Myeloproliferative disorders
• Clonal hematopoiesis (stem cell
disorder)
• Marrow hypercellularity
• Overproduction of one or more cell
lines (effective hematopoiesis)
– Exception: myelofibrosis
• Differentiation nearly normal
The “common” bcr-abl negative
myeloproliferative disorders
• Polycythemia vera
• Essential thrombocythemia
• Myelofibrosis/myeloid metaplasia
Less common conditions
•
•
•
•
•
Undifferentiated myeloproliferative disorder
Mast cell disease
Hypereosinophilic syndrome
Chronic neutrophilic leukemia
Myelodysplastic/myeloproliferative disorders
–
–
–
–
CMML
Atypical CML (BCR-ABL negative)
Juvenile CML
“Unclassifiable” MDS/MPD
JAK-2
• Tyrosine kinase involved in signaling pathways
initiated by EPO, TPO, G-CSF and other growth
factors
• V617F mutations in most cases of PV, ET, MF
– Other JAK-2 mutations (exon 12, etc) in a minority of PV
cases (almost all cases of PV have a JAK-2 mutation of
some type)
– Some cases of ET, MF lack JAK-2 mutation
• Mutation releases cells from dependence on growth
factors
• Homozygosity for mutation seen mainly in P vera,
associated with disease progression
• Specific inhibitors of the kinase now in clinical trials
Structure-function relationships in
the JAK2 receptor
Science 2014; 344:703
In Panel A, in the absence of ligand, the erythropoietin
receptor (EPOR) binds JAK2 as an inactive dimer. In
cells with wild-type JAK2 protein, the binding of
erythropoietin (Epo) to its receptor induces
conformational changes in the receptor, resulting in
phosphorylation (P) of JAK2 and the cytoplasmic tail of
the receptor. This leads to signaling through pathways
made up of Janus kinases and signal transducers and
activators of transcription (JAK–STAT),
phosphatidylinositol 3 kinase (PI3K), and RAS and
mitogen-activated protein kinase (RAS–MAPK). In cells
with the V617F mutation, the signaling is constitutively
increased, even in the absence of erythropoietin. In Panel
B, the JAK2 protein binds to multiple cytokine receptors
— EPOR, thrombopoietin receptor (MPL), granulocyte
colony-stimulating factor receptor (G-CSFR), and
probably others — that are important for hematopoietic
stem-cell biology and differentiation. Therefore, the JAK2
protein with the V617F mutation exerts its effects at
various stages of differentiation and in various lineages.
In Panel C, the development of homozygosity for the
V617F mutation is a two-step process, with the initial
point mutation followed by mitotic recombination of
chromosome 9p between the JAK2 locus and the
centromere. This results in the loss of heterozygosity but
a diploid DNA copy number.
NEJM 2006; 355:2452
NEJM 2006; 355:2452
Polycythemia vera
• Elevated RBC mass, typically high platelets
and WBC
– Some patients present with thrombocytosis and
develop erythrocytosis subsequently
• Hypercellular marrow with variable degree of
reticulin fibrosis
– Morphology fairly normal, some clustering and
dysmorphism of megas
• Splenomegaly in 70%, constitutional sx,
increased risk of arterial & venous
thrombosis (esp portal vein), microvascular
disease (erythromelalgia, pruritus, headache,
etc), hypermetabolic sx & gout
Differential diagnosis of erythrocytosis
• H&P
– COPD or other possible causes of
hypoxemia?
– Smoker?
– Splenomegaly, pruritus, erythromelalgia?
• Concomitant thrombocytosis and/or
leukocytosis?
