1. JAK inibitori nella policitemia vera
Francesco Passamonti
Università dell’Insubria Varese - Italy

2. Prediction of prognosis in PV after diagnosis
Bad factors:
Hematocrit values over 45%
Inadequately controlled PV

3. 365 JAK2-pos. PV pts treated with phlebotomy  HU
Which is the most safe hematocrit level in PV?
the prospective CYTO-PV trial
Primary composite end point: Death from CV cause or major thrombotic events (stroke, acute coronary syndrome, transient ischemic attack, PE, abdominal thrombosis, DVT, or peripheral arterial thrombosis)
Secondary end point: Primary end point + superficial-vein thrombosis
Treated to Hct <45% n = 182
365 JAK2-pos. PV pts treated with phlebotomy  HU R
1:1
Treated to Hct 45-50% n = 183
Post hoc analysis of two large randomized clinical trials (PVSG-01 and ECLAP) failed to show a different incidence of major thrombosis when HCT levels were kept in the range between 40% and 50%. Thus, there was a need for a randomized clinical trial to provide evidence-based data that would assess the usefulness of tight HCT control in reducing thrombosis.
Studio multicentrico italiano: 365 paz. di 26 centri – arruolamento: maggio 2008-febbraio 2012
We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed.
After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events.
67% HR
25% history of thrombosis
50% diagnosed within 2 y
ASA in all without contraindications
Median f-up 31 months (range )
Marchioli R et al, N Engl J Med 2013;368(1):22-33

4. Primary endpoint achieved, n (%): Secondary endpoint achieved, n (%):
To maintain the hematocrit below 45% is associated with less vascular events
Treated to Hct <45% n = 182
Treated to Hct 45-50% n = 183 R
1:1
Primary endpoint achieved, n (%):
5* (2.7)
18* (9.8)
Secondary endpoint achieved, n (%):
8 (4.4)
20 (10.9)
After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events.
About 75% were maintained per protocol Hct level.
Higher frequency and dose of HU in high Hct group.
Significantly higher WBC in high Hct group.
No difference in PLT count.
No difference in total number of deaths, fibrotic/leukemic transformation, bleeding, second cancers.
Significant differences might have been limited to:
Females
Older age group
HR pts not on systemic anticoagulation
Probability of remaining event-free
* 0 deaths in the Hct <45% arm, 4 deaths in the Hct 45-50% arm
Marchioli R et al, N Engl J Med 2013;368(1):22-33

5. Inadequately controlled PV Criteria for clinical trials
HU-non hematological toxicity (any dose)
Leg ulcers, aftosis
Gastrointestinal symptoms
Fever
HU- hematological toxicity (lowest effective dose)
Neutrophil < 1x 109/l
Platelet < 100x 109/l
Hemoglobin <10 g/dl
HU-resistance
(maximum tolerated dose)
Phlebotomies requirment
Platelet > 400x 109/l
Uncontrolled leukocytosis
HU-resistance
(maximum tolerated dose)
Unresponsive /Progressive splenomegaly
Progressive systemic symptoms
Marchioli R, et al. N Engl J Med. 2013;368: Prchal JT, et al. Polycythemia vera. Williams Hematology. 8th edition. Najean Y, et al. Blood. 1997;90(9): Mesa RA. Blood. 2009;113: Alvarez-Larrán A, et al. Blood. 2012;119(6): Barosi G et al, Br j Hematol. 2010;148(6)

6. Recorded in 137 patients (15.4%):
Inadequately controlled or HU resistant & intolerant PV The size of the problem in 890 patients
Recorded in 137 patients (15.4%):
Need for phlebotomies (3.3%)
Uncontrolled myeloproliferation (1.6%)
Failure to reduce massive splenomegaly (0.8%)
Cytopenia at the lowest HU-dose to achieve response (1.7%)
Extra-haematological toxicity (9%)
Cytopenia affected survival, progression to MF, AML
Splenomegaly affected MF
Alvarez-Larran et al; Br J Haematol Mar;172(5):786-93

7. Implications of need of phlebotomies in PV
Spanish retrospective study: 533 PV patients under HU; 16% of them required 3 or more phlebotomy per year
Implications respect to lesser need:
Higher doses of HU; Higher rate of thrombosis (20.5% vs 5.3%)
ECLAP prospective study: 793 PV treated with HU
No differences in thrombotic events per n. of phlebotomy
Alvarez Larran et al; Haematologica 2016; Barbui et al; Haematologica 2017

8. Thrombosis/patients (%)
Implication of leukocytosis permanence during PV treatment: an higher risk of thrombosis data from the prospective CytoPV study
WBC (x109/L)
Thrombosis/patients (%)
Hazard ratio (95%CI), p-value
<7.0
4/100 (4.0)
1.00
4/84 (4.8)
1.58 ( ), 0.52
8/88 (9.1)
2.69 ( ), 0.11
≥11.0
12/93 (12.9)
3.90 ( ), 0.023
Barbui et al; Blood Jul 23;126(4):560-1.

