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Jean-Jacques Kiladjian, MD, PhD Clinical Investigations Center

Saint-Louis Hospital – Paris Diderot University Paris, France

Challenging scenarios in PV

Disclosures for Jean-Jacques Kiladjian, MD, PhD

Royalty N/A

Receipt of intellectual property/ Patent holder

N/A

Consulting fee Novartis, Shire, AOP Orphan

Speakers bureau N/A

Fees for non-CME services N/A

Contracted research Novartis, AOP Orphan

Ownership interest (stocks, stock options)

N/A

Other N/A

N/A = Not Applicable (no conflicts listed) Presentation includes discussion of off-label or unapproved use of a drug or medical device

PREGNANCY IN PV

Clinical case

• 26-year-old woman

• Referred for thrombocytosis discovered during first pregnancy

• Severe complication during pregnancy: pre-eclampsia, IUGR, placental abruption, emergency cesarean delivery @ 6 months, baby died at D2

• No other significant medical or surgical history

• Asymptomatic, palpable splenomegaly 3 cm

• CBC: • WBC 17 G/L, 82% PMN

• Hemoglobin 16.2 g/dL, Ht 47%, MCV 86 fl

• Plt 818 G/L

Case n°1

• BCR-ABL1 negative; JAK2V617F positive

• Red cell mass: + 150%

• Erythropoietin: 2 U/L (low)

• Polycythemia Vera

Evolution of WHO criteria for PV 2008 2014 Proposal

Major criteria

1 Hemoglobin > 18.5 g/dL (men) > 16.5 g/dL (women) or RCM >25% of predicted

Hemoglobin > 16.5 g/dL (men) > 16 g/dL (women) or hematocrit > 49% (men) > 48% (women)

2 Presence of JAK2V617F or JAK2 exon 12 mutation

BM trilineage myeloproliferation with pleomorphic megakaryocytes

3 Presence of JAK2 mutation

Minor criteria

1 Subnormal serum erythropoietin level

Subnormal serum erythropoietin level

2 BM trilineage myeloproliferation

3 Endogenous erythroid colony growth

Adapted from Tefferi A, et al. Leukemia. 2014;28:1407-13.

Pregnancy outcome

ET

(≈140 cases)

PV

(38 cases)

“Normal” pregnancies

Successful pregnancies (surviving neonates) 60% 50%

First trimester loss 30% 21% 15%

Late pregnancy loss 5% 15% 0 - 5%

Kiladjian JJ, Hematology, EHA Educ Program. 2006;2(1):108-12

Maternal complications

ET

(≈150 cases)

PV

(36 cases)

Major thrombosis 5% 8%

Major hemorrhage 3% 3%

Kiladjian JJ, Hematology, EHA Educ Program. 2006;2(1):108-12

Cytoreductive drugs & pregnancy

• None of the cytoreductive agents has product license for

use in pregnancy

• Risk factors used to decide cytoreduction in ET and PV are

modified or controversial during pregnancy

• Impact of cytoreductive treatment on pregnancy

outcome is controversial

• No evidence-based strategy

Cytoreductive drugs & pregnancy

Fertility Teratogenicity (animals)

Fetal toxicity in reported pregnancies

Hydroxyurea Reduced spermatogenesis yes

55 pregnancies 42 live births (4 IUD, 9 abortions) 1 malformation* Perez-Encinas, 1994 Harrison, 2005

Anagrelide Disrupted implantation

? (may cross placenta)

Interferon Reduced

spermatogenesis Decreased libido

no

23 pregnancies 1 malformation* Barbui, 2004

Robinson, 2005

*same pregnancy: HU at conception, IFN after 4 months

Aspirin • Low-dose aspirin is beneficial in PV (ECLAP)

• Low-dose aspirin is safe during pregnancy (CLASP)

• Is low-dose aspirin useful during pregnancy in MPN?

• No advantage: Wright & Tefferi, 2001 (43 cases)

• Advantage: Barbui, 2004 (245 cases)

Griesshammer, 2003 (155 cases)

Passamonti, 2009 (129 cases)

Low-dose aspirin should be used during MPN

pregnancy (unless contraindication or acquired vWD)

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

CLASP, Lancet 1994; 343:619-29

Heparin

• LMW Heparin is safe and beneficial in pregnancies at high risk of

thrombosis

• LMWH was superior to aspirin in patients with thrombophilia

• Role of LMWH in MPN not clearly established

Hunt BJ et al., Thromb Haemost, 1997;77:39-43

Gris JC et al., Blood, 2004; 103:3695-9

Management - Before pregnancy

• Information of female patients of childbearing age

• Screening for thrombophilia recommended

• Start low-dose aspirin

• Patients on HU / anagrelide: gradually stop, > 3 months

wash-out period before conception

• Phlebotomy

• IFN if cytoreductive treatment is required

Management - During pregnancy

• Low-dose aspirin throughout pregnancy

• Consider IFN and prophylactic LMWH if:

