1. Arizona, USA ©2011 MFMER | 3133089-1 Ruben A. Mesa, MD Professor & Chairman, Division of Hematology & Medical Oncology Deputy Director, Mayo Clinic Cancer Center Mayo Clinic – Arizona, USA Disease Burden in MF: What are the real clinical issues?

2. Disclosures Research Funding (Clinical Trial Funding) Sbio Incyte Lilly Celgene Genentech Novartis Telik Eisai

3. Disease Burden in MF: What are Real Clinical Issues? 1. Myelofibrosis – Framing the problem 2. Cytopenias and their impact 3. Splenomegaly and Constitutional Symptoms 4. Decreased Quality of Life ©2011 MFMER | 3133089-3

4. Premature death PVET Early PMF PVET Leukemic transformation Progressive constitutional symptoms Progressive cytopenias Progressive organomegaly/EMH Overt PMF Post ET/PV MF Overt PMF Post ET/PV MF Time: Variable 3-5 years common Natural History of MPNs Short term: Vascular events Lead time: Typically years (>10) to ∞

5. Burden of Myelofibrosis Anemia/ Cytopenias Anemia/ Cytopenias Splenomegaly MF Associated Symptoms

6. Patterns of Survival and Causes of Death In 9,384 Patients with Myeloproliferative Neoplasms Diagnosed In Sweden Between 1973 and 2008 Hultcrantz et al Blood 2010 (a3071)

7. Clonal MPN cells Enlarged Spleen Anemia Symptoms Fever Weight Loss Night Sweats Itching Bone pain Fatigue Fibrosis In Marrow

8. IPSET (ET – 3 groups) Survival Thrombosis Risk PV Risk (4 groups) Survival Leukemia Rates DIPSS (PMF – 4 groups) Survival Age≥ 60 (2pts) vs. < 60≥70 (3pts) 60-69 (2pts), <60 ≥65 (1pt) vs. <65 Leukocytes≥ 11 (1pt) vs. < 11 x 10 9 /L ≥15 (1 point) vs. <15 x 10 9 /L >25 (1pt) vs. ≤25 x 10 9 /L Hemoglobin<10 (2 pts) vs. ≥10g/dL Constitutional Symptoms Present # (1pt) vs. Absent Blasts≥1% (1pt) vs. <1% Prior Thrombosis Yes (1 point) vs. No Risk Group Point Cutoffs 0; 1-2; 3-4 pts.0; 1-2; 3; 4 pts.0; 1-2; 3-4; ≥4 pts. Evolving MPN Prognostic Scales Tefferi ASH 2011 Passamonti Blood 2012 Passamonti Blood 2010 # = >10% Weight Loss over prior 6 months, Night Sweats, Unexplained Fever

9. Cervantes et al. Blood 2009;113:2895-2901 0 Factors 1 Factor 2 Factors 3-5 Factors

10. ©2011 MFMER | 3133089-10 Causes of Death in Primary Myelofibrosis

11. Survival after MPN Blast Phase

12. ©2011 MFMER | 3133089-12 Mesa et. al. ASH 2012 Prevalence of MF in the USA

13. ©2011 MFMER | 3133089-13 Wang et. al. ASH 2012 Analysis of the impact and burden of illness of myelofibrosis in the USA

14. Burden of Vascular Events Retrospective Review of 707 patients with PMF ©2011 MFMER | 3133089-14 Barbui et. al. Blood 2010;115:778-782

15. Woman Ironing 1904 Guggenheim, New York, NY Pablo Picasso (1881-1973)

16. Disease Burden in MF: What are Real Clinical Issues? 1. Myelofibrosis – Framing the problem 2. Cytopenias and their impact 3. Splenomegaly and Constitutional Symptoms 4. Decreased Quality of Life ©2011 MFMER | 3133089-16

