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Current Approaches to Current Approaches to the Diagnosis and the Diagnosis and Management of Non-CML Management of Non-CML Myeloproliferative Myeloproliferative Disorders Disorders

Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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Page 1: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Current Approaches to Current Approaches to the Diagnosis and Management the Diagnosis and Management

of Non-CML of Non-CML Myeloproliferative DisordersMyeloproliferative Disorders

Page 2: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative 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

Page 3: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 4: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 5: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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.

Page 6: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Grantor

This activity is made possible by an unrestricted educational grant from Shire US Inc.

Produced ByJonathan Wood & Associates

Page 7: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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.

Page 8: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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.

Page 9: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 10: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Overview:Epidemiology, Etiology, and

Pathophysiology

Page 11: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Chronic Myeloproliferative Disorders

Four well-characterized subgroups:

• Polycythemia vera (P Vera)

• Essential thrombocythemia (ET)

• Agnogenic myeloid metaplasia (AMM)

• Chronic myelogenous leukemia (CML)

HS Gilbert

Page 12: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 13: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 14: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

RBC

MyM

P VeraET

PLTS

MyM

WBC

Phenotypes of MPDs

HS Gilbert

Page 15: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 16: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 17: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 18: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 19: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 20: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 21: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 22: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 23: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 24: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 25: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 26: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 27: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 28: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 29: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Natural History

Page 30: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Natural History of ET and P Vera

• Hemorrhage

• Myeloid metaplasia

• Myelofibrosis

• Myelodysplastic syndrome

• Acute leukemia

• Thrombosis

HS Gilbert

Page 31: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 32: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 33: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 34: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

RM Petitt

Photo

Page 35: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 36: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 37: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 38: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Hepatic Venogram of Budd-Chiari Syndrome in ET

CM Kessler

Page 39: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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).

Page 40: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 41: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 42: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Timeline of MPDs

HS Gilbert

P Vera

ET

MyM

MF

LeukemiaMDS

Page 43: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Platelet Physiology

Page 44: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Peripheral Blood Showing Massive Platelet Clumping and a Basophil

x 1000; Reduced 5% for Reproduction SM Fruchtman

Page 45: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Bone Marrow Biopsy Showing Prominent Megakaryocytic Hyperplasia

x 100; Reduced 5% for Reproduction SM Fruchtman

Page 46: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 47: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 48: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

What Is the Pathophysiology of Bleeding and Thrombosis in ET

?

• Platelet number

• Platelet function

• Platelet turnover

• Other factors

SM Fruchtman

Page 49: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 50: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 51: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Adapted from Coller BS. Circulation. 1995;92:2373.

GP IIb/IIIa receptor

Platelet

Fibrinogen

Platelet Aggregation

CM Kessler

Page 52: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Platelets at Rest

CM Kessler

Page 53: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Activated Platelets

CM Kessler

Page 54: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 55: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Platelet Structure

CM Kessler

Page 56: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 57: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 58: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 59: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 60: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 61: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 62: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 63: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 64: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 65: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 66: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 67: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 68: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 69: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 70: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 71: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 72: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Diagnosis and Diagnostic Issues

Page 73: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Current Approaches to Diagnosing ET and P Vera

HS Gilbert

Page 74: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 75: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 76: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 77: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 78: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Thrombosis

• DVT

• PE

• CVA/TIA/Retinal/MI

• Hepatic & portal vein thrombosis

• Digital ischemia

• Erythromelalgia

• Miscarriage

SM Fruchtman

Page 79: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 80: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 81: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Bleeding

• Skin

• Mucous membranes

• GastrointestinalBy trauma

SM Fruchtman

Page 82: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 83: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 84: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 85: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 86: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 87: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 88: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 89: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 90: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 91: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 92: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 93: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 94: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 95: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 96: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 97: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 98: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 99: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 100: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

PVSG-01:Thrombosis-Related Risk Factors

• Multivariate Analysis– Randomization to phlebotomy– Age >70 years– Previous thrombosis

SM Fruchtman

Page 101: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 102: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 103: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 104: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 105: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 106: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 107: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 108: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 109: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 110: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 111: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 112: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 113: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 114: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 115: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 116: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 117: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 118: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 119: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 120: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 121: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 122: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Treatment

Page 123: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Treatment: Essential Thrombocythemia

Page 124: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 125: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Conditions Suggesting Urgent Treatment

