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La polyglobulie de Vaquez : clinique et traitement
Jean-Jacques KILADJIAN
Hôpital Saint-Louis, Université de Paris
Inserm CIC 1427
Cas clinique
• Patiente de 32 ans, céphalées et fatigue
• Splénomégalie (1 cm sous rebord costal)
• Hb – 15. g/dl – Hct – 46%
• Leucocytes – 9.1 G/L
• Plaquettes – 650 G/L
• JAK2V617F +
• Diagnostic de TE
• Patiente de 32 ans, céphalées et fatigue
• Splénomégalie (1 cm sous rebord costal)
• Hb – 15. g/dl – Hct – 46%
• Leucocytes – 9.1 G/L
• Plaquettes – 650 G/L
• JAK2V617F +
• Diagnostic de TE
• Masse sanguine : 130% de la théorique
• Diagnostic de PV ?
Cas clinique
WHO 2016
A1Hgb > 16.5 in M, 16.0 in W
Or HCT > 0.49 M Or > 0.48 WOr increased red cell mass > 125%
A2BM with age-adjusted hypercellularity, panmyelosis, pleomorphic mature MK
A3 JAK2 mutation
B EPO
PV diagnosis A1 + A2 + A3 ORA1 + A2 and the B
Arber, Daniel A., et al. Blood. 2016
La PV masquée
WHO criteria for PV
▪ In cases with sustained absolute erythrocytosis (Hb levels >18.5 g/dL in
men or >16.5 g/dL in women, bone marrow biopsy may not be necessary
for diagnosis if major criterion 3 (JAK2) and the minor criterion (EPO) are
present.
▪ However, only by performing a bone marrow biopsy an initial fibrosis (up to
20%) may be detected that indicates a more rapid progression to overt
myelofibrosis (post-PV MF). (Barbui T et al. Blood 2012;119:2239-2241)
Normal bone marrow ET bone marrow
PV bone marrow
Courtesy of R. T. Silver
• Patiente de 32 ans, céphalées et fatigue
• Splénomégalie (1 cm sous rebord costal)
• Hb – 15. g/dl – Hct – 46%
• Leucocytes – 9.1 G/L
• Plaquettes – 650 G/L
• Diagnostic de PV, JAK2V617F +
Cas clinique
Prise en charge de la Polyglobulie de Vaquez
Age, ATCD Vasculaire Faible risque Haut risque
Contrôle des facteurs de risque CV
Aspirine faible dose
Barbui et al., Leukemia. 2018 May;32(5):1057-1069.
Prise en charge de la Polyglobulie de Vaquez
Age, ATCD Vasculaire Faible risque Haut risque
Contrôle des facteurs de risque CV
Aspirine faible dose
Landolfi et al, N Engl J Med. 2004;350(2):114-24
Prise en charge de la Polyglobulie de Vaquez
Age, ATCD Vasculaire Faible risque Haut risque
Contrôle des facteurs de risque CV
Aspirine faible dose
Age < 60 ET
pas d’ATCD vasculaireSaignées
Age > 60 ET / OU
ATCD vasculaire
Cytoréduction
1ère ligne: HU ou IFNα
Age, ATCD Vasculaire Faible risque Haut risque
Contrôle des facteurs de risque CV
Aspirine faible dose
Age < 60 ET
pas d’ATCD vasculaireSaignées
Age > 60 ET / OU
ATCD vasculaire
Cytoréduction
1ère ligne: HU ou IFNα
Hematocrite cible < 45 %
Marchioli et al. N Engl J Med. 2013;368(1):22-33
Prise en charge de la Polyglobulie de Vaquez
PV – Risques au cours du temps
MF - LeukemiaThrombosis
Passamonti, Haematologica, 2003
❑ Thromboses
❑ Artérielles
❑ Veineuses
❑ Hémorragies
Myélofibrose
Myélodysplasie
Leucémie aigue
Court / moyen terme Long terme
PV – Risques au cours du temps
