Transcript in newly-diagnosed pv?

Good Samaritan Medical Center, West Palm Beach, FL
Guest Speaker
Michael Savona, MD
Associate Professor of Medicine
Director, Hematology Early Therapeutics Program
Vanderbilt-Ingram Cancer Center, Nashville, TN
Vardiman JW. Blood. 2009;114(5):937-51.
PREVALENCE OF MPNs PER 100,000 INDIVIDUALS
PV
ET
Age-Adjusted P Prevalence
Per 100,000 Individuals
Primary MF + Post PV MF + Post ET MF
Mehta J. Leuk Lymphoma. 2014;55(3):595-600
2013 Sep;27(9):1874-81
WHAT DOES A PV PATIENT LOOK LIKE?
PRESENTING SIGNS AND SYMPTOMS
Geyer H. Hematology Am Soc Hematol Educ Program. 2014;2014(1):277-286.
2013 Sep;27(9):1874-81
WHAT DOES A PV PATIENT LOOK LIKE?
CLINICAL FINDINGS
Tefferi A. Leukemia. 2013;27(9):1874-81.
2013 Sep;27(9):1874-81
OVERALL SURVIVAL AFTER DIAGNOSIS
100
Median Survival = 18.9 years
80
P= 0.104
60
40
Observed
Expected
20
Number at Risk
0
1545
0
973
491
229
84
5
10
15
20
Years
Tefferi A. Leukemia. 2013;27(9):1874-81.
PART 1:
ESTABLISHING A
DIAGNOSIS
OUR PATIENT: CALVIN
• 59-year-old with left hand clumsiness and
difficulty speaking
• Review of symptoms notable for fatigue
• Family notes recent reddish complexion
• Medical history: diet-controlled
hypercholesterolemia
• No medications or drug allergies
• No hematological problems in the family
• Non-smoker, casual ETOH
CASE PRESENTATION:
EXAM AND INITIAL DATA
•
•
•
•
•
BP 176/91; oxygen saturation 95%
Plethoric, ruddy appearance
Regular heart rate and rhythm (S1S2, no M/R/G)
Palpable spleen tip
Neurological examination nonfocal
FURTHER WORKUP
• Complete blood count:
– WBC 14.9 x 109/L
– Hgb 18.8 g/dl
– Platelets 485 x 109/L
• JAK2 V617F mutated
• Epo level: 1.9 mU/mL
QUESTION
Which of Calvin’s characteristics are included
within the WHO’s criteria for diagnosis of PV?
A.
B.
C.
D.
Oxygen saturation: 95%
Platelet count: 485 x 109 L
Epo level: 1.9 mU/mL
WBC: 14.9 x 109/L
25%
A.
25%
25%
B.
C.
25%
D.
HISTORICAL PERSPECTIVE
• 1892: Vaquez disease
• 40-year-old with “cyanosis,”
vertigo, dizziness,
palpitations, and
erythrocytosis; post-mortem
exam showed marked
hepatosplenomegaly
• 1903: A new clinical entity
• Osler publishes case series:
“Chronic cyanosis,
polycythemia and an
enlarged spleen”
Osler W. Br Med J. 1904;1(2246):121-122.
DIFFERENTIAL DIAGNOSIS:
EXCLUDE OTHER CAUSES OF “POLYCYTHEMIA”
Primary Polycythemia
Secondary Polycythemia
• Congenital
– EPO-receptor
mutation
• Acquired
– Polycythemia vera
• Congenital
– VHL mutation, high affinity
Hb, methemoglobinemia
• Acquired
– Hypoxia
– Inappropriate EPO production
• *Tumors
• “Relative”
– Dehydration, diuretic use, etc.
*Tumors include cerebellar hemangioblastoma, uterine leiomyoma, pheochromocytoma,
renal cell carcinoma, hepatocellular cancer, meningioma, parathyroid adenoma
WILLIAM DAMESHEK, 1951: SPECULATIONS ON
THE MYELOPROLIFERATIVE SYNDROMES
• Recognizes overlapping features
shared by PV and the other “MPD”
•
•
•
•
Leukocytosis
Thrombocytosis
Splenomegaly
Marrow Fibrosis
“…Manifestations of proliferative activity of the
bone marrow cells, perhaps due to a hitherto
undiscovered stimulus”
Dameshek W. Blood. 1951;6(4):372-5.
