MYELOPROLIFERATIVE
NEOPLASMS
October 2014
ANGELA FLEISCHMAN
DIVISION OF
HEMATOLOGY/ONCOLOGY
MPN ARE CLONAL DISORDERS OF THE
HEMATOPOIETIC STEM CELL
Polycythemia
Vera
(PV)
Red Cells
Essential
Thrombocythemia
(ET)
Myelofibrosis
(MF)
Platelets
Marrow Fibrosis
Hematopoietic
stem cell (HSC)
JAK2V617F mutation
CALR mutation
MPN ARE CLONAL DISORDERS OF THE
HEMATOPOIETIC STEM CELL
Polycythemia
Vera
(PV)
Red Cells
Hematopoietic
stem cell (HSC)
JAK2V617F mutation
MPN ARE CLONAL DISORDERS OF THE
HEMATOPOIETIC STEM CELL
Essential
Thrombocythemia
(ET)
Platelets
Hematopoietic
stem cell (HSC)
JAK2V617F mutation
MPN ARE CLONAL DISORDERS OF THE
HEMATOPOIETIC STEM CELL
Myelofibrosis
(MF)
Marrow Fibrosis
Hematopoietic
stem cell (HSC)
JAK2V617F mutation
MOLECULAR DEFECTS IN
CLASSICAL MPNS
• JAK2 mutations (PV 96%, ET 30-50%, PMF 50%,
Blast phase MPN 50%
• CALR (calreticulin) ( 25%-35% of patients with ET and
PMF, 67-88% among JAK2 negative patients)
• BCR-ABL (CML 100%)
• Others:
– MPL mutations
– TET2 mutations
– ASXL1 mutations
– CBL mutations
– IDH1/2 mutations
– IKZF1 mutations
– LNK mutations
ACTIVATION OF EPO-RECEPTOR
(NORMAL)
P
P
JAK2
JAK2
P
P
Stat5 Stat5
P
P
Stat5 Stat5
P
P
X
Gene Transcription
ACTIVATION OF EPO-RECEPTOR
(JAK2 V617F )
P
P
JAK2V617F
JAK2V617F
P
P
Stat5 Stat5
P
P
Stat5 Stat5
P
P
X
Gene Transcription
PATIENT R.M.
•
•
•
•
•
•
59 yo man with 6 month history of itchy skin, headache
CBC reveals WBC 15.0 Hct 60% Plt 600K
Exam: obese, reddish skin, spleen tip felt, otherwise normal
PMH: none
SH: smokes
FH: father died of leukemia
PATIENT R.M.
•
•
•
•
•
•
59 yo man with 6 month history of itchy skin, headache
CBC reveals WBC 15.0 Hct 60% Plt 600K
Exam: obese, reddish skin, spleen tip felt, otherwise normal
PMH: none
SH: smokes
FH: father died of leukemia
REFERRED TO HEMATOLOGY
WHAT DO YOU DO NEXT?
PATIENT R.M.
• Serum Epo is low
• JAK2V617F mutation is present (allele burden 45%)
• Bone marrow biopsy shows hypercellular marrow, trilineage
myeloproliferation, no increased fibrosis
PATIENT R.M.
• Serum Epo is low
• JAK2V617F mutation is present (allele burden 45%)
• Bone marrow biopsy shows hypercellular marrow, trilineage
myeloproliferation, no increased fibrosis
DIAGNOSIS?
PATIENT R.M.
• Serum Epo is low
• JAK2V617F mutation is present (allele burden 45%)
• Bone marrow biopsy shows hypercellular marrow, trilineage
myeloproliferation, no increased fibrosis
DIAGNOSIS?
Polycythemia Vera
PATIENT R.M.
• Serum Epo is low
• JAK2V617F mutation is present (allele burden 45%)
• Bone marrow biopsy shows hypercellular marrow, trilineage
myeloproliferation, no increased fibrosis
DIAGNOSIS?
Polycythemia Vera
TREATMENT?
PATIENT R.M.
• Serum Epo is low
• JAK2V617F mutation is present (allele burden 45%)
• Bone marrow biopsy shows hypercellular marrow, trilineage
myeloproliferation, no increased fibrosis
DIAGNOSIS?
Polycythemia Vera
TREATMENT?
