Blood Clotting Complications in the Myeloproliferative Neoplasms

Report
Northwestern University Feinberg School of Medicine
Blood Clotting Complications in the
Myeloproliferative Neoplasms
Tampa MPN Patient Symposium
Brady L. Stein, MD MHS
April 3, 2014
A case from the hematology clinic
• 27 year-old, recently pregnant woman with
pain under her R rib cage
• Removal of her gallbladder 3 weeks prior
• Enlarged liver and spleen noted during her
surgery
• Review of her records:
– Intermittently high white blood cell and platelet
counts for ~5 years
A Case from the clinic
• Medical testing revealed extensive blood clots
occluding the large vein that drains the liver
• Complete Blood Count
– White blood cell and platelet number normal
• Diagnosed with the “Budd Chiari Syndrome”
and found to have increased blood pressure in
the abdominal system along with an enlarged
spleen
Additional evaluation
• No evidence of an inherited blood clotting
tendency
• Bone marrow biopsy
– No specific abnormalities-not diagnostic of a
specific entity
• JAK2 V617F Mutation:
– Positive, confirming that she has an MPN
Classical Myeloproliferative Neoplasms:
Shared Clinical Features
Blood clotting complications
-Epidemiology
-Signs and symptoms
-Risk factors
-Treatment strategies
-Chicago Roundtable Research
Splenomegaly
Marrow fibrosis
Disease acceleration/
transformation
ET
PV
MF
Epidemiology—How common are arterial or
venous blood clotting complications in MPN?
40
34-39%
ET
PV
MF
35
30
25
20
15
10-29%
8 to 31%
~13%
10
8 to 19%
~10%
5
0
At diagnosis
Follow-up
Elliot, MA Seminars in Thrombosis and Hemostasis 2007; Barbui, T Blood 2010; Elliot Haematologica 2010
Clotting Manifestations:
“Small Vessel” Disturbances
Erythromelalgia:
Redness, swelling,
and pain of the
extremities
Disrupt Quality but not
Quantity of Life
• Headache, Dizziness,
Transient Visual
Disturbances,
Numbness/Tingling, Color
changes or Pain in the digits
• Often responsive to aspirin
Picture from the Erythromelalgia Association Website
Clotting Manifestations:
“Large Vessel” Disturbances
• Stroke
– Transient or prolonged weakness, numbness,
difficulty with speech, vision, drooping of the face
• Heart Attack
– Chest pain, neck/jaw, or arm pain, sweating, nausea,
shortness of breath
• Deep vein thrombosis or Pulmonary Embolism
– Swelling, tightness/discomfort, redness of the
limb, typically the leg
– Chest pain, difficulty breathing, irregular heart
beats
Clotting Manifestations:
Unusual Locations and “Occult MPN”
41% will have MPN
32% will have MPN
Portal Vein
Thrombosis
Mesenteric
Vein
Thrombosis
As reviewed in Barbui et al, Blood 2013
Hepatic Vein
Thrombosis:
Budd-Chiari
Splenic Vein
Thrombosis
®Stephan Moll, MD
Thrombosis Risk Factors:
Generic, but accepted and consistent:
Age less than 60
No clotting history
High blood
pressure
Diabetes
↑Cholesterol
Age over 60
Prior blood clot
Smoking
Lower Risk
Intermediate Risk
High Risk
MPN-specific risk factors
Stem Cells
JAK2 mutation
linked to blood
clotting
Progenitors
Increased Red blood
cell count linked to
blood clotting
Increased white blood
cell count likely linked
to blood clotting
Increased Platelet
count itself NOT
linked to blood
clotting
A New Player: CALR mutations in ET and MF
P. Vera
ET: 67% with CALR
MF: 88% with CALR
CALR mutated patients appeared to have a lower Hgb and
leukocyte count, higher platelet count, and lower rate of
thrombosis
12
Klampfl et al, Late Breaking Abstracts and Klampfl, T et al. NEJM 2013
Revised Classification for ET:
IPSET
•
•
•
•
Age > 60: 1 point
History of blood clot: 2 points
Cardiovascular Risk factors: 1 point
JAK2 V617F: 2 points
Low Risk:
< 2 points
Intermediate Risk:
2 points
High Risk:
> 2 points
Barbui et al Blood 2012
Managing Thrombosis Risk
Age less than 60
No clotting
history
High blood
pressure
Diabetes
↑Cholesterol
Age over 60
Prior blood clot
Smoking
Lower Risk
Intermediate Risk
High Risk
Lifestyle
Aspirin in PV,
“Cytoreduction”
JAK2+ ET, or small Modification
vessel disturbance
This is a generic approach rather than personalized!
