Combination therapy for MPNs Who, Why and When? Ruben A. Mesa, MD Professor & Chairman, Division of Hematology & Medical Oncology Deputy Director, Mayo Clinic Cancer Center Mayo Clinic – Arizona, USA ©2011 MFMER | 3133089-1

Combination Therapies for MPNs Who, Why, When? Unmet Burden in MPN Patients ET & PV MF Evolving response criteria highlight unmet goals Rationale for Combination Strategies Clinical Trials and Off Protocol Combinations

The Natural History of MPNs Diagnosis WHO 2008 Essential Thrombocythemia Polycythemia Vera Early/ Pre-fibrotic Primary Myelofibrosis Classic Primary MF Post ET/PV MF MPN Blast Phase ©2011 MFMER | 3133089-3

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)

Burden of ET/PV MPN Associated Symptoms Macrovascular Risk Microvascular Symptoms

Burden of Myelofibrosis MF Associated Symptoms Splenomegaly Anemia/ Cytopenias

Myelofibrosis and Cytopenias (N=364) N.B. Varying times NL Hg Men 13.5 g/dL Women 12 g/dL Emanuel et. al. JCO 2012 ©2011 MFMER | 3133089-7

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

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 | 3133089-9

Why does splenomegaly in MF matter? Mechanical discomfort Pain Possible splenic infarction Early satiety adding to cachexia Splenic sequestration and exacerbation of cytopenias May delay engraftment in setting of allogeneic stem cell transplant ©2011 MFMER | 3133089-10

Symptoms in 1179 MPN Patients Mesa et. al. Cancer 2007;109:68-76 11 11

Evolution of MPN Symptom Assessment Tools MPN-SAF Languages English French German Spanish Dutch Swedish Italian Portuguese Mandarin Japanese Hebrew Vascular and Ψ Sx 9 Items MPN–SAF 2011 (27 items) Blood 2011 MPN-SAF TSS (10 items 2012) JCO 2012 Constitutional Sx 5 Items MF–SAF 2009 (19 items) Leuk Res 2009 MF-SAF 2.0 (7 items 2011) JCO 2013 Spleen Sx 4 Items Brief Fatigue Inventory (BFI) – 9 Items QOL 1 Item

MPN Symptom Burden by Quartiles 1858 MPN-SAF Respondents TSS <8 Q2 TSS 8 -17 Q3 TSS 18 - 31 Q4 TSS >32 Quartile 1 (Q1): 0-24% Quartile 2 (Q2): 25-49% Quartile 3 (Q3): 50-74% Quartile 4 (Q4): 75-100% Percentile MPN-SAF TSS

ET (N=775) PV (N=654) MF (N=423) Q1 – 30% Q2 – 26% Q3 – 24% Q4 – 20%

Present# (1pt) vs. Absent Evolving MPN Prognostic Scales IPSET (ET – 3 groups) Survival Thrombosis Risk PV Risk (4 groups) Leukemia Rates DIPSS (PMF – 4 groups) Age ≥ 60 (2pts) vs. < 60 ≥70 (3pts) 60-69 (2pts), <60 ≥65 (1pt) vs. <65 Leukocytes ≥ 11 (1pt) vs. < 11 x 109/L ≥15 (1 point) vs. <15 x 109/L >25 (1pt) vs. ≤25 x 109/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. Passamonti Blood 2012 Tefferi ASH 2011 Passamonti Blood 2010 # = >10% Weight Loss over prior 6 months, Night Sweats, Unexplained Fever

PV Symptom Burden – Clusters by Risk* Emanuel et. al. ASH 2012 * Tefferi ASH 2011 ©2011 MFMER | 3133089-16

ET Symptom Burden – Clusters by Risk IPSET* Emanuel et. al. ASH 2012 * Passamonti Blood 2012 ©2011 MFMER | 3133089-17

MF Symptom Burden - Clusters Geyer et. al. ASH 2012 ©2011 MFMER | 3133089-18

Decreased QOL in 1433 MPN Patients Scherber et. al.JCO in press 2012

Conclusions of Burden of MPNs MPN patients exist on a spectrum of Risk of vascular events Impact on survival Symptomatic Burden Risk of Progression Current information reflects unmet needs of Symptomatic improvement in many MPN patients in many Risk of disease progression Residual risk of vascular events in fewer but still relevant

