1. Update in Myeloproliferative Neoplasms
January 20, 2012

2. November 16, 2011

3. FDA Indications for Ruxolitinib (Jakafi)
Intermediate or high-risk Myelofibrosis =80-90% of MF patients JAK2V617F NOT required

4. Diagnostic Criteria for myelofibrosis
Post PV or ET MF
PMF
Must meet all 3 major and ≥2 minor criteria
Must meet both major and ≥2 minor criteria

5. JAK2V617F mutation: Not just for MPN anymore
95-97% PV >50% ET 50-60% MF 3-13% CMML 3-5% MDS (RARS & thrombocytosis) <5% AML

6. Dynamic International Prognostic Scoring System in MF
DIPSS
Obtained at any time during follow-up
0 = Low
1-2 = Intermediate-1
3-4 = Intermediate-2
5-6 = High
Passamonti et al, Blood 2010

7. DIPSS-plus 3 additional factors
The Dynamic International Prognostic Scoring System (DIPSS) plus prognostic model for primary myelofibrosis (PMF). The DIPSS and prognostic model for PMF uses 8 risk factors for inferior survival: age > 65 years, hemoglobin level < 10 g/dL, leukocyte count > 25 × 109/L, circulating blasts ≥ 1%, presence of constitutional symptoms, presence of unfavorable karyotype, platelet count < 100 × 109/L, and the presence of red cell transfusion need.40 *Please note that a transfusion-dependent patient automatically has 2 risk factors because of transfusion need (1 risk point) and hemoglobin level < 10 g/dL (1 risk point). **Constitutional symptoms constitute weight loss > 10% of baseline value in the year preceding diagnosis, unexplained fever, or excessive sweats persisting for > 1 month.38 ***Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q− 12p−, or 11q23 rearrangement.41
**Constitutional symptoms constitute weight loss > 10% of baseline value in the year preceding diagnosis, unexplained fever, or excessive sweats persisting for > 1 month
***Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q− 12p−, or 11q23 rearrangement
Tefferi, Blood 2011

8. COMFORT-I Primary endpoint Secondary endpoints
* Patients randomized to placebo will be eligible to cross over to ruxolitinib
Primary endpoint
Proportion of subjects achieving >35% reduction in spleen volume from baseline to Week 24 as measured by MRI (or CT scan in applicable subjects)
Secondary endpoints
Duration of maintenance of a >35% reduction from baseline in spleen volume among subjects initially randomized to receive INCB018424
Proportion of subjects with >50% reduction in total symptom score from baseline to Week 24 as measured by the modified MFSAF v2.0 diary

9. Percent Change From Baseline in Spleen Volume in Individual Patients at Week 24
Verstovsek, S. Presented at ASCO 2011

10. Primary Endpoint: % of Patients with ≥35% Decrease in Spleen Volume at Week 24 (ITT)
Verstovsek, S. Presented at ASCO 2011

11. Symptomatic Burden in MF
Constitutional
Symptoms
Splenomegaly
Myeloproliferation
Functioning
Percentage of patients reporting symptoms
Scherber et al, Blood 2011

12. Percent of Patients with ≥50% Decrease in Total Symptom Score at Week 24 (ITT)
Verstovsek, S. Presented at ASCO 2011

13. Proportion of Patients with ≥50% Reduction in Total Symptom Score Over Time
Verstovsek, S. Presented at ASCO 2011

14. Percent Change From Baseline in Total Symptom Score in Individual Patients at Week 24
Verstovsek, S. Presented at ASCO 2011

15. Mean Percent Change in Individual Symptoms
Verstovsek, S. Presented at ASCO 2011

16. Symptoms Return without drug

17. Increased serum cytokines in MPN
MPN patients
Mouse Model
CD40
IFN-α
IL-2R
IL-11
VCAM-1
IL-2
IL-9
MIP-1α
MMP-2
ICAM-1
MIP-1β
IL-8
IL-7
MMP-10
IL-12
TNF
IL-18
IL-13
IL-15
VEGF KC
IL-10
IL-16
IL-1α,ß
IL-6
TIMP-1
G-CSF
IFN-γ
Lower in MPN
(Tyner et al, 2010)
(Verstovsek et al, 2010 Slezak et al, 2009, Boissinot et al, 2010, Tefferi et al 2011)

