Download Evolving Therapeutic Options for Polycythemia Vera: Perspectives of

Evolving Therapeutic Options for Polycythemia
Vera: Perspectives of the Canadian
Myeloproliferative Neoplasms (MPN) Group
Shireen Sirhan, Lambert Busque, Lynda Foltz, Kuljit Grewal,
Caroline Hamm, Nicole Laferriere, Pierre Laneuville, Brian
Leber, Elena Liew, Harold J. Olney, Jaroslav Prchal, Anna
Porwit, Vikas Gupta
Clinical Lymphoma, Myeloma and Leukemia Journal
Background
Objectives
• To discuss the potential impact of the changing landscape of
PV management on daily practice
• To assist Canadian physicians in the management of PV
patients
• To standardize the management of PV across the country
Development
• Each member of the writing committee was assigned a
specific topic
– Several meetings and teleconferences were held to finalize the
content
Key Topics
• Diagnostic Approaches
– Current and proposed WHO criteria for diagnosis of PV
•
•
•
•
Prognosis and Risk Assessment
Goals of Therapy
Therapeutic Approaches
Specific Situations
Key Topics
• Diagnostic Approaches
– Current and proposed WHO criteria for diagnosis of PV
•
•
•
•
Prognosis and Risk Assessment
Goals of Therapy
Therapeutic Approaches
Specific Situations
Current and Proposed WHO Criteria for
Diagnosis of PV
2008 WHO Diagnostic Criteria for PV1
2014 Proposed Revision of WHO Diagnostic
Criteria for PV2
Major Criteria
1. Hemoglobin >185 g/L (men), >165 g/L (women), or
evidence of increased red cell volume
Hemoglobin >165 g/L (men), >160 g/L (women) or
hematocrit >49% (men) >48% (women)
2. Presence of JAK2 V617F or other functionally similar
mutation (e.g., JAK2 exon 12 mutation)
Bone marrow findings consistent with WHO criteria with
pleomorphic megakaryocytes
Presence of JAK2 mutation
Minor Criteria
1. BM biopsy showing hypercellularity for age with
trilineage myeloproliferation
Subnormal serum erythropoietin level
2. Serum erythropoietin level below the normal
reference range
3. Endogenous erythroid colony formation in vitro
Diagnosis of PV requires meeting either both major
criteria and 1 minor criterion or the first major
criterion and 2 minor criteria.
Diagnosis of PV requires meeting either all three major
criteria or the first two major criteria and one minor
criterion.
Adapted from: 1. Thiele J, et al. Lyon, France: IARC Press:2008:40-43
and 2. Tefferi A, et al. Leukemia. 2014;28(7):1407-1413.
MPN Group Positioning Regarding the
Proposed WHO Diagnostic Criteria
• We acknowledge the necessity of appropriately diagnosing masked PV
• However, there are concerns about potential misuse of these criteria for
screening for PV
• We emphasize that:
–
–
Hb levels above the suggested threshold should not be taken in isolation, but
rather in the context of other potential signs and symptoms indicative of PV.
The intent of lowering the thresholds is to more accurately differentiate
between JAK2-positive ET and mPV rather than to serve as a base for
population screening
• We suggest the cost-effectiveness analysis of the new proposed criteria
Proposed Algorithm for PV Diagnosis
Blood JAK2V617F & Erythropoietin screen
JAK2V617F Positive*
Polycythemia Vera
Needed to confirm PV in
JAKV617F negative cases
JAK2V617F Negative
Low Erythropoietin
High Erythropoietin
Screen for
JAK2exon 12 mutation
Not
Polycythemia Vera
Bone marrow biopsy
Clinical clues : Splenomegaly, thrombosis, aquagenic pruritus, and erythromelalgia
Laboratory clues: Thrombocytosis, leukocytosis, and  leukocyte alkaline phosphatase score
*Not specific for PV. The possibility of a false positive or false negative mutation test result can be addressed by the
concomitant testing of EPO level, as more than 85% of patients with PV have low serum EPO concentrations
Adapted from Tefferi A. Am J Hematol. 2013;88(6):507-516.
