Transcript Document
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
Overall Purpose
This 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 Audience
Hematologists, oncologists, and allied health professionals who care for MPD patients
Objectives
Upon completion of this course, hematologists, oncologists, and allied health professionals should be able to: • Recognize MPDs as stem cell disease • Differentiate between clonal and nonclonal thombocytosis • Describe the pathophysiology of myeloproliferative platelets • Understand leukemic transformation as a natural progression of MPDs or as a sequela of therapy • Evaluate the use of allogeneic and autologous stem cell transplantation for MPDs, including selection of candidates, use of conditioning regimens, and complications of transplantation • Diagnose accurately and treat patients with MPDs in their practice • Choose among the various treatment options • Recognize disturbances of normal hemostatic mechanisms in MPDs
Accreditation
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of Mount Sinai School of Medicine. Mount Sinai School of Medicine is accredited by ACCME to provide continuing medical education for physicians. Mount Sinai School of Medicine designates this continuing medical education activity for a maximum of 5 credits in Category 1 credit towards the AMA Physician’s Recognition Award. Each physician should claim only those hours that he/she spent in the educational activity.
Grantor
This activity is made possible by an unrestricted educational grant from Shire US Inc.
Produced By
Jonathan Wood & Associates
Faculty
Steven M. Fruchtman, MD, Chair
Clinical Director, Division of Hematology Mount Sinai School of Medicine New York, New York Disclosure: 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, PhD
Professor of Medicine Northwestern University School of Medicine Chicago, Illinois Disclosure: Consultant/Advisory Board/Speakers Bureau: Shire US Inc.
Harriet S. Gilbert, MD
Clinical Professor of Medicine Albert Einstein College of Medicine Bronx, New York Disclosure: Speakers Bureau: Shire US Inc.
Craig Kessler, MD
Professor of Medicine and Pathology Chief, Division of Hematology-Oncology Georgetown University Medical Center Washington, DC Disclosure: No commercial relationships to disclose
John M. McCarty, MD
Associate Professor Director, Bone Marrow Transplantation Program Medical College of Virginia, Virginia Commonwealth University Richmond, Virginia Disclosure: No commercial relationships to disclose
Robert M. Petitt, MD
Senior Consultant in Hematology Mayo Clinic Rochester, Minnesota Disclosure: Consultant/Advisory Board: Shire UK; Speakers Bureau: Shire US Inc.
General Disclosure
Four current therapeutic alternatives that are being used in the management of myeloproliferative disorders are cited throughout this educational slide program. Anagrelide is the only compound that the FDA has approved for the treatment of patients with thrombocythemia secondary to myeloproliferative disorders. Use of hydroxyurea, interferon , or stem cell transplant are unproven therapies that do not have an FDA indication in the treatment of the non-CML myeloproliferative disorders.
It is the policy of the Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored programs. All faculty participating in sponsored programs are expected to disclose to the audience any real or apparent conflict of-interest related to the content of their presentation, and any discussions of unlabeled or investigational use of any commercial product or device not yet approved in the United States.
Table of Contents Table of Contents
Overview: Epidemiology, Etiology, and Pathophysiology
Chronic Myeloproliferative Disorders
Four well-characterized subgroups: • Polycythemia vera (P Vera) • Essential thrombocythemia (ET) • Agnogenic myeloid metaplasia (AMM) • Chronic myelogenous leukemia (CML) HS Gilbert
Potentially Confusing Disorders
• P Vera, or CML, or AMM • Undifferentiated chronic myeloproliferative disorder • Cellular agnogenic myeloid metaplasia • Chronic myelomonocytic leukemia • Chronic basophilic, eosinophilic, or neutrophilic leukemia • Juvenile chronic myelogenous leukemia RM Petitt
MyM WBC RBC PLTS
Non-CML MPDs
Pluripotential Hematopoietic Stem Cell Monoclonal Expansion Retention of Pluripotentiality, Commitment, Differentiation, Maturation Over-Production of Functioning Circulating Hematic Populations Erythroid POLYCYTHEMIA VERA THROMBOSIS HEMORRHAGE Megakaryocyte/ Platelets ESSENTIAL THROMBOCYTHEMIA THROMBOSIS HEMORRHAGE Myeloid/Monocyte Mast cell/Basophil "Ph- CML" "CMML-OID" HYPERLEUKOCYTOSIS HYPERHISTAMINEMIA LYSOZYMURIA Extramedullary Hematopoiesis MYELOID METAPLASIA
HS Gilbert
MyM WBC RBC PLTS
Phenotypes of MPDs
ET P Vera MyM
HS Gilbert
Causes of High Platelet Counts
• Essential thrombocythemia • Other chronic myeloproliferative disorders – P Vera, MM-MF, CML • Reactive thrombocytosis • Familial thrombocythemia – High TPO, normal TPO (?abnormal c-mpl) • Myelodysplastic syndromes – CMML, 5q minus • Laboratory artifact – ANLL RM Petitt
ET: Pathophysiology
• Platelet production increased more than 5-fold – 237 million (normal 43 million) per day • Platelet survival normal • Megakaryocyte mass increased almost 4-fold – Number increased – Volume increased – Diameter increased (reflects increased ploidy) • Megakaryocyte ploidy increased – 64N and 128N cells relatively common RM Petitt
Reactive Thrombocytosis
• Acute or chronic inflammatory disease • Acute or chronic bleeding • Iron deficiency • Chronic marrow stimulation, e.g. hemolysis • Post-thrombocytopenic rebound • Disseminated malignancy • Absence of spleen (surgical, congenital, functional) • Intense exertion, parturition, trauma, epinephrine RM Petitt
Clinical Features of ET
• Median age at diagnosis = 60 years • Between 25 and 50 years, more common in women; young women in childbearing age are a subgroup with special problems • Microvascular symptoms are common; thrombotic complications exceed bleeding complications • < 5% incidence of transformation into myelofibrosis with myeloid metaplasia or acute leukemia HS Gilbert
Thrombosis in ET
• Thrombotic risk per Cortelazzo et al: – 30% in patients with prior history of thrombosis – 3% in patients with no prior history of thrombosis • Thrombotic complications in one cohort was 6.6 per patient-year (higher in > 60 y/o and those with prior history of thrombosis) HS Gilbert
Thrombosis in ET
• Increased incidence of thrombotic complications in treated patients with inadequately controlled platelet counts – Current data suggest that thrombotic complications can and do occur at relatively low platelet levels and recommend reduction of platelets to <400,000/ m L HS Gilbert
Incidence of ET
120 100 80 60 40 20 Men Women 0 <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 Age in years
SM Fruchtman
Survival After Diagnosis in ET
• ET after 10 years – Survival = 72% – Symptom-free survival = 54% • ET after 19 years – Survival = 52% – Symptom-free survival = 35% • In young patients with ET, overall survival in the first 10 years is near normal HS Gilbert
ET: Natural History (2091 Cases)
• 1294 F : 797 M = 1.62
• Mean age 56 years (SD 17, range 2-94) – 20% under age 40 years – 30% 40-60 years of age – 50% over age 60 years • Mean platelets 1.004 million/ m L (range 0.601-4.0) • Splenomegaly 22.8% • Hepatomegaly 27.0% • Karyotypic abnormality 4.9% RM Petitt
ET: Natural History (2091 Cases)
• Median follow-up 4.4 years (mean 5.1, SD 3.9) – 230 thrombotic events (11%); 65 fatal (3.1%) – 130 hemorrhagic events (6.2%); 6 fatal (0.3%) – 137 neoplastic events (6.6%) • 32 acute leukemia (1.5%); 24 fatal (1.2%) • 8 MDS (0.4%); 2 fatal (0.1%) • 31 myelofibrotic (1.5%); 3 fatal (0.15%) • 66 nonhematologic (3.2%); 3 fatal (0.15%) – 201 deaths (9.6%) RM Petitt
Classification of the Erythrocytoses
Raised PCV (Females >0.48; Male >0.51) RCM (interpreted using ICSH reference values)
Increased RCM
Absolute erythrocytosis Primary erythrocytosis
Congenital e.g.
