Myeloproliferative Neoplasms

Myeloproliferative neoplasms

a group of disorders characterized by autonomous proliferation of One or more hematopoietic elements in the Bm that foten progress to acute leukemia. The One is criteria

Essential thromobcythemia etiology

multiple mutations in stem cells
affects platelet production and function
rarely produces leukemic transformation

Essential thromobcythemia clinical features

>50Yo in men and 20-30yo in women
asymptomatic in 20%
Thrombocytosis
peripheral arterial occlusions
Bleeding
splenomegaly

Essential thromobcythemia peripheral blood

Must be >400,000
giant platelets, fragments and clumps
sometimes a moderate increase in WBC 20,000-30,000
occasional left shift with basophilia and eosinophilia
Mild anemia
HJB, NRBC and poiki

Essential thromobcythemia bone marrow

hypercellular with increased megakaryocytes
increased mitotic form, erythroid and myeloid elements
normal iron
no fibrosis
Ph1 negative

Essential thromobcythemia special tests

abnormal platelet aggrgation
prolonged time
normal to increased LAP
JAK2 in 40-60%

Essential thromobcythemia prognosis

>50yo = 50% live 5 years - die from thrombosis or bleeding
<50yo = excellent prognosis but can convert to PV, PMF, or AML

Essential thromobcythemia treatment

plateletpheresis
anticoagulants
radiation and/or chemo if it progresses

Polycythemia

a diverse group of disorders with increased RBCs

Polycythemia vera

a chronic, clonal disorder characterized by uncontrolled proliferation of predominantly erythroid cells
leukocytosis 66% of the time and thrombocytosis 50%

Polycythemia vera pathogenesis

multiple. mutations in MSC →JAK2 (others) → RBC expansion (increased RBC mass) → decrease or absent erythropoietin → middle aged to elderly men predominantly

Polycythemia vera clinical features

increased RBC mass → red face, headaches, dizziness, blurred vision, ringing ears → peripheral cyanosis (thick blood) → thromboembolism → hepatosplenomegaly → bleeding

Polycythemia vera peripheral blood

increased RBC, Hb, Hct
increased RBC mass with normal to increased plasma volume
Normo/normo with slight poiki and aniso
increased EBC with few meta/myelo, moderate basophilia
increased platelets (50%) and sometimes abnormal morphology

Polycythemia vera bone marrow

hypercellular with decreased iron
Ph1 negative but >95% have JAK2 mutation
Increased/normal LAP, increased uric acid → gout

Polycythemia vera treatment

Phlebotomy until Hct ≤50%
Repeat monthy/bimonthly → induce iron deficiency anemia
chemo if progresses

Polycythemia vera prognosis

15-20% spent → anemia → PMF and 15% develop leukemia
rest experience thrombi and hemorrhage

Primary Myelofibrosis etitology

multiple mutations in multipotential stem cell
unknown but acquired with benzene or radiation

Primary Myelofibrosis pathogenesis

myeloid proliferation (Neutrophils)
no mutation in fibroblasts but they proliferate in BM

Primary Myelofibrosis Clinical features

occurs between 60-70 yo
anemia → weakness, fatigue dyspnea, pallor
high plt → normal → thrombocytopenia/dysfunction → bleeding
extramedullary hematopoiesis (Kidney, LN) → hepatosplenomegaly
weight loss → anemia → thrombocytopenia → organomegaly → death
osteosclerosis from firboblast proliferation in BM

Primary Myelofibrosis peripheral blood

increased WBC early → can become normal or low
Left shift, <5% blasts with eosinophilia and basophilia
normo/normo anemia → iron deficiency
TEAR DROPS, Ell, BS, Retics, NRBCs
Plt → normal, high or low → giant, hypogranular → dwarf megakaryocytes

Primary Myelofibrosis bone marrow

usually a dry tap from increased fibrosis
islands of hematopoiesis
increased megakaryocytes with abnormal morphology (may drive fibrosis)

Primary Myelofibrosis Special tests

LAP = increased, normal or decreased
Ph1 negative
Prolonged bleeding time and abnormal aggregation
JAK2 in 40-60%

Primary Myelofibrosis prognosis

50% survive 5 years
35% from cardiovascular disease
25% from hemorrhage
15% from infection

Primary Myelofibrosis treatment

transfusions → EPO/G-CSF → splenectomy → prednisone → alkylating agents

CML indicence

20% of all leukemias
all ages, increased incidence in middle age, slighly favors men

CML Pathogenesis

Ionizing radiation
Alkylating agents
Toxins
Acquired mutation (Single mutation carcinogenesis) → philadelphia chromosome

Philadelphia Chromosome

discovered by Nowell/Hungerford 1960
t(9;22) WHO diagnostic criteria
BCR/ABL1 fusion gene → increased tyrpsine kinase activity → increased phosphorylation → constitutive protein activation → increased proliferation → decreased apoptosis → decreased differentiation → decreased adhesion

