1. JAK2 inhibitors and new therapeutic approaches in PV and ET
Francesco Passamonti
Division of Hematology
University Hospital, Fondazione Macchi Varese, Italy

2. Current management of PV & ET
Treatment objective
Preventing thrombotic and bleeding complications and minimizing the risk of transformation to secondary myelofibrosis or leukemia; controlling symptoms
Treating complications
General basis of treatment
PV: phlebotomy to maintain the hematocrit at less than 45% and low-dose aspirin, if not contraindicated
ET: low-dose aspirin, if microvascular disturbances and not contraindicated
Strict correction of cardiovascular risk factors
Cytoreductive therapy with hydroxyurea for:
Age > 60 years
History of thrombosis
Platelet count > 1500 x109/L
Poor tolerance of phlebotomies
Severe disease-related symptoms
Symptomatic or progressive splenomegaly
Progressive leukocytosis
Barbui et al, J Clin Oncol Feb 20;29(6):

3. Peg-Interferon in PV (90-135-180 mcg/wk)
37 PV patients untreated or treated for less than 2 years
Hematological Complete response at 12 months: 94.6%
Still on peg-IFN-α2a alone at 31 months: 78.4%
Adverse Events in 89% (grade1, 2) decreasing over time
Treatment discontinuation: 35% (24% for toxicity)
JAK2 (V617F) allele burden response
Complete: 7/29 (24%)
Partial: 14/29 (48%)
Reduction also in homoz. and 9pLOH
Targets JAK2 (V617F) clones without affecting TET2 mutant cells
% V617F
Kiladjian et al, Blood Oct 15;112(8):
Kiladjian et al. Leukemia Aug;24(8):
Months

4. Peg-Interferon in advanced PV
43 patients (median age 53 yrs, 50 months PV-duration)
Follow-up: 42 months
Overall response rate: 79%
Complete hematological response 76%
Median time to complete response: 40 days (range, 3 to 1478)
Drug-related treatment discontinuation: 20%
Molecular response
CMR: 18%
PMR (> 50%): 35%
Quintas Cardama et al, Blood 2013; 122:

5. AOP2014: a new formulation of peg-Interferon for PV
Next generation long lasting pegylated-IFN
Subcutaneous every 14 days
34 patients (dose finding & extension phases)
Median time from PV diagnosis: 24 months
71% ORR in 21 pts at week 28 (33% CR, 38% PR)
91% ORR in 11 pts at week 52 (46% CR, 46% PR)
27 pts (79%) developed drug-related AEs
Gisslinger et al., Blood 2012; Abstract 175, ASH 2012

6. Peg-Interferon–α2a in ET The Nordic Study Group on MPN
42 high-risk patients (21 PV, 21 ET); median follow-up 24 mos
Objective: to reduce PLT <400 x109/L or <600 if asymptomatic
No thromboembolic or hemorrhagic complications
At 6 months: CR=69%; failure rate=31% (13/42), drug-related treatment discontinuation: 14%
At 24 months: CR=45% (19/42); failure rate=55% drug-related treatment discontinuation: 38% (16/42)
Impairments of QoL (QLQ-C30 ) at 6 months; but at 24 months no change from baseline
Samuelsson et al, Cancer (11):

7. JAK2 reduction under IFN in ET Danish study on 102 MPN, median follow-up 42 months, (19 ET)
Clone reduced in 75% of patients
ET patients responding
JAK2 V617F reduction
% JAK2 V617F
Clone increased in 25% of patients, of whom 46% were in complete hematological response
Pre-Peg-Interferon Tx
Post-Peg- Interferon Tx
Larsen et al, Leuk Res (9):

8. Studies with Peg-Interferon in PV & ET
Randomised Trial of Peg-Interferon Versus Hydroxyurea in PV and ET. Primary Outcome: To compare hematologic response rates in patients randomised to treatment with Peg-Interferon Alpha-2a vs. Hydroxyurea in two strata of patients with high risk PV or high risk ET.
Peg-Interferon Salvage Therapy in High Risk PV and ET
Primary Outcome: To evaluate the ability of Peg-Interferon Alpha-2a to achieve Complete Response or Partial Response in patients with (1) high risk PV or (2) high risk ET or (3) splanchnic vein thrombosis.
ProudPV Trial
Phase III study to compare the efficacy and safety of the novel monopegylated interferon alpha 2b AOP2014 versus Hydroxyurea for patients with polycythemia vera.