MPN Group Positioning
Regarding Other Investigations
Bone marrow evaluation
• Limited additional value for diagnostic purpose in JAK2 V617F-positive
patients with erythrocytosis; currently it is not routinely required
• Information regarding age-adjusted bone marrow cellularity and grade of
fibrosis may have prognostic value and, as such, help in optimizing
therapeutic approaches
• In addition, a baseline BM biopsy might be essential in cases where the
diagnosis is unclear.
Cytogenetic testing
• May have prognostic value but not routinely performed in Canada
Mutations other than those involving the JAK-STAT pathway
• Increasing interest due to next-generation sequencing (NGS)
Key Topics
• Diagnostic Approaches
• Current and proposed WHO criteria for diagnosis of PV
•
•
•
•
Prognosis and Risk Assessment
Goals of Therapy
Therapeutic Approaches
Specific Situations
Risk Factors
Based on available evidence we identified risk factors for the
following 4 outcomes:
• Thrombosis
– Age and/or prior history of thrombosis*
• Overall Survival
• Age, history of thrombosis, leukocytosis, abnormal karyotype
• Transformation to PPV-MF
• JAK2 allele burden, disease duration (>10 years)
• Transformation to AML
• Age, abnormal karyotype, leukocyte count ≥15X109/L, Exposure to
P32, busulfan, and pipobroman
* the main indication for cytoreductive therapy
Risk Factors Associated with Thrombosis and
Overall Survival
1.
2.
Risk Factors for Thrombosis1
Hazard Ratio (95% Confidence interval [CI])
P-value
Age >65 (without prior thrombosis)
1.96 (1.29-2.97) P=0.0017
History of thrombosis (patients < 65)
2.00 (1.22-3.29) P=0.0061
Age > 65 years with prior thrombosis
4.35 (2.95-6.41) P<0.0001
Risk Factors for Reduced Survival2
Hazard Ratio (95% Confidence interval
[CI]) P-value
Age >61
7.4 (3.9-14.1) P<0.0001
Leukocytosis (>10.5x109/L)
3.3 (1.8-6.1) P=0.0001
History of venous thrombosis
3.9 (1.9-8.2) P=0.0002
Abnormal karyotype
3.1 (1.6-5.8) P=0.0005
Marchioli R, et al. J Clin Oncol. 2005;23(10):2224-2232.
Tefferi A, et al. Leukemia. 2013;27(9):1874-1881
Risk Factors Associated with Disease
Transformation
Risk Factors for Post-PV MF
Hazard Ratio (95% Confidence interval [CI])
P-value
JAK2 allele burden1
1.05 (1-1.1) P=0.03
Disease duration >10 years2
15.24 (4.22-55.06) P<0.0001
Risk Factors for AML
Hazard Ratio (95% Confidence interval [CI])
P-value
Age >613
6.3 (1.8-22) P=0.004
Abnormal karyotype*3
3.9 (1.2-13.1) P=0.03
Leukocyte count ≥15X109/L*3
3.9 (1.3-11.6) P=0.01
Exposure to P32, busulfan,
and pipobroman4
5.46 (1.84-16.25) P=0.0023
*Multivariable analysis; karyotype included as a covariate (n=383)
1.
2.
3. Tefferi A, et al. Leukemia. 2013S;27(9):1874-1881.
Passamonti F, et al. Leukemia. 2010;24(9):1574-1579.
Marchioli R, et al. J Clin Oncol. 2005;23(10):2224-2232. 4. Finazzi G, et al. Blood. 2005;105(7):2664-2670.