DAMESHEK’S “MYELOSTIMULATORY” FACTOR
Wild-type JAK2
JAK2 mutated PV
JAK2 V617F
mutations present
in ~95% of PV
cases
JAK2 Exon 12
mutations present
in ~2-3% of PV
cases
*Typically isolated
erythrocytosis
Similar rate of MF,
AML, thrombosis
Stein B. JAMA. 2010;303(24):2513-8.
*Passamonti F. Blood. 2011; 117(10):2813-6.
WHO CRITERIA 2008: POLYCYTHEMIA VERA
Major
Absolute erythrocytosis (>18.5 g/dL in men; >16.5
g/dL in women)
JAK2 V617F mutation or similar (JAK2 exon 12)
Minor
Subnormal EPO level (<4 mU/mL)
Bone marrow trilineage proliferation
Endogenous erythroid colony growth
*2 major and 1 minor, or 1 major and 2 minor
required for diagnosis
Thiele J. Curr Hematol Malig Rep. 2009;4(1):33-40.
“*AN ALTERNATIVE PROPOSAL”
• Hemoglobin/hematocrit is not a perfect
surrogate for increase in red cell mass
• WHO criteria identified absolute erythrocytosis in only 35%
and 63% of male and female PV patients
• Prospective, 5-year study showed 28/30 diagnosed with PV,
based on ↑RCM, JAK2, and ≥1 minor criteria, but 8 (27%)
and 18 (60%) did not meet Hct or Hgb criteria
• Red cell mass and plasma volume studies upgrade ~46% of
JAK2-positive ET patients to PV
• Epo levels are neither sensitive nor specific, as they can
be normal in PV and suppressed in ET
• EECF is neither widely available nor standardized for use
*Spivak JL. Blood. 2008;112(2):231-9; Johansson PL. Br J Haematol. 2005;129(5):701-5; Silver J. Blood.
2013;122(11):1881-6; Alvarez-Larran A. Haematologica. 2012;97(11):1704-7; Cassinat B. Leukemia. 2008;22(2):452-3.
“MASKED” PV (mPV)
397 patients with PV marrow morphology
• “Masked” (n=140) vs. overt PV (n=257)
• mPV typically male, with history of
arterial thrombosis, and ↑platelets
• Similar vascular risk, but ↑rate of
MF/AML, and ↓survival vs. overt PV
• mPV distinguished from ET by
Hgb >16/16.5, and Hct 48/49% in M/F
• Plasma volume increase can mask PV,
typically in cases of abdominal venous
thrombosis with splenomegaly
One of Osler’s patients,
Oxford 1916
*Masked PV=Hgb values below WHO threshold
Lamy T. Am J Med. 1997; 102(1):14-20; Spivak J. N Eng J Med. 2006; 355(7):737; Barbui T. Am J Hematol. 2014;89(1):52-4.
PROPOSED REVISIONS TO THE
DIAGNOSTIC CRITERIA
• Major criteria:
 Hgb >16.5 g/dl (Hct >49%) in men; >16 g/dl (>48%) in
women
 BM trilineage myeloproliferation with pleomorphic
megakaryocytes
 Presence of JAK2 mutation
• Minor criteria:
 Subnormal Epo level
Diagnosis would require all 3 major criteria
or 2 major and 1 minor criteria
Tefferi A. Leukemia. 2014;28(7):1407-13.
KEY TAKEAWAYS
• WHO criteria work well for many PV patients, but the Hgb
threshold may be inadequate for some
• Be mindful of “masked” disease
– JAK2 + ET, but generous Hct
– JAK2 + with abdominal venous thrombosis
– Pancytosis and/or splenomegaly but Hgb below threshold
– Bone marrow morphology and RCM testing may better
recognize PV in these settings
• Epo level imperfect, EEC testing not routinely available
• Updates have been proposed to WHO diagnostic criteria
PART 2:
FRONTLINE
TREATMENT OF PV
CASE REVIEW: CALVIN
• 59-year-old presents to the ER with clumsiness of
the left hand and transient difficulties with his
speech
• Fatigue is noted, along with ruddy complexion
• BP: 176/91; oxygen saturation 95%
• WBC: 14.9 x 109/L
• Hgb: 18.8 g/dl
• Platelets: 485 x 109/L
• JAK2 V617F positive
• Epo level: 1.9 mU/mL
QUESTION
Which of the following would not be
considered an appropriate first-line regimen for
Calvin?
