Upload
priscilla-glenn
View
217
Download
2
Tags:
Embed Size (px)
Citation preview
Current Approaches to Current Approaches to the Diagnosis and Management the Diagnosis and Management
of Non-CML of Non-CML Myeloproliferative DisordersMyeloproliferative Disorders
CME Enduring Material
Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders
Review Date: April, 2003
Release Date: June, 2003
Credit Available Through: June, 2005
A Continuing Medical Education Activity
Sponsored by: Mount Sinai School of Medicine
Supported by:An unrestricted educational
grant from Shire US Inc.
Credit issued by: Mount Sinai School of Medicine
Produced by: Jonathan Wood & Associates
This activity was planned and produced in accordance with the ACCME Essentials
Overall PurposeThis educational slide program, with accompanying notes pages and CD-ROM, is a compilation of experts’ slides from a series of conferences held around the country on the non-CML myeloproliferative disorders (MPDs). The program is intended to provide the latest findings and a comprehensive background on this rare group of disorders and should serve as a ready-reference for physicians in their own practices.
Target AudienceHematologists, oncologists, and allied health professionals who care for MPD patients
ObjectivesUpon completion of this course, hematologists, oncologists, and alliedhealth professionals should be able to:• Recognize MPDs as stem cell disease• Differentiate between clonal and nonclonal thombocytosis• Describe the pathophysiology of myeloproliferative platelets• Understand leukemic transformation as a natural progression of
MPDs or as a sequela of therapy• Evaluate the use of allogeneic and autologous stem cell
transplantation for MPDs, including selection of candidates, use of conditioning regimens, and complications of transplantation
• Diagnose accurately and treat patients with MPDs in their practice• Choose among the various treatment options• Recognize disturbances of normal hemostatic mechanisms in
MPDs
Accreditation
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of Mount Sinai School of Medicine. Mount Sinai School of Medicine is accredited by ACCME to provide continuing medical education for physicians. Mount Sinai School of Medicine designates this continuing medical education activity for a maximum of 5 credits in Category 1 credit towards the AMA Physician’s Recognition Award. Each physician should claim only those hours that he/she spent in the educational activity.
Grantor
This activity is made possible by an unrestricted educational grant from Shire US Inc.
Produced ByJonathan Wood & Associates
Faculty
Steven M. Fruchtman, MD, ChairClinical Director, Division of HematologyMount Sinai School of MedicineNew York, New YorkDisclosure: Grant/Research Support: Merck and Co,
Inc, Fujisawa Healthcare Inc, Shire US Inc.;
Consultant/Advisory Board: Sangstat Medical Corp, Novartis; Speakers Bureau: Shire US Inc., Merck and Co, Inc
Charles L. Bennett, MD, PhDProfessor of MedicineNorthwestern University School of MedicineChicago, IllinoisDisclosure: Consultant/Advisory Board/Speakers
Bureau: Shire US Inc.
Harriet S. Gilbert, MDClinical Professor of MedicineAlbert Einstein College of MedicineBronx, New YorkDisclosure: Speakers Bureau: Shire US Inc.
Craig Kessler, MDProfessor of Medicine and PathologyChief, Division of Hematology-OncologyGeorgetown University Medical CenterWashington, DCDisclosure: No commercial relationships to disclose
John M. McCarty, MDAssociate ProfessorDirector, Bone Marrow Transplantation ProgramMedical College of Virginia, Virginia
Commonwealth UniversityRichmond, VirginiaDisclosure: No commercial relationships to disclose
Robert M. Petitt, MDSenior Consultant in HematologyMayo ClinicRochester, MinnesotaDisclosure: Consultant/Advisory Board: Shire UK;
Speakers Bureau: Shire US Inc.
General Disclosure
Four current therapeutic alternatives that are being used in the management of myeloproliferative disorders are cited throughout this educational slide program. Anagrelide is the only compound that the FDA has approved for the treatment of patients with thrombocythemia secondary to myeloproliferative disorders. Use of hydroxyurea, interferon-, or stem cell transplant are unproven therapies that do not have an FDA indication in the treatment of the non-CML myeloproliferative disorders.
It is the policy of the Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored programs. All faculty participating in sponsored programs are expected to disclose to the audience any real or apparent conflict-of-interest related to the content of their presentation, and any discussions of unlabeled or investigational use of any commercial product or device not yet approved in the United States.
Table of ContentsTable of ContentsClick on title to start
Overview: Epidemiology, Etiology, and Pathophysiology
Natural History
Platelet Physiology
Diagnosis and Diagnostic Issues
Treatment
• Essential Thrombocythemia
• Polycythemia Vera
• Idiopathic Myelofibrosis
• Stem Cell Transplant
Cost-effectiveness
Conclusions
References/Posttest/Evaluation
Overview:Epidemiology, Etiology, and
Pathophysiology
Chronic Myeloproliferative Disorders
Four well-characterized subgroups:
• Polycythemia vera (P Vera)
• Essential thrombocythemia (ET)
• Agnogenic myeloid metaplasia (AMM)
• Chronic myelogenous leukemia (CML)
HS Gilbert
Potentially Confusing Disorders
• P Vera, or CML, or AMM
• Undifferentiated chronic myeloproliferative disorder
• Cellular agnogenic myeloid metaplasia
• Chronic myelomonocytic leukemia
• Chronic basophilic, eosinophilic, or neutrophilic leukemia
• Juvenile chronic myelogenous leukemia
RM Petitt
Non-CML MPDs
THROMBOSISHEMORRHAGE
POLYCYTHEMIAVERA
Erythroid
MYELOID METAPLASIA
Extramedullary Hematopoiesis
THROMBOSISHEMORRHAGE
ESSENTIALTHROMBOCYTHEMIA
Megakaryocyte/Platelets
HYPERLEUKOCYTOSISHYPERHISTAMINEMIA
LYSOZYMURIA
"Ph- CML""CMML-OID"
Myeloid/MonocyteMast cell/Basophil
Pluripotential Hematopoietic Stem CellMonoclonal Expansion
Retention of Pluripotentiality, Commitment, Differentiation, MaturationOver-Production of Functioning Circulating Hematic Populations
PLTS
MyM
RBC
WBC
HS Gilbert
RBC
MyM
P VeraET
PLTS
MyM
WBC
Phenotypes of MPDs
HS Gilbert
Causes of High Platelet Counts
• Essential thrombocythemia• Other chronic myeloproliferative disorders
– P Vera, MM-MF, CML
• Reactive thrombocytosis• Familial thrombocythemia
– High TPO, normal TPO (?abnormal c-mpl)
• Myelodysplastic syndromes– CMML, 5q minus
• Laboratory artifact– ANLL
RM Petitt
ET: Pathophysiology
• Platelet production increased more than 5-fold– 237 million (normal 43 million) per day
• Platelet survival normal• Megakaryocyte mass increased almost 4-fold
– Number increased– Volume increased– Diameter increased (reflects increased ploidy)
• Megakaryocyte ploidy increased– 64N and 128N cells relatively common
RM Petitt
Reactive Thrombocytosis
• Acute or chronic inflammatory disease• Acute or chronic bleeding• Iron deficiency• Chronic marrow stimulation, e.g. hemolysis• Post-thrombocytopenic rebound• Disseminated malignancy• Absence of spleen (surgical, congenital,
functional)• Intense exertion, parturition, trauma, epinephrine
RM Petitt
Clinical Features of ET
• Median age at diagnosis = 60 years• Between 25 and 50 years, more common in
women; young women in childbearing age are a subgroup with special problems
• Microvascular symptoms are common; thrombotic complications exceed bleeding complications
• < 5% incidence of transformation into myelofibrosis with myeloid metaplasia or acute leukemia
HS Gilbert
Thrombosis in ET
• Thrombotic risk per Cortelazzo et al:– 30% in patients with prior history of thrombosis– 3% in patients with no prior history of thrombosis
• Thrombotic complications in one cohort was 6.6 per patient-year (higher in > 60 y/o and those with prior history of thrombosis)
HS Gilbert
Thrombosis in ET
• Increased incidence of thrombotic complications in treated patients with inadequately controlled platelet counts– Current data suggest that thrombotic
complications can and do occur at relatively low platelet levels and recommend reduction of platelets to <400,000/L
HS Gilbert
Incidence of ET
0
20
40
60
80
100
120
<10 10–15 16–20 21–25 26–30 31–35 36–40 41–45 46–50 51–55 56–60 61–65 66–70 71–75 76–80 81-85 86–90 >90
Men
Women
Fre
qu
ency
, %
SM FruchtmanAge in years
Survival After Diagnosis in ET
• ET after 10 years– Survival = 72%– Symptom-free survival = 54%
• ET after 19 years– Survival = 52%– Symptom-free survival = 35%
• In young patients with ET, overall survival in the first 10 years is near normal
HS Gilbert
ET: Natural History (2091 Cases)
• 1294 F : 797 M = 1.62• Mean age 56 years (SD 17, range 2-94)
– 20% under age 40 years
– 30% 40-60 years of age
– 50% over age 60 years
• Mean platelets 1.004 million/L (range 0.601-4.0)
• Splenomegaly 22.8%• Hepatomegaly 27.0%• Karyotypic abnormality 4.9%
RM Petitt
ET: Natural History (2091 Cases)
• Median follow-up 4.4 years (mean 5.1, SD 3.9)– 230 thrombotic events (11%); 65 fatal (3.1%)– 130 hemorrhagic events (6.2%); 6 fatal (0.3%)– 137 neoplastic events (6.6%)
• 32 acute leukemia (1.5%); 24 fatal (1.2%)• 8 MDS (0.4%); 2 fatal (0.1%)• 31 myelofibrotic (1.5%); 3 fatal (0.15%)• 66 nonhematologic (3.2%); 3 fatal (0.15%)
– 201 deaths (9.6%)
RM Petitt
Classification of the Erythrocytoses
Increased RCM
Absolute erythrocytosis
Primary erythrocytosis
Congenital e.g. Truncation of theEpo receptor
Acquired e.g. Polycythemia vera
Secondary erythrocytosisCongenital e.g. High oxygen affinity Hb,
autonomous high Epo production
Acquired e.g. Hypoxemia, renal disease
Idiopathic erythrocytosis
Normal RCM
Apparent erythrocytosis
Raised PCV (Females >0.48; Male >0.51)
RCM (interpreted using ICSH reference values)
SM Fruchtman
Clinical Features of P Vera
• Median age at diagnosis = 60 years• Slightly more common in men• Clinical manifestations: thrombosis > hemorrhage;
microvascular symptoms (headaches, transient neurologic or ocular symptoms, distal paresthesias, or erythromelalgia) are common
• Transformation into myeloid metaplasia occurs in 10%-30% of patients observed for 10 to 25 years; natural evolution or treatment related?
• Transformation to MDS and acute leukemia – late complication; natural evolution or treatment related?
HS Gilbert
Thrombosis in P Vera
• Risk of recurrent thrombosis increases with age and in patients with a history of thrombosis:– Reported incidence for thrombotic events ranged
from 18%-61%; PVSG incidence was 10% per annum in arm treated with phlebotomy only
– Large retrospective study found 41% incidence of thrombosis before diagnosis or during follow-up
– 25% risk of recurrent thrombosis in patients with a history of thrombosis; 17% in patients with no risk
HS Gilbert
Life Expectancy in P Vera
• In P Vera, median survival exceeds 15 years in young patients.
• In P Vera, serious complications can occur in young patients. Early therapy may be advised.
HS Gilbert
Natural History
Natural History of ET and P Vera
• Hemorrhage
• Myeloid metaplasia
• Myelofibrosis
• Myelodysplastic syndrome
• Acute leukemia
• Thrombosis
HS Gilbert
ET: Complications
• Microvascular occlusion– Erythromelalgia from spontaneous aggregation
• Medium/large vessel thrombosis– Probably some baseline risk at any platelet count– May increase somewhat as platelet count rises
• Hemorrhage– Risk definitely increases as platelet count rises
• Leukemic transformation– Small but definite underlying risk– Effect of treatment
RM Petitt
Complications of ET
• Arterial thrombosis 20%(MI 4%, stroke 2%)
• Microvascular disturbances 32%(TIAs primarily, erythromelalgia)
• Hemorrhage 18%(GI or serious hemorrhage 5%)
• Venous thrombosis 6%
CM Kessler
Erythromelalgia (Erythermalgia)Attacks of severe burning, erythema, & warmth (feet > hands)
Provoked by heat, exercise, and dependency
Relieved by cold, rest, and elevation and by aspirin (?cyclooxygenase role)
Two types:
Idiopathic (60%): usually symmetrical
Secondary (40%): half asymmetric
Half of secondary cases associated with chronic MPDs:
P Vera in 60%, ET in 40%; MM & CML very rarely
Symptom attacks precede overt MPD in 85%, often by several years
M:F ratio = 2
Gangrene occurs, especially in patients with ET
RM Petitt
RM Petitt
Photo
ET: Risk of Thrombosis• 114 high-risk ET patients
– 97 (85%) over age 60– 52 (46%) with previous thrombosis– Median platelet count 788,000
(533,000-1,240,000)/μL
• Randomized to hydroxyurea (56) or no treatment (58)
• After median follow-up of 27 months– 2 thrombotic events (3.6%) in hydroxyurea group– 14 thrombotic events (24%) in untreated group– Statistically significant difference (p = 0.003)
RM Petitt
ET: Risk of Thrombosis• 65 low-risk ET patients
– Age<60, no history of thrombosis, platelets<1.5 million/μL (mean 823,000)
• Compared with 65 age and sex-matched controls• Median follow-up 4.1 years• Thrombosis incidence:
– 1.91 cases per 100 patient years in ET– 1.50 cases per 100 patient years in controls
• Authors concluded that low-risk patients do not need treatment. However, this study is subject to criticism because:– Aspirin usage was not controlled– Seven previous studies all had significantly higher rates of thrombosis
in their groups of ET patients
RM Petitt
ET and Thrombosis
• 56 ET patients 1976-1992 (median age 66, median platelets 1.125 million/L at diagnosis, median follow-up 45 months); 52 received platelet-reducing agents; 41 received antiaggregating agents.
• 46 (82%) had symptoms attributable to thrombocythemia– 32 at platelet counts < 600,000/L
– 23 at platelet counts < 500,000/L
– 10 at platelet counts < 400,000/L
• 19 (34%) had severe complications (CVA, TIA, DVT, gangrene)– 10 at platelet counts < 600,000/L
– 7 at platelet counts < 500,000/L
– 2 at platelet counts < 400,000/L
• 42 (91%) improved following further reduction in platelets
RM Petitt
Hepatic Venogram of Budd-Chiari Syndrome in ET
CM Kessler
ET: Symptoms and Platelet Count
RM Petitt
1000
900
800
700
600
500
400
300
200
100
0
Pla
tele
t C
ou
nt
(×10
9 /L
)
Lowest CountsAssociated WithManifestations
Counts AfterCessation of
Manifestations
Changes in platelet counts, from the lowest counts recorded while patients were symptomatic to counts recorded on resolution of symptoms in 42 ET patients (4 patients with permanent complications are not included).