Truncation of the Epo receptor Normal RCM
Apparent erythrocytosis
Acquired e.g.
Polycythemia vera
Secondary erythrocytosis
Congenital e.g.
High oxygen affinity Hb, autonomous high Epo production Acquired e.g.
Hypoxemia, renal disease
Idiopathic erythrocytosis
SM Fruchtman
Clinical Features of P Vera
• Median age at diagnosis = 60 years • Slightly more common in men • Clinical manifestations: thrombosis > hemorrhage; microvascular symptoms (headaches, transient neurologic or ocular symptoms, distal paresthesias, or erythromelalgia) are common • Transformation into myeloid metaplasia occurs in 10% 30% of patients observed for 10 to 25 years; natural evolution or treatment related? • Transformation to MDS and acute leukemia – late complication; natural evolution or treatment related?
HS Gilbert
Thrombosis in P Vera
• Risk of recurrent thrombosis increases with age and in patients with a history of thrombosis: – Reported incidence for thrombotic events ranged from 18%-61%; PVSG incidence was 10% per annum in arm treated with phlebotomy only – Large retrospective study found 41% incidence of thrombosis before diagnosis or during follow-up – 25% risk of recurrent thrombosis in patients with a history of thrombosis; 17% in patients with no risk HS Gilbert
Life Expectancy in P Vera
• In P Vera, median survival exceeds 15 years in young patients.
• In P Vera, serious complications can occur in young patients. Early therapy may be advised.
HS Gilbert
Natural History
Natural History of ET and P Vera
• Hemorrhage • Myeloid metaplasia • Myelofibrosis • Myelodysplastic syndrome • Acute leukemia • Thrombosis HS Gilbert
ET: Complications
• Microvascular occlusion – Erythromelalgia from spontaneous aggregation • Medium/large vessel thrombosis – Probably some baseline risk at any platelet count – May increase somewhat as platelet count rises • Hemorrhage – Risk definitely increases as platelet count rises • Leukemic transformation – Small but definite underlying risk – Effect of treatment RM Petitt
Complications of ET
• Arterial thrombosis (MI 4%, stroke 2%) • Microvascular disturbances (TIAs primarily, erythromelalgia) • Hemorrhage (GI or serious hemorrhage 5%) • Venous thrombosis 20% 32% 18% 6% CM Kessler
Erythromelalgia (Erythermalgia)
Attacks of severe burning, erythema, & warmth (feet > hands) Provoked by heat, exercise, and dependency Relieved by cold, rest, and elevation and by aspirin (?cyclooxygenase role) Two types: Idiopathic (60%): usually symmetrical Secondary (40%): half asymmetric Half of secondary cases associated with chronic MPDs: P Vera in 60%, ET in 40%; MM & CML very rarely Symptom attacks precede overt MPD in 85%, often by several years M:F ratio = 2 Gangrene occurs, especially in patients with ET RM Petitt
Photo
RM Petitt
ET: Risk of Thrombosis
• 114 high-risk ET patients – 97 (85%) over age 60 – 52 (46%) with previous thrombosis – Median platelet count 788,000 (533,000 1,240,000)/μL • Randomized to hydroxyurea (56) or no treatment (58) • After median follow-up of 27 months – 2 thrombotic events (3.6%) in hydroxyurea group – 14 thrombotic events (24%) in untreated group – Statistically significant difference (p = 0.003) RM Petitt
ET: Risk of Thrombosis
• 65 low-risk ET patients – Age<60, no history of thrombosis, platelets<1.5 million/μL (mean 823,000) • Compared with 65 age and sex-matched controls • Median follow-up 4.1 years • Thrombosis incidence: – 1.91 cases per 100 patient years in ET – 1.50 cases per 100 patient years in controls • Authors concluded that low-risk patients do not need treatment. However, this study is subject to criticism because: – Aspirin usage was not controlled – Seven previous studies all had significantly higher rates of thrombosis in their groups of ET patients RM Petitt
ET and Thrombosis
• 56 ET patients 1976-1992 (median age 66, median platelets 1.125 million/ m 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/ m L – 23 at platelet counts < 500,000/ m L – 10 at platelet counts < 400,000/ m L • 19 (34%) had severe complications (CVA, TIA, DVT, gangrene) – 10 at platelet counts < 600,000/ m L – 7 at platelet counts < 500,000/ m L – 2 at platelet counts < 400,000/ m L • 42 (91%) improved following further reduction in platelets RM Petitt
Hepatic Venogram of Budd-Chiari Syndrome in ET
CM Kessler
ET: Symptoms and Platelet Count
1000 900 800 700 600 500 400 300 200 100 0 Lowest Counts Associated With Manifestations Counts After Cessation 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).
RM Petitt
Risk Factors for ET Complications
• Prior thrombotic event • Smoking (31.4% vs 6.6%) (Not well characterized) • Age > 60 years • Long duration of thrombocytosis (platelets > 600,000/ m L —not well characterized) • Other risk factors for CAD (15.1% vs 6.6%) (not well characterized) CM Kessler
Disease Burden of ET and P Vera
Annual incidence • ET • P Vera • AMM 2.5 per 100,000 2.3 per 100,000 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
ET P Vera
Timeline of MPDs
MyM MF Leukemia MDS
HS Gilbert
Platelet Physiology
Peripheral Blood
Showing Massive Platelet Clumping and a Basophil
x 1000; Reduced 5% for Reproduction SM Fruchtman
Bone Marrow Biopsy
Showing Prominent Megakaryocytic Hyperplasia
x 100; Reduced 5% for Reproduction SM Fruchtman
Photomicrographs
Showing Variation in Reticulin Content in P Vera Reticulin grade in representative fields of four biopsies: A.
“Normal” B. Slight increase C. Moderate increase D. Marked increase
Foot and Foot Silver Stain.
x250 SM Fruchtman
S S S S SS S S H0 HO Procollagen Molecule OH OH OH Glc Gal OH OH OH OH OH OH OH OH OH OH Gal OH OH OH OH (Man)n GlcNac S S S S S S S S S S S S S S (20 Å) N-Terminal Propeptide (150 Å) S S S S S S S S H0 HO Globular Domain Triple-Helical Domain Nontriple-Helical Domain Collagen Molecule (3000 Å) OH OH OH Glc Gal OH OH OH OH OH OH OH OH OH OH Ga l OH OH OH OH Triple-Helical Domain (15 Å) Nontriple-Helical Domain Nontriple-Helical Domain C-Terminal Propeptide (150 Å) ( Man)n GlcNac S S S S S S S S (100 Å) S S S S S S Schematic representation of the structure of the procollagen molecule.
Glc denotes glucose, Gal galactose, Man mannose, and GlcNac N-acetylglucosamine
SM Fruchtman
What Is the Pathophysiology of Bleeding and Thrombosis in ET
?
• Platelet number • Platelet function • Platelet turnover • Other factors SM Fruchtman
Normal Platelet Physiology
• Platelets participate in hemostasis in conjunction with blood vessels and the humoral coagulation system • Sequence of platelet functions: – Adhesion to exposed subendothelium via vWF and GPIb/IX – Aggregation (cohesion) via fibrinogen interactions with GPIIb/IIIa – Secretion or release reaction with release of dense body and alpha granule contents, FVIII, PAI-1, tPA, etc CM Kessler
Platelet Adhesion
GP IIb/IIIa Endothelium von Willebrand factor Collagen Platelet GP Ia/IIa GP Ib
Adapted from Coller BS. Circulation. 1995; 92: 2373.