9. Anagrelide vs hydroxyurea in ET The PT1 trial
809 ET patients at high risk for vascular events
Low-dose aspirin plus either anagrelide or hydroxyurea
Primary end point: actuarial risk of arterial and venous thrombosis, serious hemorrhage, or death from thrombotic or hemorrhagic causes
Anagrelide was associated with increased rates of arterial thrombosis, serious hemorrhage, and transformation to myelofibrosis, but with a decreased rate of venous thromboembolism
Harrison et al, N Engl J Med Jul 7;353(1):33-45.

10. Anagrelide vs hydroxyurea in ET a non inferiority trial, 259 WHO-diagnosed ET at HR
No significant differences regarding incidences of major arterial (7 vs 8) and venous (2 vs 6) thrombosis, severe bleeding events (5 vs 2), minor arterial (24 vs 20) and venous (3 vs 3) thrombosis and minor bleeding events (18 vs 15), or rates of discontinuation (adverse events 12 vs 15 or lack of response 5 vs 2).
Disease transformation into MF/AML was not reported
Gisslinger et al, Blood (10):

11. A Phase II study of Ruxolitinib in advanced PV and ET refractory to HU (INCB 18424-256)
Inclusion Criteria
Refractory or intolerant to HU; contraindication for HU
PV: Hct > 45% or 2 phlebotomies in prior 6 months (1 in last 3 months)
ET: Platelets > 650 x 109/L
Endpoints
Response (CR + PR) and safety, PK, PD, symptom assessments
10 mg BID
(n=7)
25 mg BID
(n=8)
50 mg QD
(n=7)
10 mg BID
(n=12)
PV=34
Part 1
Part 2
10 mg BID
(n=8)
25 mg BID
(n=8)
50 mg QD
(n=8)
25 mg BID
(n=15)
ET=39
Clinicaltrials.gov number: NCT
Part 1
Part 2

12. Ruxolitinib in the PV cohort
34 patients with PV enrolled
Median age: 58 years
Median time from PV diagnosis: 115 months
WBC >15 x109/L in 47%
PLT > 600 x109/L in 38%
Splenomegaly in 74%
Median follow-up duration: 3 years
26 remain on study
8 discontinued
Progression to MF (n=3)
Withdrawal of consent (n=2)
Patient decision to conceive
Patient complained of shortness of breath
Adverse events (n=2)
Renal neoplasm
Atrial flutter
Lack of response (n=1)
Verstovsek et al. Cancer Oct 30. doi: /cncr

13. Ruxolitinib in PV: Normalization of WBC and platelet counts
WBC count ≤10×109/L
Platelet count
≤ 400×109/L
Analyses conducted in patients with baseline WBC count >10×109/L (n=25) and patients with baseline platelet count >400×109/L (n=23)
ITT analysis: Patients who discontinued are counted as not having response for all study visits that they would have completed up to the date of analysis
Verstovsek et al. Cancer Oct 30. doi: /cncr

14. Ruxolitinib in PV: changes in palpable spleen length
NOTE: 25 patients had a palpable spleen, but 2 patients did not have a measurement recorded at baseline.
Verstovsek et al. Cancer Oct 30. doi: /cncr

15. Reduction in PV-associated symptoms
Clinically meaningful improvements in pruritus, night sweats, and bone pain observed within 4 weeks of initiating therapy and sustained through Week 144
ITT analysis: Patients who discontinued are counted as not having response for all study visits that they would have completed up to the date of analysis.
Verstovsek et al. Cancer Oct 30. doi: /cncr

