Myeloproliferative
Neoplasms 2015
Robert J. Jacobson MD, FACP , FRCP(C).
Florida Cancer Specialists
Affiliate Professor of Biological Sciences
Charles E. Schmidt School of Medicine
Florida Atlantic University, Boca Raton, FL
1
Stem Cells and
Hematopoietic Differentiation
• Hematopoietic stem
cells capable of
– Self-renewal
– Differentiation
• Differentiation and
proliferation
controlled by
molecular signals
– Contact with stromal
cells in bone marrow
– Growth factors
2
Myeloproliferative Neoplasms (MPN)
- Clonal Hematopoietic stem cell diseases
- Overproduction of terminally differentiated
cells of the myeloid lineage
• Ph+ Chronic Myeloid Leukemia (CML)
• Polycythemia Vera (P. Vera)
• Essential Thrombocythemia (ET)
• Primary Myelofibrosis (PMF)
3
CML Epidemiology and Etiology
 In the US, there were 4,870 cases in 2010 and an
expected 5,430 cases in 2012
 15% of all adult leukemias
 Incidence increases significantly with age
– Median age: ~ 67 years
– Prevalence increasing due to current therapy
– Most patients present in CP
 Majority of CML-related deaths due to progression to
AP/BC
– 50% of CML patients are asymptomatic at diagnosis
 Risk factors
– Radiation exposure
4
Most CML Patients Are Diagnosed in
the Chronic Phase
Chronic Phase 80%
Blast Phase 10%
5
CML with Philadelphia Chromosome
t (9; 22)
6
CML Pathogenesis:
Philadelphia (Ph) Chromosome
 CML first cancer demonstrated to have underlying genetic
abnormality
• Associated with Ph chromosome
 Result of translocation between chromosomes 9 and 22
 Detected in approx. 95% of patients with CML
7
Clinical Presentation of Ph+ CML
8
Treatment of CML
• Imatinib (Gleevec), developed by Dr. Brian Druker at
Oregon Health & Sciences University and Novartis
pharmaceutical company in mid-1990.
• Also found to be effective in other blood cancers and
GIST by inhibiting different TK proteins.
• World-wide sales now $28 billion in the 10 years from
2001-2011.
• Now 4 drugs, second generation tyrosine kinase
inhibitors available to treat CML.
• Drugs continue throughout life.
9
Imatinib Mechanism of Action
10
Treatment of CML
• 4 Targeted drugs which block the action of tyrosine
kinase (TKIs):
– Imatinib (Gleevec)
– Dastinib (Sprycel)
– Nilotinib (Tasigna)
– Bosutinib (Bosulif)
• Side Effects
– Skin rash
– Fluid retention
– Diarrhea
– Vascular thrombosis
• Omacetaxine (Synribo) or Homoharringtonine
(alkaloid) approved use when 2 TKIs have failed
11
Event-Free Survival and Survival
Without AP/BC on First-Line Imatinib
12
Survival Rates for Stem Cell
Transplantation
13
‘Inverted Iceberg’ Schematic of CML burden
and reduction over time.