CM Kessler
Platelet Aggregation GP IIb/IIIa receptor Platelet Fibrinogen
Adapted from Coller BS. Circulation. 1995;92:2373.
CM Kessler
Platelets at Rest
CM Kessler
Activated Platelets
CM Kessler
Normal Platelet Physiology
• Platelet activation redistributes phosphatidylserine (PS) from the inner leaflet of the platelet membrane to the outer surface; mediated by enzyme phospholipid scramblase • Exposure of PS is critical to expression of platelet procoagulation activity; provide VIIa-TF, Xa, IXa, and VIIIa binding sites CM Kessler
Platelet Structure
CM Kessler
Normal Platelet Physiology (Cont’d )
• Platelet activation induced or modulated by: – Agonist–receptor ligand interaction - activates membrane-bound phospholipases C and A, which hydrolyze phosphatidylinositol on the inner leaflet; mediated by GTP – Inositol triphosphate (IP3) functions as messenger to mobilize Ca +2 ions from intracellular stores – Diacylglycerol (DAG) activates protein kinase C phosphorylation of 47kD pleckstrin GPIIb/IIIa activation CM Kessler
Platelet Biochemistry
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 CM Kessler
Coagulation Pathway
Intrinsic pathway Extrinsic pathway (Activated within minutes) (Activated within seconds) Contact activation Tissue damage XII XIIa III (Tissue factor) TF VIIa XI XIa, Ca 2 VII IX IXa Ca 2-
ATIII
PF3, Ca+2
TFPI
VIII
PS-PC
VIIIa X Xa V Va Irreversible platelet aggregation
Thrombin (IIa)
Fibrin & blood cells Soluble fibrin XIII XIIIa Ca+2 Cross-linked fibrin clot Fibrinogen Ca 2 PL X Prothrombinase complex Prothrombin (II) KEY Conversion to Causes conversion or release Inhibition of CM Kessler
Functional Abnormalities of Platelets in MPDs
• Prolonged bleeding times - detected in 17% of MPDs; more often seen in AMM than other MPDs; no correlation with bleeding symptoms • Platelet aggregation responses – Spontaneous hyperaggregability in ET – Impaired aggregation to some or all agonists • Impaired epinephrine response most common, but not pathognomonic of MPDs ADP(39%), collagen(37%), epinephrine(57%) CM Kessler
Functional Abnormalities of Platelets in MPDs (Cont’d)
• platelet 2-adrenergic receptors • Impaired dense granule release • Decreased membrane surface glycoproteins • Defective Ca +2 mobilization, TxA 2 formation, lipoxygenase accumulation • Loss of HMW multimers of vWF protein; inversely related to platelet count; improved post cytoreduction CM Kessler
Disorders of Platelet Function
• Clinically manifests as mucocutaneous bleeding, excess hemorrhage posttrauma & surgery, easy bruising, menorrhagia, etc.
• Usually prolonged bleeding time • Platelet aggregation and secretion studies often reveal defect but usually do not predict severity of clinical manifestations • Acquired defects >> inherited defects CM Kessler
Acquired Platelet Dysfunction in MPDs
• Platelets most likely to develop from an abnormal clone of stem cells • Abnormal function may result from enhanced platelet activation in vivo • Platelet abnormalities contribute to the mortality and morbidity of MPD; impact of thrombosis is greater than that of bleeding • Hemorrhagic and thrombotic complications may occur separately or simultaneously; often unpredictable since asymptomatic individuals may have platelet dysfunction CM Kessler
Platelet Disorders in MPDs
• Bleeding and thrombosis less common in CML versus other MPDs • Bleeding more frequent in AMM versus other MPDs; thrombosis not common in AMM • Hemorrhage usually from GI and GU tracts; risks of spontaneous bleeding with platelets > 2,000,000/ m L; exacerbated by ASA CM Kessler
Platelet Disorders in MPDs (Cont’d)
• Thrombotic events can be arterial and/or venous, often in portal, hepatic, splenic, cerebral sinuses • DVT, PE, AMI, CVA, and PAO all reported in MPDs, often underestimated as platelet mediated events (Underlying etiology is complex; platelet abnormalities may be contributory) • Microvascular arterial thrombi may occur— erythromelalgia, neurologic symptoms, visual complaints CM Kessler
Platelet-Mediated Thrombosis in ET
CM Kessler
Evidence for TPO/Mpl Axis in MPDs
• In 17 patients with ET: – normal to high plasma TPO levels – all patients with strikingly reduced c-Mpl mRNA and protein • normal levels of GPIIb/IIIa – No aberrant pTYR activity in response to TPO stimulation • In 12 patients (10 P Vera, 2 IM): – normal to high plasma TPO levels – all patients with scant or absent c-Mpl protein expression – reduced or absent pTYR activity in response to TPO stimulation • TPO and anagrelide have opposing effects
Observation TPO
Megakaryocyte size Mean ploidy Megakaryocyte colony # Megakaryocyte colony size 50% 32-65 N 7-10 X 5-6 X
Anagrelide
22% 8-16 N 57% 31% J McCarty
Hypothesis:
• Since myeloproliferative disorders are associated with abnormalities of TPO and c-Mpl • Since the biologic effects of TPO and anagrelide appear to act in opposition in vitro • Does anagrelide induce its thrombocytopenic effect by modulating TPO/c-Mpl-specific molecular events in human stem cells?
J McCarty
Consequences of TPO/Mpl Binding
1.
TPO binding dimerizes Mpl on cell surface 2. Causes autophosphorylation of associated JAK/STAT and other pTYR and pSER signaling pathways 3. Activated early acting transcription factors induce transcription of megakaryocyte-specific gene sets 4. Mpl/TPO complex internalized and degraded leading to loss of both receptor and bound TPO 5. Newly synthesized Mpl receptor monomers are refreshed at cell surface Anagrelide may interfere at these steps J McCarty
Effect of Anagrelide on hTPO- or hIL-3-Stimulated Liquid Culture of Human CD34 + Stem Cells 8000 7000 6000 5000 4000 3000 2000 1000 0 12 day stimulation with hTPO 100ng/mL Megakaryocyte number 180000 160000 140000 120000 100000 80000 60000 40000 20000 0 8000 7000 6000 5000 4000 3000 2000 1000 0 12 day stimulation with hIL-3 200U/mL Total mononuclear cell number 180000 160000 140000 120000 100000 80000 60000 40000 20000 0
J McCarty
Summary Findings
• Anagrelide inhibits CFU-Mk in human CD34 + • Antiproliferative effects: – specific for TPO, not IL-3 – specific for megakaryocyte lineage cells – do not affect total MNC number • Anagrelide species-specific effect determined by Mpl • Anagrelide affects pTYR activity in TPO-stimulated, but not IL-3-stimulated, cells and lines • Anagrelide exhibits TPO-specific inhibition of cell proliferation and pTYR activity.
J McCarty
Potential Mechanisms of Anagrelide Action
Anagrelide may act at several steps: 1. May act as inhibitor of TPO binding 2. May inhibit proximal steps of TPO/Mpl-associated phosphotyrosine or phosphoserine signaling pathways 3. May interfere with TPO/Mpl associated megakaryocyte specific gene expression 4. May prevent internalization of bound TPO/Mpl complex 5. May curtail production and cell surface expression of Mpl monomers J McCarty
Diagnosis and Diagnostic Issues
Current Approaches to Diagnosing ET and P Vera
HS Gilbert
ET and P Vera: Initial Considerations
• Diagnosis—confirm • Symptoms at presentation • Assessment of risk—age, risk factors for thrombosis • Discussion of treatment alternatives with patient SM Fruchtman
Diagnosis of P Vera vs ET
• Primary Erythrocytosis – Acquired abnormality of marrow - Polycythemia vera – Congenital abnormality - truncation of erythropoietin receptor • Secondary Erythrocytosis – Acquired - secondary to hypoxemia, renal disease, etc – Abnormalities of the Hgb molecule or autonomous high erythropoietin production • Diagnosis: Measure erythropoietin levels – Elevated hematocrit and low erythropoietin levels – No other symptoms – Patient has P Vera HS Gilbert
Differential Diagnosis of Thrombocytosis
I.