Risk Factors for ET Complications
• Prior thrombotic event (31.4% vs 6.6%)
• Smoking (Not well characterized)
• Age > 60 years (15.1% vs 6.6%)
• Long duration of thrombocytosis(platelets > 600,000/L—not well characterized)
• Other risk factors for CAD (not well characterized)
CM Kessler
Disease Burden of ET and P Vera
Annual incidence• ET 2.5 per 100,000• P Vera 2.3 per 100,000• AMM 1.3 per 100,000
Cases and rate of growth• 93,000 patients
– 53,000 ET– 40,000 P Vera
• 10% per year growth
HS Gilbert
Timeline of MPDs
HS Gilbert
P Vera
ET
MyM
MF
LeukemiaMDS
Platelet Physiology
Peripheral Blood Showing Massive Platelet Clumping and a Basophil
x 1000; Reduced 5% for Reproduction SM Fruchtman
Bone Marrow Biopsy Showing Prominent Megakaryocytic Hyperplasia
x 100; Reduced 5% for Reproduction SM Fruchtman
Photomicrographs Showing Variation in Reticulin Content in P Vera
SM Fruchtman
Reticulin grade in
representative fields
of four biopsies:
A. “Normal”B. Slight increaseC. Moderate increaseD. Marked increase
Foot and Foot Silver Stain. x250
Procollagen Molecule
S S
SS
S S
S S
H0
HO
S S
S S
S S
SS
S S
SS
S S
GlcNac(Man)n
GlcGal Gal
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OHOH
OH
OH
OH
OH
OH
S S
SS
S S
S S
H0
HO
S S
S S
S S
SS
S S
SS
S S
GlcGal Gal
GlcNac(Man)n
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OHOH
OH
OH
OH
OH
OH
N-TerminalPropeptide
(150Å)
Collagen Molecule(3000 Å)
C-TerminalPropeptide
(150Å)
(100Å)(20Å)
GlobularDomain
Triple-Helical DomainNontriple-Helical Domain
Nontriple-HelicalDomain
Triple-Helical Domain
Nontriple-HelicalDomain
(15Å)
Schematic representation of the structure of the procollagen molecule.Glc denotes glucose, Gal galactose, Man mannose, and GlcNac N-acetylglucosamine
SM Fruchtman
What Is the Pathophysiology of Bleeding and Thrombosis in ET
?
• Platelet number
• Platelet function
• Platelet turnover
• Other factors
SM Fruchtman
Normal Platelet Physiology
• Platelets participate in hemostasis in conjunction with blood vessels and the humoral coagulation system
• Sequence of platelet functions:– Adhesion to exposed subendothelium via vWF and
GPIb/IX– Aggregation (cohesion) via fibrinogen interactions
with GPIIb/IIIa– Secretion or release reaction with release of dense
body and alpha granule contents, FVIII, PAI-1, tPA, etc
CM Kessler
CollagenGP Ia/IIa
GP Ib
GP IIb/IIIa
Endothelium
von Willebrand factor
Platelet
Adapted from Coller BS. Circulation. 1995; 92: 2373.
Platelet Adhesion
CM Kessler
Adapted from Coller BS. Circulation. 1995;92:2373.
GP IIb/IIIa receptor
Platelet
Fibrinogen
Platelet Aggregation
CM Kessler
Platelets at Rest
CM Kessler
Activated Platelets
CM Kessler
Normal Platelet Physiology
• Platelet activation redistributes phosphatidylserine (PS) from the inner leaflet of the platelet membrane to the outer surface; mediated by enzyme phospholipid scramblase
• Exposure of PS is critical to expression of platelet procoagulation activity; provide VIIa-TF, Xa, IXa, and VIIIa binding sites
CM Kessler
Platelet Structure
CM Kessler
Normal Platelet Physiology (Cont’d)
• Platelet activation induced or modulated by:– Agonist–receptor ligand interaction - activates
membrane-bound phospholipases C and A, which hydrolyze phosphatidylinositol on the inner leaflet; mediated by GTP
– Inositol triphosphate (IP3) functions as messenger to mobilize Ca+2 ions from intracellular stores
– Diacylglycerol (DAG) activates protein kinase Cphosphorylation of 47kD pleckstrinGPIIb/IIIa activation
CM Kessler
COX=cyclooxygenase DTS=dense tubular system PKC=protein kinase C
DAG=diacylglycerol PIP2=phosphoinositol biphosphate TXA2=thromboxane A2
G-proteins = mediate interaction of cell surface receptors with intracellular efectors
Platelet Biochemistry
CM Kessler
Coagulation Pathway Intrinsic pathway Extrinsic pathway
(Activated within minutes) (Activated within seconds)
Contact activation Tissue damage
XII XIIa III (Tissue factor)
XI XIa, Ca2- TF- VIIa VII
IX IXa PF3, Ca+2
Xa XCa2-
PL
Thrombin (IIa) Prothrombin (II)
Fibrinogen
Irreversible plateletaggregation
Fibrin & blood cells KEY
Conversion to
Causes conversionor release
Inhibition of
Prothrombinase complex
Ca2-
VIII VIIIa
X
V Va
Soluble fibrin
XIII XIIIa Ca+2
Cross-linked fibrin clot
TFPIATIII
PS-PC
CM Kessler
Functional Abnormalities of Platelets in MPDs
• Prolonged bleeding times - detected in 17% of MPDs; more often seen in AMM than other MPDs; no correlation with bleeding symptoms
• Platelet aggregation responses– Spontaneous hyperaggregability in ET– Impaired aggregation to some or all agonists
• Impaired epinephrine response most common, but not pathognomonic of MPDs
ADP(39%), collagen(37%), epinephrine(57%)
CM Kessler
Functional Abnormalities of Platelets in MPDs (Cont’d)
platelet 2-adrenergic receptors• Impaired dense granule release• Decreased membrane surface glycoproteins
• Defective Ca+2 mobilization, TxA2 formation, lipoxygenase accumulation
• Loss of HMW multimers of vWF protein; inversely related to platelet count; improved post cytoreduction
CM Kessler
Disorders of Platelet Function
• Clinically manifests as mucocutaneous bleeding, excess hemorrhage posttrauma & surgery, easy bruising, menorrhagia, etc.
• Usually prolonged bleeding time• Platelet aggregation and secretion studies often reveal
defect but usually do not predict severity of clinical manifestations
• Acquired defects >> inherited defects
CM Kessler
Acquired Platelet Dysfunction in MPDs
• Platelets most likely to develop from an abnormal clone of stem cells
• Abnormal function may result from enhanced platelet activation in vivo
• Platelet abnormalities contribute to the mortality and morbidity of MPD; impact of thrombosis is greater than that of bleeding
• Hemorrhagic and thrombotic complications may occur separately or simultaneously; often unpredictable since asymptomatic individuals may have platelet dysfunction
CM Kessler
Platelet Disorders in MPDs
• Bleeding and thrombosis less common in CML versus other MPDs
• Bleeding more frequent in AMM versus other MPDs; thrombosis not common in AMM
• Hemorrhage usually from GI and GU tracts; risks of spontaneous bleeding with platelets > 2,000,000/L; exacerbated by ASA
CM Kessler
Platelet Disorders in MPDs (Cont’d)
• Thrombotic events can be arterial and/or venous, often in portal, hepatic, splenic, cerebral sinuses
• DVT, PE, AMI, CVA, and PAO all reported in MPDs, often underestimated as platelet-mediated events (Underlying etiology is complex; platelet abnormalities may be contributory)
• Microvascular arterial thrombi may occur—erythromelalgia, neurologic symptoms, visual complaints
CM Kessler
Platelet-Mediated Thrombosis in ET
• Risk factors for thrombosis in ET– Age– Prior thrombotic event– Inadequate control of thrombocytosis– Presence of risk factors for CAD, CVA, etc– In vitro spontaneous megakaryocyte colony formation– Increased risk of recurrent first trimester
miscarriages, premature labor, IUFGR (intrauterine fetal growth retardation), abruptio placentae
CM Kessler
Evidence for TPO/Mpl Axis in MPDs• In 17 patients with ET:
– normal to high plasma TPO levels– all patients with strikingly reduced c-Mpl mRNA and protein
• normal levels of GPIIb/IIIa– No aberrant pTYR activity in response to TPO stimulation
• In 12 patients (10 P Vera, 2 IM):– normal to high plasma TPO levels– all patients with scant or absent c-Mpl protein expression– reduced or absent pTYR activity in response to TPO stimulation
• TPO and anagrelide have opposing effects
Observation TPO Anagrelide
Megakaryocyte size 50% 22% Mean ploidy 32-65 N 8-16 N
Megakaryocyte colony # 7-10 X 57%
Megakaryocyte colony size 5-6 X 31%
J McCarty
Hypothesis:
• Since myeloproliferative disorders are associated with abnormalities of TPO and c-Mpl
• Since the biologic effects of TPO and anagrelide appear to act in opposition in vitro
• Does anagrelide induce its thrombocytopenic effect by modulating TPO/c-Mpl-specific molecular events in human stem cells?
J McCarty
Consequences of TPO/Mpl Binding1. TPO binding dimerizes Mpl on cell
surface2. Causes autophosphorylation of
associated JAK/STAT and other pTYR and pSER signaling pathways
3. Activated early acting transcription factors induce transcription of megakaryocyte-specific gene sets
4. Mpl/TPO complex internalized and degraded leading to loss of both receptor and bound TPO
5. Newly synthesized Mpl receptor monomers are refreshed at cell surface Anagrelide may interfere at these steps
J McCarty
Effect of Anagrelide on hTPO- or hIL-3-Stimulated Liquid Culture of Human CD34+ Stem Cells
J McCarty
12 day stimulation with hTPO100ng/mL
0
100020003000
400050006000
70008000
020000400006000080000100000120000140000160000180000
Megakaryocyte number
12 day stimulation withhIL-3 200U/mL
0
1000
2000
3000
4000
5000
6000
7000
8000
020000400006000080000100000120000140000160000180000
Total mononuclear cell number
Vehicle
Anagrelide 5 ng/mL
Anagrelide 500 ng/mL
Anagrelide 500 g/mL
Vehicle
Anagrelide 5 ng/mL
Anagrelide 500 ng/mL
Anagrelide 500 g/mL
Summary Findings
• Anagrelide inhibits CFU-Mk in human CD34+ cells• Antiproliferative effects:
– specific for TPO, not IL-3– specific for megakaryocyte lineage– do not affect total MNC number
• Anagrelide species-specific effect determined by Mpl• Anagrelide affects pTYR activity in TPO-stimulated, but
not IL-3-stimulated, cells and lines• Anagrelide exhibits TPO-specific inhibition of cell
proliferation and pTYR activity.
J McCarty
Potential Mechanisms of Anagrelide Action
Anagrelide may act at severalsteps:1. May act as inhibitor of TPO binding2. May inhibit proximal steps of
TPO/Mpl-associated phosphotyrosine or phosphoserine signaling pathways
3. May interfere with TPO/Mpl- associated megakaryocyte-specific gene expression
4. May prevent internalization of bound TPO/Mpl complex
5. May curtail production and cell surface expression of Mpl monomers
J McCarty
Diagnosis and Diagnostic Issues
Current Approaches to Diagnosing ET and P Vera
HS Gilbert
ET and P Vera: Initial Considerations
• Diagnosis—confirm
• Symptoms at presentation
• Assessment of risk—age, risk factors for thrombosis
• Discussion of treatment alternatives with patient
SM Fruchtman
Diagnosis of P Vera vs ET
• Primary Erythrocytosis– Acquired abnormality of marrow - Polycythemia vera– Congenital abnormality - truncation of erythropoietin receptor
• Secondary Erythrocytosis– Acquired - secondary to hypoxemia, renal disease, etc– Abnormalities of the Hgb molecule or autonomous high
erythropoietin production
• Diagnosis: Measure erythropoietin levels– Elevated hematocrit and low erythropoietin levels– No other symptoms– Patient has P Vera
HS Gilbert
Differential Diagnosis of ThrombocytosisI. Essential thrombocythemiaII. Other chronic myeloproliferative disorders
A. Polycythemia veraB. Chronic granulocytic leukemiaC. Myelofibrosis/agnogenic myeloid metaplasiaD. Overlap myeloproliferative disorders
III. Myelodysplastic syndromes associated with thrombocytosisA. 5q-syndromeB. Idiopathic refractory sideroblastic anemia
IV. Reactive thrombocytosisA. Blood loss and/or iron deficiencyB. SplenectomyC. Hemolytic anemiaD. MalignancyE. MyelophthisisF. Chronic inflammatory disordersG. InfectionH. Drug inducedI. Rebound from thrombocytopeniaJ. Exercise
SM Fruchtman
Proposed Diagnostic Criteria—ETI. Platelet count >600,000/L
II. Hematocrit <40, or normal RBC mass (Males <36 mL/kg, females <32 mL/kg)
III. Stainable iron in marrow or normal serum ferritin or normal RBC mean corpuscular volume (otherwise Fe trial)
IV. No Philadelphia chromosome or bcr/abl gene rearrangement
V. Collagen fibrosis of marrow
A. Absent or
B. <1/3 biopsy area without both marked splenomegaly and leukoerythroblastic reaction
VI. No cytogenic or morphologic evidence for MDS
VII. No cause for reactive thrombocytosisSM Fruchtman
Thrombosis
• DVT
• PE
• CVA/TIA/Retinal/MI
• Hepatic & portal vein thrombosis
• Digital ischemia
• Erythromelalgia
• Miscarriage
SM Fruchtman
Essential Thrombosis
• Most patients are asymptomatic (estimated to be up to 2/3)
• However, catastrophic thrombotic complications are seen
• Frequently a syndrome of young women. Thus, issues of management during pregnancy are important
SM Fruchtman
Reduced expression of the thrombopoietin receptor Mpl is characteristic of polycythemia vera and idiopathic myelofibrosis.
The abnormality appears to distinguish polycythemia vera from other forms of erythrocytosis.
