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BCR-ABL NEGATIEVE MPN (PV,

ET, PMF): WANNEER MOETEN

WE ER AAN DENKEN?

Gregor Verhoef, Pentalfa sessie 19

november 2015

67 jarige vrouw

• Consultatie allergie ivm wisselende abdominale klachten

met lossere stoelgang.

• sinds 2 jaar hevige jeuk na nemen van warm bad

• Labo: Hb 17.8 g/dL

RBC 5.79 x 1012/L

Htc 0.54%

WBC 12.3 x 109/L

Trombo’s 513 x 109/L

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67 jarige vrouw

• Hb>16,5 g/dL

• JAK2V617F aanwezig

• Subnormale erythropoietine Spiegel

• (2 majeure, 1 minor criterium)

Diagnose van polythemia Vera

Clinical presentation PV• Incidence: 1.9/100.000 new cases per year, median age 60 years

• Male to female ratio: 2.8 versus 1.3

• Incidentally!

o Hb, Htc, WBC, Platelets, LDH

• Hypertension (46%)

• Pruritis (36%)

• Palpable spleen (36%)

• Erythromelalgia (29%)

• Arterial thrombosis (16%)

• Venous thrombosis (7%)

• Major hemorrhage (4%)

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Physical findings that suggest PV

• Injection of the conjunctival small vessels/engorgement of

the veins of the optic fundus

• Facial plethora

• Hepato/splenomegaly

• Excoriation of the skin (pruritis)

• Stigmata of a prior arterial or venous thrombotic event

• Gouty arhritis and tophi

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WHO criteria Polycythemia Vera 2001A1. rode bloedcel massa >25% boven gemiddelde, of Hb >18.5 g/dL (mannen) of >16.5 g/dl (vrouwen)

A2. Geen oorzaak voor secundaire polycythemie

1. niet familiair

2. geen EPO verhoging door

a. hypoxie (arterieel pO2 ≤92%)

b. hoge affiniteit Hb voor O2

c. getruceerde EPO receptor

d. EPO productie door tumor

A3. Splenomegalie

A4. clonale cytogenetische afwijkingen (geen t(9;22) of BCR-ABL fusie),

A5. endogene in vitro CFU-E vorming

B1. trombocytose >400 x 109/L

B2. leukocyten >12 x 109/L

B3. beenmergbiopt met prominente toename erytro- en megakaryocytaire reeks

B4. laag serum EPO

Nodig zijn: [A1 & A2 & A3/4/5] of [A1 & A2 & 2B criteria]

JAK 2 V617F

mutatie

• William Vainchenker:

o Epo-independent growth characteristics of PV progenitors

• Kralovicso Precise mapping of minimal 9p

loss of heterozygosity region

• Gary Gilliland and Green

o Analysis of tyrosine kinome

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WHO criteria Polycythemia Vera 2008

A1. rode bloedcel massa >25% boven gemiddelde, of Hb >18.5 g/dL (11.6 mmol/l)

(mannen) of >16.5 g/dl (10.3 mmol/l)(vrouwen) of Hb >17 g/dL (mannen) of >15 g/dl

(vrouwen) in combinatie met toename ≥2 g/dL niet toe te schrijven aan correctie Fe

tekort

A2. Aanwezigheid van JAK2V617F or vergelijkbare mutatie (JAK2 exon 12)

B1. endogene in vitro CFU-E vorming

B2. laag serum EPO

B3. beenmergbiopt met prominente toename erytro- en megakaryocytaire reeks

Nodig zijn: [A1 & A2 & één B] of [A1 & twéé B criteria]

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PV: risk stratification

Low risk - age below 60 years

- no history of trombosis

- absence of cardiovascular risk

factors (DM, smoking, cholesterol,

AHT ao.)

