la polyglobulie de vaquez : clinique et traitement

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



• Hb – 15. g/dl – Hct – 46%



• 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



• Hb – 15. g/dl – Hct – 46%



• 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.





Landolfi et al, N Engl J Med. 2004;350(2):114-24





Age < 60 ET

pas d’ATCD vasculaireSaignées

Age > 60 ET / OU

ATCD vasculaire

Cytoréduction

1ère ligne: HU ou IFNα




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


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


• 9 AML

• 4 MDS

Median FU: 16.3 years


➢ 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.



• Hb – 15. g/dl – Hct – 46%




• 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.



• Hb – 15. g/dl – Hct – 46%






• 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



• Hb – 15. g/dl – Hct – 46%






• 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

la polyglobulie de vaquez : clinique et traitement

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