SM Fruchtman
Mpl and P Vera
Bleeding
• Skin
• Mucous membranes
• GastrointestinalBy trauma
SM Fruchtman
Polycythemia Vera Study Group (PVSG) Five Protocols
Polycythemia Vera # Patients Initiated
PVSG-01 Prospective, randomized-Phlebotomy vs 32P vs chlorambucil
431 1967
PVSG-05 Prospective, randomized-Phlebotomy, aspirin, dipyridamole vs 32P
178 1977
PVSG-08 Phase II, efficacy-Hydroxyurea
51 1977
Essential Thrombocythemia
PVSG-10 Prospective, randomized-Melphalan vs 32P
55 1975
PVSG-12 Phase II, efficacy-Hydroxyurea
29 1977
SM Fruchtman
ET: 1975 PVSG Diagnostic Criteria
• Platelet Count in excess of 1,000,000/L
• Marked megakaryocytic hyperplasia
• Abundant platelet clumps
• Normal red cell mass (adequate iron)
• No Philadelphia chromosome
• No significant myelofibrosis
RM Petitt
ET: 1983 PVSG Diagnostic Criteria
• Platelet Count in excess of 600,000/L
• Marked megakaryocytic hyperplasia
• Abundant platelet clumps
• Normal red cell mass (adequate iron)
• No Philadelphia chromosome
• No significant myelofibrosis
RM Petitt
ET: 1996 Swedish Diagnostic Criteria• A1 Platelets in excess of 600,000/L• A2 Normal red cell mass, or <125% of mean predicted
value with stainable marrow iron or failed iron trial• A3 No Philadelphia chromosome• A4 Megakaryocytic hyperplasia and/or increased ploidy; no
fibrosis
• B1 Splenomegaly on isotopic scan or ultrasound• B2 Unstimulated growth of BFU-E and/or CFU-Meg• B3 Normal sedimentation rate and fibrinogen
• All four “A” criteria = ET• A1 + A2 + A3 + any two “B” criteria = ET
RM Petitt
ET: 1997 Revision of 1983 PVSG Criteria
• Platelet count in excess of 600,000/L• Hematocrit under 40% or normal red cell mass• Normal marrow iron or serum ferritin or MCV• No Philadelphia chromosome or bcr/abl
rearrangement• No collagen fibrosis, or less than 1/3 of biopsy
area (without splenomegaly and leukoerythroblastosis)
• No cytogenetic or morphologic evidence of MDS• No cause for reactive thrombocytosis
RM Petitt
PVSG Criteria for the Diagnosis of P Vera
A1 Increased RBC massMale: 36 mL/kgFemale: 32 mL/kg
B1 Thrombocytosis:Platelet count >400,000/L
A2 Normal arterial O2 saturation ( 92%)
B2 Leukocytosis: >12,000/L(no fever or infection)
A3 Splenomegaly B3 Increased leukocyte alkaline phosphatase (LAP >100)
B4 Increased serum B12/bindersB12: (>900 pg/mL)Unbound B12 binding capacity (>2200 pg/mL)
Diagnosis of polycythemia vera virtually certain in the presence of A1+A2+A3 orA1+A2+ any two from category B.
SM Fruchtman
Diagnostic and Confirmative Criteria of P Vera Proposed by the PVSG
A Diagnostic criteria B Confirmative criteria
A1 Raised red cell massmale >36 mL/kgfemale >32 mL/kg
B1 Thrombocythemiaplatelet count >400,000/L
A2 Absence of any cause of secondary erythrocytosis by clinical and laboratory investigations
B2 Granulocytes >100,000/L and/or raised neutrophil alkaline phosphatase score in the absence of fever or injection
A3 Histopathology of bone marrow by biopsy
a. increase of celluarity, panmyelosisb. increase and clusters of enlarged
megakaryocytes with hyperploid nuclei
c. reticulin fibers (optional)
B3 Splenomegaly on palpation or isotope/ultrasound scan
B4 Erythroid colony formation in absence of EPO: spontaneous EEC
A1+A2+A3 is consistent with early stage P Vera (so called “idiopathic erythrocytosis”)A1+A2+A3 plus any from the category B establishes overt P VeraA3+B1 is consistent with essential thrombocythemiaA3+B3 and/or B4 is consistent with a primary myeloproliferative disorder
SM Fruchtman
Proposed Diagnostic Criteria for P VeraA1 Raised red cell mass
(>25% above mean normal predicted value)
B1 Thrombocytosis(platelet count >400,000/L)
A2 Absence of cause of secondary polycythemia
B2 Neutrophil leukocytosis (neutrophil count >10,000/L)
A3 Palpable splenomegaly B3 Splenomegaly demonstrated on isotope/ultrasound scanning
A4 Clonality marker e.g. Abnormal marrow karyotype
B4 Characteristic BFU-E growth or reduced serum erythropoietin
A1+A2+A3 or A4 establishes P VeraA1+A2+two of B establishes P Vera
SM Fruchtman
ET: 1999 British Diagnostic Criteria
• Platelets exceeding 400,000/L (600,000/L for trials)
• No cause for secondary thrombocytosis (congenital or acquired)
• No other cause for myeloproliferative thrombocythemia (P Vera, CML, AMM-MF, MDS)
• Compatible marrow histology– Increased, clustered large megakaryocytes– Hyperlobulated megakaryocyte nuclei– No collagen fibrosis or osteosclerosis
RM Petitt
ET: 1999 Dutch Diagnostic Criteria
• Diagnostic Criteria:– A1 Platelets exceeding 400,000/L without reactive cause– A2 Increased, clustered, mature giant megakaryocytes
with hyperploid nuclei– A3 No preceding myeloproliferative or myelodysplastic
disease • Confirmation Criteria:
– B1 Normal or elevated LAP score, normal ESR, no fever– B2 Marrow cellularity normal or slightly increased; no or
minimal reticulin fibrosis– B3 Palpable splenomegaly, or >11 cm on U/S or CT– B4 Spontaneous erythroid and/or megakaryocyte colony
growth
RM Petitt
2002 WHO Classification of Chronic MPDs
Chronic myelogenous leukemia (bcr/abl +)
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia
Polycythemia vera
Chronic idiopathic myelofibrosis
Essential thrombocythemia
Chronic myeloproliferative disease, unclassifiable
RM Petitt
Survival Time (%) for Patients in Various Treatment Groups
2 4 6 8 10 12 14 16
Years of duration of the disease
100
50
5
Various combinations with X-ray therapyX-ray therapy32P and/or chlorambucilVenesectionUntreated
SM Fruchtman
Cumulative Survival on Study
0 100 200 300 400 500 600 700 800Time in weeks
1.0
0.8
0.6
0.4
0.2
0.0
Cu
mu
lati
ve s
urv
ival
Breslow X2 = 4.394 p=.1111 Logrank X2 = 9.650 p=.00802 2
Legend Total Events
Phlebotomy 134 54
Chlorambucil 141 8232P 156 83
SM Fruchtman
Cumulative Survival After 7 Years on Study
0 100 200 300 400 500 600Time in weeks after 7 years
1.0
0.8
0.6
0.4
0.2
0.0
Cu
mu
lati
ve s
urv
ival
Breslow X2 = 16.968 p=.0002 Logrank X2 = 16.465 p=.00032 2
Legend Total EventsPhlebotomy 59 16Chlorambucil 63 3532P 92 41
SM Fruchtman
PVSG-01: Thrombosis (On Study Events) 1/1/86
0 100 200 300 400 500 600 700 800Time in weeks
1.0
0.9
0.8
0.7
0.6
0.5
Cu
mu
lati
ve s
urv
ival
Legend Total Events
Phlebotomy 134 51
Chlorambucil 141 4132P 156 51
Comparison Statistics
X2 p
Breslow 8.54 .01
Logrank 4.89 .09
2
SM Fruchtman
Causes of Death by Treatment GroupPhlebotomy CLB 32P Total
Number at start 134 141 156 431
Number of deaths 53 82 79 214
Causes of death Percent
Thrombosis 17.2 13.5 13.5 44.2
Hemorrhage 0.0 4.3 3.8 8.1
Leukemia/Lymphoma 1.5 20.6 11.5 33.6
Cancer 4.5 9.9 9.6 24.0
Spent/MF 0.7 2.1 1.3 4.1
Other 15.7 7.8 10.9 34.4
SM Fruchtman
Survival Probability in Patients > 70 years
0 50 100 150 200 250 300 350 400Weeks since randomization
1.00
.80
.60
.40
.20
0
Cu
mu
lati
ve p
rob
abil
ity
of
surv
ivin
g P
()
32P
Chlorambucil
Phlebotomy
Age >70
SM Fruchtman
PVSG-01: Initial Thrombotic Event (On Study Events)
Type of event Number % of events
Cerebral vascular accident 51 35
Myocardial infarction 18 12
Peripheral arterial occlusion 13 9
Pulmonary infarction 8 6
Venous thrombosis(other than thrombophlebitis)
6 4
Deep vein thrombophlebitis 32 22
Miscellaneous 18 12
Total 146 100
SM Fruchtman
PVSG-01:Thrombosis-Related Risk Factors
• Multivariate Analysis– Randomization to phlebotomy– Age >70 years– Previous thrombosis
SM Fruchtman
PVSG-01: Matched Pair Analysis
For each patient with thrombosis, a thrombosis-free control patient of similar age, sex, treatment group, and time on study was selected.
Most recent hematocrits and platelet counts were not different. Hematocrit over 52% and platelet counts over 1,500,000/L were rare.
SM Fruchtman
Hematologic Parameters and Relative Odds of Thrombosis:
Matched Pairs Case-Control Study
Hematologic parameterEstimated odds of thrombosis p-value*
Platelets (x103/L)
1,000 vs <1,000 0.7 >0.9
600 vs <600 1.4 >0.5
450 vs <450 0.9 >0.9
Hematocrit (%)
52 vs <52 1.3 >0.5
47 vs <47 1.2 >0.5
>45 vs 45 1.1 >0.9*From Mantel-Haenszel Chi-Square. SM Fruchtman
2
Risk Factors Associated with ThrombosisCox-Model Multivariate Analysis
431 Patients
Risk factorEstimated relative risk T*
Testof model
Phlebotomy vs 32P 1.7 2.3
Chlorambucil vs 32P 0.8 -0.7 X4=43.0
History of thrombosis 2.1 3.3 p<.001
Age (70 vs 50) 2.3 4.5
T*1.96 indicated significant association with incidence of thrombosis (p0.05)
SM Fruchtman
Age-Specific Therapy for P Vera
Age Initial choice of therapy
>70 years 32P
50–70 years Phlebotomy (Hydroxyurea, 32P)
<50 years Phlebotomy (Hydroxyurea)
SM Fruchtman
Survival
On study Phlebotomy CLB 32P
Median time to death (yrs)
12.5 8.9 11.4
Maximum follow-up (yrs)
17.5 18.2 16.6
SM Fruchtman
Polycythemia Vera
Hydroxyurea 15 mg/kg/dayand adjusted as needed
Hydroxyurea 30 mg/kg/day
Prior myelosuppressiveRx
(RT or Chemo)
No prior Rx orphlebotomy
One Week
SM Fruchtman
PVSG-08
Clinical and Laboratory Characteristics at Initial Evaluation by Treatment and Protocol
PVSG-01 Phlebotomy
PVSG-08 Hydroxyurea
Evaluation 134 51
Prior thrombosis % 14.2 35.3
Hematocrit % 61.7±7.5 52.9±8.1
RBC X 108/L 7.16±1.09 6.60±0.86
Platelets X 103/L 505±24.6 778±63.6
<600,000/L 76 47
600,000-1,000,000/L 17 31
>1,000,000/L 7 22
SM Fruchtman
Sex and Age at Initial Evaluation by Treatment and Protocol
PVSG-01 Phlebotomy
PVSG-08 Hydroxyurea
Number 134 51
Male (%) 54.5 52.9
<50 years 11.2 11.8
50–70 years 31.3 31.4
70 years 11.9 9.8
Female (%) 45.5 47.1
<50 years 9.7 15.7
50–70 years 25.4 25.5
70 years 10.4 5.9
SM Fruchtman
Comparative Incidence of Thrombosis by Year by Protocol and Treatment Group
Cumulative %
Protocol Year 1 Year 2
A. On study events
HU (PVSG-08 NPT) 2.8±4.0 6.6±3.7
Phlebotomy (PVSG-01) 8.7±2.5 14.0±3.2
B. All events
HU (PVSG-08 NPT) 5.9±3.3 7.9±3.8
Phlebotomy (PVSG-01) 9.0±2.5 15.8±3.2
SM Fruchtman
Comparative Incidence of Thrombosis by Protocol and Treatment Group
(On Study, First 378 Weeks)
ProtocolTotal
patients # Events %
HU (PVSG-08 NPT) 51 5 9.8
Phlebotomy (PVSG-01) 134 44 32.8
Wilcoxon X21=5.58 p=.018
Logrank X21=6.80 p=.009
SM Fruchtman
Comparative Incidence of Acute Leukemia by Protocol and Treatment
Protocol PatientsTotal # events %
On study events, first 795 weeks of study
HU-NPT (PVSG-08)
Phlebotomy (PVSG-01)
Wilcoxon X21=1.305
Logrank X21=1.791
51
134
p=.2532
p=.1808
3
2
5.9
1.5
All events HU-NPT (PVSG-08)
Phlebotomy (PVSG-01)
Wilcoxon X21=2.749
Logrank X21=2.344
51
134
p=.0973
p=.1258
5
5
9.8
3.7
SM Fruchtman
PVSG-01: Leukemia by Treatment
ProtocolTotal
patients # events %
On study events, first 795 weeks of study
CHL 141 24 17.0
32P 156 17 10.9
Phlebotomy 134 2 1.5
Wilcoxon X21=14.718 p.0001
Logrank X21=20.938 p.0001
SM Fruchtman
Survival by Prior Therapy and Protocol
Protocol PatientsTotal # events %
On study events, first 795 weeks of study
HU-NPT (PVSG-08)
Phlebotomy (PVSG-01)
Wilcoxon X21=3.241
Logrank X21=2.227
51
134
p=.0718
p=.1356
16
54
31.4
40.3
All events HU-NPT (PVSG-08)
Phlebotomy (PVSG-01)
Wilcoxon X21=2.300
Logrank X21=1.847
51
134
p=.1293
p=.1742
20
74
39.2
55.2
SM Fruchtman
Risk of Leukemic Transformation with Myelosuppressive Therapy
Therapy Polycythemia vera (%)P Vera, MF,
ET
No treatment or aspirin – 0/11
Phlebotomy 2/18 (11) 2/18
Hydroxyurea 1/16 (6) 2/2532P 0/2 0/2
Alkylating agent – 0/1
More than 1 myelosuppressive agent
1/4 (25) 1/5
IFN- 0/2 0/2
SM Fruchtman
PVSG-05Eligibility 1. No previous treatment except phlebotomy
2. Disease diagnosed within four years3. Fulfillment of diagnostic criteria4. No chronic disorder requiring long-term ASA
Phlebotomy to HCT 40%
Randomization
PhlebotomyPrn to maintain
Hct <45%ASA 300 mg TID
Dipyridamole 75 mg TID
32P2.7 mc/M2 i.v.Q 12 wks prn
(limit 5 mc/dose)Phlebotomy for Hct >45%
Increase dose by 25% if no response
SM Fruchtman
PVSG-05: Thrombosis and Hemorrhage-Free Cumulative Survival
0 10 20 30 40 50 60 70 80 90 100 110Time in weeks
1.00
0.95
0.90
0.85
Cu
mu
lati
ve s
urv
ival
Comparison Statistics
X2 p
Breslow 2.8 .09
Logrank 3.1 .08
2
Legend Treatment Total in Group EventsPhleb/Persantine/ASA 88 7
P-32 90 2
SM Fruchtman
0 10 20 30 40 50 60 70 80 90 100 110Time in weeks
1.00
95
90
85
80
Cu
mu
lati
ve s
urv
ival
Comparison Statistics
X2 P
Breslow 8.660 0.0033
Logrank 9.018 0.0027
2
Legend Treatment Total in Group EventsPhleb/Persantine/ASA 88 13
P-32 90 2
SM Fruchtman
PVSG-05: Thrombosis and Hemorrhage-Free Cumulative Survival
Summary of 91 Patients with Thrombocytosis Treated with PVSG Protocols
Treatment protocol
Median follow-up
(years)Total
patientsNo. AML (all dead)
No. died
of other causes
No. alive at last
follow-up
HU only 8.2 22 1 7 1432P only 5.6 16 2 5 9
Melphalan only 4.4 14 1* 6 7
Melphalan + HU 10.5 10 0 4 632P + HU 8.4 9 1 2 6
HU + other 7.7 7 5 1 1
Melphalan + 32P 4.5 4 1* 2 1
Melphalan + 32P + HU 9.2 2 0 0 2
No treatment 4.4 7 1 2 4
Total study population 7.0 91 12 29 50
*AMLs in patients in ET [?MF] category.SM Fruchtman
The Mount Sinai Myeloproliferative Study Jan 1986–Dec 1998
Disorder studied # of patients
# of specimens
# of technically inadequate specimens
# of evaluable patients
P Vera 167 234 23.4(10%)
156
ET 40 40 8.0(20%)
32
MM/MF 63 90 18.90(20%)
56
SM Fruchtman
The Mount Sinai Myeloproliferative Study Jan 1986–Dec 1998
Disorder# of
patientsNormal
karyotype
Normal with nonclonal
abnormalities
Normal at Dx/Abnormal on
follow-upAbnormal
at Dx
P Vera 156 10969.8%
53.2%
53.2%
3723.7%
ET 32 2784.3%
13.1%
0 412.5%
MM/MF 56 3053.5%
00
00
2646.4%
SM Fruchtman
Frequency of Chromosomal AbnormalitiesP Vera MM/MF
Abnormality% of total
% of abnormal
% of total
% of abnormal
del (20) (q11q12) 4.4 18.9 5.3 11.5
+8 3.8 16.2 1.7 3.8
+9 3.2 13.5 0 0
del (7q) 3.2 13.5 0 0
-7/t (7p) 0 0 10.7 23
del (9q)/i (9q) 2.5 10.8 0 0
abnormalities 1p 1.9 8.1 7.1 0
t (16q) 1.9 8.1 0 0
del (13)(q12-13q14-21) 0 0 12.5 26.9
-5 0 0 5.3 11.5SM Fruchtman
Treatment
Treatment: Essential Thrombocythemia
Treatment Goals for ET
• No therapy to eliminate malignant stem cell clone
• Direct therapy at reducing mortality and life-threatening complications
• In high-risk ET, reduce platelets 600,000/µL; ? 450,000/L
• No adequate prospective, randomized, controlled studies
CM Kessler
Conditions Suggesting Urgent Treatment
• Symptomatic coronary artery disease
• Transient ischemic attacks
• Major hemorrhage
• Active thrombosis/pulmonary embolism
HS Gilbert
Urgent Treatment of ET
• Platelet apheresis - typically 1-3 treatments with target platelet count < 400,000/L
• Hydroxyurea - target platelet count < 400,000/L
• Nitrogen mustard, 0.4 mg/kg if apheresis not available
HS Gilbert
ET: Prognostic Factors (2091 Cases)
• Favorable factors– Platelets less than 700,000/L– Treatment with antiaggregating or cytostatic drugs
• Unfavorable factors– Previous thrombosis– Older patients– Platelets exceeding 1.5 million/L at diagnosis– Platelets exceeding 1.0 million/L at follow-up
RM Petitt
Treatment of ET
There is evidence that ET is a heterogeneous disorder both clinically and on a stem/progenitor cell level.