22q-

Ph1 chromosome
22/9
“short 22”

CML stage 1

chronic phase
6.3 years
asymptomatic (minimal) proliferative stage)

CML stage 2

accelerated phase
8 years
additional mutations
symptomatic

CML stage 3

blast crisis
weeks to months
acute leukemia

CML chronic phase symptoms

mild anemia (malaise, fever, fatigue)
high cell turnover (sweating, weight loss, aching bones)

CML Accelerated phase → blast crisis symptoms

chocking RBCs
choking platelets (bleeding, retinal hemorrhages, hematuria)
choking WBCs (infection)
high cell turnover (gouty arthritis, hepatosplenomegaly)

CML peripheral blood

increased WBC (75% > 100,000)
no to mild anemia
Deep left shit (Meta, myelo, pro)
occasional blast
basophilia, eosinophilia
thrombophilia - large platelets

CML bone marrow

increased M:E ratio (10:1 to 50:1)
Ph1
All stages of myeloid maturation

CML other lab findings

decreased LAP
increased uric acid and LDH

CML poor prognosis

splenomegaly
Increased WBC > 100,000
increased blasts (>1 in PB or >5% in BM)
extreme basophilia
extreme thrombocytosis
thrombocytopenia
abnormal karyotypes other than Ph1

Former therapy for Chronic phase CML

melphan (alkeran)
Busulfan (alkylating agent)
Hydroxyura
dibromomannitol

Former therapy for accelerated or blast crisis phase CML

aggressive chemo to achieve remission
cytosine arabinoside + thioguanine

Bone marrow transplant for CML

succeful before blast crisis, semi-successful after

Tyrosine kinase inhibitor

CML current therapy
gleevec 400 mg daily
discovered 1999 and FDA approved in 2001

Gleevec resistance

raise dose to 600-800 mg/day
dasatinib or nilotinib

Blast crisis

chemo is unsuccessful (mean survival = 10 weeks)
Gleeves is semi-successful

ET

Platelets - +++ increased
RBC, Hbg, Hct - normal/low
WBC - normal/high
Immatire Neut - Rare
LAP - Normal/increased
Ph1 - Absent
Spleen Size - Normal/increased 
BM fibrosis - absent/increased
JAK2 - 50%

PV

Platelets - increased (50%)
RBC, Hbg, Hct - +++ increased
WBC - increased (66%)
Immatire Neut - none
LAP - normal/increased
Ph1 - Absent
Spleen Size - increased
BM fibrosis - absent/increased
JAK2 - >95%

PMF

Platelets - increased/decreased/normal
RBC, Hbg, Hct - decreased
WBC - + - ++ increased
Immatire Neut - ++ increased
LAP - increased/decreased/normal
Ph1 - absent
Spleen Size - increased
BM fibrosis - +++ increased
JAK2 - 50%

CML

Platelets - increased or decrease
RBC, Hbg, Hct - normal/low
WBC - +++ increased
Immatire Neut - +++ increased
LAP - decreased
Ph1 - present
Spleen Size - increased
BM fibrosis - absent/increased
JAK2 - negative

CNL

Definition - neutrophilia, no infection, not CML
Prevalence - rare
Genetics - CSFR3 gene, Ph1 neg
Labs - neutrophilia > 25 (>80% segs)
Treatment - Chemo, JAK2 inhibitor, BMTx
Prognosis - poor without treatment

CEL

Definition - eosinophilia, not reactive, not PDGFR
Prevalence - very rare, M:F 9:1
Genetics - r/o PDGFRA, PDGDFRB, FGFR1
Labs - Leukocytosis > 30, eosinophilia
Treatment - steroids, chemo, TKI, Tx
Prognosis - slow progression

JMML

Definition - Neutrophilia, monocytosis, children
Prevalence -rare
Genetics - RAS genes (NRAS, KRAS, PTPN11)
Labs - Neutrophila, monocytosis, thrombocytopenia
Treatment - chemo then BMTx
Prognosis - Poor without transplant

MPN-U

Definition - does not meet any MPN
Prevalence - 20% of MPNs
Genetics - PH1 neg, BCR:ABL1 neg
Labs - variable
Treatment - varies
Prognosis - Ph1 - CML, early MPN, fibrotic MPNs

Myeloid/Lymphoid Neoplasms with eosinophilia

either lymphoid ot myeloid proliferation
Leukocytosis with eosinophilia
defined by rearrangement of genes that activate tyrosine kinases
affects m,ales more often
7 types

3 primary mutations that drive Myeloid/Lymphoid Neoplasms with eosinophilia

PDGFRA, PDGFRB, FDGF1

Secondary Myeloid neoplasms

develops because of
cytotoxic therapy
Down’s syndrome
germline predisposition