Key Topics
• Diagnostic Approaches
• Current and proposed WHO criteria for diagnosis of PV
•
•
•
•
Prognosis and Risk Assessment
Goals of Therapy
Therapeutic Approaches
Specific Situations
Goals of Therapy
• Prevention of occurrence or recurrence of thrombosis
– By decreasing the risk of thrombosis survival is extended
• Control of Hct and normalization of other blood
counts
• Mitigation of disease-related symptoms
Control of Cardiovascular Risk factors
• Currently, there are no specific data informing lipid or blood
pressure target ranges for individuals with PV
– It is prudent to manage atherosclerotic risk factors (including
hypertension, hyperlipidemia, diabetes) and encourage smoking
cessation
• Clinicians should refer to the Framingham Heart Study and the risk
assessment tool incorporated into Canadian guidelines for general
prevention of cardiovascular disease1
• Based on available data, Hct target <45% is the widely accepted
standard of care in routine clinical practice.2
– Hematocrit > 45 is associated with a significantly higher death rate due to
cardiovascular events or major thrombosis when compared with
hematocrit <45%
– The data is limited by the quality of available studies
1. Anderson TJ, et al. Can J Cardiol. 2013;29(2):151-167.
2. Marchioli R, et al. N Engl J Med. 2013;368(1):22-33.
Cardiovascular Risk Assessment
WHO TO SCREEN
Men 40 years of age and women 50 years of age or post-menopausal
(consider earlier in ethnic groups at increased risk, such as South Asians or First Nations individuals)
OR
All patients with the following conditions, regardless of age
• Current cigarette
• Family history of
smoking
hyperlipidemia
• Diabetes
• Erectile dysfunction
• Arterial hypertension
• Chronic kidney
• Family history of
disease
premature CVD
• Inflammatory
disease
• HIV infection
• COPD
• Clinical evidence of
atherosclerosis or
abdominal aneurysm
• Clinical manifestation
of hyperlipidemia
• Obesity (BMI >27)
HOW TO SCREEN
For all: History and examination, LDL, HDL, TG, non-HDL (will be calculated from profile), glucose, eGFR
Optional: apoB (instead of standard lipid panel), urine albumin:creatinine ratio
(if eGFR <60, hypertension, diabetes)
Framingham risk score <5%
Repeat every 3-5 years
Anderson TJ, et al. Can J Cardiol. 2013;29(2):151-167.
Framingham risk score 5%
Repeat every year
Importance of Keeping Hematocrit < 45%
Death from Cardiovascular Causes
or Major Thrombotic Events
1.0
Total Cardiovascular Events
1.0
Low HCT
0.9
Low HCT
0.9
P=0.004 by log-rank test
0.8
High HCT
High HCT
Hazard Ratio
0.7
Low HCT 5/182 (2.7%) 1.00
High HCT 18/183 (9.8%) 3.91 (95% CI, 1.45–10.53)
0.0
0.6
0
6
12
18
24
30
36
42
P=0.01 by log-rank test
0.8
48
Risk of CV death or major thrombotic event
is significantly higher when HCT > 45%
Hazard Ratio
0.7
Low HCT 8/182 (4.4%) 1.00
High HCT20/183 (10.9%) 2.69 (95% CI, 1.19–
6.12)
0.0 0.6
0
6
12
18
24
30
36
42
48
Significantly higher probability of CV
event in patients with HCT > 45%
Hematocrit between 45 and 50% is associated with a significantly higher death
rate due to cardiovascular events or major thrombosis when compared with
hematocrit <45% (HR = 3.91, 95% CI 1.45-10.53, P = 0.004)
Marchioli R, et al. N Engl J Med. 2013;368(1):22-33.
Correlation Between White Blood Cells and
Hematocrit
White-Cell Count (x10-3/mm3)
• Significantly higher WBC count in the high-HCT group
Low HCT
High HCT
vs low-HCT group
75th Percentile
Median
25th Percentile
13
12
75th Percentile
Median
25th Percentile
11
10
9
8
7
6
5
4
0
0
6
12
18
24
30
36
42
Months
HCT: hematocrit; WBC: white blood cell
Marchioli R, et al. N Engl J Med. 2013;368(1):22-33
MED/JAKp/0001
Key Topics
• Diagnostic Approaches
• Current and proposed WHO criteria for diagnosis of PV
•
•
•
•
Prognosis and Risk Assessment
Goals of Therapy
Therapeutic Approaches
Specific Situations
Phlebotomy
Advantages
• Immediate reduction of Hct
• Well tolerated
– Some patients might
experience fatigue after the
procedure; this might be
managed by adequate
hydration
*Cytoreduction is recommended in patients at
high risk for thrombosis
1.