16. Patient characteristics – ET (n=39)
Age, years 51
Female
64%
Months from Diagnosis 88
Refractory to HU
87%
No. Prior Therapies
1 (1-3)
Hct %
41.0
Platelet count, x109/L
849 (mean 1009)
Leukocyte count, x109/L
8.2
Splenomegaly
Size, cm (range)
4 (10%)
5 (3-7)
JAK2V617F positive
65%
JAK2V617F allele burden
16%
Verstovsek et al, Blood 2010; Abstract 313.

17. 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
Verstovsek et al, Blood 2010; Abstract 313.

18. Response rate for Ruxolitinib
PV overall response rate (m-ELN): 97%
Complete response: 59%, as their best response
Partial response: 38%, as their best response
ET Overall response rate (mELN): 90%
Complete response: 26% CR
Partial response: 64%
Criteria:
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
Verstovsek et al. Cancer Oct 30. doi: /cncr

19. Ruxolitinib in PV: Phase 3 Trial The RESPONSE Study
(oral) 10 mg bid
HU resistance or intolerance (ELN criteria)
q3mo phlebotomy requirement
Palpable spleen with MRI-confirmed vol. of ≥ 450 cm3
Platelet > 100K
N = 100
1o Endpoint Failure
Disease Progression
Crossover
HCT
40–45% inclusive
Randomised
Best Available
Therapy
N = 100
Week 32
Week 80
Enrolment completed
Special protocol assessment agreement reached with FDA
Primary composite endpoint: haematocrit control in the absence of phlebotomy and ≥ 35% reduction in spleen volume at week 32
Secondary endpoints: complete haematological remission at week 32; % of patients who maintain primary endpoint response for ≥ 48 weeks
NCT

20. Response trial Press release
Study of ruxolitinib met primary endpoint, improving two key measures of disease control in patients with polycythemia vera
Ruxolitinib is the first selective JAK 1/2 inhibitor to demonstrate efficacy in a Phase III trial for treating polycythemia vera

21. Other phase-III trials with ruxolitinib in PV
MAJIC: A randoMised study of best Available therapy versus JAK Inhibition in patients with high risk PVor ET who are resistant to or intolerant of HC
RELIEF: Patients who remain symptomatic on HC
RESPONSE-II: Per RESPONSE trial, but patients with no palpable spleen

22. Other investigated drugs
Givinostat (29 PV / ET / MF JAK2-pos)
13 PV/ET: 1 CR, 6 PR, 4 NR, 2 off study
16 MF: spleen reduction in 38%; 2 CI and 5 SD
Givinostat (2 doses) plus Hydroxyurea (44 PV res. to HD HU)
ORR (CR+PR): 55% for givinostat 50
ORR: 50% for givinostat 100
Imetelstat (13 ET, failure or intolerance)
ORR: 100% (11/13 CR after a median of 6.1 weeks)
Partial molecular response 6/7 patients (85.7%)
AE: GI, fatigue, infections (85.7%), neutropenia (78.6%)
Vorinostat (19 ET, 44 PV)
81% responded: PR (N=20), CR (N=5), by ELN criteria
Discontinuation rate: 52% (drug-related 44%)
Rambaldi et al. British Journal of Haematology 2010; 150: ; Finazzi et al. British Journal of Haematol 2013; 161, 688–694; Baerlocher et al. Blood 2012; 120: Abstract 179.; Andersen et al. British Journal of Haematology, 2013, 162, 498–508.

23. Conclusions Hydroxyurea is a widely used therapy in PV and ET
Peg-inteferon is effective on the clinical phenotype and on the clone, but advantage over conventional therapy is still to be demonstrated
JAK inhibition with ruxolitinib seems effective in PV and ET and superior to BAT in term of hematocrit control, and spleen size reduction