• Serum EPO
• JAK-2 mutation testing
Polycythemia Vera
Natural History
• Life expectancy decreased (3 deaths/100
pts/yr)
• Cardiovascular mortality increased 1.4x
• Major thrombosis in 3/100pts/yr
• Risk of death from leukemia increased 36fold
• Progressive myelofibrosis
NEJM 2004; 350:99
NEJM 2004; 350:99
Oxygen delivery vs Hematocrit
180
Oxygen Transport
160
140
120
100
80
60
40
20
0
0
20
40
60
80
Hct
J Clin Invest 1963;42:1150
Vaso-occlusion in P vera
Thrombosis in myeloproliferative disorders
• 41% of deaths in PV from cardiovascular
causes
–
–
–
–
15% coronary dz
8% CHF
8% non hemorrhagic stroke
8% PE
• Complex pathophysiology
– Abnormal RBC/WBC/plt function
– Activated PMNs/cytokines affect vascular
endothelium
– Prothrombotic microparticle release
– Increased whole blood viscosity
Risk factors for thrombosis in
myeloproliferative disorders
• Hx of thrombosis
• Disease category (PV > ET, MF)
• Cardiovascular risk factors (lipids, blood pressure,
smoking, diabetes)
• Age
• OCP therapy (splanchnic vein clots)
• JAK2 mutation status/allele burden
• High hematocrit (PV) & WBC
– Extreme thrombocytosis increases bleeding risk
• Thrombophilic genetic traits?
Prothrombotic effects of erythrocytosis
Barbui et al. Blood 2013;122:2176-2184
Hematology 2005:201
Recommendations for treatment of
patients with polycythemia vera
•
•
•
•
Keep Hct < 45 (plebotomy)
Low dose ASA unless contraindicated
Manage reversible risk factors (BP, lipids, smoking)
Consider cytoreduction if:
– Intolerant to phlebotomy
– Thrombocytosis or substantial leukocytosis
– Symptomatic splenomegaly
• Choice of cytoreductive therapy:
– Age < 40: Interferon-alpha
– Age > 40: hydroxyurea
– Anagrelide or busulfan for patients intolerant of, or not
responsive to, above choices
Hematology 2005:201
Aspirin vs placebo in P vera
Essential thrombocytosis
• Thrombocytosis (typically > 600K) with
variable leukocytosis, normal RBC count
• About 50% have JAK2 mutation
• Normal to mildly hypercellular marrow with
marked increase in megakaryocytes, often
with clustering
• Minimal reticulin fibrosis
• Splenomegaly in about 50%
• Many patients asymptomatic at diagnosis
• Increased risk of arterial and venous
thrombosis as well as hemorrhage
Thrombocytosis
Differential diagnosis
• Essential thrombocythemia
• Other MPD
P vera
Myelofibrosis
CML
• Myelodysplasia (5q- et al)
• Reactive
Inflammation
Surgery/trauma
Non-myeloid malignancy
Iron deficiency
Hemolysis
Acute blood loss
Absence of spleen
Rebound following thrombocytopenia
Hematology 2005:201
Essential Thrombocytosis
Natural History
•
•
•
•
•
1-2 cases/100,000/yr
Most patients >50, but occurs in young adults
Woman more often affected than men
Life expectancy normal to slightly decreased
Patients > 60, or with prior thrombosis, at
increased risk for thrombotic events
• Very high platelet counts (>1.5 million) increase
risk of bleeding, not thrombosis
• Risk of myelofibrosis about 8% at 10 years
• Risk of AML about 1% overall
Essential Thrombocytosis
Treatment
• Low-risk patients (young, no vascular risk factors)
may not require treatment
• Aspirin decreases thrombotic events
• Hydroxyurea
• Anagrelide
• Interferon
• Other: busulfan (leukemogenic)
Recommendations for treatment of
patients with essential thrombocytosis
• Manage reversible risk factors (BP, lipids, smoking)
• If hx of thrombosis, or age >60, or plts > 1.5 million:
