Good Samaritan Medical Center, West Palm Beach, FL 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
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Good Samaritan Medical Center, West Palm Beach, FL Guest Speaker Michael Savona, MD Associate Professor of Medicine Director, Hematology Early Therapeutics.
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Good Samaritan Medical Center, West Palm Beach, FLGood Samaritan Medical Center, West Palm Beach, FL
Guest SpeakerMichael Savona, MDAssociate Professor of MedicineDirector, Hematology Early Therapeutics ProgramVanderbilt-Ingram Cancer Center, Nashville, TN
Vardiman JW. Blood. 2009;114(5):937-51.
PREVALENCE OF MPNs PER 100,000 INDIVIDUALS
Mehta J. Leuk Lymphoma. 2014;55(3):595-600
Primary MF + Post PV MF + Post ET MF PV ET
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
Tefferi A. Leukemia. 2013;27(9):1874-81.
WHAT DOES A PV PATIENT LOOK LIKE?CLINICAL FINDINGS
2013 Sep;27(9):1874-81
OVERALL SURVIVAL AFTER DIAGNOSIS
Tefferi A. Leukemia. 2013;27(9):1874-81.
Median Survival = 18.9 years
ObservedExpected
100
0
80
60
40
20
P= 0.104
0 20105 15
Years
Number at Risk
1545 84491973 229
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
A. Oxygen saturation: 95%
B. Platelet count: 485 x 109 L
C. Epo level: 1.9 mU/mL
D. WBC: 14.9 x 109/L
A. B. C. D.
25% 25%25%25%
Which of Calvin’s characteristics are included within the WHO’s criteria for diagnosis of PV?
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”
Thiele J. Curr Hematol Malig Rep. 2009;4(1):33-40.
*2 major and 1 minor, or 1 major and 2 minor required for diagnosis
“*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)
One of Osler’s patients,
Oxford 1916
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*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
Tefferi A. Leukemia. 2014;28(7):1407-13.
• 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
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
QUESTIONQUESTION
A. Phlebotomy (P) alone
B. P + Aspirin (A) alone
C. P + A + hydroxyurea
D. P + A + ruxolitinib
E. P + A + interferon alfa
A. B. C. D. E.
20% 20% 20%20%20%
Which of the following would not be considered an appropriate first-line regimen for Calvin?
TREATMENT GOALS TREATMENT GOALS FOR NEWLY-DIAGNOSED PVFOR NEWLY-DIAGNOSED PV
o No clear indication for, or contraindication to, aspirino 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 RESULTSECLAP RESULTS
Probability of survival free of MI, stroke, death from CV disease, PE, or DVT
Landolfi R. N Engl J Med. 2004;350(2):114-124.
RR 0.40; [0.18,0.91]; P=0.03Note: there were more smokers in the placebo group; HCT median was 46 during follow-up, with 25% of pts with HCT >48
CONCLUSIONS FROM ECLAPCONCLUSIONS 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 CARDIOVASCULAR EVENTS AND INTENSITY OF PV TREATMENTINTENSITY 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 TARGETSCYTO-PV STUDY TARGETS
• Two study armsoMore 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 TREATMENTCV EVENTS AND INTENSITY OF TREATMENT
Marchioli R. N Engl J Med. 2013;368(1):22-33.
1.1 per 100 person-years in the low-hematocrit group 4.4 per 100 person-years
in the high-hematocrit group
WHAT ABOUT INTERFERON (IFN) WHAT ABOUT INTERFERON (IFN) IN NEWLY-DIAGNOSED PV?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.)
• 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
“In patients having inadequate response to or intolerant of
hydroxyurea”
Ruxolitinib Approved in PV December 4, 2014
“In patients having inadequate response to or intolerant of
hydroxyurea”
+ to +++ Strength of Evidence
WHAT DOES INTOLERANCE/RESISTANCE TO HYDROXYUREA IN PV MEAN?