Combination Therapies for MPNs Who, Why, When? Unmet Burden in MPN Patients ET & PV MF Evolving response criteria highlight unmet goals Rationale for Combination Strategies Clinical Trials and Off Protocol Combinations

New Response Criteria for MPNs ELN (PV & ET), IWG-MRT (MF) (Blood 2013) Complete Response X Partial Response Clinical Improvement Stable Disease No response Relapse Other Responses Molecular Cytogenetic &

New Response Criteria for MPNs ELN ET (Blood 2013) ≥ 10pt Improvement MPN-SAF TSS

New Response Criteria for MPNs ELN ET (Blood 2013)

New Response Criteria for MPNs ELN PV (Blood 2013)

New Response Criteria for MPNs ELN PV (Blood 2013)

New Response Criteria for MPNs IWG-MRT MF (Blood 2013) Complete Response Partial Response

New Response Criteria for MPNs IWG-MRT MF (Blood 2013)

New Response Criteria for MPNs IWG-MRT MF (Blood 2013)

New Response Criteria for MPNs IWG-MRT MF (Blood 2013) Cytogenetics/ Molecular

Revised MPN Response Criteria New response criteria remain clinically derived and focus on resolution of marrow histologic changes, blood counts, spleen size, symptom improvement, and lack of vascular events or progression All require over 12 weeks of benefit to be counted as response Value and measurement of stability (clinically or histologically) still not captured Validation of value of response levels needed ©2011 MFMER | 3133089-31

Combination Therapies for MPNs Who, Why, When? Unmet Burden in MPN Patients ET & PV MF Evolving response criteria highlight unmet goals Rationale for Combination Strategies Clinical Trials and Off Protocol Combinations

MPNs – Individualizing Combinations The Internists Disease Goal – Prevent Vascular Events Goal – Improve Cytopenias Goal – Improve Spleen and Sx Goal – Cure High Risk Disease ET PV MF Allo SCT GVH Rx ID Rx Other JAK2 Inhib CV Risk Control JAK2 Inhib CYTOREDUCTIVE PHLEB IMIDs ASA

Medical Therapies in MPN Pre JAK2 Inhibitors – Efficacy Summary Yes No Occasional Not Reported Yet Myelofibrosis Polycythemia Vera Essential Thrombocythemia Spleen Const. Sympt. Anemia Survival  Counts Vasc Events ASPIRIN Hydroxyurea Anagrelide Androgens ESAs Interferons IMIDS Ruxolitinib Hypomethylation ©2011 MFMER | 3133089-34

JAK1 & 2 Inhibitors in MPNs – Efficacy Summary Yes No Occasional Not Reported Yet Ongoing Trials Myelofibrosis Polycythemia Vera Essential Thrombocythemia Spleen Const. Sympt. Anemia Survival  Counts Vasc Events Ruxolitinib - Approved P III P II SAR302503 – PIII Ongoing (MF) Pacritinib- CYT387 LY2784544 P I NS-018 BMS-911543 CEP701 ©2011 MFMER | 3133089-35

MPNs – Plateau vs. Decline Clinical Status ET – Possible Plateau Asymptomatic Thrombocytosis No Vascular Events ET – Possible Plateau 2 Symptomatic Thrombocytosis Sinus Venous Thrombosis PV – Possible Plateau 2 Symptomatic Erythrocytosis No Vascular Events MF on Successful JAK2 Rx Improving Weight Decreased Spleen Improved Survival Post PV MF 6 Months worsening Fatigue 10 kg weight loss Massive spleen Time ©2011 MFMER | 3133089-36

JAK2 Inhibition in MF Potential Targets of Combinations Preventing JAK2 inhibitor cytopenias Overcoming existing cytopenias Normalization of splenomegaly Normalization of marrow changes Delaying “progression” Further extension of survival Normalization of cytokines Improved QoL/symptom resolution ©2011 MFMER | 3133089-37

Combination Therapies for MPNs Who, Why, When? Unmet Burden in MPN Patients ET & PV MF Evolving response criteria highlight unmet goals Rationale for Combination Strategies Clinical Trials and Off Protocol Combinations

