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Arizona, USA ©2011 MFMER | 3133089-1 Ruben A. Mesa, MD Professor & Chairman, Division of Hematology & Medical Oncology Deputy Director, Mayo Clinic Cancer.

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Presentation on theme: "Arizona, USA ©2011 MFMER | 3133089-1 Ruben A. Mesa, MD Professor & Chairman, Division of Hematology & Medical Oncology Deputy Director, Mayo Clinic Cancer."— Presentation transcript:

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

2 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

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

4 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)

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

6 Burden of Myelofibrosis Anemia/ Cytopenias Anemia/ Cytopenias Splenomegaly MF Associated Symptoms

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

8 Cytopenias and their impact MF ©2011 MFMER | 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

9 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 |

10 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 |

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

12 Evolution of MPN Symptom Assessment Tools MF–SAF 2009 (19 items) Leuk Res 2009 MF-SAF 2.0 (7 items 2011) JCO 2013 MF–SAF 2009 (19 items) Leuk Res 2009 MF-SAF 2.0 (7 items 2011) JCO 2013 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 MPN-SAF Languages English French German Spanish Dutch Swedish Italian Portuguese Mandarin Japanese Hebrew MPN-SAF Languages English French German Spanish Dutch Swedish Italian Portuguese Mandarin Japanese Hebrew

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

14 ET (N=775) PV (N=654) MF (N=423) Q1 – 30%Q2 – 26% Q3 – 24%Q4 – 20% Q1 – 17%Q2 – 21% Q3 – 26% Q4 – 36% Q1 – 25%Q2 – 23% Q3 – 26%Q4 – 26%

15 IPSET (ET – 3 groups) Survival Thrombosis Risk PV Risk (4 groups) Survival Leukemia Rates DIPSS (PMF – 4 groups) Survival Age 60 (2pts) vs. < 6070 (3pts) (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 Blasts1% (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

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

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

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

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

20 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

21 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

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

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

24 New Response Criteria for MPNs ELN ET (Blood 2013)

25 New Response Criteria for MPNs ELN PV (Blood 2013)

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

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

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

31 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 |

32 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

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

34 Medical Therapies in MPN Pre JAK2 Inhibitors – Efficacy Summary MyelofibrosisPolycythemia Vera Essential Thrombocythemia SpleenConst. Sympt. AnemiaSurvival Counts Const. Sympt. Vasc Events Counts Const. Sympt. Vasc Events ASPIRIN Hydroxyurea Anagrelide Androgens ESAs Interferons IMIDS Ruxolitinib Hypomethylation ©2011 MFMER | Not Reported Yet Not Reported Yet Yes No Occasional

35 JAK1 & 2 Inhibitors in MPNs – Efficacy Summary MyelofibrosisPolycythemia Vera Essential Thrombocythemia SpleenConst. Sympt. AnemiaSurvival Counts Const. Sympt. Vasc Events Counts Const. Sympt. Vasc Events Ruxolitinib - ApprovedP III P II SAR – PIII Ongoing (MF) P II Pacritinib- PIII Ongoing (MF) P II CYT387P II LY P I NS-018 BMS CEP701P II ©2011 MFMER | Not Reported Yet Not Reported Yet Yes No Occasional Ongoing Trials

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

37 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 |

38 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

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40 Morphologic change after IFN therapy in a patient with primary myelofibrosis (After Median 3 years of Rx). Silver R T et al. Blood 2011;117: Silver et. al. Blood Early PMF (MF

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

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

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

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

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

46 CP Long Term Complications of MPNs Surgical Therapy of Splenomegaly

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

48 Survival after Transplantation Scott B L et al. Blood 2012;119:

49 Overall Survival by Age BU 10 mg/kg Flu 180 mg/m 2 Kröger et al, Blood, 114:5264, 2009

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

51 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 JMascarenhas J Leuk Res Sep;34(9): Leuk Res.

52 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) Azacitidine for MDS and AML post-MPN Thepot S et al. Blood 2010;116: Median survival: 11 months

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

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

55 DAC Inhibitors LBH589 (Panobinostat) Mascarenhas et. al. ASH 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 patient with MF. 3 Good responses and decrease in pruritus Vorinostat (SAHA) MPD-RC trial in combination with 5-AZA

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

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

58 MPN-QOL International Study Group 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 ©2011 MFMER | Supported by a grant from the MPN Foundation

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

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61 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


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