ASA (81mg/day) and phlebotomize to Hct <45%
Encourage weight loss and smoking cessation
POLYCYTHEMIA VERA
Diagnosis
Standard
Therapies
WHO CRITERIA FOR POLYCY THEMIA VERA
REQUIRES MEETING EITHER BOTH MAJOR CRITERIA AND ONE
MINOR CRITERIA OR THE FIRST MAJOR CRITERIUM AND 2 MINOR
CRITERIA
MAJOR CRITERIA:
1. HEMOGLOBIN > 18.5G/DL IN MEN, >16.5 G/DL IN WOMEN, OR
EVIDENCE OF INCREASED RED CELL VOLUME
2. PRESENCE OF JAK2V617F MUTATION OR OTHER FUNCTIONALLY
SIMILAR MUTATION (EG., EXON 12 MUTATION)
MINOR CRITERIA:
1. BM BIOPSY SHOWING HYPERCELLULARIT Y FOR AGE WITH
TRILINEAGE MYELOPROLIFERATION
2. SERUM EPO BELOW REFERENCE RANGE
3. ENDOGENOUS ERY THROID COLONY FORMATION IN VITRO
THERAPEUTIC GOALS IN PV
PREVENT THROMBOSIS
CONTROL DISEASE-RELATED SYMPTOMS
TREATMENT STRATEGIES
Reduction of CV risk factors
Antiplatelet therapy (aspirin)
Phlebotomy (goal hct <45%)
Cytoreduction (hydrea)
ALL PATIENTS
HIGH RISK PATIENTS
(age >60 or prior thrombosis)
PATIENT S.S.
65 yo woman found to have a plt count of 700K
on 2 consecutive yearly exams
Reactive?
Primary (ET)?
CAUSES OF THROMBOCY TOSIS
Myeloid malignancy
Essential thrombocythemia
Po l yc y t h e m i a ve r a
P r i m a r y mye l o fi b r o s i s
C h r o n i c mye l o i d l e u ke m i a
Re f r a c t o r y a n e m i a w i t h r i n g e d s i d e r o b l a s t s a n d t h r o m b o c y t o s i s
M ye l o d y s p l a t i c s y n d r o m e a s s o i c a t e d w i t h i s o l a te d d e l ( 5 q )
Reactive (secondar y thrombocytosis
B l o o d l o s s o r i r o n d e fi c i e n c y
I n fe c t i o n o r i n fl a m m a t i o n
Disseminated malignancy
D r u g e f f e c t ( v i n c r i s t i n e , e p i n e p h r i n e , AT R A )
Hyposplenism or congenital absence of spleen
Hemolytic anemia
Fa m i l i a l t h r o m b o c y t o s i s
M u t a t i o n s i n T P O , M P L , JA K 2 V 617 I o r u n k n ow n g e n e s
Spurious thrombocytosis
C r yo g l o b u l i n e m i a
C y to p l a s m i c f r a g m e n t a t i o n a c c o m p a ny i n g mye l o i d o r l y m p h o i d n e o p l a s i a
Re d c e l l f r a g m e n t a t i o n
BONE MARROW BIOPSY
JAK2V617F not present
ESSENTIAL
THROMBOCYTHEMIA
Diagnosis
Standard
Therapies
WHO DIAGNOSTIC CRITERIA FOR ET
MUST MEET ALL 4 CRITERIA:
 Sustained platelet count ≥450 x 109/L
 Bone marrow biopsy specimen showing proliferation mainly of
the megakaryocytic lineage with increased numbers of
enlarged, mature megakaryocytes; no significant increase or
left-shift of neutrophil granulopoiesis or erythropoiesis
 Not meeting WHO criteria for PV, PMF, CML, MDS or other
myeloid neoplasm
 Demonstration of JAK2 V617F or other clonal marker, or in the
absence of a clonal marker, no evidence for reactive
thrombocytosis
CALRETICULIN MUTATIONS IN MPN
 In December 2013 2 groups identified calreticulin (protein
designated CRT, gene designated CALR) in MPN
 Present in >65% of ET and MF patients without JAK2V617F
mutation
 Does not occur in PV
 Patients either have JAK2V617F or CALR NOT both
 CRT is an ER chaperone protein and on the cell surface serves
as an “eat me” signal for phagocytes
TREATMENT GOALS IN ET
REDUCE RISK OF BLOOD CLOTS
RELIEVE SYMPTOMS
BLOOD CLOT RISK ASSESSMENT IN ET
High risk
Age > 60 y
Prior thrombosis
Platelets >1500 ×
109/L
Aspirin +
cytoreductive agent
No high-risk features
Low risk
Intermediate risk
Age < 40 y
Age 40-60 y
Aspirin alone
(and encourage to reduce
cardiovascular risk factors as much
as possible (smoking, weight, etc)
CHOICE OF CY TOREDUCTIVE AGENT
Age group
< 40 y
First line
Interferon
40-75 y
Hydroxyurea
> 75 y
Hydroxyurea
Second line
Hydroxyurea
Anagrelide
Interferon
Anagrelide
Anagrelide
Pipobroman
Busulphan
Radioactive
phosphorus
PATIENT J.L.