• Previous major thrombosis or hemorrhage (pregnant or not)

• Platelet count > 1000 x 109/L

• Severe complication during previous pregnancy

Management - Delivery

• Stop aspirin 2 weeks before delivery, replaced

by prophylactic LMWH

• Stop LMWH 12 to 24 hours before delivery

Management - Puerperium

• Restart LMWH continued for at least 6 weeks

• Close monitoring of maternal blood counts (rebound)

• If cytoreduction is required, breastfeeding is

contraindicated

Conclusion - Pregnancy in PV

• Pregnancy is possible in PV patients

• But it should be considered and managed as a “high-

risk” pregnancy, like in other prothrombotic states

• Close collaboration between hematologists and

obstetricians is crucial

• Information of all MPD patients is essential to avoid

unanticipated pregnancy

SPLANCHNIC VEIN THROMBOSIS

Clinical case

• 25-year-old woman

• Admitted for abdominal pain

• Ascites, jaundice, hepatomegaly + 8 cm, splenomegaly + 10 cm

• Ultrasonography, then CT-scan: Budd-Chiari Syndrome

• CBC: • WBC 14 G/L, 82% PMN

• Hemoglobin 12 g/dL, MCV 72 fl

• Plt 390 G/L

• JAK2V617F positive

Diagnosed with MPN

Splanchnic vein thromboses

Hepatic veins Primary Budd-Chiari syndrome

Portal vein Acute: Pylephlebitis, Pylethrombosis Chronic: Portal cavernoma

BCS: Improved survival over 3 decades

Valla D-C. Gut 2008;57:1469-1478

Copyrighted material

Valla D-C. Gut 2008;57:1469-1478

Therapeutic strategy

Splanchnic vein thromboses

Hepatic veins/ Terminal IVC Primary Budd-Chiari syndrome

Portal vein Acute: Pylephlebitis, Pylethrombosis

Chronic: Portal cavernoma

Portal vein thrombosis

Bleeding Ascites MOF

Intestinal Ischemia

Uncomplicated Acute PVT

Abdominal Pain SIRS

Chronic PVT

Bleeding Encephalopathy

Collateral veins (cavernoma)

Portal hypertension

Prothrombotic diseases in BCS & PVT

Myeloproliferative neoplasms %

Antiphospholipid syndrome %

Inherited disorders %

Others (PNH, Behcet, IBD, …) %

Any of the above %

50 35

15 15

35 35

10 10

65 65

BCS PVT

From Janssen HL, et al. Blood 2000;96:2364-2368. Denninger MH, et al. Hepatology 2000;31:587-91.

Primignani M, et al Hepatology 2006;44:1528-34

V617F JAK2 + BMB +

V617F JAK2 - BMB +

V617F JAK2 - BMB -

V617F JAK2 + BMB -

25%

7%

12% 44%

(n=241) 0

%

100

56%

87%

Myeloproliferative neoplasms in SVT

No MPL515 No JAK2 exon 12


Smalberg J H et al. Blood 2012;120:4921-4928

MPL515: 3/305 tested cases (meta-analysis)

JAK2 exon 12: 0/268 tested cases (meta-analysis)

1 case report (Colaizzo, Blood 2007)

CALR: 4/209 (Turon et al., J Hepatol. 2014)

6/308 (French cohort, unpublished)


241 patients with SVT

JAK2V617F positive (n= 94)

JAK2V617F negative (n= 147)

P

Females 62% 48% 0.048

Splenomegaly (cm) 5 [0-11] 0 [0-2] <.001

Kiladjian JJ et al. Blood 2008; 111(10):4922-9





P

Hemoglobin, g/dL 13.4 12.8 0.012

Hematocrit, % 43% 39% <.001

Neutrophils 5.2 3.7 <.001

Platelets 333 159 <.001





Q1 - Q3 interval

Hemoglobin, g/dL 13.4 12 - 15

Hematocrit, % 43% 39 - 47

Neutrophils 5.2 3.7 - 9

Platelets 333 239 - 456





Q1 - Q3 interval

Hemoglobin, g/dL 13.4 12 - 15

Hematocrit, % 43% 39 - 47

Neutrophils 5.2 3.7 - 9

Platelets 333 239 - 456

RCM > 125% 61.3%

KiladjianJJ et al. Blood 2008; 111(10):4922-9





P

APLS 14% 17% NS

F.V or F.II mutations 9.6% 11% NS

PC, PS, AT deficiency

10.5% 9.5% NS


Myeloproliferative neoplasms in SVT:

Cytoreduction or Not?