Essential thrombocythemia II. Other chronic myeloproliferative disorders A. Polycythemia vera B. Chronic granulocytic leukemia C. Myelofibrosis/agnogenic myeloid metaplasia D. Overlap myeloproliferative disorders III. Myelodysplastic syndromes associated with thrombocytosis A. 5q-syndrome B. Idiopathic refractory sideroblastic anemia IV. Reactive thrombocytosis A. Blood loss and/or iron deficiency B. Splenectomy C. Hemolytic anemia D. Malignancy E. Myelophthisis F. Chronic inflammatory disorders G. Infection H. Drug induced I. Rebound from thrombocytopenia J. Exercise SM Fruchtman
Proposed Diagnostic Criteria —ET
I.
II.
III.
IV.
V.
Platelet count >600,000/ m L Hematocrit <40, or normal RBC mass (Males <36 mL/kg, females <32 mL/kg) Stainable iron in marrow or normal serum ferritin or normal RBC mean corpuscular volume (otherwise Fe trial) No Philadelphia chromosome or bcr/abl gene rearrangement 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 thrombocytosis SM Fruchtman
Thrombosis
• DVT • PE • CVA/TIA/Retinal/MI • Hepatic & portal vein thrombosis • Digital ischemia • Erythromelalgia • Miscarriage SM Fruchtman
Essential Thrombosis
• Most patients are asymptomatic (estimated to be up to 2/3) • However, catastrophic thrombotic complications are seen • Frequently a syndrome of young women. Thus, issues of management during pregnancy are important SM Fruchtman
Mpl and P Vera
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
Bleeding
• Skin • Mucous membranes • Gastrointestinal By trauma SM Fruchtman
Polycythemia Vera Study Group (PVSG) Five Protocols
Polycythemia Vera PVSG-01
Prospective, randomized Phlebotomy vs 32 P vs chlorambucil
PVSG-05
Prospective, randomized Phlebotomy, aspirin, dipyridamole vs 32 P
PVSG-08
Phase II, efficacy Hydroxyurea
Essential Thrombocythemia PVSG-10
Prospective, randomized Melphalan vs 32 P
PVSG-12
Phase II, efficacy Hydroxyurea
# Patients
431 178 51 55 29
Initiated
1967 1977 1977 1975 1977 SM Fruchtman
ET: 1975 PVSG Diagnostic Criteria
• Platelet Count in excess of 1,000,000/ m L • Marked megakaryocytic hyperplasia • Abundant platelet clumps • Normal red cell mass (adequate iron) • No Philadelphia chromosome • No significant myelofibrosis RM Petitt
ET: 1983 PVSG Diagnostic Criteria
• Platelet Count in excess of 600,000/ m L • Marked megakaryocytic hyperplasia • Abundant platelet clumps • Normal red cell mass (adequate iron) • No Philadelphia chromosome • No significant myelofibrosis RM Petitt
ET: 1996 Swedish Diagnostic Criteria
• A1 Platelets in excess of 600,000/ m L • A2 Normal red cell mass, or <125% of mean predicted value with stainable marrow iron or failed iron trial • A3 No Philadelphia chromosome • A4 Megakaryocytic hyperplasia and/or increased ploidy; no fibrosis • B1 Splenomegaly on isotopic scan or ultrasound • B2 Unstimulated growth of BFU-E and/or CFU-Meg • B3 Normal sedimentation rate and fibrinogen • All four “A” criteria = ET • A1 + A2 + A3 + any two “B” criteria = ET RM Petitt
ET: 1997 Revision of 1983 PVSG Criteria
• Platelet count in excess of 600,000/ m L • Hematocrit under 40% or normal red cell mass • Normal marrow iron or serum ferritin or MCV • No Philadelphia chromosome or bcr/abl rearrangement • No collagen fibrosis, or less than 1/3 of biopsy area (without splenomegaly and leukoerythroblastosis) • No cytogenetic or morphologic evidence of MDS • No cause for reactive thrombocytosis RM Petitt
PVSG Criteria for the Diagnosis of P Vera
A1 Increased RBC mass Male: 36 mL/kg Female: 32 mL/kg A2 Normal arterial O 2 ( 92%) saturation B1 Thrombocytosis: Platelet count >400,000/ m B2 Leukocytosis: >12,000/ m L (no fever or infection) L A3 Splenomegaly B3 Increased leukocyte alkaline phosphatase (LAP >100) B4 Increased serum B 12 /binders B 12 : (>900 pg/mL) Unbound B 12 binding capacity (>2200 pg/mL) Diagnosis of polycythemia vera virtually certain in the presence of A1+A2+A3 or A1+A2+ any two from category B.
SM Fruchtman
Diagnostic and Confirmative Criteria of P Vera Proposed by the PVSG
A Diagnostic criteria
A1 Raised red cell mass male >36 mL/kg female >32 mL/kg A2 Absence of any cause of secondary erythrocytosis by clinical and laboratory investigations A3 Histopathology of bone marrow by biopsy a. increase of celluarity, panmyelosis b. increase and clusters of enlarged megakaryocytes with hyperploid nuclei c. reticulin fibers (optional)
B Confirmative criteria
B1 Thrombocythemia platelet count >400,000/ isotope/ultrasound scan m L B2 Granulocytes >100,000/ m L and/or raised neutrophil alkaline phosphatase score in the absence of fever or injection B3 Splenomegaly on palpation or 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 Vera A3+B1 is consistent with essential thrombocythemia A3+B3 and/or B4 is consistent with a primary myeloproliferative disorder SM Fruchtman
Proposed Diagnostic Criteria for P Vera
A1 Raised red cell mass (>25% above mean normal predicted value) A2 Absence of cause of secondary polycythemia A3 Palpable splenomegaly A4 Clonality marker e.g. Abnormal marrow karyotype A1+A2+A3 or A4 establishes P Vera A1+A2+two of B establishes P Vera B1 Thrombocytosis (platelet count >400,000/ m L) B2 Neutrophil leukocytosis (neutrophil count >10,000/ m L) B3 Splenomegaly demonstrated on isotope/ultrasound scanning B4 Characteristic BFU-E growth or reduced serum erythropoietin SM Fruchtman
ET: 1999 British Diagnostic Criteria
• Platelets exceeding 400,000/ m L (600,000/ m L for trials) • No cause for secondary thrombocytosis (congenital or acquired) • No other cause for myeloproliferative thrombocythemia (P Vera, CML, AMM-MF, MDS) • Compatible marrow histology – Increased, clustered large megakaryocytes – Hyperlobulated megakaryocyte nuclei – No collagen fibrosis or osteosclerosis RM Petitt
ET: 1999 Dutch Diagnostic Criteria
• Diagnostic Criteria: – A1 Platelets exceeding 400,000/ m L without reactive cause – A2 Increased, clustered, mature giant megakaryocytes with hyperploid nuclei – A3 No preceding myeloproliferative or myelodysplastic disease • Confirmation Criteria: – B1 – B2 Normal or elevated LAP score, normal ESR, no fever Marrow cellularity normal or slightly increased; no or minimal reticulin fibrosis – B3 – B4 Palpable splenomegaly, or >11 cm on U/S or CT Spontaneous erythroid and/or megakaryocyte colony growth RM Petitt
2002 WHO Classification of Chronic MPDs
Chronic myelogenous leukemia (bcr/abl +) Chronic neutrophilic leukemia Chronic eosinophilic leukemia Polycythemia vera Chronic idiopathic myelofibrosis Essential thrombocythemia Chronic myeloproliferative disease, unclassifiable RM Petitt