20%
A.
B.
C.
D.
E.
20%
20%
B.
C.
20%
20%
Phlebotomy (P) alone
P + Aspirin (A) alone
P + A + hydroxyurea
P + A + ruxolitinib
P + A + interferon alfa
A.
D.
E.
TREATMENT GOALS
FOR NEWLY-DIAGNOSED PV
• Reduce cardiovascular complications
• Improve disease-related symptoms
• Prevent transformation to myelofibrosis (1520%) and/or leukemia (3-5%)
• Improve overall survival (median 14 years)
• ?? Reduce/eliminate JAK2 allele burden
• ?? Reduce/eliminate other clones (eg, TET2)
Tefferi A. Leukemia. 2013;27(9):1874-1881.
STANDARD FIRST-LINE TREATMENT
FOR NEWLY-DIAGNOSED PV
•
•
•
•
•
Phlebotomy
Aspirin
Hydroxyurea
Interferon?
Lifestyle modifications
–
–
–
–
–
Counseling about risk of thrombosis and hemorrhage
Smoking cessation, weight control, exercise
Management of HTN/DM/HL in susceptible patients
Avoidance of oral contraceptives
DVT prophylaxis (exercises, activity, enoxaparin
sodium for long flights [controversial] or sedentary
periods)
LOW-DOSE ASPIRIN IN PV: ECLAP STUDY
• Hypothesis: There is increased synthesis of platelet
thromboxane in PV that can be suppressed by
aspirin 100 mg daily
• 528 patients: 253 aspirin 100 mg daily, 265 placebo
• Inclusion Criteria:
o No clear indication for, or contraindication to, aspirin
o No significant comorbidities
• Primary endpoints:
o Cumulative rates of nonfatal MI, stroke, or death from CV
disease +/- PE or major venous thrombosis
Landolfi R. N Engl J Med. 2004;350(2):114-124.
ECLAP RESULTS
Probability of survival free of MI, stroke, death from CV disease, PE, or DVT
RR 0.40; [0.18,0.91]; P=0.03
Note: there were more smokers in the placebo group;
HCT median was 46 during follow-up, with 25% of pts with HCT >48
Landolfi R. N Engl J Med. 2004;350(2):114-124.
CONCLUSIONS FROM ECLAP
• Aspirin significantly reduced primary
endpoint by 60%
– Significant decrease in combined endpoint of nonfatal MI,
nonfatal stroke, PE, deep venous thrombosis, or death
from any cause
– Significant decrease in rates of thrombosis
– No significant difference in rates of major adverse events
– No significant reduction in overall and cardiovascular
mortality
– No significant increase in major bleeding events
Landolfi R. N Engl J Med. 2004;350(2):114-124.
CARDIOVASCULAR EVENTS AND
INTENSITY OF PV TREATMENT
• Cytoreductive Therapy in Polycythemia Vera
– (CYTO-PV) study
• 365 adults w/JAK2+ PV, all treated with:
– Low-dose aspirin
– Phlebotomy (250-500 cc QOD until target HCT) and/or
– Hydroxyurea (0.5-1 g daily until plt <400K)
• Hydroxyurea (HU) recommended for:
– Patients at high risk for thrombosis (age >65 years,
previous thrombosis) or
– Progressive thrombocytosis or splenomegaly
Marchioli R. N Engl J Med. 2013;368(1):22-33.
CYTO-PV STUDY TARGETS
• Two study arms
o More intensive Tx (target hct = <45%)
o Less intensive Tx (target hct = 45 to 50%)
• Primary end point: Time until death from CV
complications or major thrombotic events
• Planned target was 1,000 patients, but slow
enrollment and competing trials prevented
completion
Marchioli R. N Engl J Med. 2013;368(1):22-33.
CV EVENTS AND INTENSITY OF TREATMENT
1.1 per 100 person-years
in the low-hematocrit group
4.4 per 100 person-years
in the high-hematocrit group
Marchioli R. N Engl J Med. 2013;368(1):22-33.
WHAT ABOUT INTERFERON (IFN)
IN NEWLY-DIAGNOSED PV?