• MPN with a history of thrombosis: high risk, indication for cytoreductive therapy

• But, the majority of patients have blood counts within the normal range…

• No definitive evidence for, or against, cytoreductive therapy in MPNs with SVT

Conclusion - MPN and SVT

• MPNs are the first cause of “idiopathic” SVT

• Additional prothrombotic states are found in 15%-30% of patients

• 80%-90% of these MPN are JAK2V617F positive, about 2% are CALR mutated and less than 1% display an MPL mutation

• The favorable impact of specific MPN therapy on overall outcome has not been demonstrated

INTOLERANCE TO HYDROXYUREA

Clinical case

• 64-year-old man diagnosed with PV at age 52

• Managed with phlebotomy alone for 8 years

• HU initiated due to increasing symptoms (pruritus) and frequency of phlebotomy to maintain Hct <45%

• Titrated HU to 1.5 g

• After 4 years, patient experienced leg ulcers

• HU discontinued following 8 months with problematic leg ulcer requiring visits to wound care

• How would you manage this patient’s PV?

• Therapy

“The choice of second-line myelosuppressive drugs for PV

should be carefully evaluated because some drugs

administered after hydroxyurea may enhance the risk of

acute leukemia”

Age, Vascular events Low risk High risk

Low dose aspirin

Age > 60 and/or

Vascular event

Cytoreduction

1st line: HU or IFNα

Management: 2011 ELN Recommendations

Barbui T, J Clin Oncol. 2011 Feb 20;29(6):761-70

• Second-line therapy

• Busulphan, and 32P are second-line therapies reserved for

patients with short life expectancy

• IFN alpha (off label)

Management: 2011 ELN Recommendations

Barbui T, J Clin Oncol. 2011 Feb 20;29(6):761-70

Advantages of IFNα in PV

Reduction of the MPN clone

Kiladjian JJ, Hematology Am Soc Hematol Educ Program. 2012;2012:561-6

M0 M12 M24 M36 M48 M60 M72

50%

100%

0

%V

61

7F


Clinical remissions without cytoreductive therapy

• 27% of patients in hematological CR off-therapy after

IFN discontinuation


26% stopped for toxicity immune disorder (n=2, auto-Abs) allergy (n=2) neutropenia (n=1) after 9 months depression, fatigue (n=1) after 14 months peripheral neuropathy (n=1) after 12 months liver enzyme elevation (n=1) after 12 months arthralgia (n=1) after 27 months

Kiladjian JJ, Hematology Am Soc Hematol Educ Program. 2012;2012:561-6


Clinical remissions without cytoreductive therapy

Reduce incidence of vascular events?

Alter natural history of MPN?

clinical-hematological CR

molecular CR

histopathological CR


peg-IFN-2a

Phase 2 (MPD-RC 111) ongoing

Phase 3 (MPD-RC 112) ongoing

Phase 3 in DK (DALIAH)

peg-IFN -2b (AOP 2014)

Phase 2 completed (PEGINVERA)

Phase 3 ongoing (PROUD-PV)

Ongoing studies of IFNα in PV

Ruxolitinib Proves Superior to Best Available Therapy in a Prospective, Randomized, Phase 3 Study (RESPONSE) in

Patients with Polycythemia Vera Resistant to or Intolerant Of Hydroxyurea

Alessandro M. Vannucchi,1 Jean-Jacques Kiladjian,2 Martin Griesshammer,3 Tamas Masszi,4 Simon Durrant,5 Francesco Passamonti,6 Claire N. Harrison,7 Fabrizio Pane,8 Pierre Zachee,9 Ruben Mesa,10 Shui He,11 Mark M.Jones,11 William

Garrett,11 Jingjin Li,12 Nathalie Francillard,13 Dany Habr,12 Srdan Verstovsek14

1University of Florence, Florence, Italy; 2Hôpital Saint-Louis et Université Paris Diderot, Paris, France; 3Johannes Wesling Clinic, Minden, Germany; 4St. István and St. László Hospital, Budapest, Hungary; 5Royal Brisbane & Women’s Hospital, Brisbane, Australia; 6Ospedale di Circolo e Fondazione Macchi,

Varese, Italy; 7Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 8University of Naples Federico II, Naples, Italy; 9ZNA Stuivenberg, Antwerp, Belgium

10Mayo Clinic Cancer Center, Scottsdale, AZ, USA; 11Incyte Corporation, Wilmington, DE, USA; 12Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 13Novartis Pharma S.A.S., Rueil-Malmaison, France;

14The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Vannucchi AM et al., EHA 2014 abst. LB2436

Conclusion – Second-line therapy

• There is no approved drug for second-line therapy in PV

• A concern for second-line therapy after HU is the cumulative

risk of leukemia with a second chemotherapy

• In patients intolerant or resistant to hydroxyurea, current

guidelines suggest the use of IFN-alpha

• However, there are some contra-indications and about 20% of

patients develop intolerance to IFN

• There is a need for new therapies, and ruxolitinib may be an

alternative second line therapy in selected patients

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