9. ESMO Guidelines for PV
Vannucchi et al, Ann Oncol Sep;26 Suppl 5:v85-99

10. Second line treatment in PV: interferons
French PVN1 Study
N=37, newly diagnosed
CHR in 95% (82% CR)
No thrombosis in 6 yrs
CMR in 8 (28%)
Sustained improvements after discontinuation
89% with AE’s (grade 1/2)
Discontinuation rate: 8% at 1yr 1, 24% overall
Ropeginterferon
N=51
Median 17 ms from dx, 33% treated with HU
(not HU resistant/intolerant)
47% CR, 43% PR
CMR in 21%
1 TIA, 1 DVT during study period
88% with AE’s
20% discontinued
(pruritus, fatigue, arthralgia, HA, diarrhea, flu-like sx most common)
MDACC
N=43; ~50% treat naive;
Median follow-up: 83 months
ORR: 79%
CHR 76%
Median time to CR: 40 days
Failure to achieve CMR: more likely to have/acquire non-driver mutations
G3/4 AEs: 10-17% of pts/yr, over long term (fatigue, cytopenias, depression)
Thrombosis and progression can occur
Discontinuation rate: 22%
Kiladjian et al; Blood 2008
Turlure, et al ASH 2011 Abs 280
Clinical, hematological, morphological, and molecular responses
Turlure:
13/20 dc’s received no further therapy, and 10/13 still in hematological CR off therapy after 28 months—29% could stop w/o requiring further therapy
Gissingler et al; Blood 2015
Quintas-Cardama et al, Blood 2013
Masarova et al Lancet Haem 2017
Front-line studies (Proud PV, ASH 2016 Abs 479) and (MPD-RC 111, ASH 2016 Abs 475) showed non-inferiority vs. HU

11. Ruxolitinib in PV: Phase 3 trials RESPONSE and RESPONSE 2
Ruxolitinib, 10 mg bid
HU resistance or intolerance (ELN criteria)
q3mo phlebotomy requirement
Palpable spleen with MRI-confirmed vol. of ≥ 450 cm3
Platelet > 100K
N = 110
1o Endpoint Failure
Disease Progression
Crossover
HCT
40–45% inclusive
Randomised
Best Available
Therapy
N = 112
Week 32
Week 80
Week 28 in Response-2
NO Splenomegaly in Response-2
Primary composite endpoint: haematocrit control (phlebotomy independence from week 8 to 32, with ≤ 1 phlebotomy post randomization) in the absence of phlebotomy and 35% reduction in spleen volume at week 32 (this latter absent in Response 2)
Secondary endpoints: complete haematological remission at week 32 (absence of phlebotomy requirement, PLT count ≤ 400 x 109/L, and WBC count ≤ 10 × 109/L); % of patients who maintain primary endpoint response for ≥ 48 weeks; Symptom improvement (MPN-SAF diary) and quality of life (EORTC QLQ-C30; PGIC).
Vannucchi et al, N Engl J Med Jan 29;372(5):426-35; Passamonti et al, Lancet Oncol Dec 1. pii: S (16)

12. Individual Components of Primary Endpoint
RESPONSE study: haematocrit control and 35% reduction in spleen volume at Week 32
Primary Endpoint
Individual Components of Primary Endpoint
P < .0001
OR, (95% CI, ) 60 38 21 20 1 1
Vannucchi et al, N Engl J Med Jan 29;372(5):426-35

13. RESPONSE study: durability of primary endpoint
Graph is adopted from RUX Graphics/New Figures 2a
20/25 (80%) ruxolitinib-treated patients had a durable primary response defined as maintenance for 48 weeks after initial response
3 of the 5 without durable response were classified as nonresponders because of missing assessments
The probability of maintaining the primary response in the ruxolitinib arm for at least 80 weeks from time of response was 92%
Verstovsek et al. Haematologica 2016

14. RESPONSE-2 study: haematocrit control at w 28
OR, 7.28 (95% CI, )
In patients who received interferon at any time in the BAT arm (n = 13; at randomization or after a regimen change), 4 (30.8%) achieved Hct control at week 28
Significantly more patients randomized to ruxolitinib achieved Hct control without phlebotomy (primary endpoint) compared with those randomized to BAT
Passamonti et al, Lancet Oncol Dec 1. pii: S (16)
OR, odds ratio.