Thus, the dilemma exists as to when to employ agents that either lower the platelet number and/or inhibit platelet function.
SM Fruchtman
Risk-Based Treatment for ET
• Low risk– Age < 60 years– Platelets < 1,500,000/L– No history of thrombosis– No cardiovascular risks
• No treatment or low-dose aspirin
HS Gilbert
Risk-Based Treatment for ET
• Intermediate risk– Age < 60 years – No history of thrombosis– Platelet counts > 1,500,000/L or– Cardiovascular risk factors
HS Gilbert
Risk-Based Treatment for ET
• Intermediate-risk treatment– Treat cardiovascular risk factors– Avoid aspirin if platelet counts
> 1,500,000/L – No treatment or anagrelide; hydroxyurea or
IFN-
HS Gilbert
ET: The High-Risk Patient
• Age 60 or greater
• Previous thrombosis (or comorbid disposition such as DM, PVD, HTN or thrombophilia)
• Platelets exceeding 1.0 or 1.5 million/L
• Peripheral myeloid immaturity
RM Petitt
Risk-Based Treatment for ET
• High risk– Age 60 years or
History of thrombosis
• Hydroxyurea and low-dose aspirin; anagrelide
• IFN-, 32P, busulfan, pipobroman
HS Gilbert
ET: The Risks of Observation
• Thrombosis– A baseline risk which does not increase significantly as platelets
rise to exceedingly high levels– Risk aggravated by unrecognized thrombophilic states
• Hemorrhage– Risk increases significantly as platelets rise above
1.5 million/L– Acquired vonWillebrand disease with high platelet counts
• Leukemic transformation– All chronic myeloproliferative disorders have an underlying risk
of transformation to acute leukemia. This risk is independent of any treatment and is estimated to be 90% in CML, 7%-10% in MM-MF, 1.5% in P Vera, and 1%-2% in ET
RM Petitt
Risk of Elevated Platelets in ET
• Is there clear evidence that elevated platelet levels are bad?– In symptomatic patients?– In asymptomatic patients with very high
platelet counts?– In patients with mild to moderate
thrombocythemia?– What is the role of plateletpheresis?
CM Kessler
Risk of Elevated Platelets: New Data
• Regev et al: Thrombotic complications not uncommon in ET, even at low platelet levels. Recommendation: Symptomatic patients with relatively low platelet counts be treated and platelets be reduced to low-normal range
• Storen, Tefferi: Long-term anagrelide study. All thrombohemorrhagic complications occurred at platelet counts of > 400,000/L. Normalization of platelets may be required to minimize risk
CM Kessler
ET: The Risks of Treatment
Treatment-related adverse events reflect agent(s) chosen, dose and duration of therapy:
• Leukemic transformation
• Bone marrow suppression
• Less severe cardiac, dermatologic, gastrointestinal and neurologic side effects
RM Petitt
ET: Treatment• Antiaggregating agents• Platelet apheresis• Myelosuppressive agents
– Alkylating agents– Radiophosphorus– Hydroxyurea
• Maturation Modulators– IFN-2A, recombinant– Anagrelide
• Bone marrow transplantation• Combinations of above
RM Petitt
Aspirin
• Suppression of thromboxane biosynthesis, which is increased in P Vera and ET patients, can be achieved with low-dose aspirin (~50 mg/day)
• Prevention of thrombosis? Under study
• Control of microvascular symptoms at low-dose in patients without a bleeding diathesis
SM Fruchtman
Busulfan
• Busulfan in ET– WEEK 1 - 4 mg per day– WEEKS 2, 3 and 4 - 2 mg per day– TO RESPONSE - 2 mg every other day
• Median cumulative dose - 124 mg and duration 3 months
HS Gilbert
ET and Busulfan Treatment
• 75 patients (mean age 48; F:M = 1.5)– Splenomegaly 49%– Hepatomegaly 38%– Thrombosis 29%– Hemorrhage 19%
• 64 (83%) treated with busulfan– Mean follow-up 9.2 years– 53% died– 18% developed leukemia– 19% developed thrombosis
RM Petitt
Busulfan
• Myleran, registered trademark of Glaxo Wellcome• 2 mg tablets• Bifunctional alkylating agent (not a nitrogen mustard
analog)• 2003 Physicians’ Desk Reference,* p. 1595:
“MYLERAN is contraindicated in patients in whom a definitive diagnosis of chronic myelogenous leukemia has not been firmly established.”
*copyright 2003 by Medical Economics Company, Inc., Montvale, NJ
RM Petitt
Hydroxyurea (HU)
• Risk of thrombosis: Hydroxyurea reduced the risk of thrombosis from 24% to <4% in a randomized study of high-risk ET patients
• Leukemic conversion: Several nonrandomized studies have supported or refuted a significant increase in leukemic conversion with long-term use of hydroxyurea– In ET, rates range from 0%-5.5%– In P Vera, rates range from 2.1%-10%
SM Fruchtman
ET and Hydroxyurea Treatment
• 75 high-risk patients (mean age 62)– Treated with hydroxyurea– Mean follow-up 6.9 years– 6 (8%) developed leukemia
• Mean age 65 (35-75)• Mean hydroxyurea exposure 7.2 years
• 20 low-risk patients– No treatment (some on aspirin)– No leukemia
RM Petitt
ET and Hydroxyurea Treatment
• 114 randomized high-risk ET (56 HU, 58 no Rx)– 15 on busulfan before randomization– 13 on hydroxyurea before randomization– 29 controls changed to hydroxyurea during study
(26 thrombosis)
• Original follow-up median 27 months. After 73 months:– Survival same; thrombosis rate 9% vs 45% (p = <0.0001)
• Conclusion:– Sequential use of busulfan and hydroxyurea carries increased
risk of second malignancies• One cancer (breast) in untreated group• Seven in hydroxyurea group (5 hematologic:2 ANLL,
2 MDS, 1 CLL)
RM Petitt
Hydroxyurea for Patients with ET and a High Risk of Thrombosis
• Prospective randomized trial of 114 patients with ET– Age >60 years or– Previous thrombosis or both– Platelet count <1,500,000/L
(uncomfortable with randomization)
• Randomization– HU vs control (no HU)– 70% were already on antiplatelet agents
SM Fruchtman
Probability of Thrombosis-Free Survival in 114 Patients with Essential Thrombocythemia Treated with
Hydroxyurea or Left UntreatedP
late
let
Co
un
t (X
10-3/m
m3 )
0 6 12 18 24 30 36Months
1200
1000
800
600
400
SM Fruchtman
Control (n=58)
Hydroxyurea (n=56)
Probability of Thrombosis-Free Survival in 114 Patients with Essential Thrombocythemia Treated with
Hydroxyurea or Left Untreated
The p value is for the difference between the two groups (by the log-rank test). The median follow-up was 27 months. Tick marks indicate surviving patients who were continuously free of thrombosis.
Th
rom
bo
sis-
free
surv
ival
(%
)
0 6 12 18 24 30 36 42 48
Months after randomization
100
80
60
40
20
0p=0.005
SM Fruchtman
Hydroxyurea (n=56)
Control (n=58)
Thrombosis in 114 Patients with ETType of thrombosis Hydroxyurea group
(N=56)Control group
(N=58)
no. (%)
Arterial 2 (100) 11 (79)
Transient ischemic attacks 0 5
Digital microvascular ischemia 0 5
Stroke 1 1
Myocardial infarction 1 0
Venous 0 3 (21)
Superficial thrombophlebitis 0 2
Ileofemoral venous thrombosis 0 1
Total (% of treatment group) 2 (3.6) 14 (24)**There was a difference of 20.4 percentage points in the rate of thrombosis betweenthe groups (95 percent confidence interval, 8.5 to 32 percent; chi-square with Yates’correction, 8.3; 1 df; p=0.003).
SM Fruchtman
Hydroxyurea: Adverse Reactions
• Hematologic– Bone marrow depression (leukopenia, anemia,
thrombocytopenia)
• Gastrointestinal– Stomatitis, anorexia, nausea, vomiting, diarrhea, constipation
• Dermatologic– Rash, painful ulceration, erythema, hyperpigmentation,
squamous cell skin cancers, dermatomyositis-like changes
• Neurologic– Headache, dizziness, hallucinations, convulsions (all rare)
• Systemic– Fever, chills, malaise, asthenia
RM Petitt
Photo
HS Gilbert
Hydroxyurea and Acute Leukemia in MPDs
50 consecutive MPD patients (30 P Vera, 10 ET, 10 MF) were treated with hydroxyurea (HU), largely for high platelet counts or symptomatic splenomegaly.
9 (18% of total) developed ANLL, and 1 MDS
7/9 (14% of total; 3 P Vera, 1 ET, 3 MF) were treated solely with hydroxyurea
average time from CMPD to ANLL = 6.3 years
average duration of HU treatment = 3.9 years
RM Petitt
Evolution to AML and MDS By Cytoreductive Agent in 357 ET Patients
Cases of AML or MDSAgent No. of ET patients treated No. (%)
32P
Alone 29 2 (7)And other agents* 11 1 (9)Total 40 3 (7.5)
Busulfan
Alone 35 1 (3)And other agents* 6 1 (17)Total 41 2 (5)
HU
Alone 201 7 (3.5)And other agents† 50 7 (14)Total 251 14 (5.5)
Pipobroman
Alone 12 0 (0)And other agents* 31 5 (16)Total 43 5 (12)
Untreated 31 0 (0)*Generally HU; †Generally pipobroman. SM Fruchtman
ET and AML/MDS
Median follow-up 98 months (12 yrs)Total 17; AML (6) or MDS (11)
7 HU & other agents (pipobroman, 5; 32P, 1; Busulfan, 1)7 HU alone (3.5%)2 32P1 BusulfanMedian interval between dx of ET & dx AML/MDS 84 months
7 Patients with AML/MDS & 17Pdeletion received HU3/7 received only HU
SM Fruchtman
Acquired DNA Mutations and HU
Patient Population # of patientsAge in years (mean ± 1SD)
Median HU exposure
Adults with SCD 30
No HU exposure 15 27±12 None
Short HU exposure 15 29±9 24 months
Children with SCD 34
Short HU exposure 17 11±3 7 months
Longer HU exposure 17 13±3 30 months
Adults with MPD 27
Low HU exposure 15 57±17 0 months
Prolonged HU exposure 12 62±16 11 years
Normal controls 32 43±15 None
SM Fruchtman
Acquired DNA Mutations and HU (Cont’d)
HPRT assay VDJ assay
Patient population CE (%) ML X 10-6 Events per g DNA
Adults with SCDNo HU exposureShort HU exposure
15.1±12.312.4±8.2
19.1±19.116.7±10.9
1.07±0.381.14±0.38
Children with SCDShort HU exposureLonger HU exposure
13.2±6.120.9±10.2
11.2±6.79.2±7.8
1.58±0.871.82±1.20
Adults with MPDLow HU exposureProlonged HU exposure
12.8±8.912.2±8.4
37.3±37.641.1±29.3
1.06±0.730.64±0.29
Normal adult controls 16.0±8.7 25.8±24.8 1.04±0.38
SM Fruchtman
Thrombotic Complications In 68 Patients with ET Who Had Long-Term Follow-up,
According to Treatment Strategy
*p<0.001 (X2=17.3, 1 df) for the comparison with watchful waiting.†Denotes treatment with busulfan or hydroxyurea.‡p<0.02 (X2=6.0) for the comparison with watchful waiting.§p<0.02 (X2=8.6) for the comparison with watchful waiting.