– Hydroxyurea
– Low dose ASA unless for plts > 1.5 m
– 2nd line: Anagrelide or interferon-alpha
• Age < 60, no other risk factors:
– Low dose ASA
Hematology 2005:201
Myelofibrosis
• 0.5-1.5 cases/100,000/yr
• Most patients >60
• Marrow fibrosis with extramedullary hematopoiesis
in spleen, liver, many other tissues
– “Prefibrotic” stage with hypercellular marrow &
abnormal megakaryocytes
• Peripheral leukoerythroblastosis, teardrop cells,
often with anemia. WBC and platelet counts may be
high, normal or low
• Splenomegaly, constitutional symptoms
• Poor prognosis: marrow failure, AML in 5-30%
Improving survival in MF
Median survival 6.5 yrs
Median survival 4.5 yrs
J Clin Oncol 2012;30:2981
DDx of Marrow Fibrosis
• Myeloproliferative disorders
• MF > > P vera, ET, CML
• Other heme neoplasm
• Megakaryocytic leukemia
• Hodgkins
• Hairy cell leukemia
• Non-heme cancer
• Non-malignant conditions
• Renal osteodystrophy
• Autoimmune disease
• Vitamin D deficiency
Mayo Clin Proc 2004;79:503
SPLENOMEGALY IN MYELOFIBROSIS
Myelofibrosis
Treatment
• Supportive care
– Transfusions
– Splenectomy
• Thalidomide/lenalidomide (low dose)
– Reduce transfusion requirements, reduce spleen size
• Chemotherapy (limited data; myelosuppression
often dose-limiting)
– Cladribine
– Azacytidine/decitabine
– Low dose cytarabine
• Marrow transplant in selected patients
• JAK inhibitor therapy: Ruxolitinib (inhibits JAK-1
and JAK-2)
Ruxolitinib treatment of myelofibrosis
Spleens shrink
Symptoms improve
Better survival
NEJM 2012;366:799
Eosinophilia
•
•
•
•
Non-clonal/secondary (common)
Clonal
Idiopathic hypereosinophilic syndrome
Familial (very rare)
Mild:
Moderate:
Severe:
AEC 500-1500
AEC 1500-5000
AEC > 5000
Hypereosinophilia
(AEC > 5000)
•
•
•
•
•
•
•
•
•
•
•
•
Parasitic infection
Drug reaction
Allergic gastroenteritis
Eosinophilic fasciitis
Churg-Strauss syndrome
Pulmonary eosinophilia
Eosinophilia-myalgia syndrome
IL-2 therapy
Hyper-IgE syndrome
AML
Eosinophilic leukemia
Hypereosinophilic syndrome
Clinical manifestations of
hypereosinophilia
• Skin: pruritus, angioedema, ulcers, papular or
nodular lesions
• Heart: endocardial fibrosis, valvular disease, mural
thrombi, cardiomyopathy, incr troponin
• Lungs: infiltrates, nodules, pleural effusion
• Neurologic: poly- or mononeuropathy, transverse
myelitis, optic neuritis, CNS vasculitis
• GI: hepatosplenomegaly, gastroenteritis, sclerosing
cholangitis
• Heme: marrow fibrosis, cytopenias
• Kidney: thrombotic microangiopathy
Secondary Eosinophilia
• Infection
– Usually parasitic
• Allergy
– Asthma, allergic rhinitis, dermatitis, urticaria/angioedema,
drug reaction
• Autoimmune/inflammatory disorders (many)
• Paraneoplastic
– Solid tumors, lymphomas (Hodgkin>NHL)
• Endocrinopathy
– Adrenal insufficiency, growth hormone deficiency
• Clonal T-cell disorder (→ IL-5)
Most cases with IL-5 overproduction
Clonal Eosinophilia
• Acute leukemia (AML>ALL)
• Chronic myeloid disorders
– CML (bcr-abl)
– Systemic mastocytosis (c-Kit)
– 8p11 myeloproliferative disorder (FGFR-1)
– PDGFRA and PDGFRB mutations
– “Classic” MPD (JAK-2)
– MDS
– Chronic eosinophilic leukemia
Clonal eosinophilic disorders caused by
mutations in tyrosine kinase genes
• PDGFRA, PDGFRB
– May be cytogenetically silent→ FISH testing for dx
– Marrow fibrosis, incr mast cells, elevated tryptase
→ variant of mast cell dz?