• Symptomatic coronary artery disease

• Transient ischemic attacks

• Major hemorrhage

• Active thrombosis/pulmonary embolism

HS Gilbert

Page 126: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 127: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 128: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 129: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 130: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 131: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 132: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 133: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 134: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 135: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 136: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 137: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 138: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 139: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 140: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 141: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 142: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 143: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 144: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 145: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 146: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 147: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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)

Page 148: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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)

Page 149: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 150: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 151: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Photo

HS Gilbert

Page 152: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 153: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 154: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 155: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 156: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 157: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 158: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 159: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 160: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Photo

HS Gilbert

Page 161: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 162: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Women of Childbearing Age with ET

• High risk– IFN- and low-dose aspirin

• All others– No treatment or low-dose aspirin

HS Gilbert

Page 163: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 164: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 165: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 166: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 167: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 168: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 169: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Anagrelide: Precise & Specific (Cont’d)

• No effect on DNA synthesis– No apparent association with oncogenesis– No apparent leukemogenicity

SM Fruchtman

Page 170: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 171: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 172: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 173: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 174: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 175: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 176: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 177: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 178: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 179: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 180: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 181: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 182: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 183: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 184: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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 (%)

Page 185: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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)

Page 186: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 187: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 188: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 189: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 190: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Anagrelide

Pairing MPD Phenotype and Therapy

HS Gilbert

ETPLTS

MyM

RBC

WBC

Page 191: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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-

Page 192: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 193: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Treatment: Polycythemia Vera

Page 194: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 195: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 196: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 197: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 198: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 199: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 200: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 201: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 202: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 203: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 204: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 205: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 206: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 207: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 208: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 209: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 210: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Photo

HS Gilbert

Page 211: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 212: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 213: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Photo

HS Gilbert

Page 214: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 215: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 216: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Hydroxyurea

P Vera

Elderly orfailed other

agents

Pairing MPD Phenotype and Therapy

PLTS

MyM

RBC

WBC

HS Gilbert

Page 217: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 218: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Spent Phase

• Anemia• Splenomegaly• Nucleated RBC• Tear-drop forms

SM Fruchtman

Page 219: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

SM Fruchtman

Page 220: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 221: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 222: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 223: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Treatment: Idiopathic Myelofibrosis

(Myelofibrosis with Myeloid Metaplasia; Agnogenic Myeloid Metaplasia)

Page 224: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 225: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Medical Management of IMF

• Transfusional support• Others:

– Androgens– Hydroxyurea– Low-dose splenic RT– Erythropoietin– Interferons– Anagrelide

• Splenectomy

SM Fruchtman

Page 226: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 227: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 228: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

We NEED Antifibrosing Therapies

• Marrow

• Lung

• Liver

• Skin

• Penis

SM Fruchtman

Page 229: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 230: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 231: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 232: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Anagrelide IFN Hydroxyurea

Effect of Therapy on Control of Proliferation

PLTS

MyM

RBC

WBC

HS Gilbert

Page 233: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

IFN

P Vera

MyM

Pairing MPD Phenotype and Therapy

PLTS

MyM

RBC

WBC

HS Gilbert

Page 234: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Anagrelide

Hydroxyurea

IFN

MyM

P Vera ET

Combined Agent Therapy in MPDs

HS Gilbert

Page 235: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 236: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 237: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 238: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 239: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 240: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Treatment: Stem Cell Transplant

Page 241: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Experimental

• Therapies for idiopathic myelofibrosis

• Allogeneic stem cells

• Autologous stem cells

SM Fruchtman

Page 242: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 243: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 244: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 245: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 246: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 247: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 248: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Cost-effectiveness

Page 249: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 250: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 251: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 252: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 253: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 254: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 255: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 256: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 257: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 258: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

CL Bennett

Markov Model

Page 259: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 260: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 261: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Limitations

• No reliable estimate of leukemic risk

CL Bennett

Page 262: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 263: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Conclusions

Page 264: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 265: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 266: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

Modern Therapeutic Options in MPD

Essential Thrombocythemia

Hydroxyurea

Anagrelide

ASA

32P

IFN-

PlateletpheresisSM Fruchtman

Page 267: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 268: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

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

Page 269: Current Approaches to the Diagnosis and Management of Non-CML Myeloproliferative Disorders

References

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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.

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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.

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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.

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