Survival Time (%) for Patients in Various Treatment Groups
100 Various combinations with X-ray therapy X-ray therapy 32 P and/or chlorambucil Venesection Untreated 50 5 2 4 6 8 10 12 Years of duration of the disease 14 16
SM Fruchtman
Cumulative Survival on Study
1.0
0.8
0.6
0.4
0.2
0.0
0 Legend Phlebotomy Chlorambucil 32 P Total 134 141 156 Events Breslow X 2 2 = 4.394 p=.1111
54 82 83 Logrank X 2 2 = 9.650 p=.0080
100 200 300 400 500 Time in weeks 600 700 800
SM Fruchtman
Cumulative Survival After 7 Years on Study
1.0
0.8
0.6
0.4
0.2
0.0
0 Legend Phlebotomy Total 59 Chlorambucil 63 32 P 92 Events 16 35 41 Breslow X 2 2 = 16.968 p=.0002 Logrank X 2 2 = 16.465
p=.0003
100 200 300 400 Time in weeks after 7 years 500 600
SM Fruchtman
PVSG-01: Thrombosis (On Study Events) 1/1/86
1.0
0.9
0.8
0.7
0.6
0.5
0 100 Comparison Statistics Breslow Logrank X 2 2 8.54
4.89
p
.01
.09
200 Legend Phlebotomy Chlorambucil 32 P Total 134 141 156 Events 51 41 51 300 400 500 Time in weeks 600 700 800
SM Fruchtman
Causes of Death by Treatment Group
Number at start Number of deaths
Causes of death
Thrombosis Hemorrhage Leukemia/Lymphoma Cancer Spent/MF Other
Phlebotomy
134 53
CLB
141 82
Percent
17.2
0.0
1.5
4.5
0.7
15.7
13.5
4.3
20.6
9.9
2.1
7.8
32 P
156 79 13.5
3.8
11.5
9.6
1.3
10.9
Total
431 214 44.2
8.1
33.6
24.0
4.1
34.4
SM Fruchtman
1.00
.80
Survival Probability in Patients > 70 years
Age >70 32 P Chlorambucil .60
Phlebotomy .40
.20
0 0 50 100 150 200 250 300 Weeks since randomization 350 400
SM Fruchtman
PVSG-01: Initial Thrombotic Event (On Study Events)
Type of event
Cerebral vascular accident Myocardial infarction Peripheral arterial occlusion Pulmonary infarction Venous thrombosis (other than thrombophlebitis) Deep vein thrombophlebitis Miscellaneous Total
Number
51 18 13 8 6 32 18 146
% of events
35 12 9 6 4 22 12 100 SM Fruchtman
PVSG-01: Thrombosis-Related Risk Factors
• Multivariate Analysis – Randomization to phlebotomy – Age >70 years – Previous thrombosis SM Fruchtman
PVSG-01: Matched Pair Analysis
For each patient with thrombosis, a thrombosis-free control patient of similar age, sex, treatment group, and time on study was selected.
Most recent hematocrits and platelet counts were not different. Hematocrit over 52% and platelet counts over 1,500,000/ m L were rare.
SM Fruchtman
Hematologic Parameters and Relative Odds of Thrombosis:
Matched Pairs Case-Control Study Estimated odds of thrombosis p-value* Hematologic parameter Platelets (x10 3 /
m
L)
1,000 vs <1,000 600 vs <600 450 vs <450
Hematocrit (%)
52 vs <52 47 vs <47 >45 vs 45 *From Mantel-Haenszel Chi-Square.
0.7
1.4
0.9
1.3
1.2
1.1
>0.9
>0.5
>0.9
>0.5
>0.5
>0.9
SM Fruchtman
Risk Factors Associated with Thrombosis Cox-Model Multivariate Analysis
Risk factor
Phlebotomy vs 32 P Chlorambucil vs 32 P History of thrombosis
431 Patients Estimated relative risk
1.7
0.8
2.1
T*
2.3
-0.7
3.3
Test of model
X 2 4 =43.0
p
<.001
Age (70 vs 50) 2.3
4.5
T* 1.96 indicated significant association with incidence of thrombosis (
p
0.05) SM Fruchtman
Age-Specific Therapy for P Vera
Age
>70 years 50 –70 years <50 years
Initial choice of therapy
32 P Phlebotomy (Hydroxyurea, 32 P) Phlebotomy (Hydroxyurea) SM Fruchtman
Survival
On study
Median time to death (yrs) Maximum follow-up (yrs)
Phlebotomy CLB
12.5
8.9
17.5
18.2
32 P
11.4
16.6
SM Fruchtman
PVSG-08
Polycythemia Vera Prior myelosuppressive Rx (RT or Chemo) No prior Rx or Hydroxyurea 30 mg/kg/day One Week Hydroxyurea 15 mg/kg/day and adjusted as needed phlebotomy
SM Fruchtman
Clinical and Laboratory Characteristics at Initial Evaluation by Treatment and Protocol
Evaluation Prior thrombosis % Hematocrit % RBC X 10 8 / m L Platelets X 10 3 / m L <600,000/ m L 600,000-1,000,000/ m L >1,000,000/ m L
PVSG-01 Phlebotomy
134 14.2
61.7
±7.5
7.16
±1.09
505 ±24.6
76 17 7
PVSG-08 Hydroxyurea
51 35.3
52.9
±8.1
6.60
±0.86
778 ±63.6
47 31 22 SM Fruchtman
Sex and Age at Initial Evaluation by Treatment and Protocol
Number Male (%) <50 years 50 –70 years 70 years Female (%) <50 years 50 –70 years 70 years
PVSG-01 Phlebotomy
134 54.5
11.2
31.3
11.9
45.5
9.7
25.4
10.4
PVSG-08 Hydroxyurea
51 52.9
11.8
31.4
9.8
47.1
15.7
25.5
5.9
SM Fruchtman
Comparative Incidence of Thrombosis by Year by Protocol and Treatment Group Cumulative % Year 1 Year 2 Protocol
A. On study events HU (PVSG-08 NPT) Phlebotomy (PVSG-01) B. All events HU (PVSG-08 NPT) Phlebotomy (PVSG-01) 2.8
±4.0
8.7
±2.5
5.9
±3.3
9.0
±2.5
6.6
±3.7
14.0
±3.2
7.9
±3.8
15.8
±3.2
SM Fruchtman
Comparative Incidence of Thrombosis by Protocol and Treatment Group
(On Study, First 378 Weeks) Protocol
HU (PVSG-08 NPT)
Total patients
51
# Events
5
%
9.8
44 32.8
Phlebotomy (PVSG-01) Wilcoxon X 2 1 =5.58
Logrank X 2 1 =6.80
134
p
=.018
p
=.009
SM Fruchtman
Comparative Incidence of Acute Leukemia by Protocol and Treatment
On study events, first 795 weeks of study
Protocol
HU-NPT (PVSG-08) Phlebotomy (PVSG-01) Wilcoxon X 2 1 =1.305
Logrank X 2 1 =1.791
All events HU-NPT (PVSG-08) Phlebotomy (PVSG-01) Wilcoxon X 2 1 =2.749
Logrank X 2 1 =2.344
Patients
51 134
p
=.2532
p
=.1808
51 134
p
=.0973
p
=.1258
Total # events
3 2 5 5
%
5.9
1.5
9.8
3.7
SM Fruchtman
PVSG-01: Leukemia by Treatment
Protocol Total patients
On study events, first 795 weeks of study
# events
CHL 141 24 32 P Phlebotomy Wilcoxon X 2 1 =14.718
Logrank X 2 1 =20.938
156 134
p
.0001
p
.0001
17 2
%
17.0
10.9
1.5
SM Fruchtman
Survival by Prior Therapy and Protocol
On study events, first 795 weeks of study
Protocol
HU-NPT (PVSG-08) Phlebotomy (PVSG-01) Wilcoxon X 2 1 =3.241
Logrank X 2 1 =2.227
All events HU-NPT (PVSG-08) Phlebotomy (PVSG-01) Wilcoxon X 2 1 =2.300
Logrank X 2 1 =1.847
Patients
51 134
p
=.0718
p
=.1356
p p
51 134 =.1293
=.1742
Total # events
16 54
%
31.4
40.3
20 74 39.2
55.2
SM Fruchtman
Risk of Leukemic Transformation with Myelosuppressive Therapy
Therapy
No treatment or aspirin Phlebotomy Hydroxyurea 32 P Alkylating agent More than 1 myelosuppressive agent IFN
Polycythemia vera (%)
– 2/18 (11) 1/16 (6) 0/2 – 1/4 (25) 0/2
P Vera, MF, ET
0/11 2/18 2/25 0/2 0/1 1/5 0/2 SM Fruchtman
Eligibility
PVSG-05
1. No previous treatment except phlebotomy 2. Disease diagnosed within four years 3. Fulfillment of diagnostic criteria 4. No chronic disorder requiring long-term ASA Phlebotomy to HCT 40% Randomization
Phlebotomy Prn to maintain Hct <45% ASA 300 mg TID Dipyridamole 75 mg TID 32 P 2.7 mc/M 2 i.v.
