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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 2001 A1. 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
•
Kralovics o
•
Epo-independent growth characteristics of PV progenitors 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 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
target Hct < 0.45
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PV should be suspected in any patient with: • Increased hemoglobin/hematocrit in combination with 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) o
• • • • •
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
MCV
78
MCH
28
27-32 pg
MCHC
32
30-35 g/dL
reticulocyten
25
20-100
WBC
9.7
4-10 x 109/L
4.4-6.0 x 1012/L 76-96 fL
<0
promyelocyten
<0
myelocyten
2-5 %
metamyelocyten staven
2
segmenten
75
eosinofielen
1
2-5 % 38-75 % <6 % <1 %
basofielen lymfocyten
16
monocyten
3
20-50 % 2-10 150-450 x 109/L
bloedplaatjes
1378
ferritine
40
bilirubine totaal
0.9
<1 mg/dL
0.4
<0.5 mg/dL
direct CRP
2
LDH
640
13-150 µg/dL
<5 240-480 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 phenomenon
livedo 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 stratification Low 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 contraindication)
• low dose ASA
Intermediate risk
• treat C-V risk factors ‘aggressively’ • in some patients: BP reduction (decision on individual base)
• low dose ASA
High risk
• 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
MCV
78
MCH
28
27-32 pg
MCHC
32
30-35 g/dL
reticulocyten
10
WBC
26.7
4.4-6.0 x 1012/L 76-96 fL
20-100 4-10 x 109/L <0
promyelocyten
2
myelocyten
4
<0
metamyelocyten
3
2-5 %
staven
2
segmenten
68
eosinofielen
1
2-5 % 38-75 % <6 % <1 %
basofielen lymfocyten
16
monocyten
3
20-50 % 2-10
bloedplaatjes
98
150-450 x 109/L
ferritine
40
13-150 µg/dL
bilirubine totaal
0.9
<1 mg/dL
0.4
<0.5 mg/dL
direct
Man, 73 jaar Vermoeid, gewichtsverlies, pijn linker bovenbuik, forse hepatosplenomegalie
CRP
2
LDH
640
<5 240-480 U/L
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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
Transfusienood
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 o o
PV: 7%, resp 12-21% ET: 1-2%, resp 2-4% PMF: afhankelijk van risicofactoren (cytogenetica, <100x109/L trombocyten): 12-31%
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