15. Response-2: proportion of patients receiving phlebotomies up to week 28
≤ 2
> 4
No. of Phlebotomies
More than 80% of patients in the ruxolitinib arm did not have a phlebotomy, compared with 40% in the BAT arm
The total number of phlebotomies was much higher in the BAT arm than in the ruxolitinib arm (98 vs 19)
Passamonti et al, Lancet Oncol Dec 1. pii: S (16) 9

16. Time to Subsequent Phlebotomy Eligibility
BAT vs Ruxolitinib Nonresponders
Verstovsek S, et al. ASH Abstract 3201.

17. Normalization of iron status/MCV over time with ruxolitinib
Verstovsek S, et al. Leuk Res. 2017;56:52–59.

18. RESPONSE-2 study: WBC count over time
Rux
Median WBC Count, × 109/L
Week
Ruxolitinib, n = 74 68 65 66 69 69 67 68
BAT, n = 75 69 71 70 69 69 61 40
WBC counts in the ruxolitinib arm were ≤ 10 × 109/L from week 8 onward, whereas they remained > 10 × 109/L in the BAT arm
Passamonti et al, Lancet Oncol Dec 1. pii: S (16)

19. Thromboembolic complications with ruxolitinib in the Response studies
Response: at the Week 80 analysis, the rates of thromboembolic events per 100 patient- years of exposure were 1.8 in the ruxolitinib arm vs. 8.2 in the BAT arm
Response-2: there was 1 thromboembolic event in the ruxolitinib arm and 3 in the BAT arm
“Thrombosis/embolism (vascular access-related)” is defined as (in CTCAE version 3.0):
Grade 1: NA
Grade 2: Deep vein thrombosis or cardiac thrombosis; intervention (e.g., anticoagulation, lysis, filter, invasive procedure) not indicated
Grade 3: Deep vein thrombosis or cardiac thrombosis; intervention (e.g., anticoagulation, lysis, filter, invasive procedure) indicated
Grade 4: Embolic event including pulmonary embolism or life-threatening thrombus
Grade 5: Death
When we search the online version 3.0, there are no hits for “thrombophlebitis”. However, version 4.03 ( lists “superficial thrombophlebitis” as “A disorder characterized by a blood clot and inflammation involving a superficial vein of the extremities” (there is no mention of non-superficial thrombophlebitis)
Vannucchi et al, N Engl J Med Jan 29;372(5):426-35; Passamonti et al, Lancet Oncol Dec 1. pii: S (16)

20. RESPONSE and RESPONSE -2 studies:
improvement of symptomatology

21. Response-2: Safety Hematologic
Patients, %
Ruxolitinib
(n = 74)
BAT (n = 75)
Grade 1/2
Grade 3
Grade 4
Anemia
55.4
42.7
Thrombocytopenia
8.1
22.7
1.3
Leukopenia
16.0
Other Adverse Events of Interest Up to Week 28
Patients, n (%)
Ruxolitinib (n = 74)
BAT (n = 75)
Infections
All infections
23 (31.1)
18 (24.0)
Grade 3 or 4
3 (4.1)a
1 (1.3)b
Herpes zoster
1 (1.4)
Nonmelanoma skin cancers
All NMSCs
1 (1.4)c
1 (1.3)d
There was 1 AE after treatment discontinuation of ruxolitinib, grade 2 middle ear infection
Passamonti et al, Lancet Oncol Dec 1. pii: S (16)

22. Active trials/Novel agents in PV
Study
Study Population
Preliminary Findings
Rationale
MPD-RC 111:
Peg IFN Salvage
High risk w/ HU intolerance/resistance
(or prior AVT)
N/A
To investigate peg-IFN as salvage therapy
MPD-RC 112:
Peg-IFN vs HU
Front-line, high risk population
Non-inferiority in response rates, interim analysis
To investigate peg-IFN as 1st line therapy
PROUD-PV
Ropeginterferon vs HU
257 Rx-naïve or HU-treated PV w/o intolerance or CHR
Non-inferiority in CHR between 2 groups at 12 m
To test efficacy of a novel agent, dosed bi-weekly
COMBI-trial
Peg-IFN with Ruxolitinib
(Denmark)
30 pts with PV (N=20), post-PVMF, or primary MF
-15/20 PV pts had CHR
  -Statistically significant ↓ in JAK2%
Anemia (n=15), neutropenia (n=13), and TCP (n=6)
Provide control of inflammatory symptoms with JAK inhibition along with anti-clonal activity with IFN
RG7388 (MDM2 inhibitor) in Pts w/ PV and ET
High risk, or low risk w/ sx
Prior resistance/intolerance
Includes pilot combo with peg-IFN if non-response to single agent RG7388
Aim is to activate the p53 pathway and induce apoptosis.
Givinostat
Phase 1B/2 Dose escalation
Prelim efficacy
PV in need of treatment
To test concept of HDAC inhibition in PV