14
CML Treatment Cessation of TKIs
• If relapse occurs, it develops within the first 6 months
after the treatment stopped
• About 40%—50% of patients have no recurrence if
their initial leukemic burden was low and they had
been on treatment for a long duration (> 10 years)
• Ongoing studies investigating second generation TKIs
e.g. nilotinib and achieving more rapid MMR > 4 – 5
logs
• Current recommendation is to continue with TKI
treatment for life
• Patients may not be able to tolerate TKI and alternative
drug chosen
15
Ph Negative MPN
Majority of the patients have the gene mutation
JAK2V617F
• Polycythemia vera
• Essential Thrombocythemia
• Primary Myelofibrosis
16
Diagnosis of Polycythemia Vera
Major Criteria
1. Hgb level > 18.5 g/dL in men, >16.5 g/dL in women
2. Presence of the JAK2V617F mutation (in 95% of patients)
Minor Criteria
1. Bone marrow biopsy showing hypercellularity
2. Serum Epo level below normal range
3. Endogenous erythroid colony formation in vitro
PV is likely if:
A. Both major criteria and at least 1 minor criterion are met, or
B. First major criterion and at least 2 minor criteria are met
Epo = erythropoietin; Hgb = hemoglobin; JAK = Janus-associated kinase; PV= polycythemia vera
17
Clinical Features of P. Vera
• Fever, weight loss
• Pruritis
• Plethoric facies
• Cyanosed digits
• Splenomegaly
• Thrombotic events
• Transformation to
leukemia
• Myelofibrosis
18
JAK2V617F and STAT Pathways
19
Treatment of Polycythemia Vera (PV)
•
•
•
•
•
Control and maintain Hct levels <45%
Manage disease-related complications of PV
Phlebotomy to maintain Hct levels <45%
Low-dose aspirin in appropriate patients
Hydroxyurea or IFNα as first-line cytoreductive
therapy at any age
• Patients with inadequate response to or
intolerance of HU use Ruxolitinib (Jakifi) JAK2
inhibitor
Hct = hematocrit; HU = hydroxyurea; IFNα = interferon- α
20
Essential Thrombocythemia
• Elevated platelet count often in excess of 1
million/dL, RBC and WBC normal
• JAK2V617F mutation in 50% of patients
• Thrombosis/hemorrhagic complications
• Splenomegaly can develop, especially if
transformation to Myelofibrosis (MF)
• Low dose aspirin, anegrelide, hydroxyurea used
• Clinical trials underway with JAK2 inhibitors
• Patients can live >10 years
21
JAK2 and Other Mutations in MPN
22
Myelofibrosis with
Myeloid Metaplasia
• JAK2 mutation in 60% of patients
• Myelofibrosis is a clonal
hematologic malignancy with
reactive marrow fibrosis
• Primary myelofibrosis, or PMF, entered the scientific
discourse in 1879 with varied nomenclature
–Agnogenic myeloid metaplasia
–Myeloid metaplasia with myelofibrosis
–Chronic idiopathic myelofibrosis
• Patients with an antecedent diagnosis of PV or ET are
diagnosed with PPV-MF or PET-MF
23
Peripheral Blood and Bone Marrow in Myelofibrosis
Red blood cells, tear-drop shape
Bone marrow fibrosis
A leukoerythroblastic blood smear
Reticulin stain of marrow
24
Understanding Myelofibrosis
• Myelofibrosis can be risk stratified by:
low risk intermediate risk 1 & 2  high risk
–Bone marrow fibrosis
–Symptom burden
–Splenomegaly
–Cytopenias
• Although the exact cause of myelofibrosis is unknown,
multiple mechanisms are key features of the disease
–Genetic mutations: JAK2, CALR and MPL
–Excessive production of cytokines
–Increased JAK1 signaling
25
Cytokines Play a Key Role
in Myelofibrosis
26
Overactive JAK-STAT Signaling is
Present in all Patients with Myelofibrosis
27
Clinical Relevance of the Progressive
Pathology of Myelofibrosis
28
Diagnosing primary Myelofibrosis:
All major criteria plus ≥2 minor WHO criteria are required for diagnosis
29
Risk Stratification in Myelofibrosis
30
Burden of Disease:
Symptoms of Myelofibrosis
31
Examining the causes of mortality in PMF
32
Diagnosing PPV-MF or PET-MF
33
Geyer and Mesa, ASH 2014
34
Myelofibrosis
Status
Agent
↓
↓
↑
Spleen Const. HB
Sympt
.
+++
+++
-
Approved
Ruxolintinib
(MF)
(INCB18424)
Phase III (PV)
Phase III (MF) Pacritnib+++
(SB1518)
Phase III (MF) Momelotinib +++
Phase II
(CYT387)
(PV/ET)
Polycythemia Vera
↑
↓
↓
SURV Phleb Const.
Sympt
.
++
+++
+++
+++
-
Unk
+++
-
Unk
Unk
Unk
↓
Vasc
Event
s
Unk
Unk
35
Summary & Conclusions
• Myeloproliferative neoplasms are characterized
by distinct and specific genetic findings and
clinical presentations
• The translocation t(9:22) and mutation
JAK2V617F are responsible for the abnormal
clonal production of cells derived from the
myeloid lineage
• Therapies are now available directed against the
specific tyrosine kinases (BCR-ABL) or genetic
pathways (JAK-STAT) that cause the uncontrolled
marrow cellular growth
36