2.
Kim J, Wessling-Resnick M. J Nutr Biochem. 2014;25(11):1101-1107.
Tobiasson M, et al. Med Oncol. 2010;27(1):105-107.
Disadvantages
• Inconvenience
• Does not decrease the
platelet or leukocyte
counts*
• Frequent phlebotomies may
– Lead to iron deficiency,
abnormal red blood cell
morphology, and eventually
reactive thrombocytosis.
– Rarely, phlebotomy-induced
iron deficiency might lead to
complications such as
cognitive problems and
restless leg syndrome1,2
Antiplatelet Drugs and Anticoagulants
• Low-dose Aspirin® is recommended for all PV patients without
contraindications1
• For patients with acute thrombotic events, acute antithrombotic therapy,
as per general thrombosis management is recommended (LMWH followed
by warfarin)
– There is no consensus regarding the optimal duration of anticoagulation
• Due to high rate of recurrence of thrombosis, an individualized risk-factor
based approach is recommended
– German and Austrian consensus guidelines recommend assessment after 3-6
months2
• Aspirin® is a reasonable option after 3-6 months of warfarin and cytoreduction in
patients with VTE at initial diagnosis
• Long-term anticoagulation may be favored in patients with high-risk features
(recurrent, splanchnic, or life-threatening VTE) and low bleeding risk
1. Barbui T, et al. J Clin Oncol. 2011;29(6):761-770.
2. Kreher S, et al. Ann Hematol. 2014;93(12):1953-1963
Cytoreductive Therapy
• In addition to patients with high risk of thrombosis (>60 years of age
and/or prior history of thrombosis) cytoreductive therapy can be
considered in:
– Extreme thrombocytosis with platelet count ≥1500x109/L
– Progressive leukocytosis ≥25x109/L
– Symptomatic splenomegaly
– Severe disease-related symptoms
– Intolerance to phlebotomy, especially in patients with compromised
cardiac function, inability to comply with phlebotomy requirements, or
poor venous access
Treatment Algorithm Suggested by the Canadian
MPN group
Risk Stratification
Low-risk
Age <60 years and no history of thrombosis
High-risk
Age >60 years and/or prior thrombosis
1. Cardiovascular risk factors modifications to prevent thrombotic complications
2. Low-dose Aspirin to reduce risk of cardiovascular events
3. Phlebotomy to control erythrocytosis by maintaining hematocrit <45%
• Progressively increasing leukocyte and/or
platelet count
• Enlarging spleen
• Uncontrolled disease-related symptoms
• Poorly tolerated phlebotomy
*If hydroxyurea and/or IFN-α-resistant/intolerant
**If not used front-line
Cytoreduction
Front-line
• Hydroxyurea
• IFN-α
Second-line*
• Hydroxyurea or IFN-α**
• Ruxolitinib
• Busulfan, anagrelide, participation in clinical trials
Hydroxyurea: Efficacy in Preventing Thrombosis
in PV Patients
Investigator
PVSG 081
Najean et
al2
Kiladjian et al3
Number,
Follow-up
Intervention
Comparator
Thrombosis Rates
51 patients
15.2 years
HU
(prospective)
Phlebotomy
(134 historical
controls)
HU: 9.8%*
Phlebotomy: 32.8%*
292 pts (<65
yrs)
7 years
HU
(randomized)
Piprobroman
No significant
difference
285 pts
16 yrs
HU
(randomized)