18. TNF is elevated in MPN and correlates with JAK2V617F allele burden
Fleischman et al, Blood 2011

19. Elevated IL-8 and IL-2R associated with decreased survival in PMF
Intermediate-1
All patients
Intermediate-2
Tefferi et al, JCO 2011

20. Consequences of Increased Inflammation
HSC
exhaustion
Stress
hematopoiesis
Constitutional Symptoms
-weight loss
-fatigue
-fever

21. Impact of Ruxolitinib on inflammatory cytokines
Verstovsek et al, NEJM 2010

22. Ruxolitinib decreases inflammatory cytokines
Verstovsek et al, NEJM 2010

23. JAK inhibitors: not just for MPN

24. Hematology Laboratory Values
*Patients are included at their worst on study grade regardless of whether this represents a change from their baseline
Grade 3 and 4 anemia and thrombocytopenia were more common in those with
higher baseline grade
Discontinuation of treatment because of anemia and thrombocytopenia was rare
(1 patient in each treatment group for each event
Verstovsek, S. Presented at ASCO 2011

25. Non-hematologic Adverse Events Observed in at Least 10% of Ruxolitinib-Treated Patients
Verstovsek, S. Presented at ASCO 2011

26. Mean hemoglobin and Red Blood Cell Products Over Time
Verstovsek, S. Presented at ASCO 2011

27. Red Blood Cell Transfusions
Verstovsek, S. Presented at ASCO 2011

28. JAK2V617F allele burden
Percentage of JAK2V617F mutant allele can be quantitatively measured (available at OHSU), but clinical relevance is unknown

29. Low JAK2V617F allele burden in PMF has negative impact

30. Low V617Fallele burden associated with shorter survival in PMF
Guglielmelli et al, Blood 2009

31. Causes of Death in PMF
Cervantes et al, Blood 2009.

32. COMFORT-I Overall Survival*
* COMFORT-I was not designed nor powered to demonstrate a statistically significant difference in overall survival within the timeframe of the study endpoint. Patients who remain in COMFORT-I continue to be followed.
Incyte, JP Morgan Healthcare conference Jan 9,2012

33. Ruxolitinib Dosing
For plts X 109/L: OHSU currently enrolling for clinical trial of ruxolitinib in thrombocytopenic patients with MF
Jakafi prescribing information packet

34. Dose adjustment for thrombocytopenia
Hold Drug for platelets <50 X 109/L
Jakafi prescribing information packet

35. Drug Interactions:
Strong CYP3A4 inhibitors will increase levels of ruxolitinib, with strong CYP3A4 inhibitors dose reduction is recommended. Patients should be closely monitored and dose titrated based on safety and efficacy.
No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer.
Patients should be closely monitored and the dose titrated based on safety and efficacy
Jakafi prescribing insert

36. How to prescribe Ruxolitinib

37. Comparing various JAK inhibitors
Drug
Target
Phase
Disease
Efficacy
Toxicity
INCB18424
JAK2, JAK1
Approved
III MF
PV/ET
Splenomegaly, symptoms
Anemia, thrombocytopenia
TG101348, (SAR302503)
JAK2, FLT3 II
Anemia, thrombocytopenia, gastrointestinal
SB1518
Gastrointestinal
CEP701
MF, PV/ET
Gastrointestinal, anemia, thrombocytopenia
CYT387
JAK1, JAK2 I
Splenomegaly, symptoms, anemia
First dose effect, cytopenias LY
JAK2
MF, ET/PV
NPR
AZD1480
JAK2, JAK3
I/II
NS018

38. Clinical trials of non-JAK2 targeted therapies for MPN
Drug
Target
Phase
Disease
Efficacy
Toxicity
RAD001
mTOR II MF
Splenomegaly, symptoms
Minimal
Pomalidomide
IMiD
III
Anemia
PEG-IFNa-2a
Biological
PV/ET
Erythrocytosis, thrombocytosis, symptoms
Myelosuppression, depression
LBH589
HDAC
Splenomegaly, anemia
Anemia, thrombocytopenia, gastrointestinal

39. Lenalidomide for MF Mayo Clinic - Blood. 2006 Aug 15;108(4):1158-64.
68 patients; lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia.
MD Anderson - J Clin Oncol Oct 1;27(28):
40 patients; lenalidomide 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) on days 1 through 21 of a 28-day cycle for six cycles with prednisone taper. ORR 30% for anemia and 42% splenomegaly by IWG-MRT criteria.
ECOG Phase 2 (E4903) - Blood Nov 25;116(22):
48 patients; lenalidomide 10mg daily + prednisone taper; anemia improved in 19% and splenomegaly in 10% by IWG-MRT criteria.