Morphologic change after IFN therapy in a patient with primary myelofibrosis (After Median 3 years of Rx). Silver et. al. Blood 2011 17 “Early” PMF (MF<Grade 3) IWG (11 low, 6 Int 1) INFa2b or PEG Infa-2a IWG-MRT 2 CR, 7 PR, 1 CI (59% Response) Morphologic change after IFN therapy in a patient with primary myelofibrosis. (A-D) Before treatment (2002). (A) The area of myelofibrosis (left), with preserved residual foci of hematopoiesis, and abnormal megakaryocyte morphology (right). (B) Abnormal megakaryocyte morphology. (C) 2+ reticulin fibrosis. (D) Collagen fibrosis. (E-H) After treatment (2009). (E) Improved bone marrow architecture, hematopoiesis, and megakaryocyte morphology. (F) Improved megakaryocyte morphology and increased normoblastic erythropoiesis. (G) Minimal reticulin fibrosis. (H) Absent collagen fibrosis. Gowin et. al. ASH 2011 17 “Early” PMF (MF<Grade 3) PEG Infa-2a IWG-MRT 1 CR, 2 PR, 1 CI (29% Response) Silver R T et al. Blood 2011;117:6669-6672

Ruxolitinib Vs. Hydroxyurea (RELIEF) Single Agent Trials in MPNs (Select) ET/PV STUDY (ET and PV) MPD-RC 112 Peg Inf a2a vs. Hydroxyurea (PH III) NCT01259856 STUDY (ET and PV) MPD-RC 111 Peg Inf a2a AFTER Hydroxyurea (PH III) NCT01259856 STUDY (PV) AOP Peg Inf a2a vs Hydroxyurea (PH III) NCT01230775 STUDY COMBINATION (PV) Ruxolitinib Vs. Hydroxyurea (RELIEF) NCT01632904

Combination Therapies in MPNs ET and PV NON STUDY COMBINATION Hydroxyurea Plus Anagrelide NON STUDY COMBINATION Hydroxyurea Plus PEG INFa 2a/b NON STUDY COMBINATION ASA Plus Clopidrogel FUTURE STUDY COMBINATION JAK2 Inhibitor Plus PEG INFa 2a/b

Single Agent Trials in MPNs (Select) MF (Accruing JAK2 Inhibitors) STUDY (JAK2/FLT3 Inhibitor) Fedratinib (SAR302503) AFTER Ruxolitinib (PH II) NCT011523171 NCT01420783 (ET and PV Phase II after Hydroxyurea) STUDY (JAK2/FLT3 Inhibitor) NS-018 (PH I/II) NCT01423851 STUDY (JAK2/FLT3 Inhibitor) Pacritinib (SB1518) (PH III vs. BAT) NCT01773187 STUDY (JAK2 Inhibitor – Also ET and PV) LY2784544 (PH I/II) NCT01520220

Single Agent Trials in MPNs (Select) MF (Accruing Non JAK 2 Inhibitors) STUDY (Interferons) Peg Interferon α2b in “Early” MF Cornell Lead: NCT01758588 STUDY (Activin - ActRIIA-IgG1Fc) Sotatercept (ACE 011) MDACC: NCT01712308 STUDY (Telomerase Inhibitor) Imetelstat (GRN163L) Mayo Clinic (Rochester): NCT01731951 STUDY (JAK1 Inhibitor) INCB039110 (PH II) NCT01633372

Oral Arsenic Trioxide (+/- Ascorbic Acid) Single Agent Trials in MPNs (Select) MF (Accruing Non JAK 2 Inhibitors) STUDY (HSP90 Inhibitor) AUY 922 NCT01668173 STUDY Oral Arsenic Trioxide (+/- Ascorbic Acid) MDACC: NCT01014546

Long Term Complications of MPNs Surgical Therapy of Splenomegaly CP1044663-33

Long Term Complications of MF Splenectomy Update 2004 - Survival by Indication Mechanical Anemia Portal Hypertension Thrombocytopenia P=N.S.

Survival after Transplantation Scott B L et al. Blood 2012;119:2657-2664

Overall Survival by Age BU 10 mg/kg Flu 180 mg/m2 Kröger et al, Blood, 114:5264, 2009

Combination Therapies in MPNs MF (Non Medicine Combinations) NON STUDY COMBINATION Splenectomy Then JAK2 Inhibitor NON STUDY COMBINATION JAK2 Inhibitor Plus Splenic XRT STUDY COMBINATION Ruxolitinib Then Allo Stem Cell Tx Trial: MPD-RC 114 NCT01790295 French Trial NCT01795677

Decitabine for AML post-MPN 7 patients treated Age 72 (45-81) 4/7 improved symptoms 7/7 improved splenomegaly 4/7 improved anemia 3/7 achieved complete morphologic remission with incomplete platelet recovery (CRi) Mascarenhas J Leuk Res. 2010 Sep;34(9):1246-9.