• IFN controls counts and can produce
hematologic remission
• Progressively decreases JAK2 mutated clones
and can induce molecular remission
• No evidence of leukemogenicity
• Pegylated formulation generally well-tolerated,
but still associated with important side effects
(flu-like symptoms, depression, autoimmune
manifestations, ocular toxicity, etc.)
Kiladjian JJ. Leukemia. 2008;22(11):1990-8; Kiladjian JJ. Blood. 2008;112(8):3065-72.
TREATMENT OF PV WITH PIPOBROMAN
• Kiladjian et al (2011)
• 285 patients (all <65 years old)
• Two study arms:
o HU 25 mg/kg/d, followed by maintenance
(10-15 mg/kg/d)
o Pipobroman 1.25 mg/kg/d, followed by
maintenance (0.4-0.7 mg/kg/d)
Kiladjian JJ. J Clin Oncol. 2011;29(29):3907-13.
OVERALL SURVIVAL DATA
Kiladjian JJ. J Clin Oncol. 2011;29(29):3907-13.
TREATMENT-RELATED RISK FACTORS FOR
TRANSFORMATION TO AML AND MDS
Treatment
Odds Ratio
95% CI
None
1.0
Reference
Radioactive phosphorus (P32)
1.5
0.8 to 2.8
Alkylating agent only
0.9
0.4 to 2.1
HU only
1.2
0.6 to 2.4
Mixed treatment (2 or 3)
2.9
1.4 to 5.9
Bjorkholm M. J Clin Oncol. 2011;29(17):2410-5.
RISK OF TRANSFORMATION TO AML/MDS
RELATIVE TO CUMULATIVE DOSE
Treatment
Odds Ratio
95% CI
HU, g
1-499
500-999
≥1,000
1.5
1.4
1.3
0.6 to 2.4
0.6 to 3.4
0.5 to 3.3
Radioactive phosphorus (P32), MBq
1-499
500-999
≥1,000
1.5
1.1
4.6
0.6 to 3.3
0.5 to 2.2
2.1 to 9.,8
Alkylating agents, g
1-499
500-999
≥1,000
1.1
1.7
3.4
0.5 to 2.3
0.6 to 5.0
1.1 to 10.6
Bjorkholm M. J Clin Oncol. 2011;29(17):2410-5.
KEY TAKEAWAYS
• Aspirin, phlebotomy and hydroxyurea remain the mainstays
of therapy for PV
• Reduction of HCT to at least <45% is associated with
significant clinical benefit
• Hydroxyurea is not associated with a significant
independent risk for leukemia, but the issue is still of
concern with long-term use and/or higher doses
• Pegylated interferon can also be considered for newly
diagnosed PV
• The role of ruxolitinib in newly diagnosed PV is under
investigation
PART 3:
INADEQUATE
RESPONSE TO
HYDROXYUREA
OUR PATIENT: JOSEPH
• 71-year-old diagnosed with PV 3 years ago on
the basis of erythrocytosis, thrombocytosis, and
JAK2-V617F mutation in the setting of an
unprovoked deep vein thrombosis
• Managed successful for 3 years with low-dose
aspirin, phlebotomy (goal HCT≤45%), and
hydroxyurea (500 g twice daily)
• Presents today with a non healing leg ulcer,
fatigue, pruritus, and occasional night sweats
• Patient still requires occasional phlebotomy
HISTORY
• Past medical history
– Squamous Cell Carcinoma
(SCC)
– Multiple actinic keratosis
• Surgical history
– Mohs for SCC (2013)
– Right inguinal hernia repair
(2010)
• Medications
– Aspirin 81 mg/day
– Hydroxyurea 500 mg 2x/day
– Atorvastatin 20 mg/day
• Social history
– Former Smoker (quit
2008)
– Retired attorney
– Divorced 1986
– Remarried 2001
• Family history
– Mother had essential
thrombocythemia
– Father with myocardial
infarction at age 68
PHYSICAL EXAM
•
•
•
•
HEENT: Within normal limits
CV/Lungs: Within normal limits
Spleen: 3 cm below left costal margin
Skin: Scar on forehead from Mohs surgery,
numerous actinic keratoses
LABS
• Complete Blood Count
–
–
–
–
Hemoglobin: 16.7 g/dL
Hematocrit: 51%
Leukocytes: 16.4 x 109/L
Platelets: 640 x 109/L
• Peripheral smear
– Leukocytosis, thrombocytosis, no nucleated red
blood cells, no blasts
• Ferritin decreased, TIBC increased
• Chemistries: Within normal limits
QUESTION
What would be the most accurate description of
Joseph’s clinical status with respect to PV?