High risk - age 60 years or older

- history of thrombosis

PV: management

target Hct < 0.45

Low risk - flebotomy

- low dose ASA (75-100 mg/d if no

contra indication)

- manage C-V RF aggressively

High risk- flebotomy

- low dose ASA (75-100 mg if no C-I)

- cytoreductive therapy (HU of

IFNα)

- manage C-V RF aggressively

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PV should be suspected in any patient with:

• Increased hemoglobin/hematocrit in combination with

o In patients with Budd-Chiari syndrome or portal, splenic, or

mesenteric vein thrombosis (even with normal Hb/Htc)

• Splenomegaly

• Thrombocytosis and/or leukocytosis

• Thrombotic complications

• Erythromelalgia or pruritis

• Microvascular symptoms (headaches, visual disturbance,

parasthesias)

Labowaarden Referentiewaarden

Patiënt 60 jaar vrouw man

Hemoglobine 15 12-16 g/dL 14-18 g/dL

hematocriet 50 37-47 % 40-54 %

Rode bloedcellen 5.7 3.9-5.6 x 1012/L 4.4-6.0 x 1012/L

MCV 78 76-96 fL

MCH 28 27-32 pg

MCHC 32 30-35 g/dL

reticulocyten 25 20-100

WBC 9.7 4-10 x 109/L

promyelocyten <0

myelocyten <0

metamyelocyten 2-5 %

staven 2 2-5 %

segmenten 75 38-75 %

eosinofielen 1 <6 %

basofielen <1 %

lymfocyten 16 20-50 %

monocyten 3 2-10

bloedplaatjes 1378 150-450 x 109/L

ferritine 40 13-150 µg/dL

bilirubine totaal 0.9 <1 mg/dL

direct 0.4 <0.5 mg/dL

CRP 2 <5

LDH 640 240-480 U/L

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ET: beenmerg

Patient 60 jaar, trombocytose

• Trombocyten> 450 x 109/L

• CALR mutatie aanwezig

• Beenmergbiopt: suggestief voor ET

• Geen WHO criteria voor PV, IMF, CML, MDS of andere

entiteit

Diagnose van essentiële trombocytemie

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Clinical aspects ET• Incidence: 2.5 new cases/100.000, median age 60 years

• Female to male ratio: 2:1

• 50% asymptomatic

• 40 % vasomotor symptoms

o Headache

o Syncope

o Atypical chest pain

o Acral paresthesia

o Livido reticularis

o Erythromelalgia

o Transiant visual disturbances

• Thrombosis (18%) and hemorrhage (26%), major resp. 7 and 4%

ET and skin lesions

erythromelagia acrocyanosis

Raynaud’s

phenomenonlivedo

reticularis

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WHO criteria Essentiële Trombocytemie 2008

Proposed criteria

1. Trombocyten ≥450 x 109/L

2. Beenmergbiopt met voornamelijk megakaryocytaire toename met

atypische grote megakaryocyten. Geen belangrijke afwijkingen aan rood en

wit

3. Voldoet niet aan WHO criteria PV, IMF, CML, MDS of andere entiteit

4. Aanwezigheid van JAK2V167F of andere clonale merker, of, in

afwezigheid van clonale merker geen aanwijzingen voor secundaire

trombocytose

Voor diagnose ET zijn alle vier criteria noodzakelijk

ET: risk stratificationLow risk - younger < 60 yr

- no history of thrombosis

- BP < 1500000/µl

Intermediate risk- no ‘clear cut’ definition (not low, not

high)

- ‘operational definition’: low risk

patients with one or more of the

following risk factors: CV disease,

diabetes, smoking, hypertension,

familial thrombophilia, ea.

High risk - older > 60 yr

- history of thrombo-embolic event(s)

- BP > 1500000/µl

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ET: management

Low risk • low dose ASA (if no contra-

indication)

Intermediate risk• low dose ASA

• treat C-V risk factors

‘aggressively’

• in some patients: BP reduction

(decision on individual base)

