Myeloproliferative

Disorders / Neoplasms
Intro for the Internist
Satish Shanbhag MBBS, MPH
Assistant Professor of Medicine and Oncology
Johns Hopkins University School of Medicine
 Objectives

Internist focused review of the presentation,

diagnostic workup, treatment and prognosis
of the common myeloproliferative neoplasms
Disclosures

• None
 Stem Cell Basis of Hematopoiesis

Stem cells

Progenitors

Blood

Normal Myeloproliferative
disease
 The Chronic Myeloproliferative Disorders

• Acquired hematopoietic stem cell disorders

characterized by overproduction of one or more
of the formed (mature) elements of the blood
• Complicated by bone marrow expansion,
extramedullary hematopoiesis (liver, spleen, l.n) ,
myelofibrosis and transformation to acute
leukemia
• Transition between phenotypes common with
latency period of decades
 The Big 4

• Chronic myeloid leukemia

• Polycythemia vera
• Essential thrombocythemia
• Primary myelofibrosis

• Chronic Eosinophilic leukemia

• Systemic Mastocytosis
Chronic Myeloid Leukemia

• Unregulated proliferation of myeloid cells in

the bone marrow and accumulation of these
cells in the blood
• Increased mature granulocytes (neutrophils,
eosinophils and basophils) and their
precursors in the blood
• Characteristic chromosomal translocation
called the Philadelphia chromosome
• Bcr-abl translocation detectable in the blood
by karyotyping, FISH or PCR.
 Ph Chromosome → bcr-abl gene
Chromosome 9 q+

Chromosome 9

Philadelphia Chromosome
(or 22q-)

Chromosome 22

bcr-abl

bcr
P 210 FUSION PROTEIN WITH CONSTITUTIVE
TYROSINE KINASE ACTIVITY
abl

Melo. Blood. 1996;88:2375.

Pasternak et al. J Cancer Res Clin Oncol. 1998;124:643.
Typical presentation of chronic phase CML
 CML: Clinical Presentation

• Chronic Phase ~ 85% • Accelerated Phase

and Blast crisis
• Common symptoms:
– fatigue More aggressive
– weight loss/anorexia disease with increased
– Early satiety blasts and poorer
– asymptomatic in ~ 50% prognosis

• Common signs:
– palpable splenomegaly
– basophilia
Faderl et al. Ann Intern Med. 1999;131:207. Goldman. Curr Opin Hematol. 1997;4:277.
 CML: Pre-Imatinib Survival
1.0
CML Phase Total Dead
Cumulative proportion surviving

0.9
Chronic 2449 1043
0.8 Accelerated 479 276
Blastic 285 219
0.7
0.6
0.5 5 mo 28 mo 71 mo

0.4
0.3
0.2
0.1
0
0 1 2 3 4 5 6 7 8
Years from referral
 Imatinib Mesylate –
Targeted therapy in cancer
• BCR-Abl tyrosine kinase enzyme exists only in clonal
cancer cells and not in normal patient cells

• Imatinib is a Tyrosine-kinase inhibitor which prevents the

BCR-Abl enzyme product from initiating the signalling
cascade necessary for cancer development, thereby
causing cancer cell apoptosis

• More ‘POTENT’ TKIs Nilotinib, Bosutinib, Dasatinib,

Ponatinib have subsequently been developed.

• Bone marrow / stem cell transplant for select patients

 Survival in newly diagnosed CP-CML by year of therapy.

Kantarjian H et al. Blood 2012;119:1981-1987

©2012 by American Society of Hematology

DASATINIB
JAK2 V617F in Myeloid Disease
One mutation, many phenotypes

Disease JAK2 V617F

Prevalence
PV 97%
ET 60%
PMF 60%
• Janus kinase 2 (JAK2), is a gene on the short
arm of chromosome 9 that encodes for a
cytoplasmic tyrosine kinase
• A mutation in the JAK2 gene leads to
constitutive tyrosine phosphorylation activity
that promotes hypersensitivity to cytokines /
growth factors and induces epo-independant
erythrocytosis.
Signal transduction lesions in the MPN

JAK2 G5073770T JAK2V617F

Scott, et al Lancet 2005

 JAK2V617F : phenotypes of disease

JAK2V617F

ET
Transition between PV
phenotypes common with
latency period of decades
PMF
 Bone Marrow Biopsy

Normocellular bone marrow

http://serpins.med.unc.edu/~fcc/Biology134_Folder/hem_cd/Large/05/0518.jpg
 Bone Marrow Biopsy

Hypercellularity and clustering of atypical

megakaryocytes
Polycythemia Vera
Why is he erythrocytotic?
 Polycythemia Vera

• Elevated totally body red cell mass; Hgb, Hct

are surrogate markers
• Rule out dehydration, epo driven erythrocytosis
• Chronic disease with median survival of > 15-20
years with current therapy
 Diagnostic Criteria for PV (PVSG)
Major criteria Minor criteria
1. Increased red cell mass 1. Platelet count >400,000/microL
2. White blood cell count
Males: ≥36 mL/kg
>12,000/microL*
Females: ≥32 mL/kg 3. Serum vitamin B12 >900 pg/mL
2. Arterial oxygen saturation ≥92 %
3. Splenomegaly

Low serum epo levels

JAK 2 V617F mutation
Pancytosis
Bone Marrow panmyelosis
 Objectives of therapy

1. Symptom control – prevent pruritus,

headaches
2. Prevent thromboses

1. Phlebotomy (goal Hct <45% men or <42% female )

2. Aspirin 81 mg po qd
3. Cytoreductive agents such as hydroxyurea
Essential Thrombocythemia
ET  secondary myelofibrosis
 Essential Thrombocythemia

• Chronic non-reactive thrombocythemia that

does not fit criteria for other MPNs
– Headache
– Syncope
– Atypical chest pain
– Livedo reticularis
– Erythromelalgia (burning pain of the hands or feet associated
with erythema and warmth)
• 60% patients positive for JAK2 V617F
 Treatment

• Young low risk patients may not need any

therapy or just a baby aspirin daily

• Higher risk patients (those with prior h/o clots or

elderly) benefit from cytoreduction with
Anagrelide or Hydroxyurea

n engl j med 353;1 july 7, 2005

 Thrombocytosis and
Acquired VW syndrome
 Primary Myelofibrosis
• Megakaryocyte proliferation and atypia, usually accompanied by
reticulin and/or collagen deposition in the marrow

• Demonstration of a clonal marker (eg, JAK2 or MPL)

• Leukoerythroblastosis on smear

• does not met criteria for other MPN

• Splenomegaly

• Anemia
Bone marrow in PMF

Modern Pathology (2012) 25, 1193–1202

 Blood smear in PMF

http://imagebank.hematology.org/Content%5C969%5C1180%5C1180_full.JPG
 PMF / secondary myelofibrosis

• PMF carries the worst prognosis among the

MPNs, although survival is still measured in
years
• PV and ET can show gradual progression to
secondary myelofibrosis over decades
 Therapies for PMF

• Bone marrow transplant is the only cure

• Ruxolitinib (JAK inhibitor) is a recently approved
drug for treating symptomatic PMF that also
reduces splenomegaly
• Hydroxyurea, Thalidomide and its derivatives
have also been studied but not FDA approved
 Hopkins500: Natural History

Diagnosis 10 years 20 years

ET
PV
PMF
AML

N=405 N=283 N=57

slide courtesy Dr.Alison Moliterno

 Thanks

• Dr. Doug Smith and Dr.Alison Moliterno for

sharing slides and images