Managing MPN-specific Risk Factors
JAK2:
JAK inhibitors
Interferon
Investigational
agents
Stem Cells
Progenitors
RBC
Phlebotomy for PV:
Hematocrit lowering
<45%
Plts
WBC
Hydroxyurea
JAK2 inhibitors
Interferons
Platelet count alone
should not dictate
therapy unless > 1.5
million
The “lowly hematocrit”
• Target hematocrit (Hct) for patients with PV debated
for decades
• 365 patients with PV, randomized to low Hct (< 45%)
vs. high Hct (45-50%)
• Four-fold lower rate of serious cardiovascular
complications in low Hct (4.4%) vs. high Hct (10.9%)
group
• But…white cell count remained higher in the high
Hct group
• Going forward, phlebotomy target to goal Hct < 45%
Marchioli et al NEJM 2013
Spivak NEJM 2013
Is Anagrelide Coming back?
ANAHYDRET
• PT-1 study suggested hydroxyurea/aspirin was superior to
anagrelide/aspirin in ET patients in the prevention of arterial
blood clots
• 259 ET patients, randomized to hydroxyurea or anagrelide
• No difference between the 2 drugs in the following:
– Major or minor arterial or venous blood clots
– Severe bleeding
– Discontinuation rates
– Myelofibrosis or leukemia not seen
• Conclusion: Anagrelide does not appear to be
inferior to Hydroxyurea in the prevention of blood
clotting
Gissingler et al Blood 2013
Are younger MPN patients at low risk for blood clotting
complications?
Informal Case Discussion
Chicago Roundtable
Laura Michaelis
Olatoyosi Odenike
Damiano Rondelli
Jamile Shammo
Brady Stein
Research Question
Draft proposal,
submit to each
institution’s review
board
Medical Chart
Review
6 monthly “dinner rounds to attract community providers
Our Results
Characteristic
Younger PV
Older PV Patients
Patients (≤ 45 yrs) N=84 (≥ 65 yrs)
N=120
% Women
% MPN Family History
Avg Disease Duration
Avg white blood cell
count (x 109/L)
JAK2 mutation, %
JAK2 Burden, %
76
10
8 years
9.2
55
11
4.5 years
13.4
98
51
95
66
No real differences in Aspirin, Phlebotomy, or Hydroxyurea Use
Stein et al Leuk Lymphoma 2013
Our Results
18
Overall rate of blood clotting:
27% vs. 31% (Younger vs. Older)
16
14
12
10
8
6
4
2
0
Deep vein Abdominal
or
vein blood
pulmonary
clot
embolism
Heart
attack
TIA
Stroke
Age > 65 (N=84)
Multiple
events
Other
Age < 45 (N=120)
Stein et al Leuk Lymphoma 2013
How do our results compare to other studies?
Portal Vein
Thrombosis
Mesenteric
Vein
Thrombosis
Splenic Vein
Thrombosis
Hepatic Vein
Thrombosis:
Budd-Chiari
• 475 cases reviewed of abd vein
clotting
• Majority (88-93%) JAK2 V617F
positive
• Typically younger (44 yrs) women
(61%)
• 22% presented ~40 mos before an
official MPN diagnosis!
• Clinical trials evaluating Ruxolitinib
and Peg-interferon in this patient
population
Pieri et al, ASH Abstract 2013
Our study: conclusions
• Overall clotting complications similar by age
group, but the locations differ
– Younger women particularly at risk for clotting of
the abdominal veins
• These clotting complications can be quite
serious
– Our patient required a procedure to lower the
pressure in the abdominal blood pressure system
– Likely to require blood thinners indefinitely
• Our understanding of the mechanisms of
blood clotting in the MPN is incomplete
Many factors can influence MPN-thrombosis
Increased Hematocrit/Blood
viscosity
Increased white cell count
and activated WBC’s
Type of mutation, burden
JAK2 > CALR
JAK2 allele burden
MPN-associated
thrombosis
Activated Platelets
Blood cell membrane
fragments
(Microparticles)
Advanced Age
Prior history of blood
clotting
Type of MPN
PV, “masked PV”
Prefibrotic MF, ET
MF
Activation of
the blood
vessel lining
Gender
Inflammation
Adapted from McMahon and Stein, Seminars in Thrombosis and Hemostasis 2012
“Masked PV:” ASH abstract 1581 (Barbui et al)
Questions and Goals for the Future….
• How do we personalize the risk classification
to avoid over or under-treatment?
– Develop reproducible assays to measure JAK2
burden, markers of blood cell/vessel activation,
microparticles
• What is the ideal blood thinning agent?
– Warfarin for those with venous clotting, but for how long
(limited or indefinite (abdominal veins))
– Injected blood thinners? “Target Specific” blood thinners?
• Is there a role for twice daily Aspirin or
Aspirin/Clopidogrel?
• Will JAK inhibitors impact clotting rates?
Thank you for your attention

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