40. Pomalidomide +/- prednisone in treatment of anemia in MF
Tefferi et al, JCO 2009

41. Phase II trial of pomalidomide alone in MF
Low dose pomalidomide alone (0.5mg/d) in 58 MF patients with anemia
Response limited to JAK2V617F mutated patients
24% of V617F+ patients responded in terms of anemia and 9/10 became transfusion independent
Response predicted by basophilia in first month of treatment
58% of patients with plts ≤ 100K experienced >50 % increase in plt count
Begna et al, Leukemia 2011

42. rIFN-α may reverse fibrosis in early PMF
Silver et al, Blood 2011

43. Peg-IFN-alpha2a for PV/ET
Kiladjian et al Blood 2008;112:3065:
37 patients; 95% had hematologic CR; only 3 stopped tx at 12 months. Decreased JAK2V617F allele burden in 90%. Molecular CR in 7 patients mcg weekly.
Quintas-Cardama et al JCO 2009;27:5418:
40 PV/39 ET; one prior cytoreductive treatment; 70%/76% hematologic CR; 14%/6% molecular CR. Only 10% of patients discontinued due to toxicity; no grade 4 toxicities; grade 3 were not frequent but included pain, fatigue, dyspnea, and pruritis. Tolerability of PEG-IFN-alpha-2a at 90 mcg weekly was excellent.
Phase III trials comparing Hydroxyurea vs. Pegasys are underway (upfront high risk PV or ET; HU-resistant or refractory).

44. PEG-IFNα induces hematologic response in PV/ET
Start at 90µg/week, with goal of 135µg/week
Tolerable dosing
Kiladjian et al, Blood 2008

45. 90µg/wk PEG-IFNα-2a induces molecular response in PV/ET
Quintas-Cardama et al, JCO 2009

46. Toxicities Associated with PEG-IFNα-2a
-PEG-IFNα-2a 90µg/week
-10% of patients discontinued due to IFN related toxicity
Quintas-Cardama et al, JCO 2009

47. The curative approach: allogenic SCT
Conditioning N
Study
Median Age
Donor
TRM (%) OS
Myeloablative
551
Retr 42
RD=36 URD=20 27
47% (5-y)
562 43
RD=40
URD=9
58% (3-y)
Reduced-Intensity
1033
Prosp FluBu+ATG 55
RD=33 URD=70 16
67% (5-y) 66
Prosp FluMel+/-ATG
RD=32 URD=34
RD=16 URD=33
RD=78% (2-y) URD=44% (1y)
Obstacles: -Donor availability High TRM
-Advanced patient age Still ill defined morbidity
-Comorbidities Impact of cGVHD
1Guardiola et al, Blood Deeg et al, Blood Alchalby et at, Blood Rondelli, ASH 2011 Abst 1750.

48. Treatment Algorithm for myelofibrosis
DIPSS/DIPSS-plus
Low, Int-1
Int-2/high
asymptomatic
symptomatic
Consider SCT
Yes No
observation
*conventional drug therapy
*ruxolitinib
MyA 45-50y
RI 45-65
refractory
Investigational
drug therapy

49. Treatment of Anemia: Conventional Approach
-Prednisone
-Danazol/Androgens
-Erythropoietin stimulating agents (ESA)
15-20% response,
Short lived
-Thalidomide + Prednisone ≈ 20% response, neurotoxicity
-Lenalidomide ≈ 20% response, myelosuppression
Best in pts with del(5q31)
-Splenectomy up to 50-75% response
duration ≈ 1yr
-RBC transfusions

50. Treatment goals Prevent thrombosis Prevent hemorrhage
Alleviate constitutional symptoms
Minimize primary and iatrogenic disease progression
Improve QOL and survival