Objectifs de la prise en charge : recommandations ELN
Barbui T, JCO 2011; 29:761
Goals of therapy in patients with PV and ET
To avoid first occurrence and/or recurrence of thrombotic and bleeding complications
To minimize the risk of acute leukemia and post-PV/post-ET myelofibrosis
To control systemic symptoms
To treat complications (thrombosis and hemorrhage)
To manage risk situations (eg, pregnancy, surgery)
Marchioli et al, J Clin Oncol. 2005;23(10):2224-32
Eviter complications vasculaires
Causes of Deaths (n= 164)
Cardio-vascular 45%
Cancer 19%
Hematological transformation 13%
• Etude ECLAP
• Suivi médian : 2.8 ans
•Causes de décès :
Minimiser le risque leucémique
Données de registre
• ECLAP median F-U: 2.8 yearsTherapy-related MDS/AML
Finazzi et al, Blood. 2005, 105(7):2664-70
Minimiser le risque leucémique
✓ Analyses in 1997
✓ Median FU: 9 years
✓ 13 leukemic events
• 9 AML
• 4 MDS
✓ Analyses in 1997
✓ Median FU: 9 years
✓ 13 leukemic events
• 9 AML
• 4 MDS
Median FU: 16.3 years
✓ 51 leukemic events
➢ 41 AML
➢ 10 MDS
• Median overall survival:
• 17 years (95% CI: 15.4 - 19.4)
• Causes of deaths (n=95):
➢MDS/AML: 54%
➢Vascular event: 19%
➢Solid tumor: 12%
ECLAP - Causes of Deaths
Cardio-vascular 45%
Cancer 19%
Hematological transformation 13%
• Evolution to AML/MDS
10 years 15 years 20 years
Total cohort 9.8% 24% 34%
HU (ITT) 6.6% 16.5% 24%
Pipo (ITT) 13% 34% 52%
HU (PP) 7.5% 14% 22%
Pipo (PP) 12% 37% 56%
HU (alone, n=94) 7.3% 11% 17%
Pipo (alone, n=130) 14.6% 34% 49.4%
Principales recommandations internationales
BCSH, British Committee for Standards in Hematology, ELN, European LeukemiaNet, ESMO, European Society of Molecular Oncology.
ELN ESMO BCSH
• Phlebotomy and low dose aspirin (all
pts)
• HU or IFN for high- risk pts
• Ruxolitinib or interferon-α in
patients who are intolerant or have
inadequate response to HU
• Busulphan Ok for older pts
• Phlebotomy and low dose aspirin (all
pts)
• HU or IFN for high- risk pts
• Ruxolitinib may be considered as
second line therapy for high risk pts
who are resistant/ refractory to HU
• Phlebotomy and low-dose aspirin as
first-line therapy
• Cytoreduction (mainly HU and IFN)
as second-line therapy, with agent
depending on patient age
Barbui T, et al. Leukemia. 2018 May;32(5):1057-1069. Vannucchi AM et al, Annals of Oncology. 2015(S5);v85-v99. McMullin, MF et al. Br J Haematol. 2005;130(2):174-95.McMullin, MF et al. Br J Haematol. 2007;138(6):821-2.
• Patiente de 32 ans, céphalées et fatigue
• Splénomégalie (1 cm sous rebord costal)
• Hb – 15. g/dl – Hct – 46%
• Leucocytes – 9.1 G/L
• Plaquettes – 650 G/L
• Diagnostic de PV, JAK2V617F +
• Aspirine faible dose et saignées
• Après 12 mois plaquettes 1 200 G/L : début peg-IFNa 2a (hors AMM)
Cas clinique
EVIDENCE FOR SUPERIOR EFFICACY AND DISEASE MODIFICATION AFTER THREE YEARS OF PROSPECTIVE
RANDOMIZED CONTROLLED TREATMENT OF POLYCYTHEMIA VERA PATIENTS WITH ROPEGINTERFERON ALFA-2B VS.