TreatmentThrombotic
EventsDuration of Follow-up Incidence
No. Person-yr Events/100 person-yr
Watchful waiting 27 127 21.3
Low-dose aspirin 5 139 3.6*
Cytoreduction† 10 113 8.9‡
Low-dose aspirin and cytoreduction
0 40 0§
CM Kessler
ET and Interferon Treatment
• Antiproliferative effect on CFU-MK and CFU-GEMM– Nonleukemogenic, nongonadotoxic
• Usual daily doses 1–5 million units daily, 3-7 x weekly– Gradual response: peripheral 1-3 months, marrow
9-12 months• 26 ET patients
– Median age 48– Dose-limiting side effects in 24%– 88% responded (62% CR, 26% PR)– Responders crossed over to pipobroman after
12 months
RM Petitt
IFN-In essential thrombocythemia• Produces platelet reduction (80%-100% response
rate), resolution of splenomegaly, and control of disease-associated symptoms
• May be used in high-risk women with ET of childbearing age or those who are pregnant
• ~20% of patients may not tolerate IFN because of side effects (esp. flu-like symptoms, fatigue, nausea, depression, fever, chills, arthralgias, autoimmune disorders). Higher rates in elderly individuals
SM Fruchtman
Photo
HS Gilbert
Management of ET During Pregnancy
Options
1. Observe—? Medical–legal issues
2. ASA
3. ASA & heparin
4. IFN-
5. Platelet apheresis for emergencies
SM Fruchtman
Women of Childbearing Age with ET
• High risk– IFN- and low-dose aspirin
• All others– No treatment or low-dose aspirin
HS Gilbert
Anagrelide
For thrombocytosis accompanying any MPD
• Indicated for the treatment of patients with thrombocythemia secondary to MPDs to reduce the elevated platelet count and risk of thrombosis and to ameliorate associated symptoms, including thrombohemorrhagic events
SM Fruchtman
Anagrelide: Observed Effects
• Reduces platelet count• Reduces platelet turnover rate (elevated in ET)• May reduce megakaryocyte number• Reduces megakaryocyte diameter• Reduces megakaryocyte volume• Normalizes megakaryocyte ploidy
Anagrelide reduces megakaryocytic hyperproliferation and
megakaryocytic differentiation
RM Petitt
Anagrelide
• Starting dose - 0.5 mg, orally, 4 times per day
• OK to cross over with hydroxyurea
• 15% of patients will discontinue
• Manufacturer’s target < 600,000/L; our target < 400,000/L
HS Gilbert
ET Patient Response to Anagrelide
• Platelet counts lowered in 7 to 14 days
• Sustained response in patients followed for up to 4 years (p<.001 vs baseline)
• Response seen in 242 patients who had failed previous therapy to reduce platelets
82%Overall
Response Rate*
(p<0.05)
88%Overall
Reduction in ET-Related Symptoms
(p<0.05)
CM Kessler
ET: Reduction in Serious Complications with Anagrelide
• Reported serious complications of thrombocythemia decreased by 82% after 235 patients took anagrelide for 4 months
35
5
30
25
20
15
10
1-4 5-8 9-12
Preinfarction angina
GI bleeds
TIAs
Months on anagrelide therapy
Se
rio
us
co
mp
lic
ati
on
s
CM Kessler
Anagrelide: Precise & Specific
• Dose-related reduction of platelet production resulting from a decrease in megakaryocyte hypermaturation
• Clinically insignificant effect on white blood cells
• A slight reduction (~5%) in Hb and PCV occurs with prolonged anagrelide therapy
SM Fruchtman
Anagrelide: Precise & Specific (Cont’d)
• No effect on DNA synthesis– No apparent association with oncogenesis– No apparent leukemogenicity
SM Fruchtman
Anagrelide
How effective is it?
• Only 19% of patients failed to respond (had <20% reduction in platelet count) in a population that included a large number of nonresponders to other agents.
HS Gilbert
Anagrelide
What is unique about it?
• It is the only cytoreductive agent that has specificity for platelets. Therapy targeted at platelets spares the red blood cells and neutrophils in patients who have normal or reduced circulating levels of these cells.
HS Gilbert
Anagrelide
What is its safety and toxicity profile?
• In the analysis of 577 patients, the drop- out rate from toxicity was 16% in over 5 years of experience. In the analysis of 942 patients, there were no deaths attributable to anagrelide.
HS Gilbert
Anagrelide: Adverse Reactions
161 of the original 942 patients (17.1%) stopped anagrelide treatment, citing the following reasons:
Headache 40 (25%) (4.2% of all treated)Diarrhea 19 (12%) (2.0% of all treated)Edema 18 (11%) (1.9% of all treated)Palpitations 17 (11%) (1.8% of all treated)Abdominal Discomfort 12 (7%) (1.3% of all treated)
RM Petitt
Adverse Reactions Leading toDiscontinuation of Anagrelide
Type of Adverse Reaction in 577 patients
Number (%) Discontinued
Neurologic (headache, confusion) 30 (21)
Gastrointestinal (nausea, abdominal pain, diarrhea)
25 (28)
Cardiac (congestive heart failure, edema) 23 (21)
Pulmonary 2 (1)
Other 14 (11)
HS Gilbert
Anagrelide Study Patients
90% of the original study group of 942 patients had already received other treatment for their myeloproliferative disorders:
Hydroxyurea 651 (67%)
Alkylating Agents 198 (21%)
IFN 94 (10%)
Radiophosphorus 66 (7%)
Other 27 (3%)
RM Petitt
Long-term Experience with Anagrelide in Young ET Patients
• Retrospective series of 35 patients (ages 17-48 years) who received anagrelide before 1992
• 82% of 33 responding patients remained on anagrelide for a median of 10.8 years
• Of these, 66% were CRs, 34% were PRs
CM Kessler
Long-term Experience with Anagrelide in Young ET Patients (Cont’d)
• All thrombohemorrhagic complications occurred at a platelet count of > 400,000/L
• Complete normalization of platelet counts may be required to minimize residual hemorrhagic risk during therapy
• Initial side effects decreased with time; long-term treatment was associated with mild to moderate anemia
CM Kessler
Contraindications to Anagrelide
• Uncontrolled congestive heart failure– Aggravation by additional fluid retention
• Pregnancy– Fetus at risk for transplacental drug exposure
• Lactation– Infant at risk for drug ingestion
RM Petitt
Anagrelide Maintenance Doses (mg/day)
RM Petitt
6 mos. 12 mos. 18 mos.
P Vera 2.8 2.8 2.8
ET 2.4 2.5 2.3
CML 2.3 2.1 2.1
OMPD 2.1 1.8 1.7
Long-term Anagrelide Treatment
40 patients started on treatment 1985-1988:4 nonresponders2 lost to follow-up9 deaths
3 blast transformation of CML2 colon cancer2 myocardial infarction2 unknown
25 evaluable after 10 or more years of treatment
RM Petitt
Long-term Anagrelide Treatment
25 older patients with chronic myeloproliferative disorders taking anagrelide for 15 or more years:
6 developed mild renal insufficiency (creatinines 2-3)
all poorly controlled hypertensives
azotemia appeared 3-11 years after starting
maintenance dose decreased as creatinine rose
19 have had no change in dosage or response
34 young women treated with anagrelide for >10 years:
no changes in renal function
RM Petitt
Anagrelide Study 301: Overview
Safety Efficacy 3,660 1,618
2251 1409 934 684 ET Non-ET ET Non-ET
462 954 208 476P Vera CML, MF, P Vera CML,MF, (12.6%) OMPD (12.9%) OMPD
SM Fruchtman
Anagrelide Study 301: Response Definitions
Complete response
Platelets <600,000/L
or
50% reduction from baseline at least 4 weeks after starting anagrelide therapy
Partial response
20%-50% reduction from baseline
SM Fruchtman
Anagrelide Study 301: Response (Efficacy Population)
SM Fruchtman
100
63.7
11.5
75.7
0
20
40
60
80
100
120
All Patients CompleteResponse
PartialResponse
TotalResponse
Percent (%)
Anagrelide Study 301: Response in Patients with Platelets 1,500,000/L
SM Fruchtman
Total Median time to n Response response (days)
(%) (95% CI)
ET Patients 116 99 64 (85.3) (53-76)
Non-ET 158 125 63 (79.1) (54-81)
Anagrelide Study 301:Transformation of ET Patients (n=2251)
n Median cumulative dose (mg)
AL transformation 47 342**p=0.005
Non-transformed 2180† 746*
†22 additional patients had other transformations and 2 patients were misdiagnosed
SM Fruchtman
Anagrelide Study 301: Safety Conclusions
1. Essential thrombocythemia (n=2251)– Maximum F/U = 7.1 yrs– Conversion to AL/MDS = *2.1%
2. Polycythemia vera– Maximum F/U = 7.0 yrs– Conversion to AL/MDS = *2.8%
3. Patients treated with anagrelide for >3 yrs; 0% of ET and 0.26% of P Vera patients transformed
*All received prior cytoreductive therapy
SM Fruchtman
Anagrelide – Physicians’ Considerations
Why do I need to add anagrelide to my therapeutic armamentarium?
What is unique about anagrelide?
How effective is anagrelide?
What is anagrelide’s safety & toxicity profile?
What factors affect decision to treat?
What outcome can I expect?
HS Gilbert
Evidence-Based Clinical Data in ET
• Comparative phase III clinical trials for rare diseases such as ET are difficult to carry out
• No head-to-head data in ET to compare therapeutic agents (hydroxyurea, anagrelide, IFN-, etc)– Shire US initiated head-to-head trial.
Discontinued due to inadequate recruitment in HU arm
CM Kessler
Anagrelide
Pairing MPD Phenotype and Therapy
HS Gilbert
ETPLTS
MyM
RBC
WBC
HS Gilbert
Combined Agent Therapy in MPDs
Treatment of ET: ANAG + IFN-
0
20
40
60
80
100
120
0 14 34 54 78 86 98 114
128
Weeks
SPL
PLTSX10-4
WBC
PCV
ANAG IFN-
Algorithm for Treatment of Thrombocythemia
ASA
Asymptomatic
Low RiskAge < 40
Age 40-60 Plts 600,000 - 1,000,000/L
Anagrelide
Other proliferation minimal
IFN-Hydroxyurea
Other proliferationsignificant
Plts > 1,000,000/LAge >60
SymptomaticComorbidities
THROMBOCYTHEMIA
HS Gilbert
Treatment: Polycythemia Vera
Objectives of Treatment
• Reduce hematocrit to < 45%
• Reduce platelets to < 400,000/L
• Reduce spleen size
• Eliminate monoclonal stem cells
• Promote polyclonal hematopoiesis
• Prevent myelofibrosis
• Avoid leukemogenic therapy
HS Gilbert
Risk-Based Treatment for P Vera
• Low risk– Age < 60 years– Platelets < 1,500,000/L– No history of thrombosis– No cardiovascular risks
• Phlebotomy, target Hct < 45%, and consider low-dose aspirin
HS Gilbert
Risk-Based Treatment for P Vera
• Intermediate risk– Age < 60 years – No history of thrombosis– Platelet counts > 1,500,000/L or– Cardiovascular risk factors
HS Gilbert
Risk-Based Treatment for P Vera
• Intermediate-risk treatment– Phlebotomize to Hct <45%– Treat cardiovascular risk factors– Avoid aspirin if platelet counts
> 1,500,000/L – Consider IFN-, hydroxyurea, or anagrelide
HS Gilbert
Risk-Based Treatment for P Vera
• High risk– Age 60 years or– History of thrombosis
• Phlebotomy and hydroxyurea; consider low-dose aspirin, IFN-, anagrelide
HS Gilbert
Risk-Based Treatment for P Vera
• High risk– Age > 70 years– Phlebotomy and hydroxyurea and consider
low-dose aspirin, radioactive phosphorous; busulfan can be considered
HS Gilbert
Women of Childbearing Age with P Vera
• Phlebotomy, target Hct < 45% (42%)
• Low-dose aspirin optional - avoid if platelets > 1,500,000/L
• For high-risk patients, phlebotomy and IFN-
HS Gilbert
Diagnostic ParametersRequired Diagnostic Parameters Present
Phlebotomize to Normal Hct
Rise in Hct to 55% Within 1 Yearor 10% Rise in 3 Months
Randomization
PhlebotomyPrn to maintain
Hct <45%
32P2.7 mc/m2 IVQ 12 wks prn
(limit 5 mc/dose)Phlebotomy for Hct >45%
Chlorambucil10 mg po qd x 6 wks;
then qd alternate monthsAdjust dose for responsePhlebotomy for Hct >45%
SM Fruchtman
Normal and Low Cerebral-Blood-Flow Measurements in Relation to Hematocrit
040 1 2 3 4 045 6 7 8 9 0 50 1 2 3 4 055 6 7 8 9 060 1 2 0 63
Hematocrit
Normal CBF
Low CBF
5
4
3
2
1
1
2
3
4
No
of
mea
sure
men
ts
SM Fruchtman
Relationship of Cerebral Blood Flow to Hematocrit
0.45 0.50 0.55 0.60Hematocrit
60
50
40
30
20
10
CB
F m
L/1
00g
/min
SM Fruchtman
Sequelae of Treatment
• Phlebotomy to reduce Hct is first-line therapy in P Vera. Sequela is iron deficiency that is usually well tolerated. Frequency of phlebotomy usually decreases with time.
• Low-dose ASA is often effective in preventing symptomatic platelet aggregation in thrombocythemia. Sequela is hemorrhage that is usually minor.