– Male predominance
– Imatinib-responsive (100-400 mg/d)
• FGFR1
– Associated with 8p11 translocations
– Stem cell disorder → aggressive MPD associated
with T-lymphoblastic lymphoma
– High dose chemotherapy + allo-HSCT
Chronic eosinophilic leukemia
WHO diagnostic criteria
•
•
•
•
•
•
Eosinophil count > 1500
No Ph chromosome or BCR-ABL fusion
No PDGFRB, PDGFRA or FGFR1 rearrangement
Blast count in blood and marrow < 20%
No inv (16) or other variant characteristic of AML
Presence of clonal cytogenetic or molecular
abnormality OR blasts >2% in blood or >5% in
marrow
Idiopathic Hypereosinophilic Syndrome
• Persistent moderate or severe eosinophilia (AEC >
1500) with end-organ damage
• Other causes of eosinophilia ruled out
• Male predominance
• Can evolve into overt myeloid or lymphoid neoplasm
• Potentially fatal – 10 yr survival < 50%
• Treatment
– Asymptomatic: corticosteroids vs watchful waiting
– Symptomatic patients: corticosteroids, IFNα, hydroxyurea,
imatinib, various myelosuppressive agents
Laboratory evaluation of
hypereosinophilia
•
•
•
•
Marrow biopsy with cytogenetics
FISH for PDGFR mutations
Serum tryptase
T-cell immunophenotyping and gene rearrangement
study
• Serum IL-5
• Serum IgE
• Screen for organ damage
– Echo, troponin level
– CXR, PFTs
Classification of Mast Cell Disease
WHO classification and frequency in Mayo Clinic series
• Indolent – often limited to skin (urticaria
pigmentosa (46%)
• Associated with myeloproliferative disorder
(40%)
• “Aggressive” mastocytosis – with
lymphadenopathy & eosinophilia (12%)
• Mast cell leukemia (1%)
Blood 2009;113:5727
WHO Diagnostic Criteria
for Mast Cell Disease
• Major: multifocal dense infiltrates of mast
cells (15+) in marrow or other
extracutaneous organs
• Minor
– >25% spindle shaped or otherwise atypical MC
– c-KIT codon 816 mutation
– MC in marrow or other extracutaneous organ
express CD2 and/or CD25
– Serum tryptase persistently >20 ng/ml in the
absence of another clonal myeloid disorder
Diagnosis requires major + 1 minor criterion or
at least 3 minor criteria
Stuff in mast cell granules that could
make you sick
Metcalfe, Blood 2008;112:946
Clinical & laboratory features of
mast cell disease
• Skin: Urticaria pigmentosa, Darier sign
(dermatographism), telangiectasias
• Lymphadenopathy
• Hepatosplenomegaly
• Constitutional symptoms
• Recurrent anaphylaxis
• GI symptoms (N/V, diarrhea, abd pain, peptic ulcer)
• Elevated serum/urinary histamine levels
• Elevated serum tryptase (96%)
• Cytopenias
• Eosinophilia
• Coagulopathy (heparin in mast cells) – rare
• Lytic or blastic bone lesions
ISM: Indolent MCD
SM-ANMD: associated with
clonal non-mast cell lineage
disease
ASM: Aggressive MCD
MCL: Mast cell leukemia
Blood 2009; 113: 5727
Mastocytosis in bone marrow
H&E
Tryptase
Mastocytosis in bone marrow
Skin findings in mast cell disease
Dermatographism
Urticaria pigmentosa
Telangiectasia macularis eruptiva perstans
Molecular biology of mast cell disease
• A majority of patients have D816V
mutation in c-KIT tyrosine kinase gene
(imatinib-insensitive)
– A minority have other mutations, may be
imatinib-sensitive
– Occasionally found together with JAK2 V617F
• Some patients have eosinophilia &
PDGFRA mutation (imatinib-responsive)
Treatment of mast cell disease
•
•
•
•
•
Antihistamines, PPIs
Vit D/Calcium, bisphosphonates
Glucocorticoids
Epinephrine (for anaphyactic reactions)
For aggressive disease:
– Interferon
– Imatinib (if there is an imatinib-sensitive mutation)
• Other TKIs (dasatinib, nilotinib)?
– Cladribine
– Combination chemotheapy
– Allo-HSCT
Survival of patients with MCD
Blood 2009; 113: 5727