HYDROXYUREA/BEST AVAILABLE TREATMENT
HEINZ GISSLINGER, CHRISTOPH KLADE, PENCHO GEORGIEV, DOROTA KROCHMALCZYK, LIANA GERCHEVA-KYUCHUKOVA, MIKLOS EGYED, VIKTOR ROSSIEV, PETR DULICEK, ARPAD ILLES, HALYNA PYLYPENKO, LYLIA SIVCHEVA, JIRI MAYER, VERA YABLOKOVA,
KURT KREJCY, BARBARA GROHMANN-IZAY, HANS C. HASSELBALCH, ROBERT KRALOVICS,AND JEAN-JACQUES KILADJIAN
ASH 2018
Month 24
Efficacy Analysis
up to 3.6 years
Safety AnalysisMonth 12Month 0
Ropeginterferon alfa-2b phase III development in PV: PROUD-PV and CONTINUATION-PV Studies
% o
f re
sp
on
de
rs
0
10
20
30
40
50
60
70
80
90
100
Assessment visit
M3-
A
M6-
A
M9-
A
M12
-A (E
OT in
PR)
M15
-A (C
O-M
3)
M18
-A (C
O-M
6)
M21
-A (C
O-M
9)
M24
-A (C
O-M
12)
M27
-A (C
O-M
15)
M30
-A (C
O-M
18)
M33
-A (C
O-M
21)
M36
-A (C
O-M
24)
AOP2014
Control
AOP2014 (stat. significant RR)
Control (stat. significant RR)
18
39
45
62 61 62
72 71
67
7375
71
21
70 69
75
6669
5249
52
59 58
51
RR:0.84 RR:0.56 RR:0.66 RR:0.85 RR:0.94 RR:0.90 RR:1.37 RR:1.42 RR:1.31 RR:1.29 RR:1.31 RR:1.38
Complete hematologic response (CHR)
Study MonthResponder/N Responder % Responder/N Responder % P-value RR [95% CI]
(AOP2014/Control)
Ropeg (N=95) Control (N=76)
MONTH 12 (EOT in PR) 59/95 62.1 57/76 75.0 0.1201 0.85 [0.70-1.04]
MONTH 24 67/95 70.5 33/67 49.3 0.0111 1.42 [1.08-1.87]
MONTH 36 67/95 70.5 38/74 51.4 0.0122 1.38 [1.07-1.79]
Fu
ll A
nal
ysis
Set
% o
f re
sp
on
de
rs
0
10
20
30
40
50
60
70
80
90
100
Assessment visit
M3-
A
M6-
A
M9-
A
M12
-A (E
OT in
PR)
M15
-A (C
O-M
3)
M18
-A (C
O-M
6)
M21
-A (C
O-M
9)
M24
-A (C
O-M
12)
M27
-A (C
O-M
15)
M30
-A (C
O-M
18)
M33
-A (C
O-M
21)
M36
-A (C
O-M
24)
AOP2014
Control
AOP2014 (stat. significant RR)
Control (stat. significant RR)
26
44
50
6866 66
57
51
42
3331
27
RR:0.44 RR:0.84 RR:1.12 RR:1.94 RR:1.98 RR:2.31
JAK2 (V617F) - Molecular response
Study MonthResponder/N Responder % Responder/N Responder % P-value RR [95% CI]
(AOP2014/Control)
Ropeg (N=95) Control (N=76)
MONTH 12 (EOT in PR) 41/94 43.6 38/75 50.7 0.5001 0.84 [0.62-1.15]
MONTH 24 (LOCF) 64/94 68.1 25/75 33.3 0.0001 1.99 [1.40-2.84]
MONTH 36 (LOCF) 62/94 66.0 20/74 27.0 <0.0001 2.31 [1.56-3.42]
Mo
lecu
lar
resp
on
se a
t
asse
ssm
ent
visi
ts -
LO
CF
imp
uta
tio
n -
FA
S
JAK2 (V617F) - relative change from baseline
Study MonthRopeg(N=95)
Control (N=76)
P-value AOP2014/Control [95% CI]
JAK2V617F mean relative changes from baseline (%) LOCF
MONTH 12 (EOT in PR) -27.63 -39.97 0.2001 13.79 (-7.31 to 34.89)
MONTH 24 (LOCF) -45.41 -10.97 0.0022 -32.95 (-54.05 to -11.85)
MONTH 36 (LOCF) -44.98 4.84 <0.0001 -48.33 (-69.51 to -27.15)
JA
K2 V
617 [
%],
mean
an
d S
D
0
10
20
30
40
50
60
70
80
Time since first administration in PROUD-PV Study
Scree
ning
Day
0
M3-A
M6-A
M9-A
M12
-A (EOT in
PR)
M15
-A (CO-M
3)
M18
-A (CO-M
6)
M21
-A (CO-M
9)
M24
-A (CO-M
12)
M27
-A (CO-M
15)
M30
-A (CO-M
18)
M33
-A (CO-M
21)
M36
-A (CO-M
24)
AOP2014 Control
n=94 n=95 n=95 n=95 n=95 n=95 n=95 n=95 n=95 n=95 n=95
n=74 n=76 n=76 n=76 n=76 n=76 n=76 n=76 n=76 n=76 n=76
J
AK
2 V
617 [
%]
- re
lati
ve c
han
ge f
rom
baselin
e,
mean
an
d S
D
-160
-140
-120