A.
B.
C.
D.
E.
Complete response
Partial remission
Intolerant of hydroxyurea
Resistant to hydroxyurea
Evidence of progression
to post-PV MF
20%
A.
20%
20%
B.
C.
20%
D.
20%
E.
RESPONSE CRITERIA FOR PV (≥12 WEEKS)
Complete
Remission
•
•
•
•
Resolution of PV signs
≥10 pt. MPN TSS
Near normal counts
No progressive disease
or vascular event
• Bone marrow remission
& ≤Gr 1 reticulin fibrosis
Partial
Remission
•
•
•
•
Molecular Response
Resolution of PV signs
≥10 pt. MPN TSS
Near normal counts
No progressive disease
or vascular event
Peripheral blood
granulocytes
•CR – Eradicated
mutation
•PR - ≥50% allele
burden, ≥20% allele
burden at baseline
Progressive Disease = Post- PV MF, MDS, or AML
Barosi G. Blood. 2013:121(23):4778-4781.
Assessing MPN Burden
WHO Diagnosis Does Not Tell Whole Story
Vascular Events
• PV/ET > MF
• Counts matter
• Can be
unrecognized
•
•
•
•
Baseline Health
AGE/ Medicines
Comorbidities
Progression
PV/ET to MF
PV/ET to AML
MF to AML
? 2nd MDS
Cytopenias
• MF> ET/PV
• Anemia
• MF 75%
• TX Dep 25%
• TPN 30%
Splenomegaly
• MF> ET/PV
• Pain not always a
function of size
•
•
•
•
MPN Symptoms
MF>PV>ET
Multifactorial
Some ET/PV > MF
Cytoreductive rx frequently
not effective
PRIMARY COMMERCIALLY AVAILABLE MPN DRUGS
ET
Hydroxyurea
Interferon/
Peg-INF
Anagrelide
Ruxolitinib
+++
++
++
+
Ruxolitinib Approved in PV
December 4, 2014
PV
++
MF
+
+ to +++
Strength of Evidence
++
+
+++
+
+
+++
EXPERIMENTAL –
OFF LABEL
“In patients having inadequate
response to or intolerant of
hydroxyurea”
RESISTANCE
WHAT DOES INTOLERANCE/RESISTANCE
TO HYDROXYUREA IN PV MEAN?
1.
2.
3.
4.
Need for phlebotomy (HCT<45%)
PLT >400 x 109/L and WBC >10 x 109/L
Failure to reduce spleen by > 50%
No reduction of spleen symptoms
INTOLERANCE
1.
1. After > 3 Months
2. At maximum
tolerated dose
or 2 g/day
Cytopenias (any)
–
–
–
2.
3.
4.
5.
6.
Please Note
ANC <1.0 x 109/L
Hemoglobin <100 g/l
Platelets <100 x 109/L
Please Note
Leg ulcers
GI toxicity
Fever
Mucocutaneous manifestations
Skin cancers
At lowest dose to
achieve either a
PR or CR
Barosi G et. al. Br J Haematol. 2009;148:961-3.
CASE CONTINUATION
• Joseph undergoes a repeat bone marrow
aspirate and biopsy.
• Results:
– 1+ out of 3+ fibrosis, normal cytogenetics.
– Diagnosis:
– PV patient intolerant to hydroxyurea
• Ruxolitinib 10 mg twice daily is initiated
QUESTION
Which of the following is among the goals of
ruxolitinib therapy in PV?
A. Control of hematocrit
B. Reduction in
splenomegaly, if present
C. Reduction in pruritus
D. Prevention of vascular
events
E. All of the above
20%
A.
20%
20%
B.
C.
20%
D.
20%
E.
