risk  IPSS: low- or int-1  WHO: RA, RARS, and 5q- Patient profile  Candidates for allografts  Life expectancy > 1 yr and no comorbidities that limit progress  A need to preserve organ function  Candidates for allografts 16. NCCN. Clinical practice guidelines in oncology: MDS. v1.2012. 17. Bennett JM. Am J Hematol. 2008;83:858-861.

17. clinicaloptions.com/oncology Clinical Focus LymphomaAcuteMyelo-AplasticCML orOther MyelomaLeukemiadysplasiaAnemiaMPD 19. Pullarkat V, et al. Bone Marrow Transplant. 2008;42:799-805. 10,000 8000 6000 4000 2000 0 Median Pretransplant Serum Ferritin (ng/mL) Pretransplantation Iron Overload in Adult Patients Undergoing HSCT

18. clinicaloptions.com/oncology Clinical Focus 20. Alessandrino EP, et al. Haematologica. 2010;95:476-484.  Posttransplantation outcome of transfusion-dependent patients receiving standard conditioning according to serum ferritin level Probability of overall survival 0.2 0.4 0.6 0.9 0 Cumulative Proportion Surviving Mos 0204060 80100120140 160 0.1 0.3 0.5 0.7 1.0 Ferritin <1000 ng/mL Ferritin 1000–1999 ng/mL Ferritin 2000–3000 ng/mL Ferritin >3000 ng/mL HR: 1.40 (P =.01) 0.8 Probability of non-relapse mortality 0.2 0.4 0.6 0.9 0 Nonrelapse Mortality (Probability) Mos 020406080100120140160 0.1 0.3 0.5 0.7 1.0 Ferritin < 1000 ng/mL Ferritin 1000-1999 ng/mL Ferritin 2000-3000 ng/mL Ferritin > 3000 ng/mL HR: 1.42 (P =.03) 0.8 Secondary Iron Overload Effects Post- transplantation Outcome in MDS Patients

19. clinicaloptions.com/oncology Clinical Focus 21. Lee JW, et al. Bone Marrow Transplant. 2009;44:793-797. SF > 1000 ng/mL SF < 1000 ng/mL ICT P =.001 0.2 0.4 0.6 0.8 1.0 0 0 12 24 36 48 60 SF > 1000 ng/mL SF < 1000 ng/mL ICT P <.001 0 12 24 36 48 60 0.2 0.4 0.6 0.8 1.0 0 OS Rate Event-Free Survival Mos From Transplantation Iron Chelation Prior to HSCT: Survival Outcomes

20. clinicaloptions.com/oncology Clinical Focus Deferasirox Therapy in Patients With Sickle Cell Disease 23. Vichinsky E, et al. Br J Haematol. 2011;154:387-397.  Dose was based on baseline LIC  Median serum ferritin reduce by 35% by Yr 4  Only 21% of patients remained on study at end of 5 yrs Serum ferritinDeferasirox dose Mos Median Relative Change in Serum Ferritin (%) 20 10 15 5 -5 0 -10 -20 -15 -25 -35 -30 -40 30 25 20 15 10 5 0 Mean Deferasirox Dose (mg/kg/day) 60575451484542393633302724211815129630 2025293840506165818895Patients, n

21. clinicaloptions.com/oncology Clinical Focus  In a study comparing patient preferences, patients were more willing to continue taking deferasirox than deferoxamine by end-of-study (84% vs 11%, respectively; P <.001) [25]  Reducing the number of IV infusions of deferoxamine, by using high-dose deferoxamine administered over 48 hrs every 2-4 wks, was shown to be safe and effective for reduction of iron overload in sickle cell disease [26] 24. Neufeld EJ. Hematology Am Soc Hematol Educ Program. 2010;2010:451-455. 25. Vichinsky E, et al. Acta Haematol. 2008;119:133-141. 26. Kalpatthi R, et al. Pediatr Blood Cancer. 2010;55:1338-1342. Table [24] DeferoxamineDeferasiroxDeferiprone AdvantagesLong-term safety record Highly effective Strongest chelator Oral administration Daily dosing Oral administration Better cardiac protection compared to deferoxamine Allows aggressive iron chelation when iron stores are low with minimal excess toxicity DisadvantagesParenteral administration Local skin reactions May be inferior to deferiprone for cardiac protection Challenging patient compliance GI disturbance limits tolerability Many patients have inadequate response at MTD Not yet demonstrated to reduce cardiac siderosis GI disturbances and joint pain limit tolerability Rare agranulocytosis and neutropenia Chelator Properties That Affect Compliance

22. clinicaloptions.com/oncology Clinical Focus Chelator Properties That Affect Compliance  Box warnings –Noted more often when administered in excess of iron burden  Deferoxamine: ocular and auditory disturbances, acute renal failure, hepatic dysfunction, adult respiratory distress syndrome, growth retardation in children  Deferasirox: renal failure, hepatic failure, gastrointestinal hemorrhage  Deferiprone: agranulocytosis, infection (leading to death) 28. Neufeld EJ. Hematology Am Soc Hematol Educ Program. 2010;2010:451-455. Table [1] DeferoxamineDeferasiroxDeferiprone AdministrationSC or IV, continuous infusion 5-7 days/wk Oral suspensionOral tablet Common AEsLocal skin reaction, hearing loss, late bone problems Rash, GI disturbances, diarrhea, mild changes in creatinine, proteinuria, transaminases GI disturbances, joint pain, arthritis Severe AEsRetinopathy, acute pulmonary distress Peptic ulcers, liver or renal dysfunction leading to failure, cytopenias Agranulocytosis, neutropenia Cost$$$$$$$-$$

23. clinicaloptions.com/oncology Clinical Focus Comparison Study of Deferasirox vs Deferoxamine in β-Thalassemia Patients  Phase III trial in β-thalassemia patients aged 2 yrs or older [29]  Patients randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline LIC 29. Cappellini MD, et al. Blood. 2006;107:3455-3462.  Deferasirox < 20 mg/kg/day failed to consistently lower LIC and serum ferritin DFO Mean Serum Ferritin Change From Baseline (μg/L ± SD) 2000 1000 0 -1000 -2000 -3000 < 3 mg Fe Baseline LIC: DFXDFODFX < 3-7 mg Fe DFODFXDFODFX > 7-14 mg Fe > 14 mg Fe DFO Mean LIC Change From Baseline (Fe/g ± SD) 10 0 -10 -20 < 3 mg Fe Baseline LIC: DFXDFODFX < 3-7 mg Fe DFODFXDFODFX > 7-14 mg Fe > 14 mg Fe

24. clinicaloptions.com/oncology Clinical Focus Iron Overload Summary  Iron chelation therapy is effective at reducing serum ferritin levels, cardiac events and diabetes in patients with blood transfusion–related iron overload  Iron chelation therapy can improve survival after HSCT and in lower-risk MDS  Compliance is a major issue in successful treatment –Advent of orally available chelators, it is hoped, will increase compliance  Each chelator has its own unique safety profile

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