Q 12 wks prn (limit 5 mc/dose) Phlebotomy for Hct >45% Increase dose by 25% if no response
SM Fruchtman
PVSG-05: Thrombosis and Hemorrhage-Free Cumulative Survival
1.00
0.95
0.90
0.85
0 Legend Treatment Total in Group Events Phleb/Persantine/ASA 88 7 P-32 90 2 10 Comparison Statistics Breslow X 2 2 2.8
p
.09
Logrank 3.1
.08
20 30 40 50 60 70 Time in weeks 80 90 100 110
SM Fruchtman
PVSG-05: Thrombosis and Hemorrhage-Free Cumulative Survival
1.00
95 90 85 80 0 Legend Treatment Total in Group Events Phleb/Persantine/ASA 88 13 P-32 90 2 10 20 30 40 50 60 70 Time in weeks 80 90 100 110 Comparison Statistics Breslow X 2 2 8.660
P
0.0033
Logrank 9.018
0.0027
SM Fruchtman
Summary of 91 Patients with Thrombocytosis Treated with PVSG Protocols Treatment protocol
HU only 32 P only Melphalan only Melphalan + HU 32 P + HU HU + other Melphalan + 32 P Melphalan + 32 P + HU No treatment Total study population
Median follow-up (years)
8.2
5.6
4.4
10.5
8.4
7.7
4.5
9.2
4.4
7.0
Total patients
22 16 14 10 9 7 4 2 7 91
No. AML (all dead)
1 2 1* 0 1 5 1* 0 1 12
No. died of other causes
7 5 6 4 2 1 2 0 2 29
No. alive at last follow-up
14 9 7 6 6 1 1 2 4 50 *AMLs in patients in ET [?MF] category.
SM Fruchtman
The Mount Sinai Myeloproliferative Study
Jan 1986 –Dec 1998 Disorder studied
P Vera ET MM/MF
# of patients
167
# of specimens
234 40 63 40 90
# of technically inadequate specimens
23.4
(10%) 8.0
(20%) 18.90
(20%)
# of evaluable patients
156 32 56 SM Fruchtman
The Mount Sinai Myeloproliferative Study
Jan 1986 –Dec 1998 Disorder
P Vera
# of patients
156
Normal karyotype
109 69.8%
Normal with nonclonal abnormalities
5 3.2%
Normal at Dx/ Abnormal on follow-up
5 3.2%
Abnormal at Dx
37 23.7% ET 32 0 MM/MF 56 27 84.3% 30 53.5% 1 3.1% 0 0 0 0 4 12.5% 26 46.4% SM Fruchtman
Frequency of Chromosomal Abnormalities
Abnormality
del (20) (q11q12) +8 +9 del (7q) -7/t (7p) del (9q)/i (9q) abnormalities 1p t (16q) del (13)(q12-13q14-21) -5
% of total P Vera % of abnormal
4.4
3.8
3.2
3.2
18.9
16.2
13.5
13.5
0 2.5
1.9
1.9
0 0 0 10.8
8.1
8.1
0 0
% of total MM/MF % of abnormal
5.3
1.7
0 0 11.5
3.8
0 0 10.7
0 7.1
0 12.5
5.3
23 0 0 0 26.9
11.5
SM Fruchtman
Treatment
Treatment: Essential Thrombocythemia
Treatment Goals for ET
• No therapy to eliminate malignant stem cell clone • Direct therapy at reducing mortality and life-threatening complications • In high-risk ET, reduce platelets 600,000/µL; ? 450,000/ m L • No adequate prospective, randomized, controlled studies CM Kessler
Conditions Suggesting Urgent Treatment
• Symptomatic coronary artery disease • Transient ischemic attacks • Major hemorrhage • Active thrombosis/pulmonary embolism HS Gilbert
Urgent Treatment of ET
• Platelet apheresis - typically 1-3 treatments with target platelet count < 400,000/ m L • Hydroxyurea - target platelet count < 400,000/ m L • Nitrogen mustard, 0.4 mg/kg if apheresis not available HS Gilbert
ET: Prognostic Factors (2091 Cases)
• Favorable factors – Platelets less than 700,000/ m L – Treatment with antiaggregating or cytostatic drugs • Unfavorable factors – Previous thrombosis – Older patients – Platelets exceeding 1.5 million/ m L at diagnosis – Platelets exceeding 1.0 million/ m L at follow-up RM Petitt
Treatment of ET
There is evidence that ET is a heterogeneous disorder both clinically and on a stem/progenitor cell level.
Thus, the dilemma exists as to when to employ agents that either lower the platelet number and/or inhibit platelet function.
SM Fruchtman
Risk-Based Treatment for ET
• Low risk – Age < 60 years – Platelets < 1,500,000/ m L – No history of thrombosis – No cardiovascular risks • No treatment or low-dose aspirin HS Gilbert
Risk-Based Treatment for ET
• Intermediate risk – Age < 60 years – No history of thrombosis – Platelet counts > 1,500,000/ m L or – Cardiovascular risk factors HS Gilbert
Risk-Based Treatment for ET
• Intermediate-risk treatment – Treat cardiovascular risk factors – Avoid aspirin if platelet counts > 1,500,000/ m L – No treatment or anagrelide; hydroxyurea or IFN HS Gilbert
ET: The High-Risk Patient
• Age 60 or greater • Previous thrombosis (or comorbid disposition such as DM, PVD, HTN or thrombophilia) • Platelets exceeding 1.0 or 1.5 million/ m L • Peripheral myeloid immaturity RM Petitt
Risk-Based Treatment for ET
• High risk – Age 60 years or History of thrombosis • • Hydroxyurea and low-dose aspirin; anagrelide IFN , 32 P, busulfan, pipobroman HS Gilbert
ET: The Risks of Observation
• Thrombosis – A baseline risk which does not increase significantly as platelets rise to exceedingly high levels – Risk aggravated by unrecognized thrombophilic states • Hemorrhage – Risk increases significantly as platelets rise above 1.5 million/ m L – Acquired vonWillebrand disease with high platelet counts • Leukemic transformation – All chronic myeloproliferative disorders have an underlying risk of transformation to acute leukemia. This risk is independent of any treatment and is estimated to be 90% in CML, 7%-10% in MM-MF, 1.5% in P Vera, and 1%-2% in ET RM Petitt
Risk of Elevated Platelets in ET
• Is there clear evidence that elevated platelet levels are bad?
