1. Why do we need new drugs in PV and ET?

2. BCSH Guidelines: Hydroxycarbamide 1st Line
PV ET

5. Limitations of Hydroxycarbamide in PV and ET
Poor control of symptoms
Resistance:
Failure to normalise blood counts
Fails to normalise vascular risks
Persistent splenomegaly
Side effects
Leukaemogenicity?
Lack of disease modifying effect
Lack of ability to reduce late myeloid transformation

6. Limitations of Hydroxycarbamide in PV and ET
Poor control of symptoms
Resistance:
Failure to normalise blood counts
Fails to normalise vascular risks
Persistent splenomegaly
Side effects
Leukaemogenicity?
Lack of disease modifying effect
Lack of ability to reduce late myeloid transformation

7. Symptomatic burden prevalent across all MPN
Mesa R. et. al. Cancer 2007;109:68-76

8. Systemic symptoms: pruritus
Efficacy
Among 1,953 PV patients from 10 studies, 42% (31%-69%) reported pruritus
Reportedly associated with significant impairment of QoL in 19/44 (43%) of the patients in one study
Agent
JAK2 inhibitors
mTOR inhibitor
HDAC inhibitors
Interferon
Paroxetine/Fluoxetine
H1-H2 blockers
Anti-allergic
Myelosuppression
Phlebotomy
Saini KS et al., Eur J Clin Inv 2010; 40:828-34

9. Limitations of Hydroxycarbamide in PV and ET
Poor control of symptoms
Resistance:
Failure to normalise blood counts
Fails to normalise vascular risks
Persistent splenomegaly
Side effects
Leukaemogenicity?
Lack of disease modifying effect
Lack of ability to reduce late myeloid transformation

15. Resistance in 11%; Intolerance 13%

16. Limitations of Hydroxycarbamide in PV and ET
Poor control of symptoms
Resistance:
Failure to normalise blood counts
Fails to normalise vascular risks
Persistent splenomegaly
Side effects
Leukaemogenicity?
Lack of disease modifying effect
Lack of ability to reduce late myeloid transformation

17. 184 of 3411 (5%) developed side effects
167 mucocutaneous
16 fever
1 pneumonitis
Am J Hematology, 2012

18. Intolerance to HU 3,411 MPN pts 1 Side Effects 184 pts (5%) *
No Side Effect
2,831 pts
Pneumonitis
1 pt
Fever
16 pts (8.5%)
Mucosal/cutaneous
167 pts (91%)
* 11% in PT-12
12% in 3
1 Antonioli E et al., Am J Hematol 2012, In press; 2 Harrison c et al, NEJM 2005; 353:33-45; 3 Hernandez-Boluda JC et al, BJH 2010; 152:81-8

19. Limitations of Hydroxycarbamide in PV and ET
Paucity of randomised trials in PV
Poor control of symptoms
Resistance:
Failure to normalise blood counts
Fails to normalise vascular risks
Persistent splenomegaly
Side effects
Leukaemogenicity?
Lack of disease modifying effect
Lack of ability to reduce late myeloid transformation

20. Risk factors for transformation in PV
Marchioli et al, JCO, 2005

22. Choice of second line treatments
Relax treatment targets
Erythropoietin to help control anaemia in selected patients
Anagrelide
Interferon
standard
pegylated
Alkylating agents
P32
Investigatory agents
Combination treatment
Transplant
Very little prospective trial data on which to base decisions
Use non leukaemogenic agents where possible

23. Cortelazzo, 1995

25. Interferon: Non-leukaemogenic

29. Forthcoming MPD RC PEGASYS studies
Phase 2
168 JAK2V617F +ve
ET/PV patients HU
resistant/refractory
and
20 patients with
splanchnic vein
thrombosis
Phase 3
612 JAK2V617F +ve
ET/PV patients
diagnosed within 3
years of trial entry
Randomised between
PEGASYS + aspirin and
HU + aspirin

30. Current status of experimental therapies
HDAC inhibitors – panobinostat, givinostat, vorinostat
JAK 2 inhibitors

31. Durable Responses with the JAK1/JAK2 Inhibitor, INCB018424, in Patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory or Intolerant to Hydroxyurea (HU) Srdan Verstovsek1, Francesco Passamonti2, Alessandro Rambaldi3, Giovanni Barosi4, Peter Rosen5, Richard Levy6, Edward Bradley6, William Garrett6, Kris Vaddi6, Nancy Contel6, Victor Sandor6, Reid Huber6, Lee Schacter7, Elisa Rumi2, Elisabetta Gattoni4, Elisabetta Antonioli8, Lisa Pieri8, Mario Cazzola2, Hagop Kantarjian1, Tiziano Barbui3, Alessandro M. Vannucchi Annual Meeting of the American Society of Hematology December 6, 2010
1Department of Leukemia, University of Texas MD Anderson Cancer Research Center, Houston,Tx, 2Division of Hematology, University of Pavia, Fondazione Istituto di Ricovero e Cura a Carattere, Scientifico Policlinico San Matteo, Pavia, Italy, 3Division of Hematology, Ospedali Riuniti, Bergamo, Italy, 4Unit of Clinical Epidemiology and Center for the Study of Myelofibrosis, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia, Italy,5 Tower Cancer Research Foundation, Beverly Hills, Ca,6Incyte Corporation, Wilmington, De, 7Pfizer Corporation, New York,,8Section of Hematology, Deparment of Critical Care, University of Florence, Italy