17. Myelofibrosis and Cytopenias (N=364) ©2011 MFMER | 3133089-17 Emanuel et. al. JCO 2012 N.B. Varying times NL Hg Men 13.5 g/dL Women 12 g/dL

18. ©2011 MFMER | 3133089-18 Cervantes et. al. Blood 2009 N.B. All Primary MF At Diagnosis Myelofibrosis and Cytopenias (N=1054)

19. Cytopenias and their impact MF ©2011 MFMER | 3133089-19 Anemia Fatigue Dyspnea Organ Dysfunction Anemia Fatigue Dyspnea Organ Dysfunction Thrombocytopenia Hemorrhage Thrombocytopenia Hemorrhage Leukopenia Infection Leukopenia Infection > > Normal Energy Levels Hemoglobin – Transfusions & Energy Levels 10g/dL 8g/dL

20. Disease Burden in MF: What are Real Clinical Issues? 1. Myelofibrosis – Framing the problem 2. Cytopenias and their impact 3. Splenomegaly and Constitutional Symptoms 4. Decreased Quality of Life ©2011 MFMER | 3133089-20

21. Myelofibrosis and Splenomegaly 89% of MF with palpable splenomegaly (at diagnosis) Multi-institutional database of 1054 patients at time of diagnosis of PMF (Cervantes et. al. Blood 2009) 64% with palpable splenomegaly (By physician report) Median spleen size 7.4 cm BLCM International prospective MPN symptom study N=329 MF patients (Emanuel et. al. JCO 2012) ©2011 MFMER | 3133089-21

22. Why does splenomegaly in MF matter? 1. Mechanical discomfort 2. Pain 3. Possible splenic infarction 4. Early satiety adding to cachexia 5. Splenic sequestration and exacerbation of cytopenias 6. May delay engraftment in setting of allogeneic stem cell transplant ©2011 MFMER | 3133089-22

23. Symptoms in 1179 MPN Patients Mesa et. al. Cancer 2007;109:68-76

24. Evolution of MPN Symptom Assessment Tools MF–SAF 2009 (19 items) MF-SAF 2.0 (7 items 2011) JCO in Press MF–SAF 2009 (19 items) MF-SAF 2.0 (7 items 2011) JCO in Press Brief Fatigue Inventory (BFI) – 9 Items Brief Fatigue Inventory (BFI) – 9 Items Spleen Sx 4 Items Spleen Sx 4 Items Constitutional Sx 5 Items Constitutional Sx 5 Items QOL 1 Item Vascular and Ψ Sx 9 Items Vascular and Ψ Sx 9 Items MPN–SAF 2011 (27 items) Blood 2011 MPN-SAF TSS (10 items 2012) JCO 2012 MPN–SAF 2011 (27 items) Blood 2011 MPN-SAF TSS (10 items 2012) JCO 2012

25. All for measurement of the Validated Brief Fatigue Inventory Scherber et. al. 2011

26. Vascular Psychiatric Spleen/ Proliferation Related Cytokine Related QOL Scherber et. al. 2011

27. MPN-SAF (N=1433) Myeloproliferative Neoplasm Symptom Assessment Form Emanuel et. al. JCO 2012

28. MPN-SAF (N=1433) Myeloproliferative Neoplasm Symptom Assessment Form P<0.001 Mean TSS (0-10 Point Scale) Emanuel et. al. JCO 2012

29. Polycythemia Vera Mean 21.8 (SD=16.31) Essential Thrombocythemia Mean 18.7 (SD=15.33) Myelofibrosis Mean 25.3 (SD=17.2)

30. TSS MF Subtypes (N=284) Myeloproliferative Neoplasm Symptom Assessment Form P = N.S. Between MF Subtypes Mean TSS (0-10 Point Scale) Emanuel et. al. JCO 2012