SIX WEEKS LATER
• Joseph reports marked decrease in fatigue,
pruritus, and night sweats
• Spleen no longer palpable
• Leg ulcer is healing
• Hemoglobin 14.0 g/dL (without phlebotomy),
leukocytes 11 x 109/L, and platelets 390 x 109/L
RUXOLITINIB (SINGLE AGENT) IN PV
Extended
Treatment
Phase
Week 208
•Resistance to
or intolerance
of HU (modified
ELN criteria)
•Phlebotomy
requirement
•Splenomegaly
Pre-randomization
(Day -28 to Day -1)
Hct 40%-45%
Randomized (1:1)
Ruxolitinib
10 mg BID
n = 110
Crossover to
ruxolitinib
Week 208
BAT
n = 112
Week 32
(Primary analysis)
Week 80
Compared to BAT, results showed that ruxolitinib led to:
1. Superior control of hematocrit
2. Superior reduction in splenomegaly
3. Superior reduction in PV-related symptoms
4. Trend for less thrombotic events
Vannucchi et al. EHA 2014. Abstract LB-2436.
RESPONSE TRIAL: CHANGE IN PV SYMPTOMS
20
7.9
3.9
00
-20
−20
−4.4
0.0
1.4
5.0
16.7
11.1
15.7
0.4
−2.1
−4.2
−51.5 −49.6
-60
−60
−44.0 −41.8
−37.1
−61.1
−65.9 −64.1
-80
−80
−80.2
−100.0 −99.5
17.2
0.0
-40
−40
-100
−100
10.9
Rux
Improvement
Median Change From Baseline, %
40
Median Percentage Changes From Baseline at Week 32 in
Individual MPN-SAF Symptom Scores
BAT
−94.9 −93.9
-120
−120
Mesa R. ASH 2014. Abstract 709.
Kiladjian JJ
TOXICITY PROFILES OF PV AGENTS
Drug
Common Adverse Effects
Hydroxyurea
Interferon alfa
Ruxolitinib
•
•
•
•
•
Stomatitis
Leg ulcers
Dry skin, acne
Neutropenia
Elevated LFTs
• Gastric pain,
diarrhea
• Fatigue
• Headache
• Headache
• Fatigue
• Abdominal Pain • Dyspnea
• Diarrhea
Najean Y. Blood. 1997;90(9):3370-7; Kiladjian JJ. Blood. 2008;112(8):3065-72;
Mesa R. ASH 2014. Abstract 709.
POSSIBLE ALGORITHM OF THERAPY OF PV IN 2015
Assess Symptom
Quartile
by MPN 10
Q1:TSS <8
Q2:TSS 8-17
Q3:TSS 18-31
Q4:TSS ≥32
Diagnosis of PV
Assess MPN Risk Score & Symptoms
Control Hematocrit (<45%)
Low-dose aspirin in appropriate patients
Decide on need for concurrent cytoreduction
based on risk and symptoms
NO
Monitor for symptom burden,
vascular events, progression
Worsening symptom burden
Vascular event, progression
Phlebotomy intolerance
YES
Front Line Cytoreduction
HU, or HU vs. INF Clinical Trial
Worsening symptom burden
Vascular event, progression
HU Resistance/ Intolerance
Consider ruxolitinib, INF (if not previously
received), or JAK2 clinical trial
KEY CASE TAKEAWAYS
• Polycythemia vera is a heterogeneous disease
• A subset of patients have worsening symptoms,
splenomegaly, and difficulty with hematocrit
control
• Hydroxyurea is largely considered front-line
cytoreductive therapy for high-risk PV patients,
but some patients have an inadequate response
based either on resistance or intolerance
• Ruxolitinib is FDA-approved for patients with PV
who have an inadequate response or are
intolerant of hydroxyurea
ACTIVITY POST-TEST
QUESTION
According to the WHO, which of the following
would be included among the characteristics
that qualify a patient for diagnosis of PV?
A.
B.
C.
D.
Oxygen saturation >95%
Platelet count: 485 x 109 L
Epo level: 1.9 mU/mL
WBC: 14.9 x 109/L
25%
A.
25%
B.
25%
C.
25%
D.
QUESTION
Which of the following would not be
considered an appropriate first-line regimen for
the treatment of PV?
20%
A.
B.
C.
D.
E.
20%
20%
B.
C.
20%
20%
Phlebotomy (P) alone
P + Aspirin (A) alone
P + A + hydroxyurea
P + A + ruxolitinib
P + A + interferon alfa
A.
D.
E.
QUESTION
Which of the following is among the goals of
ruxolitinib therapy in PV?
A. Control of hematocrit
B. Reduction in
splenomegaly, if present
C. Reduction in pruritus
D. Prevention of vascular
events
E. All of the above
20%
A.
20%
20%
B.
C.
20%
D.
20%
E.