32. Phase II Study of INC424 in Patients with Advanced ET and PV
Eligibility Criteria:
Refractory or intolerant to hydroxyurea (HU) or HU contraindicated
PV: Hct > 45% OR phlebotomy 2 times in last 6 months, with at least one phlebotomy in last 3 months
ET: Platelets > 650 x 109/L unless on therapy
Polycythemia vera (N=34)
10 mg BID
(n=7)
25 mg BID
(n=8)
50 mg QD
(n=7)
10 mg BID
(n=12)
Part 1
Part 2
Essential Thrombocythemia (N=39)
10 mg BID
(n=8)
25 mg BID
(n=8)
50 mg QD
(n=8)
25 mg BID
(n=15)
Part 1
Part 2
Srdan Verstovsek et at ASH, December 6, 2010

33. PV Results: Splenomegaly and WBC
80% of patients with palpable splenomegaly (n=25) achieved ≥ 50% reduction as of the last follow-up (68% achieved complete resolution of palpable splenomegaly)
Leukocytosis (>15x109/L) was present in 15 patients at baseline:
73% normalized WBC as of the last follow-up visit
Srdan Verstovsek et at ASH, December 6, 2010

34. PV Results: Platelet Counts and symptoms
Mean Symptom Severity Scores
Pruritus
Bone Pain
Thrombocytosis (>600 x109/L) was present in 13 patients at baseline: platelets normalized in 69% as of the last follow-up visit
Night Sweats
Srdan Verstovsek et at ASH, December 6, 2010

35. PV Response Response Criteria - European LeukemiaNet1
CR: Hct < 45% without phlebotomy, platelet count < 400,000, WBC < 10,000, normal spleen, no disease-related symptoms (pruritus, headache, microvascular disturbances)
PR: Hct < 45% OR response in > 3 of the other criteria
97% overall response
50% CR
47% PR (spleen measured by palpation)
1Barosi et al., Blood 113: , 2009

36. PV – ASH 2012 update
97% OR; 79% OR at 48 weeks, maintained in 74% at week 144

40. Platelet Count Reduction in ET
49% achieved normal platelet counts and 79% achieved <600,000
or a ≥50% reduction as of last follow-up visit
13 of 14 subjects with baseline platelet counts >1,000,000 have achieved a greater than 50% reduction

41. ET Response Response Criteria - European LeukemiaNet1
CR: Platelet count < 400 x109/L, WBC < 10 x109/L, normal spleen, no disease-related symptoms (pruritus, headache, microvascular disturbances)
PR: Platelet count < 600 x109/L OR decrease > 50% from baseline
90% overall response
26% CR
64% PR
1Barosi et al., Blood 113: , 2009

42. MAJ C
A RandoMised study of best Available therapy versus JAK Inhibition in patients with high risk Polycythaemia Vera or Essential Thrombocythaemia who are resistant or intolerant to HydroxyCarbamide
TAP

43. Trial Schema 1:1 Randomisation Ruxolitinib Best Available Therapy
PV: N = 90 patients per arm. ET: N = 55 patients per arm Patients stratified by disease type
Ruxolitinib
PV patients - 10 mg twice daily
ET patients – 25mg twice daily
Commence within 1 week of randomisation
Best Available Therapy
Commence within 1 week of randomisation
BAT - any active agent but not solely venesection or supportive care
Complete or Partial Response
Continue Ruxolitinb and Follow-up for 5 years total
FU minimum 2 monthly
No response observed at 1 Year
Continue Follow-up for 5 years
Frequency at Investigators discretion
Screening
Patients with Polycythaemia vera or Essential Thrombocythaemia who are resistant to or intolerant of hydroxycarbamide
Response assessed by European LeukemiaNet criteria within 1 year
Change therapy

44. Summary
Hydroxycarbamide is a well established and highly effective first line treatment for patients with ET and PV
Patients who “fail” hydroxyurea treatment are at high risk of disease related complications
Second line therapies are suboptimal and there is an unmet need for new agents for these hydroxycarbamide resistant patients
Experimental therapy with JAK2i, pegylated interferon or HDACi show promise in these patients

45. Questions?