31. Prevalence of “Constitutional” Symptoms in 1433 MPN Patients Emanuel et. al. JCO 2012 * - P<0.001 * * * *

32. Severity of “Constitutional” Symptoms in 1433 MPN Patients * - P<0.001 * * * * Itching Emanuel et. al. JCO 2012

33. Spleen Derived Symptoms in 1433 MPN Patients PrevalenceSeverity * P<0.001 * * * * * Emanuel et. al. JCO 2012

34. Prevalence of “End Organ” Symptoms in 1433 MPN Patients * P<0.001 * * * * * Emanuel et. al. JCO 2012

35. Severity of “End Organ” Symptoms in 1433 MPN Patients * P<0.001 * * * * Emanuel et. al. JCO 2012

36. The Kiss 1907 Österreichische Galerie Belvedere Vienna Gustav Klimt (1862-1918)

37. MF Symptom Burden (MFSB) NET Effect Time on Medical Therapy Disease Syx MFSB Prior to Treatment Initiation *Treatment-associated toxicity Disease Syx Rx Tox* MFSB After Treatment Initiation 37 Degree of Benefit (MFSB “Relief”

38. MPN-SAF 10 Item Total Symptom Score (TSS) Symptom1 to 10 (0 if absent) ranking* 1 is most favorable and 10 least favorable Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your WORST level of fatigue during past 24 hours (No Fatigue) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) Circle the one number that describes how, during the past week how much difficulty you have had with each of the following symptoms Filling up quickly when you eat (Early satiety)(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) Abdominal discomfort(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) Inactivity(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) Problems with concentration - Compared to prior to my MPD (Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) Night sweats(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) Itching (pruritus)(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) Bone pain (diffuse not joint pain or arthritis)(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) Fever (>100 F)(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Daily) Unintentional weight loss last 6 months(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) Emanuel et. al. JCO 2012

39. Myelofibrosis Mean 25.3 (SD=17.2)

40. ©2011 MFMER | 3133089-40 Myelofibrosis (N=329) Symptom Burden - Clusters Geyer et. al. ASH 2012

41. ©2011 MFMER | 3133089-41 Myelofibrosis Symptom Burden - Clusters Mean =11.8 (s7.8) Mean =28.9(s9.2) Mean =44.5(s9.4) Mean =65.9(s6.5) Geyer et. al. ASH 2012

42. ©2011 MFMER | 3133089-42 Cluster 1: Fatigue Dominant – Few Lab Abnormalities (46%; 69% PMF, 20% Post-ET MF, 11% Post-PV MF) Lowest rate of cytopenias (65% - Anemia 56%, thrombocytopenia 20%) Mean palpable spleen length = 6.0 cm Geyer et. al. ASH 2012

43. ©2011 MFMER | 3133089-43 Cluster 2: Cognitive Complaints & Splenomegaly (32%; 65% PMF, 20% Post-ET MF, 15% Post-PV MF) Mean palpable spleen length = 8.7 cm Geyer et. al. ASH 2012

44. ©2011 MFMER | 3133089-44 Cluster 3: Nighttime and Cognitive Complaints (16%; 64% PMF, 25% Post-ET MF, 15% Post-PV MF) Mean palpable spleen length = 7.0 cm Geyer et. al. ASH 2012

45. ©2011 MFMER | 3133089-45 Cluster 4: Severe Fatigue – Few End Organ Complaints (6%; 81% PMF, 14% Post-ET MF, 5% Post-PV MF) Highest rate of cytopenias (77% - Anemia 41%, thrombocytopenia 71%) Highest rate of prior vascular events and transfusion dependence Mean palpable spleen length = 6.7 cm (no prior splenectomies) Geyer et. al. ASH 2012

46. ©2011 MFMER | 3133089-46 Myelofibrosis Symptom Burden Clusters (N=329) Cluster 1 (N=150)Cluster 2 (N=105)Cluster 3 (N=53) Cluster 4 (N=21) Difference in each symptom between clusters all p<0.001 Geyer et. al. ASH 2012