High risk • low dose ASA

• reduce BP to < 400000/µl

• treat C-V risk factors

Labowaarden Referentiewaarden

Patiënt 60 jaar vrouw man

Hemoglobine 9.8 12-16 g/dL 14-18 g/dL

hematocriet 32 37-47 % 40-54 %

Rode bloedcellen 3.8 3.9-5.6 x 1012/L 4.4-6.0 x 1012/L

MCV 78 76-96 fL

MCH 28 27-32 pg

MCHC 32 30-35 g/dL

reticulocyten 10 20-100

WBC 26.7 4-10 x 109/L

promyelocyten 2 <0

myelocyten 4 <0

metamyelocyten 3 2-5 %

staven 2 2-5 %

segmenten 68 38-75 %

eosinofielen 1 <6 %

basofielen <1 %

lymfocyten 16 20-50 %

monocyten 3 2-10

bloedplaatjes 98 150-450 x 109/L

ferritine 40 13-150 µg/dL

bilirubine totaal 0.9 <1 mg/dL

direct 0.4 <0.5 mg/dL

CRP 2 <5

LDH 640 240-480 U/L

Man, 73 jaar

Vermoeid, gewichtsverlies,

pijn linker bovenbuik, forse

hepatosplenomegalie

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PMF bloed: teardrop cells, erytroblast

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Proposed criteria for PMF WHO 2008

Proposed criteria for PMF

Major criteria

1. Presence of megakaryocyte proliferation and atypia, usually accompanied by either

reticulin and/or collagen fibrosis, or, in the absence of significant reticulin fibrosis, the

megakaryocyte changes must be accompanied by an increased bone marrow cellularity

characterized by granulocytic proliferation and often decreased erythropoiesis

2. Not meeting WHO criteria for PV, CML, MDS or other myeloid neoplasm

3. Demonstation of JAK2V167F or other clonal marker (MPL515W>L/K), or in the

absence of a clonal marker, no evidence of bone marrow fibrosis due to underlying

inflammatory or other neoplastic diseases

Minor criteria

1. Leukoerythroblastosis

2. Increase in LDH

3. Anemia

4. Palpable splenomegaly

Diagnosis of PMF requires meeting all three major criteria and two minor criteria

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Clinical manifestations

• Incidence: 1.5 per 100.000, median age 67 years

• Severe fatigue (60%)

• Symptoms due to large spleen (40%)

• Weight loss, fever, bone pain, night sweats (15%)

• Pruritis (16%)

• Asymptomatic (20%), then presentation with

splenomegaly, hepatomegaly or abnormal blood findings

• Thrombotic event during or prior diagnosis: 13%

Clinical manifestations

• Splenomegaly 80%

• Hepatomegaly 55%

• Extramedullary hematopoiesis other than hepatosplenomegaly:

o In or surrounding vertebral column

o Lymph nodes

o Retroperitoneum

o Lungs or pleura

o Genitourinary system

o Skin

o Other

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Laboratory findings

• Anemia < 10 g/dL: 50% (<8 g/dL: 20%)

• Marked eucocytosis (11%) and thrombocytosis (13%)

• Leukopenia (8%) and thrombocytopenia (26%)

• Leukoerythroblastic blood picture

• AF, LDH, uric acid, vitamin B12

Prognostische scoreberekeningssystemen voor primaire

myelofibrose

Prognostic

score

leeftijd Hb (g/dL) WBC Blast pb Constitutionele

symptomen

Trombo’s karyotype Transfusie-

nood

IPSS >65 jr

1 punt

<10

1 punt

>25

1 punt

≥1%

1 punt

+

1 punt

NG NG NG

DIPSS >65 jr

1 punt

<10

2 punten

>25

1 punt

≥1%

1 punt

+

1 punt

NG NG NG

DIPSS Plus DIPSS laag risioc: 0 punten

DIPSS intermediair-1: 1 punt

DIPSS intermediair-2: 2 punten

DIPSS hoog risico: 3 punten

<100

1 punt

Ongunstig:

1 punt

Afhankelijk

1 punt

IPSS risicogroep Score Mediane overleving

Laag risico 0 135

Intermediair-1 1 95

Intermediair-2 2 48

Hoog risico >2 27

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PMF should be suspected in any patient with:

• Splenomegaly and leukoerythroblastic blood picture

• Pre-fibrotische PMF blijft een uitdaging. Vooral de

expertise van de patholoog kan richting geven

(beoordeling megakaryocyten met dd ET versus PMF

• nauwkeurige opvolging en herhalen van beenmerg

PV, ET en PMF

• Leukemische ontaarding en post-MF

o PV: 7%, resp 12-21%

o ET: 1-2%, resp 2-4%

o PMF: afhankelijk van risicofactoren (cytogenetica,

<100x109/L trombocyten): 12-31%