– In symptomatic patients?
– In asymptomatic patients with very high platelet counts?
– In patients with mild to moderate thrombocythemia?
– What is the role of plateletpheresis?
CM Kessler
Risk of Elevated Platelets: New Data
• Regev et al: Thrombotic complications not uncommon in ET, even at low platelet levels. Recommendation: Symptomatic patients with relatively low platelet counts be treated and platelets be reduced to low-normal range • Storen, Tefferi: Long-term anagrelide study. All thrombohemorrhagic complications occurred at platelet counts of > 400,000/ m L. Normalization of platelets may be required to minimize risk CM Kessler
ET: The Risks of Treatment
Treatment-related adverse events reflect agent(s) chosen, dose and duration of therapy: • Leukemic transformation • Bone marrow suppression • Less severe cardiac, dermatologic, gastrointestinal and neurologic side effects RM Petitt
ET: Treatment
• Antiaggregating agents • Platelet apheresis • Myelosuppressive agents – Alkylating agents – Radiophosphorus – Hydroxyurea • Maturation Modulators – IFN 2A, recombinant – Anagrelide • Bone marrow transplantation • Combinations of above RM Petitt
Aspirin
• Suppression of thromboxane biosynthesis, which is increased in P Vera and ET patients, can be achieved with low-dose aspirin (~50 mg/day) • Prevention of thrombosis? Under study • Control of microvascular symptoms at low dose in patients without a bleeding diathesis SM Fruchtman
Busulfan
• Busulfan in ET – WEEK 1 - 4 mg per day – WEEKS 2, 3 and 4 - 2 mg per day – TO RESPONSE - 2 mg every other day • Median cumulative dose - 124 mg and duration 3 months HS Gilbert
ET and Busulfan Treatment
• 75 patients (mean age 48; F:M = 1.5) – Splenomegaly 49% – Hepatomegaly 38% – Thrombosis 29% – Hemorrhage 19% • 64 (83%) treated with busulfan – Mean follow-up 9.2 years – 53% died – 18% developed leukemia – 19% developed thrombosis RM Petitt
Busulfan
• Myleran, registered trademark of Glaxo Wellcome • 2 mg tablets • Bifunctional alkylating agent (not a nitrogen mustard analog) • 2003 Physicians’ Desk Reference,* p. 1595: “MYLERAN is contraindicated in patients in whom a definitive diagnosis of chronic myelogenous leukemia has not been firmly established.” *copyright 2003 by Medical Economics Company, Inc., Montvale, NJ RM Petitt
Hydroxyurea (HU)
• Risk of thrombosis: Hydroxyurea reduced the risk of thrombosis from 24% to <4% in a randomized study of high-risk ET patients • Leukemic conversion: Several nonrandomized studies have supported or refuted a significant increase in leukemic conversion with long-term use of hydroxyurea – In ET, rates range from 0%-5.5% – In P Vera, rates range from 2.1%-10% SM Fruchtman
ET and Hydroxyurea Treatment
• 75 high-risk patients (mean age 62) – Treated with hydroxyurea – Mean follow-up 6.9 years – 6 (8%) developed leukemia • Mean age 65 (35-75) • Mean hydroxyurea exposure 7.2 years • 20 low-risk patients – No treatment (some on aspirin) – No leukemia RM Petitt
ET and Hydroxyurea Treatment
• 114 randomized high-risk ET (56 HU, 58 no Rx) – 15 on busulfan before randomization – 13 on hydroxyurea before randomization – 29 controls changed to hydroxyurea during study (26 thrombosis) • Original follow-up median 27 months. After 73 months: – Survival same; thrombosis rate 9% vs 45% (
p
= <0.0001) • Conclusion: – Sequential use of busulfan and hydroxyurea carries increased risk of second malignancies • One cancer (breast) in untreated group • Seven in hydroxyurea group (5 hematologic:2 ANLL, 2 MDS, 1 CLL) RM Petitt
Hydroxyurea for Patients with ET and a High Risk of Thrombosis
• Prospective randomized trial of 114 patients with ET – Age >60 years or – Previous thrombosis or both – Platelet count <1,500,000/ m L (uncomfortable with randomization) • Randomization – HU vs control (no HU) – 70% were already on antiplatelet agents SM Fruchtman
Probability of Thrombosis-Free Survival
in 114 Patients with Essential Thrombocythemia Treated with Hydroxyurea or Left Untreated 1200 1000 800 Control (n=58) Hydroxyurea (n=56) 600 400 0 6 12 18 Months 24 30 36
SM Fruchtman
Probability of Thrombosis-Free Survival
in 114 Patients with Essential Thrombocythemia Treated with Hydroxyurea or Left Untreated 100 80 60 40 Hydroxyurea (n=56) Control (n=58) 20 p=0.005
0 0 6 12 18 24 30 36 Months after randomization 42 48
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.
SM Fruchtman
Thrombosis in 114 Patients with ET
Type of thrombosis
Arterial Transient ischemic attacks Digital microvascular ischemia Stroke Myocardial infarction Venous Superficial thrombophlebitis Ileofemoral venous thrombosis Total (% of treatment group)
Hydroxyurea group (N=56)
no. (%)
Control group (N=58)
2 (100) 0 0 11 (79) 5 5 1 1 0 0 0 2 (3.6) 1 0 3 (21) 2 1 14 (24)* *There was a difference of 20.4 percentage points in the rate of thrombosis between the groups (95 percent confidence interval, 8.5 to 32 percent; chi square with Yates’ correction, 8.3; 1 df;
p
=0.003).
SM Fruchtman
Hydroxyurea: Adverse Reactions
• Hematologic – Bone marrow depression (leukopenia, anemia, thrombocytopenia) • Gastrointestinal – Stomatitis, anorexia, nausea, vomiting, diarrhea, constipation • Dermatologic – Rash, painful ulceration, erythema, hyperpigmentation, squamous cell skin cancers, dermatomyositis-like changes • Neurologic – Headache, dizziness, hallucinations, convulsions (all rare) • Systemic – Fever, chills, malaise, asthenia RM Petitt
Photo
HS Gilbert
Hydroxyurea and Acute Leukemia in MPDs
50 consecutive MPD patients (30 P Vera, 10 ET, 10 MF) were treated with hydroxyurea (HU), largely for high platelet counts or symptomatic splenomegaly.
9 (18% of total) developed ANLL, and 1 MDS 7/9 (14% of total; 3 P Vera, 1 ET, 3 MF) were treated solely with hydroxyurea average time from CMPD to ANLL = 6.3 years average duration of HU treatment = 3.9 years RM Petitt
Evolution to AML and MDS By Cytoreductive Agent in 357 ET Patients No. of ET patients treated Cases of AML or MDS No. (%) Agent
32 P Alone And other agents* Total Busulfan Alone And other agents* Total HU Alone And other agents † Total Pipobroman Alone And other agents* Total Untreated 29 11 40 35 6 41 201 50 251 12 31 43 31 2 (7) 1 (9) 3 (7.5) 1 (3) 1 (17) 2 (5) 7 (3.5) 7 (14) 14 (5.5) 0 (0) 5 (16) 5 (12) 0 (0) *Generally HU; † Generally pipobroman.