1. Need for phlebotomy (HCT<45%)
2. PLT >400 x 109/L and WBC >10 x 109/L
3. Failure to reduce spleen by > 50%
4. No reduction of spleen symptoms
1. Cytopenias (any)– ANC <1.0 x 109/L– Hemoglobin <100 g/l– Platelets <100 x 109/L
2. Leg ulcers3. GI toxicity4. Fever5. Mucocutaneous manifestations6. Skin cancers
RE
SIS
TA
NC
EIN
TO
LER
AN
CE
Please Note
1.After > 3 Months2.At maximum tolerated dose or 2 g/day
Please Note
1.After > 3 Months2.At maximum tolerated dose or 2 g/day
Please Note
At lowest dose to achieve either a
PR or CR
Please Note
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
A. Control of hematocrit
B. Reduction in splenomegaly, if present
C. Reduction in pruritus
D. Prevention of vascular events
E. All of the aboveA. B. C. D. E.
20% 20% 20%20%20%
Which of the following is among the goals of ruxolitinib therapy in PV?
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
BAT
Week 32(Primary analysis)
Week 80
n = 110
n = 112
Crossover to ruxolitinib
•Resistance to or intolerance of HU (modified ELN criteria)
•Phlebotomy requirement
•Splenomegaly
Pre-randomization (Day -28 to Day -1)
Hct 40%-45%
Ra
nd
om
ize
d (
1:1
)
ExtendedTreatment
PhaseRuxolitinib 10 mg BID
Week 208
Week 208
Compared to BAT, results showed that ruxolitinib led to:1.Superior control of hematocrit2.Superior reduction in splenomegaly3.Superior reduction in PV-related symptoms4.Trend for less thrombotic events
Compared to BAT, results showed that ruxolitinib led to:1.Superior control of hematocrit2.Superior reduction in splenomegaly3.Superior reduction in PV-related symptoms4.Trend for less thrombotic events
Vannucchi et al. EHA 2014. Abstract LB-2436.
RESPONSE TRIAL: CHANGE IN PV SYMPTOMS
Median Percentage Changes From Baseline at Week 32 in Individual MPN-SAF Symptom Scores
Improvem
ent
−120
−100
−80
−60
−40
−20
0
20
40
Mesa R. ASH 2014. Abstract 709.
TOXICITY PROFILES OF PV AGENTSTOXICITY PROFILES OF PV AGENTS
Drug Common Adverse Effects
Hydroxyurea • Stomatitis• Leg ulcers• Dry skin, acne
• Gastric pain, diarrhea
Interferon alfa • Neutropenia• Elevated LFTs
• Fatigue• Headache
Ruxolitinib • Headache• Abdominal Pain• Diarrhea
• Fatigue• Dyspnea
Najean Y. Blood. 1997;90(9):3370-7; Kiladjian JJ. Blood. 2008;112(8):3065-72; Mesa R. ASH 2014. Abstract 709.
Kiladjian JJ
POSSIBLE ALGORITHM OF THERAPY OF PV IN 2015
Diagnosis of PV
Front Line CytoreductionHU, or HU vs. INF Clinical Trial
Consider ruxolitinib, INF (if not previously received), or JAK2 clinical trial
Assess Symptom Quartile
by MPN 10Q1:TSS <8Q2:TSS 8-17 Q3:TSS 18-31Q4:TSS ≥32 Decide on need for concurrent cytoreduction
based on risk and symptoms
YES
Monitor for symptom burden, vascular events, progression
Assess MPN Risk Score & Symptoms Control Hematocrit (<45%)
Low-dose aspirin in appropriate patients
NO
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
A. Oxygen saturation >95%
B. Platelet count: 485 x 109 L
C. Epo level: 1.9 mU/mL
D. WBC: 14.9 x 109/L
A. B. C. D.
25% 25%25%25%
According to the WHO, which of the following would be included among the characteristics that qualify a patient for diagnosis of PV?
QUESTIONQUESTION
A. Phlebotomy (P) alone
B. P + Aspirin (A) alone
C. P + A + hydroxyurea
D. P + A + ruxolitinib
E. P + A + interferon alfa
A. B. C. D. E.
20% 20% 20%20%20%
Which of the following would not be considered an appropriate first-line regimen for the treatment of PV?
QUESTION
A. Control of hematocrit
B. Reduction in splenomegaly, if present
C. Reduction in pruritus
D. Prevention of vascular events
E. All of the aboveA. B. C. D. E.
20% 20% 20%20%20%
Which of the following is among the goals of ruxolitinib therapy in PV?