Median survival: 11 months Azacitidine for MDS and AML post-MPN All (n = 54) WHO classification at progression AML (n = 26) MDS (n = 28) Responses CR, n ( % ) 10 (19) 2 (8) 8 (29) Overall response rate, n (%) 28 (52) CR + CRi + PR, n (%) 10 (38) CR + marrow CR + PR + stable with HI, n (%) 18 (64) Median survival: 11 months Thepot S et al. Blood 2010;116:3735-3742

IMiDs in MF: Summary of Clinical Data HB PLT SPLN REF THAL 29% 38% 41% Barosi 2002 THAL-PRED 62% 75% 19% Mesa 2002 LEN 22% 50% 33% Tefferi 2006 LEN-PRED ? 9% Mesa 2010 30% 42% Quintas-Cardama 2009 POM (0.5mg/day) >50% <25% POM+/-PRED 30-40% 40% <10% Tefferi 2008 53 53

Combination Therapies in MPNs MF (Approved Drug Combinations - Anemia) STUDY COMBINATION (JAK2 PLUS Androgen) Ruxolitinib Plus Danazol Mayo Clinic (AZ) and Mt. Sinai Trial: NCT01732445 STUDY COMBINATION(JAK2 PLUS Hypomethylation) Ruxolitinib Plus Azacitidine MDACC Trial: NCT01787487 STUDY COMBINATION (JAK2 PLUS IMID) Ruxolitinib Plus Lenalidomide NCT01375140

DAC Inhibitors LBH589 (Panobinostat) Givinostat (ITF2357) Mascarenhas et. al. ASH2009-2011 A794 (2011) – Monotherapy active, low dose key DeAngelo et. al. ASH 2010 A630. Monotherapy active but dose used limiting Combination trial EU Ruxolitnib plus panobinostat Givinostat (ITF2357) Rambaldi et. al BJH 2010 16 patient with MF. 3 Good responses and decrease in pruritus Vorinostat (SAHA) MPD-RC trial in combination with 5-AZA

Ruxolitinib Plus Panobinostat Combination Therapies in MPNs MF (Approved/Non Approved Drug Combinations) STUDY COMBINATION (JAK2 PLUS HDAC Inhibitors) Ruxolitinib Plus Panobinostat Mt. Sinai Trial: NCT01693601 UK Trial: NCT01433445 STUDY COMBINATION (JAK2 PLUS LOXL2 Inhibitors) Ruxolitinib Plus GS-6624 NCT01369498 STUDY COMBINATION (JAK2 PLUS rhPTX-2 (Anti-fibrosing)) Ruxolitinib Plus PRM -151 Opening Soon STUDY COMBINATION (JAK2 PLUS PI3 Kinase Inhibitor) Ruxolitinib Plus BKM120 NCT01730248

Ruxolitinib Plus LDE225 Ruxolitinib Plus Pomalidomide Combination Therapies in MPNs MF (Approved/Non Approved Drug Combinations) STUDY COMBINATION (JAK2 PLUS Hedgehog Inhibitor) Ruxolitinib Plus LDE225 NCT01787552 STUDY COMBINATION (JAK2 PLUS IMID) Ruxolitinib Plus Pomalidomide Germany (ULM): NCT01644110

MPN-QOL International Study Group www.mpn-qol.org MEASURE Trial Serial assessment of MPN symptoms and QOL in all currently available therapies SYMPTOM Trial Serial assessment of the BMT experience in MPN symptoms (and BMT/GVHD symptoms) and QOL Supported by a grant from the MPN Foundation ©2011 MFMER | 3133089-58

Individualizing MPN Pharmacotherapy Patient Goals & Input Improving Symptom Burden /HR QOL “Balancing” Spleen/ Cytoses/ Cytopenias Extending Life CURE ©2011 MFMER | 3133089-59

Acknowledgements Italy Mayo Clinic USA Sweden UK Denmark Germany 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 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 CMPD EDUCATION FOUNDATION