47. Differences Between MF-SB Clusters (N=329) Age P=0.78 Gender P=0.20 Type of MF P=0.71 DIPSS Risk Category P<0.001 Language of MPN-SAF P=0.24 Anemia Present (<11g/dL) P=0.48 Leukopenia (<3.5 x 10(9)/L) P=0.009 Thrombocytopenia (<150 x 10(9)/L) P<0.001 Spleen Size (cm BLCM) P=0.03 Prior Thrombosis P=0.06 ©2011 MFMER | 3133089-47 Geyer et. al. ASH 2012

48. ©2011 MFMER | 3133089-48 MF Symptom Burden - Clusters Geyer et. al. ASH 2012

49. Death and Life 1908 Leopold Museum Vienna Gustav Klimt (1862- 1918)

50. Disease Burden in MF: What are Real Clinical Issues? 1. Myelofibrosis – Framing the problem 2. Cytopenias and their impact 3. Splenomegaly and Constitutional Symptoms 4. Decreased Quality of Life ©2011 MFMER | 3133089-50

51. Decreased QOL in 1433 MPN Patients P<0.001 Scherber et. al.JCO in press 2012

52. What is quality of life Quality of Life Increasing ?

53. Definitions HRQOL in MPNs? Σ MPN related symptoms Medication related toxicities Problems from prior MPN complications Stressors from having their MPN Financial Emotional Intrapersonal Co-morbidities Hassle of medical care

54. EORTC QLQ-C30 Scores in MF and Other Hematologic Malignancies and Solid Tumors EORTC QLQ-C30 Myelofibrosis COMFORT-I placebo arm (N=147*) Myelofibrosis (N=96) 1 CML (N=73) 2 Myeloma (N=944) 3 Breast (N=2782) 3 Lung (N=3332) 3 Recurrent/ metastatic cancers (N=4812) 3 Global Health Status/QoL52.959.970.255.761.856.656.3 Functional Subscales Physical Functioning67.274.978.067.778.471.975.8 Role Functioning63.268.878.160.170.961.560.7 Emotional Functioning75.576.578.871.368.668.968.7 Cognitive Functioning80.177.086.178.181.582.380.5 Social Functioning66.174.984.363.277.071.370.5 Symptom Scales/Single Items Fatigue54.141.029.848.733.341.141.8 Pain29.922.610.147.128.729.733.7 Dyspnea37.029.815.52618.137.923.4 Insomnia39.133.726.928.929.831.633.6 Appetite loss33.315.113.723.218.528.128.2 = Worsening Direction

55. Conclusions 1. Myelofibrosis is a fatal illness for many, causing cytopenias, splenomegaly, constitutional symptoms and decreased quality of life 2. Symptomatic burden in MF patients exists in distinct clusters that are not merely surrogates for disease prognosis 3. The impact of MF on HrQOL is multifacted and needs to be factored in to treatment plans and goals ©2011 MFMER | 3133089-55

57. Acknowledgements Mayo Clinic Amylou Dueck, PhD Jeff Sloan, PhD Tim Beebe, PhD John Camoriano, MD Ayalew Tefferi, MD USA Robyn Scherber MPH Ron Hoffman, MD S. Verstovsek, MD Gail Roboz, MD UK Deepti Radia, MD Claire Harrison, MD Mary Francis McMullin, MD France Jean-Jacques Kiladjian Italy Tiziano Barbui, MD Alessandro Vannucchi, MD Francesco Passamonti, MD Giovanni Barosi, MD Alessandro Rambaldi, MD Maria Ferarri, MD Sweden Peter Johansson, MD, PhD Bjorn Andreasson, MD Jan Samuelsson, MD Gunnar Birgegard, MD Denmark Hans Hasselbalch, MD Germany Heike Pahl, PhD Martin Grisshammer, MD CMPD EDUCATION FOUNDATION

58. Joy 2009 Weatherburn Gallery, Naples, FL, USA Diane Leonard (1958 - )