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
140
160
Time since first administration in PROUD-PV Study
Scr
eening
Day
0
M3-
A
M6-
A
M9-
A
M12
-A (E
OT in
PR)
M15
-A (C
O-M
3)
M18
-A (C
O-M
6)
M21
-A (C
O-M
9)
M24
-A (C
O-M
12)
M27
-A (C
O-M
15)
M30
-A (C
O-M
18)
M33
-A (C
O-M
21)
M36
-A (C
O-M
24)
AOP2014 Control
n=94 n=94 n=94 n=94 n=94 n=94 n=94 n=94 n=94 n=94 n=94
n=74 n=75 n=75 n=75 n=75 n=75 n=75 n=74 n=74 n=74 n=74
Mea
n (
SD
) JA
K2
V61
7 [%
]
rela
tive
to
bas
elin
e -
LO
CF
imp
uta
tio
n -
FA
S
Treatment-related adverse events in >10% of patients
Treatment-related AE Ropeg (n=95)n (%)
Control (n=76)n (%)
Thrombocytopenia 24 (25.3%) 25 (32.9%)
Leukopenia 21 (22.1%) 23 (30.3%)
Anaemia 10 (10.5%) 22 (28.9%)
Increased gamma-GT 11 (11.6%) 2 (2.6%)
Alanine aminotransferase
increased
10 (10.5%) -
Platelet count decreased - 8 (10.5%)
Myalgia 10 (10.5%) 3 (3.9%)
Malignancies
Long-term Safety (up to 3.6 years of treatment; mean 2.7 years)
AOP 2014(n=127)
Control(n=127)
Acute leukemia 2
Basal cell carcinomaMalignant melanoma
21
Adrenal neoplasm*Glioblastoma
Spermatocytic seminoma
111
* No additional information on type of neoplasm available
Ropeginterferon alfa-2b
• Positive opinion of the Committee for Medicinal Products for Human Use (CHMP) adopted on 13 December 2018, recommending the granting of a marketing authorisation for the medicinal product intended for the treatment of polycythaemia vera without symptomatic splenomegaly.
• Was designated as an orphan medicinal product on 9 December 2011.
• The applicant for this medicinal product is AOP Orphan Pharmaceuticals AG.
• The full indication is: " indicated as monotherapy in adults for the treatment of polycythaemiavera without symptomatic splenomegaly."
• Proposed to be prescribed by physicians experienced in the management of the disease.
• Patiente de 32 ans, céphalées et fatigue
• Splénomégalie (1 cm sous rebord costal)
• Hb – 15. g/dl – Hct – 46%
• Leucocytes – 9.1 G/L
• Plaquettes – 650 G/L
• Diagnostic de PV, JAK2V617F +
• Aspirine faible dose et saignées
• Après 12 mois plaquettes 1 200 G/L : début peg-IFNa 2a (hors AMM)
• 3 ans plus tard : RCH mais taux très élevé d’Ac anti-nucléaires
Cas clinique
Adverse Events of Special Interest in PROUD/CONTI-PV
Long-term Safety (up to 3.6 years of treatment; mean 2.7 years)
AOP2014(n=127)
Control(n=127)
Endocrine disordersAutoimmune thyroiditis, Hypo-/Hyperthyroidism
5 (3.9%) 1 (0.8%)
Psychiatric disordersAnxiety, Depression, Mood altered
3 (2.4%) 1 (0.8%)
Tissue disordersRheumatoid arthritis, Sjogren‘s Syndrom
2 (1.6%) 0 (0.0%)
AMM : le ruxolitinib est indique dans le traitement des adultes atteints
de la maladie de Vaquez qui sont resistants ou intolerants a
l’hydroxyuree
Jean-Jacques Kiladjian, Pierre Zachée, Masayuki Hino, Fabrizio Pane,Tamas Masszi, Claire N. Harrison, Ruben A. Mesa, Carole B. Miller, Francesco Passamonti, Simon Durrant, Martin Griesshammer, Keita Kirito, Carles Besses, Beatriz Moiraghi, Elisa Rumi, Vittorio Rosti, Igor Wolfgang Blau, Nathalie Francillard, Tuochuan Dong, Monika Wroclawska, Alessandro M.