HS Gilbert
Some Myelosuppressive Agents Used for P Vera
Agent Pro Con
Chlorambucil Easy to administer Leukemogenic
Busulfan Greater megakaryocyte toxicity
Pulmonary fibrosis
32P Easiest to administer Leukemogenic
Vanishing expertise
Hydroxyurea Easy to administer
Decreases thrombosis when compared to Phl alone
? Long-term safety
Rare toxicities (skin)
SM Fruchtman
Some Pros and Cons of AgentsAgent Pro Con
ASA Easy to administer ? Efficacy
? Bleeding
? Dose
Hydroxyurea Easy to administer
Well tolerated
? Leukemogenic
Anagrelide Easy to administer Fluid retention
CHF
? Long-term safety
IFN ? SC route
Drop-out rate
? Long-term safety32P Intermittent administration
Easiest to give (with experience)
Leukemogenic
Vanishing expertiseSM Fruchtman
ECLAP Trial(European Collaboration on Low-Dose ASA in PV)
Eligibility
Consent
Randomization
Placebo
12 Month: Follow-up
Yearly Follow-up
Aspirin100 mg daily
SM Fruchtman
Collaborative Overview of Randomized Trials of Antiplatelet Therapy
1. 75-325 mg daily equivalent to 500-1500 mg daily
2. Risk of major bleeds small with <325 mg daily
3. Aspirin associated with 25% reduction (p<10-5) in arterial vascular events in patients at increased risk for occlusive vascular disease
4. Aspirin halves the risk of deep venous thrombosis in surgical patients
SM Fruchtman
Hydroxyurea
• Hydroxyurea (HU) with intermittent phlebotomy (PHL) is a highly efficacious treatment strategy in the management of polycythemia vera (P Vera).
• It is the most frequently employed regimen for patients requiring myelosuppression. (ASH Educational Program, 1992)
• In addition, HU is being studied for benign hematologic disorders, such as sickle cell disease.
• Thus, it is imperative to establish its long-term safety.
SM Fruchtman
Photo
HS Gilbert
IFN-
In polycythemia vera
• Controls erythrocytosis, reduces spleen size, and relieves pruritis in ~76% of patients
• Alternative to anagrelide or hydroxyurea in young patients
SM Fruchtman
TREATMENT OF P Vera: IFN
0
20
40
60
80
100
120
140
7 37 86 145 201 267
PCV
PLTS X 10-4
WBC
SPL
Long-term Effect of IFN- in MPDs
WEEKS
IFN
HS Gilbert
Photo
HS Gilbert
IFN Therapy of MPDs: Effect on Spleen and Blood Counts
-60
-50
-40
-30
-20
-10
0
Agnogenicmyeloid
metaplasia
Postpolycythemia
myeloidmetaplasia
Activepolycythemiawith myeloidmetaplasia
Polycythemiavera
% change in spleen size
% change in WBC
% change in platelets
% c
han
ge
afte
r co
urs
e #1
MPD Research Center. SM Fruchtman
Combined Agent Therapy in P Vera
0
200
400
600
800
1000
1200
1400
0 5 10 15 20 25 30 35 40
WEEKS
Platelets
HU
AGR
IFN-
PHLEB
WBC
PLTS
PCV
AGRYLIN----------------- IFN----------HU--------------
HS Gilbert
Hydroxyurea
P Vera
Elderly orfailed other
agents
Pairing MPD Phenotype and Therapy
PLTS
MyM
RBC
WBC
HS Gilbert
Leukemic Risk with Therapies for ET and P Vera
• Hydroxyurea: Risk (0%-5% in ET; 2.1%-10% in P Vera) increases when HU is combined with other agents– 14% risk of leukemic conversion with
HU + 32P, busulfan, or pipobroman in one study of 357 patients followed for median of 8 years
• Busulfan: 3% with busulfan alone• Anagrelide: No evidence of leukemogenicity in
patients treated for up to 10 years
SM Fruchtman
Spent Phase
• Anemia• Splenomegaly• Nucleated RBC• Tear-drop forms
SM Fruchtman
SM Fruchtman
Comparative Incidence of Spent Phase by Protocol and Treatment
Protocol PatientsTotal
# events %
On-study events, first 795 weeks of study
HU-NPT (08)
Phlebotomy (01)
Wilcoxon X²1 = 2.253
Logrank X²1 = 1.137
51
134
p=.1334
p=.2863
4
15
7.8
11.2
All events HU-NPT (08)
Phlebotomy (01)
Wilcoxon X²1 = 1.734
Logrank X²1 = 0.778
51
134
p=.1879
p=.3777
4
17
7.8
12.7
PVSG 8/94.
SM Fruchtman
Comparative Incidence of Spent Phase/Acute Leukemia by Protocol and Treatment
Protocol PatientsTotal
# events %
On-study events, first 795 weeks of study
HU-NPT (08)
Phlebotomy (01)
Wilcoxon X²1 = 0.119
Logrank X²1 = 0.045
51
134
p=.7301
p=.8329
7
16*
13.7
11.9
All events HU-NPT (08)
Phlebotomy (01)
Wilcoxon X²1 = 0.196
Logrank X²1 = 0.235
51
134
p=.6581
p=.6277
9
19**
17.6
14.2
PVSG 8/94.
*One case has both spent phase and acute leukemia.**Three cases have both spent phase and acute leukemia.
SM Fruchtman
Medical Management of Spent Phase P Vera
1. Transfusion support
2. Others:– Androgens – anagrelide– Low-dose splenic – erythropoietin
R.T. – hydroxyurea– Interferons – research protocols
(thalidomide, CSAtransplantation)
3. Splenectomy
SM Fruchtman
Treatment: Idiopathic Myelofibrosis
(Myelofibrosis with Myeloid Metaplasia; Agnogenic Myeloid Metaplasia)
Underlying Propensity to Develop Myelofibrosis
• Myelofibrosis is a reactive phenomenon to the abnormality of the pluripotent hematopoietic stem cell.
• The fibroblast is not part of the malignant clone. • This in contrast to acute malignant
myelofibrosis.• The fibroblast may be part of the malignant
clone.• Seen in patients with acute leukemic condition.
HS Gilbert
Medical Management of IMF
• Transfusional support• Others:
– Androgens– Hydroxyurea– Low-dose splenic RT– Erythropoietin– Interferons– Anagrelide
• Splenectomy
SM Fruchtman
Splenectomy in IMF(Tefferi ASH 1998 vs Barosi, Blood 91:3630,1998)
• Mayo data (223 cases)– Median age, 65 years– Mortality, 9%; morb., 31%– Symptoms improved in
>90%– Anemia improved in 30%– Thrombocytopenia in 25%– Leukemia in 16% at 2-yr
follow-up– Hepatomegaly in 16%– Thrombocytosis in 20%– Median postop survival 2 yrs– Platelet count <50k is risky
• Italian multicenter (87 cases)– Compared to 462 non-
splenectomized cases– Leukemia—26% vs 12%– Leukemia at 12 years after
diagnosis—55% vs 27%– Disease presentation with blasts
or low platelets is a risk factor for leukemia
– HU therapy was not a risk factor– PPMM and PTMM excluded
SM Fruchtman
Interference with Collagen Metabolism
Target Mechanism Agent
Hydroxylation Substrate modification Hydroxyproline analogues
Secretion MicrotubulesMicrofilaments
ColchicineVinblastineCytochalasin B
Polymerization Complexing chainsCleaving cross linksLysyl oxidase inhibition
D-PenicillaminePotabap-aminoproprionitrile
Degradation Increase collagenase Colchicine
SM Fruchtman
We NEED Antifibrosing Therapies
• Marrow
• Lung
• Liver
• Skin
• Penis
SM Fruchtman
Acute Leukemia and IMF in PVSG-01
Acute Leukemia
Treatment MM/MF Cases Cases Percent
Phlebotomy No
Yes
120
14
1
1
0.8
7.1
Chlorambucil No
Yes
127
14
14
5
11.0
36.032P No
Yes
140
16
12
4
8.6
25.0
Total No
Yes
387
44
27
10
7.0
23.0
SM Fruchtman
Effect of IFN- on Splenomegaly
0
5
10
15
20
25
30
35
40
1 2 3 4 5 6
POST- P Vera IMF
SPLEEN (cm) VERT + HORIZ
PRE Rx
POST Rx
HS Gilbert
Effect of IFN- on Splenomegaly
0
5
10
15
20
25
30
35
40
1 2 3 4 5 6 7 8 9 10 11 12 13 14IMF
SPLEEN (cm) VERT+HORIZ
PRE Rx
POST Rx
HS Gilbert
Anagrelide IFN Hydroxyurea
Effect of Therapy on Control of Proliferation
PLTS
MyM
RBC
WBC
HS Gilbert
IFN
P Vera
MyM
Pairing MPD Phenotype and Therapy
PLTS
MyM
RBC
WBC
HS Gilbert
Anagrelide
Hydroxyurea
IFN
MyM
P Vera ET
Combined Agent Therapy in MPDs
HS Gilbert
Three Classes of Drugs Used for Treatment of Thrombocythemia in MPDs
DRUG ANAGRELIDE HYDROXYUREA IFN-α
CLASS OF DRUG Prostaglandin synthetase inhibitor
Ribonucleoside diphosphate reductase inhibitor
Biological response modifier
MECHANISM OF ACTION
Inhibitor of megakaryocyte maturation and platelet budding
DNA synthesis inhibitor; myelosuppressive
Myelosuppressive Immunomodulatory
EFFECT ON CLONAL vs NORMAL PHPC
None; targets megakaryocytes
Nonselective Selective; reduces and/or changes MPD clone
EFFECT ON MEGAKARYOCYTES
Prevents maturation and budding
Decreases by inhibiting proliferation of PHPC
Decreases by inhibiting proliferation of PHPC
HS Gilbert
Three Classes of Drugs Used for Treatment of Thrombocythemia in MPDs
DRUG ANAGRELIDE HYDROXYUREA IFN-α
REDUCTION AND MAINTENANCE OF PLATELETS TO <400,000/µL
Achieved by titration;
Gradual reduction;
Steady maintenance while on drug.
Difficult to achieve;
Difficult to maintain;
Requires continuous drug for maintenance.
Achieved by titration;
Gradual reduction;
Steady maintenance that persists after drug stopped.
REDUCTION OF SPLENOMEGALY/MYELOID METAPLASIA
None None Spleen shrinks beginning at 2 mos, continues during 6-12 mos, and persists after drug stopped.
PREVENTION OR REVERSAL OF FIBROSIS
Potentially by effect on megakaryocytes.
None Potentially by changing MPD clone and marrow milieu.
ACUTE LEUKEMIA OR MDS TRANS-FORMATION
Unlikely
Unknown
Increased
5%-10%
Unlikely
Unknown
HS Gilbert
Three Classes of Drugs Used for Treatment of Thrombocythemia in MPDs
DRUG ANAGRELIDE HYDROXYUREA IFN-α
STABILITY OF RESPONSE DURING TREATMENT
Good Fair Good
DURATION OF EFFECT AFTER STOPPING TREATMENT
Short without rebound Short with rebound Long without rebound
SIDE EFFECTS 2-3+ 1-2+ 2-4+
USE DURING PREGNANCY
No No Acceptable
COST $5.00/capsule $1.00/capsule $8.00/MU
ACUTE LEUKEMIA/MDS TRANSFORMATION
Unknown
Unlikely
5%-10% Unknown
Unlikely
HS Gilbert
Three Classes of Drugs Used for Treatment of Thrombocythemia in MPDs
DRUG ANAGRELIDE HYDROXYUREA IFN-α
STABILITY OF RESPONSE DURING TREATMENT
Good Fair Good
DURATION OF EFFECT AFTER STOPPING TREATMENT
Short without rebound Short with rebound Long without rebound
SIDE EFFECTS 2-3+ 1-2+ 2-4+
USE DURING PREGNANCY
No No Acceptable
COST $5.00/capsule $1.00/capsule $8.00/MU
ACUTE LEUKEMIA/MDS TRANSFORMATION
Unknown
Unlikely
5%-10% Unknown
Unlikely
HS Gilbert
Side Effects of Therapy ANAGRELIDEProstaglandin Inhibition
Vasodilator:
Headache
Dizziness
Inotrope:
“Palpitations”
Renal blood flow:
Fluid retention
Lactose vehicle
Bloating, diarrhea
Nausea, vomiting
HYDROXYUREAAntimetabolite
Myelosuppression:Myelosuppression:
Neutropenia
Anemia
Dermal:
Mucositis
Hyperpigmentation
Ulceration
Gastrointestinal:
Nausea, vomiting
Bloating, diarrhea
Liver damage
Systemic:
Headache, nausea,
Asthenia
IFN-αBiologic Response Modifier
Systemic:
Fever, chills
Myalgia, fatigue
Anorexia
Cytoreductive:
Alopecia
Diarrhea
Myelosuppression:
Neutropenia
Anemia
Neurologic:
Headache, depression
Neuropathy
Immunomodulator:
Hypothyroidism
CHF, PULMONARY EDEMA
LEUKEMOGENICMUTAGENIC
HS Gilbert
Treatment: Stem Cell Transplant
Experimental
• Therapies for idiopathic myelofibrosis
• Allogeneic stem cells
• Autologous stem cells
SM Fruchtman
Allogeneic Bone Marrow Transplantation
DONOR usually HLA-matched sibling
RECIPIENT
High-dose chemotherapy± total body irradiation
c 750 ml bone marrow aspirated
from iliac crest
bone marrow graft: donor marrow infused
intravenously
± T cell depletion by monoclonal antibodies
Intensive support therapy, e.g. red cells &
platelets, antibiotics ± attempts to prevent
GVHD, e.g. cyclosporin ± methotrexate
SM Fruchtman
The Sheffield Schema for Predicting Survival
Age (yrs) Hb (g/dL) KaryotypeMedian survival
<68 10 N
A
54
22
>10 N
A
180
72
>68 10 N
A
44
16
>10 N
A
70
78
N=normal, A=abnormal SM Fruchtman
The LILLE Scoring System for Predicting Survival
No. of adverse prognostic factors Risk group Cases (%)
Median survival (months)
0 Low 47 93
1 Intermediate 45 26
2 High 8 13
Adverse prognostic factors; Hb <10g/dL, WBC <4 or >30 x 109/L
SM Fruchtman
P Vera, ET, and Allogeneic BMT
Diagnosis Age Gender
Time from DX to transplant (months) Medical RX
Spleen size
P Vera 44 F 156 Hydrea, Phl Resected
P Vera 31 F 144 Hydrea, ASA Mildly enlarged
ET 18 F 60 ASA, Persantin
Mildly enlarged
ET 49 M 37 Hydrea Mildly enlarged
ET 31 F 180 Epo, Hydrea Mildly enlarged
SM Fruchtman
Hematologic Parameters
Diagnosis WBC* Blasts Platelet* HCT%Grade of fibrosis Cytogenetics
P Vera 5.9 <1 879 38.2 3 Normal
P Vera 13.8 <1 966 40.2 1 Normal
ET 11.7 1 1,256 38.4 2-3 Normal
ET 14.8 1 252 38.6 2 Normal
ET 5.5 0 554 34.0 2-3 Normal
*x109 cells/LSM Fruchtman
Transplantation Characteristics and Outcome
Diagnosis Donor GVHD Comments
P Vera HLA IDVUD
GR 1 AcuteChronic extensive
On immunosuppressionAlive (2.1 yrs)100% Performance
P Vera HLA IDSIB
GR 2 AcuteChronic extensive
On immunosuppressionAlive (1.7 yrs)80% Performance
ET HLA IDSIB
None Alive (7.1 yrs)100% Performance
ET HLA IDSIB
Grade 3 Acute Alive (1.4 yrs)100% Performance
ET HLA IDSIB
None Alive (1.2 yrs)80% Performance
Prep Regimen BU/CyGVHD Prophylaxis CSA/MTX SM Fruchtman
Cost-effectiveness
Treatment Model: ET
• Treatment in ET: based on high-risk patients
• Treatment options include Hydroxyurea (HU), anagrelide and interferon alpha.
