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

Report
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
abl
TYROSINE KINASE ACTIVITY
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%
• Common symptoms:
–
–
–
–
fatigue
weight loss/anorexia
Early satiety
asymptomatic in ~ 50%
• Accelerated Phase
and Blast crisis
More aggressive
disease with increased
blasts and poorer
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
Cumulative proportion surviving
1.0
0.9
0.8
CML Phase
Total
Dead
Chronic
Accelerated
Blastic
2449
479
285
1043
276
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
Years from referral
6
7
8
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
PV
ET
PMF
JAK2 V617F
Prevalence
97%
60%
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
phenotypes common with
latency period of decades
PV
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
Males: ≥36 mL/kg
2. White blood cell count
>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,
2.
headaches
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
N=405
N=283
20 years
ET
PV
PMF
AML
slide courtesy Dr.Alison Moliterno
N=57
Thanks
• Dr. Doug Smith and Dr.Alison Moliterno for
sharing slides and images

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