Vannucchi, and Srdan Verstovsek
Long-term Efficacy and Safety (5 Years) in RESPONSE,a Phase 3 Study Comparing Ruxolitinib (rux) With
Best Available Therapy (BAT) in Hydroxyurea (HU)-Resistant/-Intolerant Patients (pts) With Polycythemia Vera (PV)
Poster presented at ASH Annual Meeting, San Diego, California, USA, December 1-4, 2018: abstract 1753
RESPONSE Study Design
Patient Disposition (5-Year Final Analysis)
Durability of Primary Response With Ruxolitinib
• At the time of final analysis, 6 of 25 primary responders in the ruxolitinib arm had progressed
• The K-M estimate of duration of maintaining primary response at 224 weeks (starting from week 32) was 0.74
(95% confidence interval [CI]: 0.51, 0.88).
− The K-M estimate of duration of HCT control at 224 weeks (starting from week 32) was 0.73 (95% CI: 0.60, 0.83).
− The K-M estimate of duration of maintaining at least 35% of reduction in the spleen volume at week 224 (starting from week
32) was 0.72 (95% CI: 0.34, 0.91).
• The median duration of primary response was not reached.
Durability of Complete Hematologic Remission With Ruxolitinib
• The K-M estimate of duration of maintaining CHR (HCT control, platelet count ≤ 400 × 109/L, and WBC count ≤ 10 × 109/L) for 224 weeks (starting from week 32) was 0.55 (95% CI: 0.32, 0.73) (Figure 4).
• Of the 87 patients with WBC > 10 ×109/L at baseline, 36 (41.4%) had WBC ≤ 10 × 109/L at week 256.
• Of 54 patients with platelet count > 400 × 109/L at baseline, 25 (46.3%) had platelet count ≤ 400 × 109/L at week 256.
Exposure-Adjusted Rates (per 100 Pt-Year) of Thromboembolic Events
Exposure-Adjusted Rates (per 100 Patient-Year) of Common Adverse Events
Exposure-Adjusted Rates (per 100 Patient-Year) of Second Malignancy Events
Autres options :
- Pipobroman - AMM: Traitement de la polyglobulie primitive chez les
patients intolerants ou refractaires a l’hydroxycarbamide
- Busulphan
• Patiente de 32 ans, céphalées et fatigue
• Splénomégalie (1 cm sous rebord costal)
• Hb – 15. g/dl – Hct – 46%
• Leucocytes – 6.1 G/L
• Plaquettes – 650 G/L
• Diagnostic de PV, JAK2V617F +
• Aspirine faible dose et saignées
• Après 12 mois plaquettes 1 200 G/L : début peg-IFNa 2a (hors AMM)
• 3 ans plus tard : RCH mais taux très élevé d’Ac anti-nucléaires
• Switch pour ruxolitinib
Cas clinique
Conclusions
• Le diagnostic de PV selon l’OMS 2016 inclut la BOM dans les critères
majeurs pour intégrer les “PV masquées”
• Saignées et aspirine restent les éléments de base du traitement initial
• Hydroxyurée ou Ropeginterferon sont les deux médicaments ayant l’AMM
et recommandés pour le traitement de première ligne des patients de haut
risque
• Le Ruxolitinib est une option efficace pour le traitement de seconde ligne