Piprobroman
No significant
difference
*On study events; all events, first 378 weeks—13.7% vs. 38.1%
HU: hydroxyurea; PVSG: Polycythemia Vera Study Group
1. Fruchtman SM, et al. Semin Hematol. 1997;34:17-23.
2. Najean Y, et al. Blood. 1997; 90:3370-3377.
3. Kiladjian JJ, et al. J Clin Oncol. 2011;29:3907-3913.
MPN Group Positioning on HU in PV
• Based on the perceived risk-benefit ratio, HU is widely used for the
treatment of PV in Canada and is usually well-tolerated
– The starting dose is 500 mg/day, with dose increases until the desired
response is obtained.
– When selecting an appropriate dose of HU, the clinician should
consider:
• The extent of myeloproliferation (higher doses in cases of
leukocytosis, thrombocytosis, and splenomegaly)
• Symptom burden
• The patient’s ability to tolerate higher doses
– Female patients should be advised that HU is contraindicated in
pregnancy and, therefore, appropriate contraceptive precautions
should be taken
• Although not a common problem in PV, the development of HU
resistance or intolerance needs to be further examined, especially
with the availability of other treatment options
Resistance/Intolerance to Hydroxyurea
in Polycythemia Veraa
Any of the following European LeukemiaNet (ELN) definitions
1. Need for phlebotomy to keep HCT < 45%
2. Uncontrolled myeloproliferation i.e. platelet count >400x109/L AND white blood cell
count >10x109/L
3. Failure to reduce massive splenomegalyb by more than 50% as measured by palpation,
OR failure to completely relieve symptoms related to splenomegaly
4. Absolute neutrophil count <1.0x109/L OR platelet count <100x109/L or haemoglobin
<100 g/L at the lowest dose of hydroxycarbamide required to achieve a complete or
partial clinico-haematological responsec
5. Presence of leg ulcers or other unacceptable hydroxycarbamide-related nonhaematological toxicities, such as mucocutaneous manifestations, gastrointestinal
symptoms, pneumonitis or fever at any dose of hydroxycarbamide
aAfter
3 months of at least 2 g/day of Hydroxyurea
extending by more than 10 cm from the costal margin
cComplete response was defined as: haematocrit <45% without phlebotomy, platelet count 400
x109/L, white blood cell count 10 x109 /L, and no disease related symptoms. Partial response was
defined as: haematocrit <45% without phlebotomy, or response in three or more of the other criteria
bOrgan
Adapted from Barosi G, et al. Br J Haematol. 2010;148(6):961-963.
Occurrence and Consequences of HU
Resistance/Intolerance
• A survey of 3,411 MPN patients treated with HU found a 5% incidence of
significant non-hematologic side effects1
– GI or cutaneous problems accounting for 90% of events
• HU resistance seems to be associated with:
•
Shorter survival (median 5.2 years compared to >20 years for non-resistant
patients)
•
Higher risk of transformation to PPV-MF or AML (HR,6.8; 95% CI, 3.0%-15.4%;
P <0.001).2
• HU has limited efficacy in relieving some PV-related symptoms, such as
aquagenic pruritus.3
1.
2.
3.
Antonioli E, et al. Am J Hematol. 2012;87(5):552-554.
Alvarez-Larrán A, et al. Blood. 2012 ;119(6):1363-1369
Saini KS, et al. Eur J Clin Invest. 2010;40(9):828-834.
Resistance to Hydroxyurea and Outcomes in PV
Effect of Resistance to HU on Survival
Effect of Resistance to HU on Disease
Transformation (MF & AML)
1.0
1.0
0.8
Incidence
Probability
0.8
0.6
0.4
0.2
0.0
Resistance
Non
resistance
5
10
0.4
0.2
Resistance
Non resistance
0
0.6
15
20
25
Years
0.0
0
5
10
15
20
25
Years
– Resistance to hydroxyurea was associated with higher risk of:
• Death (HR, 5.6; 95% CI, 2.7%-11.9%; P < .001)
• Transformation to AML or myelofibrosis (HR,6.8; 95% CI, 3.0%-15.4%; P <
.001)
261 PV patients with a median follow-up of 7.2 years
MF:myelofibrosis; AML: acute myeloid leukemia; HU: hydroxyurea
Alvarez-Larrán A, et al. Blood. 2012 ;119(6):1363-1369.
