1. December 10-13, 2011 San Diego, California Nonmalignant Hematology Disorders/ITP: Update CCO Independent Conference Coverage of the 2011 Annual Meeting of the American Society of Hematology* This program is supported by educational grants from *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. Jointly sponsored/Co-provided by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC

2. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Faculty Terry Gernsheimer, MD Professor of Medicine Division of Hematology University of Washington School of Medicine Puget Sound Blood Center Seattle Cancer Care Alliance Seattle, Washington Howard Liebman, MD, FACP Professor of Medicine and Pathology Keck School of Medicine of the University of Southern California Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases Norris Cancer Center Los Angeles, California

4. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Disclosures Terry Gernsheimer, MD, has disclosed that she has received consulting fees from Amgen and contracted research from Shionogi. Howard Liebman, MD, FACP, has disclosed that he has received contracted research from Amgen and Immunomedics and consulting fees from Johnson & Johnson and his spouse has received consulting fees from Alexion.

5. Thank you for accessing CCO Independent Conference Coverage of the 2011 Annual Meeting of the American Society of Hematology from San Diego, California. In the following slides, you will find highlights of the key studies from this meeting. Be sure to review the slide notes field for each slide for insightful commentary from our expert faculty.

6. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Overview  Splenectomy –Splenectomy in Pediatric ITP –Postsplenectomy Complications  Thrombopoietin Receptor Agonists –Romiplostim and Eltrombopag in Refractory Pediatric ITP –Romiplostim in Adult ITP –Romiplostim Extension Study –Eltrombopag in Elderly ITP Patients

7. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Overview  VTE Risk and Prevention –Retrospective Analysis of MAGELLAN –HITEC Substudy of PROTECT –WARFASA Study

8. Splenectomy

9. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Splenectomy in Pediatric ITP: Background  Splenectomy in refractory chronic ITP –Considered gold-standard treatment in adults –Efficacy unclear in children  Current study designed to evaluate outcomes following splenectomy for childhood ITP –Efficacy, safety, and factors associated with treatment efficacy Aladjidi N, et al. ASH 2011. Abstract 2227.

10. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Splenectomy in Pediatric ITP: Study Design  Study recruited French patients with pediatric ITP, younger than 18 yrs of age, from –CEREVANCE, prospective national cohort of children with autoimmune cytopenias –30 pediatric hematology clinics –Underwent splenectomy January 2000 - September 2009  Medical records of recruited patients analyzed retrospectively (N = 78)  Evaluated clinical outcomes, 5-yr RFS, and possible prognostic factors Aladjidi N, et al. ASH 2011. Abstract 2227.

11. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Splenectomy in Pediatric ITP: Efficacy  5-yr RFS –All patients (N = 78): 51% (95% CI: 37% to 64%) –Chronic ITP (n = 62): 48% (95% CI: 32% to 63%) Clinical Outcome, %Mo 1 Follow-up* (n = 75) Latest Follow-up* (n = 75) CR7984 PR118 No response108 CCR † --72 *Median follow-up: 41 mos (range: 1-109); 3 patients lost to follow-up. † Analysis restricted to n = 65 with > 1 yr follow-up. Aladjidi N, et al. ASH 2011. Abstract 2227.

12. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Splenectomy in Pediatric ITP: Prognostic Factors  Prognosis not significantly affected by sex, age at splenectomy, splenic vs nonsplenic platelet destruction, or response to intravenous IgG Clinical OutcomeITP Diagnosis at < 10 Yrs of Age ITP Diagnosis at ≥ 10 Yrs of Age P Value CCR, n*1928.01 No CCR, n*144 5-yr RFS, % (95% CI)  All patients30 (14-47)73 (48-88).0007  Chronic ITP33 (17-50)64 (33-88).0038 *Analysis restricted to n = 65 with > 1 yr follow-up. Aladjidi N, et al. ASH 2011. Abstract 2227.

13. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Splenectomy in Pediatric ITP: Conclusions  Splenectomy safe and effective for children with chronic ITP –72% achieved continuous CR after > 1 yr –Estimated 5-yr RFS: 51% (95% CI: 37% to 64%)  Aged 10 yrs or older at ITP diagnosis associated with improved prognosis  No OPSIs; however, ongoing risk of infection requires lifelong monitoring Aladjidi N, et al. ASH 2011. Abstract 2227.

14. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Postsplenectomy Complications: Background and Study Design  Complications associated with splenectomy include sepsis, VTE –Particular issue for patients with other immune deficiencies, autoimmune disease  Retrospective analysis of California patient record database explored frequency and correlates of VTE, sepsis among splenectomized (n = 1955) and nonsplenectomized ITP patients (n = 8797) –Inclusion criteria: principal ITP diagnosis (1991-2009), splenectomy, sepsis, or VTE –Evaluated risk factors included age, race, and comorbidities Wun T, et al. ASH 2011. Abstract 3284.

15. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Postsplenectomy Complications: VTE and Sepsis Risk ParameterVTESepsis HR (95% CI) P ValueHR (95% CI) P Value Splenectomy vs none  Occurrence < 90 days  Occurrence ≥ 90 days 0-1 comorbidities ≥ 2 comorbidities 5.1 (3.2-8.1) 2.7 (2.0-3.7) <.0001 4.5 (3.4-5.8) 2.0 (1.6-2.4) 3.1 (2.3-4.2) <.0001.0002 60 yrs or older1.5 (1.2-2.0).00182.5 (2.1-3.0)<.0001 Asian race0.2 (0.1-0.5).00071.2 (1.0-1.5).0515 ≥ 2 comorbidities  Younger than 60 yrs  60 yrs or older 1.2 (0.9-1.6).1461 3.0 (2.5-3.6) 4.1 (3.5-4.9) <.0001 Lupus diagnosis1.8 (1.2-2.8).00932.0 (1.6-2.4)<.0001 Wun T, et al. ASH 2011. Abstract 3284. Reproduced with permission.

16. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Postsplenectomy Complications: Conclusions  Splenectomy for ITP associated with increased risk of VTE and sepsis –Risks increased with 60 yrs of age or older, lupus diagnosis –Asian race associated with decreased risk of VTE and slightly increased risk of sepsis, which was lower than the overall study population –≥ 2 comorbidities increased risk of sepsis, not VTE  Higher cumulative incidence of VTE and sepsis in splenectomized vs nonsplenectomized ITP patients –Cumulative risk of VTE < 5% in splenectomy group Wun T, et al. ASH 2011. Abstract 3284.

17. Thrombopoietin Receptor Agonists

18. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim and Eltrombopag in Refractory Pediatric ITP: Background  Thrombopoietic agents frequently administered to adults with challenging ITP, but data on their use in pediatric patients are limited  Current study retrospectively evaluated efficacy and safety of romiplostim or eltrombopag in pediatric chronic refractory ITP –Weill Cornell Medical College in New York (n = 22) –Children’s Hospital Orange County in California (n = 10) Ramaswamy K, et al. ASH 2011. Abstract 2230.

19. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim and Eltrombopag in Refractory Pediatric ITP: Study Design  Retrospective review of medical records from pediatric patients with chronic refractory ITP who received romiplostim or eltrombopag  Efficacy endpoint: response –Platelet count > 50,000 cells/mm 3 for 2 consecutive wks –Platelet increase ≥ 20,000 cells/mm 3 from baseline for 2 consecutive wks –Platelet count ≥ 50,000 cells/mm 3 > 50% of treatment time  Safety endpoints: bone marrow fibrosis, liver function tests, thrombosis Ramaswamy K, et al. ASH 2011. Abstract 2230.

20. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim and Eltrombopag in Refractory Pediatric ITP: Efficacy  Younger children appeared not to respond as well; nonresponders among youngest in each group ResponseRomiplostim (n = 19) Eltrombopag (n = 13) Platelet count > 50,000 cells/mm 3 for 2 wks, % 7969 Platelet increase ≥ 20,000 cells/mm 3 for 2 wks, % 7469 Platelet count ≥ 50,000 cells/mm 3 for > 50% treatment time, % 5869 Mean time to platelet count > 50,000 cells/mm 3, wks 2.91.3 Ramaswamy K, et al. ASH 2011. Abstract 2230. Reproduced with permission.

21. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim and Eltrombopag in Refractory Pediatric ITP: Safety  Tolerable adverse event profile –No thrombosis or malignancy development  Reticulin fibrosis –Baseline: 6 of 17 with grade 1 –After treatment initiation: scores available for 10 patients –0: n = 2 –1+: n = 7 –2+: n = 1 Ramaswamy K, et al. ASH 2011. Abstract 2230.

22. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim and Eltrombopag in Refractory Pediatric ITP: Conclusions  Thrombopoietic agents romiplostim and eltrombopag effective in small group of patients with childhood chronic refractory ITP  Differences in response rate between the 2 agents should be interpreted with caution, as this was not a randomized study, and groups may not have been balanced for patient age, previous treatments, and duration of disease –Romiplostim: 79% response rate –Eltrombopag: 69% response rate  Lack of response more frequent among younger children  Adverse events infrequent Ramaswamy K, et al. ASH 2011. Abstract 2230.

23. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim in Adult ITP: Background  ITP characterized by increased platelet loss and inadequate platelet production  Existing ITP treatments work to suppress platelet destruction  Romiplostim stimulates platelet production via thrombopoietin receptor –Recommended for adults with chronic ITP as second- or third-line therapy  Current study evaluated safety, efficacy of romiplostim in large adult cohort with pretreated ITP with platelet count ≤ 30,000 cells/mm 3 or uncontrolled bleeding (N = 407) Janssens A, et al. ASH 2011. Abstract 3279.

24. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim in Adult ITP: Study Design  Prospective, open-label treatment with romiplostim 1 or 3 µg/kg/wk –Adjusted to maintain platelet count ≥ 50,000 cells/mm 3 –Maximum dose 10 µg/kg/wk –Rescue medications permitted –Concomitant ITP medications reduced when platelet count > 50,000 cells/mm 3  Primary endpoints: adverse events, antibody formation  Secondary endpoint: platelet response Janssens A, et al. ASH 2011. Abstract 3279.

25. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim in Adult ITP: Safety I Adverse Events, %Incidence Adjusted for Patient Exposure (Rate/100 Subject-Wks) All events22.5 Treatment-related events2.8 All serious events1.6 Treatment-related serious events0.2 Most common bleeding events  Contusion  Epistaxis  Petechiae 0.8 0.6 Specific events  Hemorrhage  Thrombotic/thromboembolic events  Thrombocytosis 4.1 0.2 0.1 Janssens A, et al. ASH 2011. Abstract 3279. Reproduced with permission.

26. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim in Adult ITP: Safety II  5 patients each had 1 bone marrow event –4 events consistent with bone marrow reticulin –3 events serious and related to treatment (1 case mild reticulin fibrosis, 1 case reticulin fibrosis, and 1 case diffuse reticulin fibrosis)  Hemorrhage and thrombotic/thromboembolic events typically occurred during first 24 wks of study  3 deaths during study considered related to treatment –Hemolysis after 5 wks of romiplostim, aplastic anemia after 6 mos of romiplostim (in patient with macrocytic anemia at start of study), intestinal ischemia after 6 mos of romiplostim Janssens A, et al. ASH 2011. Abstract 3279.

27. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim in Adult ITP: Efficacy  Median time to first response somewhat faster among patients who initiated romiplostim at 3 µg/kg/wk vs 1 µg/kg/wk  Median platelet counts > 50,000 cells/mm 3 from Wk 3; consistently > 100,000 cells/mm 3 in all patients from Wk 8  No detection of neutralizing antibodies to romiplostim or thrombopoietin Response, %Count 2 x Baseline and ≥ 50,000 cells/mm 3 Count Increase ≥ 20,000 cells/mm 3 From Baseline Overall platelet response9193 Patients with splenectomy8892 Patients without splenectomy9495 Janssens A, et al. ASH 2011. Abstract 3279. Reproduced with permission.

28. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim in Adult ITP: Conclusions  Romiplostin safe and effective in adults with primary ITP  Generally well tolerated –Exposure-adjusted incidence of treatment-related adverse events: 2.8/100 subject-wks –Exposure-adjusted incidence of serious treatment-related adverse events: 0.2/100 subject-wks  Rapid platelet response; counts increased to ≥ 50,000 cells/mm 3 in median of 1-2 wks in > 88% of patients –Response rates and timing unaffected by previous splenectomy Janssens A, et al. ASH 2011. Abstract 3279.

29. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim Extension Study: Background  Romiplostim often used as long-term treatment for chronic ITP  Evidence of maintained platelet response after discontinuing romiplostim –7 of 83 romiplostim-treated patients in pivotal trial of romiplostim [1] able to discontinue romiplostim and maintain platelet count  Current report presents 9 cases of sustained hemostatic platelet counts in adult ITP patients after discontinuation of romiplostim [2] 1. Kuter DJ, et al. Lancet. 2008;371:395-403. 2. Bussel JB, et al. ASH 2011. Abstract 3281.

30. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim Extension Study: Study Design  Case studies [1] of patients (n = 9) from open-label, single-arm extension of pivotal study [2] of romiplostim in patients with ITP –Selected due to maintenance of hemostatic platelet counts ≥ 6 mos after romiplostim discontinuation per protocol  Weekly romiplostim in extension study administered at same dose received in parent study or 1 µg/kg if previously received placebo –Adjusted by ≤ 1 µg/kg/wk to maintain platelet counts between 50-200 G/L, withheld if platelet count > 400 G/L, restarted if platelets count < 200 G/L at dose 1 µg/kg less than previous  Case studies examined for predictive factors: ITP duration, romiplostim duration, other treatments 1. Bussel JB, et al. ASH 2011. Abstract 3281. 2. Bussel JB, et al. Blood. 2009;113:2161-2171.

31. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim Extension Study: Results FactorPatients (N = 9) Median age, yrs (range)50 (29-79) Median ITP duration, yrs (range)1.05 (0.1-5.5) Splenectomy, %44 Median previous ITP treatments, n (range)2.5 (2-5) Median baseline platelet count, G/L (range)42 (11-358) Romiplostim  Median duration on extension study, wks (range)  Median duration on parent study, wks (range)  Dose range in extension study, μg/kg 41 (3-139) 24 (0-52) 1-15 Platelet count, G/L  During romiplostim treatment, range  Before last romiplostim dose, median (range)  After romiplostim discontinuation, range 4-849 309 (233-471) 72-611 Median time since romiplostim discontinuation, wks (range)77 (26-166) Bussel JB, et al. ASH 2011. Abstract 3281.

32. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Romiplostim Extension Study: Conclusions  Patients from larger parent study maintained stable platelet counts after discontinuing romiplostim  No clear factors identify patients who maintain platelet responses after romiplostim discontinuation –ITP duration, romiplostim duration or dosing, previous treatments not predictive in this small study population –Exploratory analysis for predictive factors suggested  Findings suggest that late-onset remission may have role in natural history of ITP Bussel JB, et al. ASH 2011. Abstract 3281.

33. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Eltrombopag in Elderly ITP Patients: Background  High risk of severe bleeding in patients with ITP and chronically low platelet counts –Risk increases with age  Eltrombopag approved for chronic ITP –In US, approved for chronic ITP unresponsive to previous therapy –In EU, approved for chronic ITP postsplenectomy  Current study evaluated safety and efficacy of eltrombopag in elderly ITP patients (65 yrs of age or older) Olney HJ, et al. ASH 2011. Abstract 3294.

34. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Eltrombopag in Elderly ITP Patients: Study Design I  Retrospective analysis of 5 prospective clinical trials [1] –TRA100773A: 6-wk study comparing eltrombopag vs placebo (n = 88); dosing 30, 50, or 75 mg/day with no escalation [2] –TRA100773B: 6-wk study comparing eltrombopag 50 mg/day vs placebo (n = 76) [3] –RAISE: 6-mo study comparing eltrombopag 50 mg/day vs placebo (n = 135) [4] –REPEAT: open-label study of intermittent treatment in 3 cycles of up to 6 wks on therapy and 4 wks off (n = 66) [5] –EXTEND: ongoing extension study of eltrombopag 50 mg/day vs placebo trial (n = 299) [6] 1. Olney HJ, et al. ASH 2011. Abstract 3294. 2. Bussel JB, et al. N Engl J Med. 2007;357:2237-2247. 3. Bussel JB, et al. Lancet. 2009;373:641-648. 4. Cheng G, et al. Lancet. 2011;377:393-402. 5. Psaila B, et al. EHA 2008. Abstract 0294. 6. Saleh MN, et al. ASH 2010. Abstract 67.

35. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Eltrombopag in Elderly ITP Patients: Study Design II  Each trial retrospectively stratified by age (18-49 yrs, 50-64 yrs, 65 yrs and older)  Response definitions for each trial –TRA100773A/B: platelets ≥ 50,000/μL at Day 43 or early withdrawal due to platelets ≥ 200,000/μL –RAISE: platelets 50,000-400,000/μL (presented as range to reflect variation across visits) –REPEAT: platelets ≥ 50,000/μL and ≥ 2 x baseline –EXTEND: platelets ≥ 50,000/μL at any time  Safety data pooled for analysis Olney HJ, et al. ASH 2011. Abstract 3294.

36. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Eltrombopag in Elderly ITP Patients: Efficacy  Eltrombopag response rates slightly higher among elderly patients Response Rate,* % 18-49 Yrs (n = 220) 50-64 Yrs (n = 148) 65+ Yrs (n = 78) TRA100773A67 100 TRA100773B506474 RAISE31-5339-6142-75 REPEAT677283 EXTEND849486 Olney HJ, et al. ASH 2011. Abstract 3294. Reproduced with permission. *Data for 50-mg/day dose only.

37. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Eltrombopag in Elderly ITP Patients: Safety  Manageable safety profile in all age groups –Adverse events reported in 87% of eltrombopag-treated patients; similar proportions across age groups –Serious adverse events in 27% of eltrombopag-treated patients –Most common adverse events included headache (31%), upper respiratory tract infection (17%), diarrhea (15%), nasopharyngitis (15%), fatigue (15%); similar incidence across age groups except fatigue (higher in older patients) –Slightly higher incidence of some nonhemorrhagic events in oldest group –Similar rates of bleeding events across all groups Olney HJ, et al. ASH 2011. Abstract 3294.

38. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Eltrombopag in Elderly ITP Patients: Conclusions  Eltrombopag safety and efficacy similar between elderly and younger ITP patients –Response rates among elderly patients numerically greater vs younger patients –Nonbleeding adverse events numerically greater vs younger patients  Manageable toxicity profile in elderly patients Olney HJ, et al. ASH 2011. Abstract 3294.

39. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Reticulin Fibrosis in EXTEND: Background and Study Design  EXTEND: open-label extension study of eltrombopag vs placebo in previous eltrombopag study of heavily pretreated chronic ITP  Thrombopoietin receptor agonists may increase bone marrow reticulin fibrosis  Morphological analysis of EXTEND bone marrow by central laboratory for evidence of reticulin fibrosis –No baseline bone marrow biopsy –Biopsy if immature or dysplastic cells on peripheral blood smear; annual biopsy requested if treated with eltrombopag > 1 yr Brynes RK, et al. ASH 2011. Abstract 528.

40. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Reticulin Fibrosis in EXTEND: Morphological Analysis  185 specimens from 110 patients (156 evaluable)  Normal cellularity and collagen in 91% of specimens  Reticulin fibrosis increased (MF ≥ 2) in 4 samples (2.6%) Characteristic, n (%)DecreasedNormalIncreased Cellularity1 (0.6)142 (91.0)13 (8.3) Trabecular bone62 (40.3)90 (58.4)0 (0) CollagenNA153 (98.1)3 (1.9) Megakaryocyte quantity0 (0)10 (6.4)146 (93.6) Myeloid quantity3 (1.9)144 (92.3)9 (5.8) Erythroid quantity0 (0)121 (77.6)35 (22.4) Brynes RK, et al. ASH 2011. Abstract 528. Reproduced with permission.

41. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Reticulin Fibrosis in EXTEND: Conclusions  Eltrombopag treatment not associated with reticulin or collagen fibrosis development in heavily pretreated chronic ITP –Lack of baseline data and irregular sampling intervals complicates interpretation  Bone marrow data do not indicate increased reticulin deposition with longer treatment  Potential association between bone marrow fibrosis and thrombopoietin receptor agonists not well understood Brynes RK, et al. ASH 2011. Abstract 528.

42. VTE Risk and Prevention

43. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Retrospective Analysis of MAGELLAN: Background  D-dimer a marker of thrombosis used as diagnostic tool for suspected VTE [1] –Elevated D-dimer levels predictive of increased risk of VTE among critically ill patients in previous trials [2]  MAGELLAN: acutely ill patients randomized to rivaroxaban 35 days vs enoxaparin 10 days + placebo [3,4] –Rivaroxaban noninferior to enoxaparin after 10 days and superior to enoxaparin/placebo after 35 days –Rivaroxaban associated with higher rates of clinically relevant bleeding 1. Adam SS, et al. Blood. 2009;113:2878-2887. 2. Fan J, et al. Clin Invest Med. 2011;34:E96-E104. 3. Cohen AT, et al. J Thromb Thrombolysis. 2011;31:407-416. 4. Cohen A, et al. ACC 2011. Abstracts 3015-3016.

44. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Retrospective Analysis of MAGELLAN: Study Design  Retrospective analysis of association between D-dimer levels and risk of VTE and rivaroxaban safety and efficacy according to D-dimer level –Outcomes assessed prospectively at Days 10 (per protocol population) and 35 (modified ITT population), post hoc Days 11-35 (modified ITT population) –Patients stratified by D-dimer levels at baseline, Days 10 and 35: high, > 2 x ULN; low, ≤ 2 x ULN  Composite primary efficacy outcome: asymptomatic and symptomatic DVT, symptomatic nonfatal pulmonary embolism, VTE-related death  Primary safety outcome: clinically relevant bleeding within 2 days Cohen AT, et al. ASH 2011. Abstract 542.

45. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Retrospective Analysis of MAGELLAN: Study Design II  Net clinical benefit outcomes –Prospective net clinical benefit: composite of primary efficacy outcome and clinically relevant bleeding –Post hoc net clinical benefit (NCB2): composite of primary efficacy outcome and major bleeding  Median baseline D-dimer level: 0.94 μg/mL (~ 2 x ULN)  High D-dimer group slightly older and higher incidence of heart failure, cancer, infection, VTE risk factors Cohen AT, et al. ASH 2011. Abstract 542.

46. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Retrospective Analysis of MAGELLAN: VTE Events  Baseline D-dimer level significant independent predictor of VTE (P <.0001) in multivariate analysis –D-dimer levels at baseline higher among patients with vs without VTE at Day 10, Day 35, and Days 11-35 in both treatment groups (rivaroxaban vs enoxaparin/placebo) –D-dimer levels at Day 10 also higher among patients with vs without VTE at Day 35 and Days 11-35 in both treatment groups  ~ 3- to 4-fold higher VTE rate in patients with baseline D-dimer > vs ≤ 2 x ULN Cohen AT, et al. ASH 2011. Abstract 542.

47. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Retrospective Analysis of MAGELLAN: Primary Efficacy and Safety  Primary efficacy event rates lower with rivaroxaban vs enoxaparin/placebo among patients with baseline D-dimer > 2 x ULN  Clinically relevant bleeding events more frequent with rivaroxaban vs enoxaparin/ placebo in both D-dimer level subgroups (> vs ≤ 2 x ULN)  Net clinical benefit event rates lower with enoxaparin/placebo vs rivaroxaban among patients with baseline D-dimer ≤ 2 x ULN Cohen AT, et al. ASH 2011. Abstract 542.

48. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP Retrospective Analysis of MAGELLAN: Conclusions  D-dimer level an independent predictor of VTE among acutely ill patients  Patients with high baseline D-dimer levels at increased risk for VTE –Rivaroxaban associated with favorable benefit/risk profile vs enoxaparin + placebo despite increased bleeding –Rivaroxaban improved VTE outcomes vs enoxaparin + placebo in patients with high D-dimer levels  D-dimer assessment at Day 10 may identify patients at risk of VTE who would benefit from extended rivaroxaban prophylaxis Cohen AT, et al. ASH 2011. Abstract 542.

49. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP HITEC Substudy of PROTECT: Background  HIT: platelet activation by antibodies against PF4/H causes thrombocytopenia and sometimes thrombosis –High incidence expected in critically ill population due to widespread heparin use and frequent low platelet counts in surgical and ICU patients  HITEC [1] substudy of PROTECT: prospective, randomized, blinded study comparing LMWH vs unfractionated heparin for prevention of VTE, DVT, and bleeding in critically ill patients [2] –Compared incidence of suspected and laboratory-confirmed HIT and evaluated predictive value 4Ts score [3] 1. Crowther MA, et al. ASH 2011. Abstract 198. 2. PROTECT Investigators. N Engl J Med. 2011;364:1305- 1314. 3. Crowther MA, et al. J Crit Care. 2010:25:287-293.

50. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP HITEC Substudy of PROTECT: Study Design  PROTECT patients with suspected HIT (n = 763 of 3746) –Platelet count < 50,000 cells/mm 3 –Unexplained platelet decrease to < 50% of baseline –Development of venous thrombosis –Other clinical suspicion of HIT –Excluded trauma, cardiac, and orthopedic surgery patients  4Ts scores determined both locally and centrally  Confirmed HIT: clinical suspicion of HIT and positive central laboratory evaluation Crowther MA, et al. ASH 2011. Abstract 198.

51. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP HITEC Substudy of PROTECT: HIT Incidence  HIT identified and adjudicated in 15/3746 (0.4%) PROTECT pts (95% CI: 0.2% to 0.7%) –Confirmed in 15/475 (3.2%) pts with laboratory testing –HIT incidence < 0.1% if DVT criterion excluded  4Ts score not predictive of adjudication-proven HIT –Risk group not correlated with confirmed HIT  High DVT incidence in pts with HIT –5/5 pts in LMWH arm, 3/10 pts in unfractionated heparin arm –74.8% in LMWH arm received open-label, nonstudy use of unfractionated heparin Crowther MA, et al. ASH 2011. Abstract 198.

52. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP HITEC Substudy of PROTECT: Conclusions  Incidence of laboratory-confirmed HIT much lower than estimated among critically ill patients [1] –Suspected in 20% of patients in ICU –Present in 3% of patients with clinical suspicion of HIT –Incidence < 1% in study patient population when DVT cases excluded  4Ts score not useful method to assess HIT risk in ICU patient population  In separate observational cohort study, anti-PF4/H antibody level not associated with HIT incidence [2] 1. Crowther MA, et al. ASH 2011. Abstract 198. 2. Ortel TL, et al. ASH 2011. Abstract 1159.

53. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP WARFASA: Background  Unprovoked VTE associated with high recurrence rate after anticoagulant discontinuation –Increased bleeding risk with warfarin anticoagulation; not suitable for extended treatment  WARFASA: randomized, double-blind, placebo-controlled study evaluated efficacy and safety of aspirin vs placebo for preventing symptomatic VTE recurrence after discontinuation of conventional anticoagulant Becattini C, et al. ASH 2011. Abstract 543.

54. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP WARFASA: Study Design  Primary efficacy outcome: objectively confirmed recurrent symptomatic VTE or VTE-related death  Primary safety outcome: major bleeding or clinically relevant nonmajor bleeding  Median duration of study treatment: 23.8 mos Patients with first symptomatic unprovoked VTE (N = 403) 2 yrs with option for extended treatment Aspirin 100 mg/day (n = 205) Placebo (n = 197) 6-18 mos oral anticoagulant until 14 days before randomization Becattini C, et al. ASH 2011. Abstract 543.

55. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP WARFASA: VTE Recurrence  Daily aspirin associated with lower risk of symptomatic VTE recurrence than placebo  Bleeding complications similar between treatment arms (1 major, 3 clinically relevant nonmajor events in each arm; 6 deaths in aspirin group, 5 in placebo group) Becattini C, et al. ASH 2011. Abstract 543. Reproduced with permission. VTE Recurrence RiskHR (95% CI)P Value Aspirin vs placebo  During study period  While on study treatment 0.58 (0.36-0.93) 0.55 (0.33-0.92).02 Adjusted for other VTE risks  Aspirin use  Older than 65 yrs of age  Male sex 0.53 (0.32-0.85) 2.26 (1.16-4.41) 2.02 (1.16-3.49).009.017.012

56. clinicaloptions.com/oncology Update on Nonmalignant Hematology Disorders and ITP WARFASA: Conclusions  WARFASA [1] –Daily aspirin following unprovoked VTE decreases risk of VTE recurrence ~ 40% compared with placebo –No increased risk of bleeding with aspirin –Aspirin may be valid alternative to other oral anticoagulants for extended treatment of VTE after first unprovoked VTE event –Study does not distinguish between potential platelet vs antiinflammatory effects  Although aspirin has been shown to be efficacious in the WARFASA study, it is important to note that the relative efficacy of warfarin for reducing VTE recurrence in patients with high risk of recurrence has been shown to be greater [2] 1. Becattini C, et al. ASH 2011. Abstract 543. 2. Palareti G, et al. N Engl J Med. 2006;355:1780-1789.

57. Go Online for More CCO Coverage of Nonmalignant Hematologic Disorders Interactive Virtual Presentations review and consider challenging patient cases with guidance from expert faculty members Interactive Case Challenges work through challenging patient cases and review the implications of treatment choices Text-Based Modules plus downloadable PowerPoint slides clinicaloptions.com/oncology