1. 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 |

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

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 MPN Associated Symptoms Macrovascular Risk
Microvascular
Symptoms

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

7. 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 |

8. 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 |

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?
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 |

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

12. 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

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

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

15. 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

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

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

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

19. Decreased QOL in 1433 MPN Patients
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)
Complete Response X
Partial Response
Clinical Improvement
Stable Disease
No response
Relapse
Other Responses
Molecular
Cytogenetic &

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)

26. New Response Criteria for MPNs ELN PV (Blood 2013)

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)

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

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
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

34. 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 |

35. 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
SAR –
PIII Ongoing (MF)
Pacritinib-
CYT387 LY
P I
NS-018
BMS
CEP701
©2011 MFMER |

36. 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 |

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

40. 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:

41. 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)
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 COMBINATION (PV)
Ruxolitinib Vs. Hydroxyurea (RELIEF)
NCT

42. 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

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

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

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

46. Long Term Complications of MPNs Surgical Therapy of SplenomegalyCP

47. Long Term Complications of MF Splenectomy Update 2004 - 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/m2
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
JAK2 Inhibitor Plus Splenic XRT
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 J Leuk Res Sep;34(9):

52. 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:

53. IMiDs in MF: Summary of Clinical DataHB
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

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 Hypomethylation)
Ruxolitinib Plus Azacitidine
MDACC Trial: NCT
STUDY COMBINATION (JAK2 PLUS IMID)
Ruxolitinib Plus Lenalidomide
NCT

55. DAC Inhibitors LBH589 (Panobinostat) Givinostat (ITF2357)
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 2010
16 patient with MF. 3 Good responses and decrease in pruritus
Vorinostat (SAHA)
MPD-RC trial in combination with 5-AZA

56. 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: NCT
UK Trial: 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 PI3 Kinase Inhibitor)
Ruxolitinib Plus BKM120
NCT

57. 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
NCT
STUDY COMBINATION (JAK2 PLUS IMID)
Ruxolitinib Plus Pomalidomide
Germany (ULM): NCT

58. 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 |

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

61. 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