• Controversy regarding best choice of agent.
CL Bennett
Available Evidence
• Comparative phase III clinical trials for rare diseases such as ET are difficult to carry out
• No head to head comparison data are available for choosing best therapeutic agent in ET
CL Bennett
Complications of Untreated ET
• Angina/MI 4.3% /year• TIA/Stroke 3.6% /year• GI or other hemorrhage 0.2% /year • Venous/Arterial thrombosis 2.9% /year
CL Bennett
Hydroxyurea
• Typical effective dose 1g/day;– Cost: $142/month
• Response rate: 80%-89%
• Often used as first-line therapy for ET
• Concerns: long-term tolerability and leukemogenicity
CL Bennett
Anagrelide
• Maintenance Dose 2.5mg daily; • Cost: $520/month • Adverse effects: Palpitations, (10%-27%),
tachycardia & other arrhythmias (< 10%), CHF exacerbation (<2%).
• Response rate: 90%
CL Bennett
IFN-
• Typical effective dose 30 MU/week; Cost (including injection supplies) $1860/month
• Withdrawal secondary to adverse effects: 25% 1st year; 25% additional in 2nd year
• Response rate: 80%
CL Bennett
Methods
• A Markov model was used to derive life-expectancy and lifetime risk of sequelae of ET and treatments.
• Data derived from the Markov model was then used in a decision tree to compare relative benefits and life-time costs of treatment and treatment-related sequelae of HU, anagrelide and IFN-.
CL Bennett
Costs of Complications
• Stroke $30,000
• MI $30,000
• GI bleed $5,000
• TIA $4,700
• Venous thrombosis $3,200
• Acute Leukemia $245,000
CL Bennett
Assumptions of Model
• Leukemia risk modeled as part of sensitivity analysis (baseline risk of 10%)
• Markov model allows for only one complication in any one cycle.
• It takes three months to evaluate efficacy of drug.
• Treatment of leukemia results in cure of ET (if survive).
CL Bennett
CL Bennett
Markov Model
Costs and cost-effectiveness estimates for a 40 year old individual with ET who is treated with HU, anagrelide, or IFN.
Drug Cost [C] Effectiveness [E] (years of life)
Marginal C/E [$/LYS]
HU $78,000 20.677
Anagre-lide
$132,000 21.266 $93,073
IFN $148,000 21.229 (Dominated)
CL Bennett
Estimated Cost/Effectiveness of Cytoreductive Therapy
Cost-effectiveness Results (Cont’d)
• $75,000 to $100,000 per life year gained is used as threshold for "cost-effective"
• For younger high-risk patients, anagrelide is clinically effective and in the range of options that are considered cost-effective
• Hydroxyurea is a cost-effective option for older individuals
• IFN- is never cost-effective
CL Bennett
Limitations
• No reliable estimate of leukemic risk
CL Bennett
CL Bennett
Conclusion
Anagrelide is a cost-effective option for younger, symptomatic patients, taking into account a risk of leukemic conversion with hydroxyurea.
Hydroxyurea is a cost-effective option for older patients.
IFN- is never cost-effective and should be restricted to situations such as pregnancy
Conclusions
A New Treatment Dynamic?
• Reduce platelets to low normal range• Is IFN- underutilized? Does it affect the clone
more than other approaches?• Is ASA warranted in all cases? Prescreen with
platelet aggregation studies?• Reserve hydroxyurea for refractory cases?• Begin treatment earlier
– Thrombotic complications are not uncommon in young patients. Early, more aggressive treatment may reduce future complications
CM Kessler
Conclusion—P Vera, ET
1. Hydroxyurea has become an old friend (? Enemy).
2. It is an excellent choice for older patients and those at risk for thrombosis.
3. No myelosuppressive therapy is an excellent option for young patients and those at low thrombotic risk.
4. Medium-dose aspirin (75-325 mg daily). The risk/benefit ratio remains to be determined.
SM Fruchtman
Modern Therapeutic Options in MPD
Essential Thrombocythemia
Hydroxyurea
Anagrelide
ASA
32P
IFN-
PlateletpheresisSM Fruchtman
Take-Home Messages
• Diagnose ET earlier– Be more suspicious– Criteria now permit diagnosis at platelet count of
400,000/L – Treat ET more aggressively– Normal platelet count should be therapeutic goal
• Use low-dose aspirin if platelet count permits– Helps counteract undetected spontaneous
aggregation– No increased bleeding risk until platelets
> 1.5 million/L
RM Petitt
Future Directions for MPD
• Anagrelide– Sustained release ?– Congeners
• IFN– Pegylated IFN – now on market– Albumin-bound IFN – coming
• Marrow curettage + autologous CD34 infusion– Better results after splenectomy?
• Angiogenesis inhibitors– Thalidomide– Over 40 others in various phases of evaluation
• Other biologic response modifiers
RM Petitt
References
References1. Tefferi A, Silverstein MN, Hoagland HC. Primary thrombocythemia.
Sem Onc 1995, 22:334-340. 2. Gilbert HS. Diagnosis and treatment of polycythemia vera,
agnogenic myeloid metaplasia, and essential thrombocythemia. In Neoplastic Diseases of the Blood. Wiernik PH, Canellos GP, Kyle RA, Schiffer CA, (eds): New York: Churchill Livingstone,1991, p 123.
3. Hachulla E, Rose C, Trillot N, Caulier-Leleu MT, Pasturel-Michon U. [What vascular events suggest a myeloproliferative disorder]?J Mal Vasc 2000, 25(5):382-387.
4. Tefferi A. Chronic myeloid disorders: Classification and treatment overview. Semin Hematol 2001, 38 (1 Suppl 2):1-4.
5. Nosslinger T, Reisner R, Gruner H, Tuchler H, Nowotny H, Pittermann E, Pfeilstocker M. Dysplastic versus proliferativeCMML--a retrospective analysis of 91 patients from a single institution. Leuk Res 2001, 25:741-747.
6. Westbrook CA, Hsu WT, Chyna B, Litvak D, Raza A, Horrigan SK. Cytogenetic and molecular diagnosis of chromosome 5 deletions in myelodysplasia. Br J Haematol 2000, 110:847-855.
7. Li S, Salhany KE. Spurious elevation of automated platelet counts in secondary acute monocytic leukemia associated with tumor lysis syndrome. Arch Pathol Lab Med 1999, 123:1111-1114.
8. Mazur EM, Rosmarin AG, Sohl PA, Newton JL, Narendran A. Analysis of the mechanism of anagrelide-induced thrombocytopenia in humans. Blood 1992, 79:1931-1937.
9. Solberg LA, Tefferi A, Oles KJ, et al. The effects of anagrelide on human megakaryocytopoiesis. Br J Haematol 1997, 99:174-180.
10. Tomer A. Effects of anagrelide on in vivo megakaryocyte proliferation and maturation in essential thrombocythemia. Blood 2002, 99:1602-1609.
11. Murphy S, Peterson P, Iland H, Laslo J. Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on the diagnostic criteria, survival and leukemic transition by treatment. Semin Hematol 1997, 34:29-39.
12. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.N Engl J Med 1995, 332:1132-1136.
13. Ruggeri M, Finazzi G, Tosetto A, Riva S, Rodeghiero F, Barbui T. No treatment for low-risk thrombocythaemia: results from a prospective study. Br J Haematol 1998, 103:772-777.
14. Michiels JJ. Aspirin and platelet-lowering agents for the prevention of vascular complications in essential thrombocythemia. Clin Appl Thromb Hemost 1999, 5:247-251.
15. Jensen MK, de Nully Brown P, Nielsen OJ, Hasselbalch HC. Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area.Eur J Haematol 2000, 65(2):132-139.
16. Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol 1999, 61(1):10-15.
17. Gugliotta L, et al. Poster 289, ISH Stockholm, September 1997.18. Georgii A, Buhr T, Buesche G, Kreft A, Choritz H. Classification and
staging of Ph-negative myeloproliferative disorders by histopath-ology from bone marrow biopsies. Leuk Lymphoma 1996, 22:15-29.
References (Cont’d)19. Berk PD, Goldberg JD, Donovan PB, Fruchtman SM, Berlin NI,
Wasserman LR. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 1986, 23(2):132-143.
20. Storen EC, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia. Blood 2001,97(4):863-866.
21. Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematol 1999,36(1Suppl 2):9-13.
22. Regev A, Stark P, Blickstein D, Lahav M. Thrombotic complications in essential thrombocythemia with relatively low platelet count.Am J Hematol 1997, 56:168-172.
23. Michiels JJ, van Genderen PJ, Lindemans J, van Vliet HH. Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia. Leuk Lymphoma 1996,22 (Suppl 1):47-56.
24. Cortelazzo S, Viero P, Finazzi G, D'Emilio A, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990, 8:556-562.
25. Kurzrock R, Cohen PR. Erythromelalgia and myeloproliferative disorders. Arch Int Med 1989, 149:105-109.
26. McKusick MA. Imaging findings in Budd-Chiari syndrome. Liver Transpl 2001, 7(8):743-744.
27. Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp S, Helmerhorst FM, Bouma BN, Rosendaal FR. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001,344:1527-1535.
28. Kutti J, Ridell B. Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Pathol Biol (Paris) 2001, 49(2):164-166.
29. Thiele J, Kvasnicka HM. Clinicopathology and histochemistry on bone marrow biopsies in chronic myeloproliferative disorders--a clue to diagnosis and classification. Pathol Biol (Paris) 2001, 49(2):140-147.
30. Ellis JT, Peterson P, Geller SA, Rappaport H. Studies of the bone marrow in polycythemia vera and the evolution of myelofibrosis and second hematologic malignancies. Semin Hematol 1986,23(2):144-155.
31. Rao GHR, ed. Handbook of Platelet Physiology and Pharmacology. Boston: Kluwer Academic, 1999.
32. Coller BS. Blockade of platelet GPIIb/IIIa receptors as an antithrombotic strategy. Circulation 1995, 92(9):2373-2380.
33. Boyles J, Fox JE, Phillips DR, Stenberg PE. Organization of the cytoskeleton in resting, discoid platelets: preservation of actin filaments by a modified fixation that prevents osmium damage.J Cell Biol 1985, 101(4):1463-1472.
34. Loftus JC, Choate J, Albrecht RM. Platelet activation and cytoskeletal reorganization: high voltage electron microscopic examination of intact and Triton-extracted whole mounts.J Cell Biol 1984, 98(6):2019-2025.
35. Bevers EM, Tilly RH, Senden JM, Comfurius P, Zwaal RF. Exposure of endogenous phosphatidylserine at the outer surface of stimulated platelets is reversed by restoration of aminophospholipid translocase activity. Biochemistry 1989, 28(6):2382-2387.
36. Bennett JS. Novel platelet inhibitors. Annu Rev Med 2001,52:161-184.
References (Cont’d)37. Kulkarni S, Dopheide SM, Yap CL, et al. A revised model of platelet
aggregation. J Clin Invest 2000, 105(6):783-791.38. Luchtman-Jones L, Broze GJ Jr. The current status of coagulation.
Ann Med 1995, 27(1):47-52.39. Wehmeier A, Sudhoff T, Meierkord F. Relation of platelet
abnormalities to thrombosis and hemorrhage in chronic myeloproliferative disorders. Semin Thromb Hemost 1997,23:391-402.
40. Jensen MK, de Nully Brown P, Lund BV, Nielsen OJ, Hasselbalch HC. Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders. Br J Haematol 2000,110:116-124.
41. Murphy S. Therapeutic dilemmas: balancing the risks of bleeding, thrombosis, and leukemic transformation in myeloproliferative disorders (MPD). Thromb Haemost 1997, 78(1):622-626.
42. Faurschou M, Nielsen OJ, Jensen MK, Hasselbalch HC. High prevalence of hyperhomocysteinemia due to marginal deficiency of cobalamin or folate in chronic myeloproliferative disorders.Am J Hematol 2000, 65:136-140.
43. Horikawa Y, Matsumura I, Hashimoto K, et al. Markedly reduced expression of platelet c-mpl receptor in essential thrombocythemia. Blood 1997, 90(10):4031-4038.
44. Moliterno AR, Hankins WD, Spivak JL. Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. N Engl J Med 1998, 338(9):572-580.
45. Le Blanc K, Andersson P, Samuelsson J. Marked heterogeneity in protein levels and functional integrity of the thrombopoietin receptor c-mpl in polycythaemia vera. Br J Haematol 2000, 108(1):80-85.
46. Matsumura I, Horikawa Y, Kanakura Y. Functional roles of thrombopoietin-c-mpl system in essential thrombocythemia.Leuk Lymphoma 1999, 32(3-4):351-358.
47. Cardier JE, Foster DC, Lok S, Jacobsen SE, Murphy MJ Jr. Megakaryocytopoiesis in vitro: from the stem cells’ perspective. Stem Cells 1996, 14(Suppl 1):163-172.
48. McCarty JM, Simanis JP, Kanamori D, Dessypris EN. Anagrelide exhibits antiproliferative effects on megakaryocyte progenitors generated from human CD34+ cells by inhibiting TPO specific, but not IL-3 specific signaling events. Blood 1999, 94(11) 1part2: 1178a.
49. McCarty JM, Melone PM, Heisey C, Dessypris EN. Differences in the species-specific activity of anagrelide is mediated through the c-mpl receptor. Blood 2000, 96(11) 1part2: 3213a.
50. Tefferi A, Solberg LA, Silverstein MN. A clinical update in polycythemia vera and essential thrombocythemia. Am J Med 2000, 109(2):141-149.
51. Tefferi A, Fonseca R, Pereira DL, Hoagland HC. A long-term retrospective study of young women with essential thrombocythemia. Mayo Clin Proc 2001, 76(1):22-28.
52. Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 1981, 304(8):441-447.
53. Marchioli R, Landolfi R, Barbui T, Tognoni G. Feasibility of randomised clinical trials in rare diseases: the case of polycythemia vera. Leuk Lymphoma 1996, 22 (Suppl 1):121-127.