MED/JAKp/0001
Hydroxyurea as Mutagen:
Myths vs. Scientific Data
• A potential hazard in using HU is a mutagenesis as a
consequence of the role of ribonucleotide reductase in DNA
repair
• Conflicting evidence due to the inherent risk of leukemic
progression in PV even when untreated
• The ELN guidelines state that HU should be used with caution
in young patients (i.e., age <40 years)1
• The use of HU in a non-malignant blood disorder, sickle cell
disease in children, does not increase the risk of
transformation to MDS/AML2
1. Barbui T, et al. J Clin Oncol. 2011;29(6):761-770
2. Schultz WH, Ware RE. Am J Hematol. 2003;74(4):249-253148(6):961-963.
Hydroxyurea: Risk of Transformation
to AML/MDS
Investigator
PVSG
081
Finazzi et
al2
Kiladjian et
al3
Tefferi et al4
Number,
Follow-up
Intervention
Comparator
AML/MDS
51 patients
15.2 years
HU (prospective)
Phlebotomy
(134 historical
controls)
HU: 6% vs. Phleb:
1.5%* (NS)
(9.8% all event)
1638 pts
2.8 yrs
(4,393 pt-yrs)
Observational
-
No association with
single-agent HU
285 pts
16 yrs
HU
(randomized)
PIP
10, 15, 20 yrs
HU: 6.6, 16.5, 24.2%
PIP: 13.1, 34.1, 52.1%
1,545 pts
6.9 yrs
Retrospective
No association with
single-agent HU
*On study-event, 795 weeks
AML: acute myeloid leukemia; HU, hydroxyurea; MDS: myelodysplastic syndromes; NS: non-significant;
PIP: piprobroman; PVSG: Polycythemia Vera Study Group
1.
2.
3.
4.
Fruchtman SM, et al. Semin Hematol. 1997;34:17-23.
Finazzi G, et al, Blood. 2005;105:2664-2670.
Kiladjian JJ, et al. J Clin Oncol. 2011;29:3907-3913.
Tefferi A, et al. Leukemia. 2013;27:1874-1881.
Interferon
• Widely used in some European jurisdictions. In Canada, the coverage by
provincial reimbursement plans for primary treatment of PV varies
between provinces
• May be considered first-line therapy, particularly in younger patients
• The dose should be titrated individually based on efficacy and toxicity.
• Currently no firm conclusion can be made on the superiority of INF over
HU and its effects on thrombosis and survival
Benefits
• The absence of leukemogenic risk
• Better disease control ( in JAK2
allele burden)
• Improvement in symptoms,
including pruritus
Disadvantages
• Side effects, including autoimmune
disorders, flu-like manifestations,
depression, heart and ocular
disease, lead to permanent
discontinuation in ~25% of patients
Ongoing randomized trial comparing HU with interferon will be critical in defining
the future role of IFN in management of PV patients (DALIAH trial; NCT01387763)
1.
2.
Kiladjian JJ, et al. Blood. 2008;112(8):3065-3072.
Quintas-Cardama A, et al. J Clin Oncol. 2009;27(32):5418-5424.
Other Therapies
Busulfan
• Safe for short-term use in the elderly population, where the
recognized risk of increased AML transformation with
prolonged use may not be clinically relevant1
Anagrelide
• Use restricted to patients in whom decreasing the platelet
count causes ongoing symptoms and HU is ineffective or not
tolerated.2
1.
2.
Shvidel L, et al. Leukemia. 2007;21(9):2071-2072.