 73 yo man with 2 years of slowly progressive anemia, fatigue
 Workup by PCP unrevealing, referred to hematology
 CBC – WBC 9.5 (1% blasts), Hct 28%, Plt 150
 Splenomegaly on exam
 BM biopsy shows 4+ fibrosis, <5 % blasts
 JAK2V617F not detected
MYELOFIBROSIS
Diagnosis
Standard
Therapies
DIAGNOSTIC CRITERIA FOR PMF
MUST MEET ALL 3 MAJOR AND 2 MINOR CRITERIA
Major criteria:
 P r e s e n c e o f m e g a ka r yo c yte p r o l i fe r a t io n a n d a t y p i a , u s u a l l y a c c o m p a n i e d b y e i t h e r
r et i c uli n o r c o l l a g e n f i b ro s i s
 N o t m e et i n g W H O c r i te r ia f o r p o l yc yt h e m ia v e r a , B C R - A B L 1 – p o s i t i ve c h r o ni c
mye l o g e n o us l e u ke m i a , mye l o d ys p l a s t i c s y n d r o me , o r o t h e r mye l o i d d i s o r d e r s
 D e m o n s t r a t io n o f JA K 2 V 617 F o r o t h e r c l o n a l m a r ke r, o r, i n t h e a b s e n c e o f t h e a b o v e
c l o n a l m a r ke r s , n o ev i d e n c e t h a t b o n e m a r row f i b ro s i s i s s e c o n d a r y to o t h e r c a u s e s
Minor criteria:




L e u ko e r y t h r o b la s to s i s ( i m m a t ur e c e l l s i n b l o o d )
I n c r e a s e i n s e r u m l a c t a te d e hy d ro g e n a s e l ev e l
Anemia
Palpable splenomegaly (enlarged spleen)
DYNAMIC INTERNATIONAL PROGNOSTIC
SCORING SYSTEM FOR MF (DIPSS)
Obtained at any time during follow-up
0 = Low
1-2 = Intermediate-1
3-4 = Intermediate-2
5-6 = High
Passamonti et al, Blood 2010
Causes of Death in PMF
31%
Leukemia
19%
Progression without leukemia
14%
Thrombosis
10%
Infection
5%
Bleeding
Portal Hypertension
4%
Secondary Neoplasm
4%
13%
Other
0%
5% 10% 15% 20% 25% 30% 35%
Cervantes et al, Blood 2009.
Symptomatic Burden in MF
Night Sweats
Weight Loss
Fever
62%
48%
29%
Early Satiety
Abdominal Discomfort
Cough
Constitutional
Symptoms
75%
72%
Splenomegaly
55%
Bone Pain
Itching
55%
54%
Fatigue
Inactivity
insomnia
Myeloproliferation
99%
76%
Functioning
74%
0%
20%
40%
60%
80%
100%
Percentage of patients reporting symptoms
Scherber et al, Blood 2011
CONSEQUENCES OF INCREASED
INFLAMMATION
HSC
exhaustion
Stress
hematopoiesis
Constitutional Symptoms
-weight loss
-fatigue
-fever
MANAGEMENT OF PMF
Treatment for anemia





Erythropoietin (growth factor)
Corticosteroids
Androgens (danazol) +/- Prednisone
Thalidomide /lenalidomide+ Prednisone
Transfusions
Treatment for splenomegaly
 Hydroxyurea
 Splenectomy
 Ruxolitinib
RUXOLITINIB (JAKAFI)
Dual JAK1/JAK2 inhibitor
FDA approved in Nov 2011 for:
Intermediate or high-risk Myelofibrosis (=8090% of MF patients)
JAK2V617F NOT required
RUXOLITINIB
WHAT IT DOES:
 Reduces spleen size
 Relieves symptoms
WHAT IT DOESN’T DO:
 Improve anemia
 Significantly reduce the JAK2 V617F allele burden
WHAT IT MAY DO:
 Retard progression of fibrosis
 Extend lifespan
TREATMENT GOALS FOR MPN
 Prevent thrombosis
 Prevent hemorrhage
 Alleviate constitutional symptoms
 Minimize primary and iatrogenic disease
progression
 Improve QOL and survival
QUESTIONS?