54 . Murphy S, Rosenthal DS, Weinfeld A, et al. Essential thrombocythemia: response during first year of therapy with melphalan and radioactive phosphorus: a Polycythemia Vera Study Group report. Cancer Treat Rep 1982, 66(7):1495-1500.
References (Cont’d)55. Laszlo J. Myeloproliferative disorders (MPD): myelofibrosis,
myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia. Semin Hematol 1975, 12:409-432.
56. Iland HJ, Laszlo J, Peterson P, et al. Essential thrombocythemia: clinical and laboratory characteristics at presentation. Trans Assoc Am Physicians 1983, 96:165-174.
57. Kutti J, Wadenvik H. Diagnostic and differential criteria of essential thrombocythemia and reactive thrombocytosis. Leuk Lymph 1996, 22 (Suppl 1):41-45.
58. Pearson TC. Evaluation of diagnostic criteria in polycythemia vera. Semin Hematol 2001, 38(1 Suppl 2):21-24.
59. Pearson TC, Messinezy M. The diagnostic criteria of polycythaemia rubra vera. Leukemia Lymph 1996, 22:87-93.
60. Pearson, TC. Diagnosis and classification of erythrocytoses and thrombocytoses. Baillieres Clin Haematol 1998, 11:695-720.
61. Michiels JJ, Kutti J, Stark P, et al. Diagnosis, pathogenesis and treatment of the myeloproliferative disorders: essential thrombocythemia, polycythemia vera and essential megakaryocytic granulocytic metaplasia and myelofibrosis.Neth J Med 1999, 54:46-62.
62. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002, 100:2292-2302.
63. Chievitz E, Thiede T. Complications and causes of death in polycythemia vera. Acta Medica Scandinavica 1962,172:513-523.
64. Fruchtman SM, Mack K, Kaplan ME, Peterson P, Berk PD, Wasserman LR. From efficacy to safety: a Polycythemia Vera Study Group report on hydroxyurea in patients with polycythemia vera. Semin Hematol 1997, 34(1):17-23.
65. Nand S, Messmore H, Fisher SG, Bird ML, Schulz W, Fisher RI. Leukemic transformation in polycythemia vera: analysis of risk factors. Am J Hematol 1990, 34(1):32-36.
66. Nand S, Stock W, Godwin J, Fisher SG. Leukemogenic risk of hydroxyurea therapy in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.Am J Hematol 1996, 52(1):42-46.
67. Randi ML, Rossi C, Fabris F, Menapace L, Girolami A. Aspirin seems as effective as myelosuppressive agents in the prevention of rethrombosis in essential thrombocythemia. Clin Appl Thromb Hemost 1999, 5(2):131-135.
68. Dewald GW, Wright PI. Chromosome abnormalities in the myeloproliferative disorders. Semin Oncol 1995, 22(4):341-354.
69. Tefferi A, Silverstein MN. Treatment of polycythaemia vera and essential thrombocythaemia. Baillieres Clin Haematol 1998, 11(4):769-785.
70. Jantunen R, Juvonen E, Ikkala E, et al. The predictive value of vascular risk factors and gender for the development of thrombotic complications in essential thrombocythemia.Ann Hematol 2001, 80:74-78.
71. Gilbert HS. Diagnosis and treatment of thrombocythemia in myeloproliferative disorders. Oncology (Huntingt) 2001, 5(8):989-996, 998; discussion 999-1000,1006,1008.
72. Harrison CN, Gale RE, Machin SJ, Linch DC. A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications. Blood 1999, 93(2):417-424.
73. Tefferi A. Recent progress in the pathogenesis and management of essential thrombocythemia. Leuk Res 2001, 25(5):369-377.
References (Cont’d)74. Briere J, Guilmin F. Management of patients with essential
thrombocythemia: current concepts and perspectives. Pathol Biol (Paris) 2001, 49:178-183.
75. Kessler CM, Klein HG, Havlik RJ. Uncontrolled thrombocytosis in chronic myeloproliferative disorders. Br J Haematol 1982, 50(1):157-167.
76. Berrebi A, Shvidel L, Shtalrid M, Klepfish A. Short course of busulphan in essential thrombocythaemia: remodelling of an old strategy. Br J Haematol 2000, 109:249-250.
77. Gugliotta L, et al. Abstract 883, EHA Paris, June 1996.78. Kiladjian JJ, et al. Abstract 887, EHA Paris, June 1996.79. Finazzi G, Ruggeri M, Rodeghiero F, Barbui T. Second
malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial. Br J Haematol 2000, 110:577-583.
80. Gilbert, HS. Historical perspective on the treatment of essential thrombocythemia and polycythemia vera. Semin Hematol 1999, 36(1 Suppl 2):19-22.
81. Chaine B, Neonato MG, Girot R, Aractingi S. Cutaneous adverse reactions to hydroxyurea in patients with sickle cell disease. Arch Dermatol 2001, 137:467-470.
82. Weinfeld A, Swolin B, Westin J, et al. Acute leukemia after hydroxyurea treatment in polycythemia vera and allied disorders: Prospective study of efficacy and leukemogenicity with therapeutic implications. Eur J Haematol 1994, 52:134-139.
83. Randi ML, Stocco F, Rossi C, Tison T, Girolami A. Thrombosis and hemorrhage in thrombocytosis: evaluation of a large cohort of patients (357 cases). J Med 1991, 22(4-5):213-223.
84. Sterkers Y, Preudhomme C, Lai JL, Demory JL, Caulier MT, Wattel E, Bordessoule D, Bauters F, Fenaux P. Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion. Blood 1998, 91(2):616-622.
85. Hanft VN, Fruchtman SR, Pickens CV, Rosse WF, Howard TA, Ware RE. Acquired DNA mutations associated with in vivo hydroxyurea exposure. Blood 2000, 95(11):3589-3593.
86. Van Genderen PJ, Michiels JJ. Hydroxyurea in essential thrombocytosis. N Engl J Med 1995, 333:802-803.
87. Lengfelder E, Griesshammer M, Hehlmann R. Interferon-alpha in the treatment of essential thrombocythemia. Leuk Lymphoma 1996, 22 (Suppl 1):135-142.
88. Lazzarino M, Vitale A, Morra E, et al. Therapy of essential thrombocythemia with alpha-interferon: results and prospects.Eur J Haematol Suppl 1990, 52:15-21.
89. Lazzarino M, Vitale A, Morra E, et al. Interferon alpha-2b as treatment for Philadelphia-negative chronic myeloproliferative disorders with excessive thrombocytosis. Br J Haematol 1989, 72:173-177.
90. Wright CA, Tefferi A. A single institutional experience with 43 pregnancies in essential thrombocythemia. Eur J Haematol 2001, 66(3):152-159.
91. Brooks WG, Stanley DD, Goode JV. Role of anagrelide in the treatment of thrombocytosis. Ann Pharmacother 1999,33(10):1116-1121.
92. Pescatore SL, Lindley C. Anagrelide: a novel agent for the treatment of myeloproliferative disorders. Expert Opin Pharmacother 2000, 1:537-546.
References (Cont’d)93. Knutsen H, Hysing J. Anagrelide in primary thrombocythemia.
Tidsskr Nor Laegeforen 2001, 121:1478-1482.94. No authors listed. Anagrelide, a therapy for thrombocythemic states:
experience in 577 patients. Anagrelide Study Group. Am J Med 1992, 92:69-76.
95. Laguna MS, Kornblihtt LI, Marta RF, Michiels JJ, Molinas FC. Effectiveness of anagrelide in the treatment of symptomatic patients with essential thrombocythemia. Clin Appl Thromb Hemost 2000, 6(3):157-161.
96. Finazzi G, Barbui T. Treatment of essential thrombocythemia with special emphasis on leukemogenic risk. Ann Hematol 1999, 78(9):389-392.
97. Tefferi A, Silverstein MN, Petitt RM, Mesa RA, Solberg LA Jr. Anagrelide as a new platelet-lowering agent in essential thrombocythemia: mechanism of action, efficacy, toxicity, current indications. Semin Thromb Hemost 1997, 23(4):379-383.
98. Silverstein MN, Petrone ME, Petitt RM, Dement MP, Vukovich RA. The safety profile of anagrelide for treatment of thrombocythemia. Blood 1996, 88(Suppl 1):583a (abstr).
99. Gilbert HS. Other secondary sequelae of treatments for myelo-proliferative disorders. Semin Oncol 2002, 29 (3 Suppl 10):22-27.
100. Package insert, anagrelide hydrochloride, Shire US Inc.101. From unpublished data.102. Shire Study Report No 13970-301. An open protocol for the use of
Agrylin (anagrelide HCl) for patients with thrombocythemia. 2002.103. Fruchtman SM, Petitt RM, Gilbert H, Fiddler G, Lyne A. Anagrelide
Study Group. Blood 2002, 100:256a.104. Gilbert HS. Current management in polycythemia vera. Semin
Hematol 2001, 38(1Suppl 2):25-28.
105. Elliott MA, Tefferi A. Interferon-alpha therapy in polycythemia vera and essential thrombocythemia. Semin Thromb Hemost 1997, 23(5):463-472.
106. Lahtinen R, Kuikka J. Cerebral blood flow in polycythaemia vera. Ann Clin Res 1983, 15(5-6):200-202.
107. Michiels JJ, Barbui T, Finazzi G, Fuchtman SM, Kutti J, Rain JD, Silver RT, Tefferi A, Thiele J. Diagnosis and treatment of polycythemia vera and possible future study designs of the PVSG. Leuk Lymphoma 2000, 36(3-4):239-253.
108. Landolfi R, Marchioli R. European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP): a randomized trial. Semin Thromb Hemost 1997, 23(5):473-478.
109. No authors listed. Collaborative overview of randomised trials of antiplatelet therapy--III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists' Collaboration. BMJ 1994, 308(6923):235-246.
110. No authors listed. Collaborative overview of randomised trials of antiplatelet therapy--II: Maintenance of vascular graft or arterial patency by antiplatelet therapy. Antiplatelet Trialists' Collaboration. BMJ 1994, 308(6922):159-168. Review.
111. No authors listed. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. BMJ 1994, 308(6921):81-106.
112. Lengfelder E, Berger U, Hehlmann R. Interferon alpha in the treatment of polycythemia vera. Ann Hematol 2000, 79(3):103-109.
References (Cont’d)113. Gilbert HS. Long term treatment of myeloproliferative disease with
interferon-alpha-2b: feasibility and efficacy. Cancer 1998, 83(6):1205-1213.
114. Butcher C, D'Andrea RJ. Molecular aspects of polycythemia vera (review). Int J Mol Med 2000, 6(3):243-252.
115. Thiele J, Kvasnicka HM, Zankovich R, Diehl V. Relevance of bone marrow features in the differential diagnosis between essential thrombocythemia and early stage idiopathic myelofibrosis. Haematologica 2000, 85(11):1126-1134.
116. Tefferi A, Mesa RA, Nagorney DM, Schroeder G, Silverstein MN. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 2000, 95(7):2226-2233.
117. Barosi G, Ambrosetti A, Centra A, et al. Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Italian Cooperative Study Group on Myeloid with Myeloid Metaplasia. Blood 1998, 91(10):3630-3636.
118. Myllyharju J, Kivirikko KI. Collagens and collagen-related diseases. Ann Med 2001, 33(1):7-21.
119. Sacchi S. The role of alpha-interferon in essential thrombocythaemia, polycythaemia vera and myelofibrosis with myeloid metaplasia (MMM): a concise update. Leuk Lymphoma 1995,19:13-20.
120. Gilbert HS. The role of anagrelide, hydroxyurea, and interferon-α in treating the thrombocythemia of myeloproliferative disease: a new approach for the millennium. International Society of Hematology Education Program Book, 1999, pp 141-143.
121. Bennett CL, Weinberg PO, Golub RM. Cost-effectiveness model of a phase II clinical trial of a new pharmaceutical for essential thrombocythemia: is it helpful to policy makers? Semin Hematol 1999, 36(1Suppl 2):26-29.
122. Lubbert M, Wijermans P, Kunzmann R, et al. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Br J Haematol 2001, 114(2):349-357.
123. Shimamoto T, Iguchi T, Ando K, et al. Successful treatment with cyclosporin A for myelodysplastic syndrome with erythroid hypoplasia associated with T-cell receptor gene rearrangements.Br J Haematol 2001, 114(2):358-361.
124. Reilly JT, Snowden JA, Spearing RL, Fitzgerald PM, Jones N, Witmore A, Potter A. Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases.Br J Haematol 1997, 98:96-102.
125. Jurado M, Deeg H, Gooley T, et al. Haemopoietic stem cell transplantation for advanced polycythaemia vera or essential thrombocythaemia. Br J Haematol 2001, 112(2):392-396.
126. Dupriez B, Morel P, Demory JL, Lai JL, Simon M, Plantier I, Bauters F. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 1996, 88:1013-1018.
127. Anderson JE, Sale G, Appelbaum FR, Chauncey TR, Storb R. Allogeneic marrow transplantation for primary myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocytosis. Br J Haematol 1997, 98(4):1010-1016.
References (Cont’d)128. Barbui T, Finazzi G, Dupuy E, Kiladjian JJ, Briere J. Treatment
strategies in essential thrombocythemia. A critical appraisal of various experiences in different centers. Leuk Lymphoma 1996,22 (Suppl 1):149-160.
129. Silverstein MN, Petitt RM, Solberg LA Jr, Fleming JS, Knight RC, Schacter LP. Anagrelide: a new drug for treating thrombocytosis.N Engl J Med 1988, 318:1292-1294.
130. Sacchi S, Tabilio A, Leoni P, Riccardi A, Vecchi A, Messora C, Falzetti F, Rupoli S, Ucci G, Martelli MF. Interferon alpha-2b in the long-term treatment of essential thrombocythemia.Ann Hematol 1991, 63:206-209.
131. Northwestern Memorial Hospital Pharmacy (for costs, dc)132. Golub R, Adams J, Dave S, Bennett CL. Cost-effectiveness
considerations in the treatment of essential thrombocythemia. Semin Oncol 2002, 29(3 Suppl 10):28-32.
133. Holloway RG, Witter DM Jr, Lawton KB, Lipscomb J, Samsa G. Inpatient costs of specific cerebrovascular events at five academic medical centers. Neurology 1996, 46:854-860.
134. Waters TM, Bennett CL, Pajeau TS, Sobocinski KA, Klein JP, Rowlings PA, Horowitz MM. Economic analyses of bone marrow and blood stem cell transplantation for leukemias and lymphoma: what do we know? Bone Marrow Transplant 1998, 21:641-650.
This ends the Non-CML MPD Slide Kit CD-ROM program. If you would like to review a slide, left click the HOUSE icon, which will return you to the Table of Contents, and proceed from there. Otherwise, left click EXIT to end program.
Explanatory notes and references accompany each slide and are located in the binder, along with the CME posttest and evaluation.
We hope you find this material useful in your practice.
Exit