Anagrelide Study Group. Am J Med. 1992;92(1):69-76
Ruxolitinib
• Emerging data (RESPONSE trial) supports its use in PV
• Based on this, MPN group recommends ruxolitinib as a
second line therapy in hydroxyurea-resistant/intolerant
patients
• Undergoing Health Canada approval process
• It is being studied in other patient populations not included in
the RESPONSE trial
• Health Canada label and access / reimbursement will have
significant impact on its use in PV
Novel Investigational Approaches for PV
Other JAK inhibitors
• Several have been investigated in PV, some of which have been
discontinued from further development due to either toxicity or lack of
efficacy (fedratinib, momelotinib, lastarutinib, XL-019)
Histone Deacetylase Inhibitors (HDACi)
• Givinostat
• Vorinostat
Combination Therapy
Key Topics
• Diagnostic Approaches
• Current and proposed WHO criteria for diagnosis of PV
•
•
•
•
Prognosis and Risk Assessment
Goals of Therapy
Therapeutic Approaches
Specific Situations
Specific Situations
Splanchnic vein thrombosis (SVT)
• Strongly associated with MPN; patients with unexplained SVT should
undergo JAK2 V617F testing
• Medical treatment of SVT includes LMWH followed by lifelong oral
anticoagulation
Perioperative thrombosis
• Perioperative optimization of cytoreductive treatment for adequate
control of Hct and platelet count is essential
• In addition, DVT prophylaxis is recommended, especially in high-risk
surgery
• Aspirin® should be discontinued one week prior to elective interventions,
if the patient’s cardiovascular status permits
Pregnancy
• Rare, due to advanced age of the majority of PV patients
• Recommendations are based mostly on expert opinion and case series.
These include:
– Tight Hct control with phlebotomy and low-dose Aspirin® throughout
the pregnancy, as well as LMWH prophylaxis for six weeks post-partum
is recommended
– Uterine artery Doppler examinations at 20 and 24 weeks to obtain an
assessment of placental function are recommended
– Interferon for Hct and platelet count control in patients with previous
thrombosis or pregnancy complications as these patients are
considered at a higher risk
– Teratogenic drugs, such as HU or anagrelide, should be stopped prior
to conception, with a three- to six-month washout period
Robinson S, et al. Haematologica. 2005;90(11):1477-83.
Griesshammer M, et al.. Blood Rev. 2008;22(5):235-45.
Transformation of the Disease
Post-PV MF
• MF evolution is difficult to foresee, although leukocyte count >15x 109/L and
allele burden >50% predicted a higher risk1,2
• The diagnosis is based on International Working Group for Myelofibrosis Research
and Treatment (IWG MRT) criteria3
• PPV-MF is managed as primary MF tailoring treatment to anemia, splenomegaly,
and constitutional symptoms
• Following progression of PV to PPV-MF, survival is predicted using IPSS4 at
diagnosis and DIPSS5 at the follow-up assessments, although these risk scores
were not specifically validated in PPV-MF
Post-PV AML
• An aggressive disease with very poor outcomes
• Intensive chemotherapy has a limited role in management unless further
consolidated by allogeneic transplant6
• Hypomethylating agents and/or experimental therapies should be considered7
1.
2.
3.
4.
Passamonti F, et al. Leukemia. 2010;24(9):1574-1579
Passamonti F, et al. Blood. 2008;111(7):3383-3387
Barosi G, et al. Leukemia. 2008;22(2):437-438.
Cervantes F, et al. Blood. 2009;113(13):2895-2901.
5. Passamonti F, et al. Blood. 2010;115(9):1703-1708.
6. Kennedy JA, et al. Blood. 2013;121(14):2725-33.
7. Passamonti F, et al. Cancer. 2005;104(5):1032-1036
Summary
• It is important that PV patients are appropriately managed
and followed on a regular basis
– Therapy should be individualized in every patient and adjusted based
on disease burden, as well as patient individual needs and preferences
• Shared-care models between centers with MPN expertise and
community healthcare providers are being explored in Canada
• These models provide access to expert centers while routine
clinical care is provided in the community