SM Fruchtman
ET and AML/MDS
Median follow-up 98 months (12 yrs) Total 17; AML (6) or MDS (11) 7 HU & other agents (pipobroman, 5; 32 P, 1; Busulfan, 1) 7 HU alone (3.5%) 2 32 P 1 Busulfan Median interval between dx of ET & dx AML/MDS 84 months 7 Patients with AML/MDS & 17P deletion received HU 3/7 received only HU SM Fruchtman
Acquired DNA Mutations and HU
Patient Population
Adults with SCD No HU exposure Short HU exposure Children with SCD Short HU exposure Longer HU exposure Adults with MPD Low HU exposure Prolonged HU exposure Normal controls
# of patients
30 15 15 34 17 17 27 15 12 32
Age in years (mean ± 1SD)
27 ±12 29 ±9 11 ±3 13 ±3 57 ±17 62 ±16 43 ±15
Median HU exposure
None 24 months 7 months 30 months 0 months 11 years None SM Fruchtman
Acquired DNA Mutations and HU (Cont’d)
Patient population
Adults with SCD No HU exposure Short HU exposure Children with SCD Short HU exposure Longer HU exposure Adults with MPD Low HU exposure Prolonged HU exposure Normal adult controls
HPRT assay CE (%) M L X 10 -6
15.1
±12.3
12.4
±8.2
19.1
±19.1
16.7
±10.9
VDJ assay Events per
m
g DNA
1.07
1.14
±0.38
±0.38
13.2
±6.1
20.9
±10.2
11.2
±6.7
9.2
±7.8
1.58
±0.87
1.82
±1.20
12.8
±8.9
12.2
±8.4
16.0
±8.7
37.3
41.1
25.8
±37.6
±29.3
±24.8
1.06
0.64
1.04
±0.73
±0.29
±0.38
SM Fruchtman
Treatment
Thrombotic Complications
In 68 Patients with ET Who Had Long-Term Follow-up, According to Treatment Strategy
Watchful waiting
Thrombotic Events
No.
27
Duration of Follow-up
Person-yr 127
Incidence
Events/100 person-yr 21.3
Low-dose aspirin Cytoreduction † 5 10 Low-dose aspirin and cytoreduction 0 *
p
<0.001 (X 2 =17.3, 1 df) for the comparison with watchful waiting.
† Denotes treatment with busulfan or hydroxyurea.
‡
p
<0.02 (X 2 =6.0) for the comparison with watchful waiting.
§
p
<0.02 (X 2 =8.6) for the comparison with watchful waiting.
139 113 40 3.6* 8.9
‡ 0 § CM Kessler
ET and Interferon Treatment
• Antiproliferative effect on CFU-MK and CFU-GEMM – Nonleukemogenic, nongonadotoxic • Usual daily doses 1–5 million units daily, 3-7 x weekly – Gradual response: peripheral 1-3 months, marrow 9-12 months • 26 ET patients – Median age 48 – Dose-limiting side effects in 24% – 88% responded (62% CR, 26% PR) – Responders crossed over to pipobroman after 12 months RM Petitt
IFN-
In essential thrombocythemia
• Produces platelet reduction (80%-100% response rate), resolution of splenomegaly, and control of disease-associated symptoms • May be used in high-risk women with ET of childbearing age or those who are pregnant • ~20% of patients may not tolerate IFN because of side effects (esp. flu-like symptoms, fatigue, nausea, depression, fever, chills, arthralgias, autoimmune disorders). Higher rates in elderly individuals SM Fruchtman
Photo
HS Gilbert
Management of ET During Pregnancy
Options 1. Observe —? Medical–legal issues 2. ASA 3. ASA & heparin 4. IFN 5. Platelet apheresis for emergencies SM Fruchtman
Women of Childbearing Age with ET
• High risk – IFN and low-dose aspirin • All others – No treatment or low-dose aspirin HS Gilbert
Anagrelide
For thrombocytosis accompanying any MPD • Indicated for the treatment of patients with thrombocythemia secondary to MPDs to reduce the elevated platelet count and risk of thrombosis and to ameliorate associated symptoms, including thrombohemorrhagic events SM Fruchtman
Anagrelide: Observed Effects
• Reduces platelet count • Reduces platelet turnover rate (elevated in ET) • May reduce megakaryocyte number • Reduces megakaryocyte diameter • Reduces megakaryocyte volume • Normalizes megakaryocyte ploidy
Anagrelide reduces megakaryocytic hyperproliferation and megakaryocytic differentiation
RM Petitt
Anagrelide
• Starting dose - 0.5 mg, orally, 4 times per day • OK to cross over with hydroxyurea • 15% of patients will discontinue • Manufacturer’s target < 600,000/ m L; our target < 400,000/ m L HS Gilbert
ET Patient Response to Anagrelide
• Platelet counts lowered in 7 to 14 days • Sustained response in patients followed for up to 4 years (
p
<.001 vs baseline) • Response seen in 242 patients who had failed previous therapy to reduce platelets
82% Overall Response Rate* (p<0.05) 88% Overall Reduction in ET-Related Symptoms (p<0.05)
CM Kessler
ET: Reduction in Serious Complications with Anagrelide
35
• Reported serious complications of thrombocythemia decreased by 82% after 235 patients took anagrelide for 4 months
30 25 20 15 Preinfarction angina GI bleeds TIAs 10 5 1-4 5-8 9-12 Months on anagrelide therapy
CM Kessler
Anagrelide: Precise & Specific
• Dose-related reduction of platelet production resulting from a decrease in megakaryocyte hypermaturation • Clinically insignificant effect on white blood cells • A slight reduction (~5%) in Hb and PCV occurs with prolonged anagrelide therapy SM Fruchtman
Anagrelide: Precise & Specific (Cont’d)
• No effect on DNA synthesis – No apparent association with oncogenesis – No apparent leukemogenicity SM Fruchtman
Anagrelide
How effective is it?
• Only 19% of patients failed to respond (had <20% reduction in platelet count) in a population that included a large number of nonresponders to other agents. HS Gilbert
Anagrelide
What is unique about it?
• It is the only cytoreductive agent that has specificity for platelets. Therapy targeted at platelets spares the red blood cells and neutrophils in patients who have normal or reduced circulating levels of these cells.
HS Gilbert
Anagrelide
What is its safety and toxicity profile?
• In the analysis of 577 patients, the drop out rate from toxicity was 16% in over 5 years of experience. In the analysis of 942 patients, there were no deaths attributable to anagrelide.
HS Gilbert
Anagrelide: Adverse Reactions
161 of the original 942 patients (17.1%) stopped anagrelide treatment, citing the following reasons: Headache Diarrhea Edema Palpitations Abdominal Discomfort 40 (25%) 19 (12%) 18 (11%) 17 (11%) 12 (7%) (4.2% of all treated) (2.0% of all treated) (1.9% of all treated) (1.8% of all treated) (1.3% of all treated) RM Petitt
Adverse Reactions Leading to Discontinuation of Anagrelide
Type of Adverse Reaction in 577 patients Neurologic (headache, confusion) Gastrointestinal (nausea, abdominal pain, diarrhea) Cardiac (congestive heart failure, edema) Pulmonary Other Number (%) Discontinued 30 (21) 25 (28) 23 (21) 2 (1) 14 (11) HS Gilbert
Anagrelide Study Patients
90% of the original study group of 942 patients had already received other treatment for their myeloproliferative disorders: Hydroxyurea Alkylating Agents IFN Radiophosphorus Other 651 198 94 66 27 (67%) (21%) (10%) (7%) (3%) RM Petitt
Long-term Experience with Anagrelide in Young ET Patients
• Retrospective series of 35 patients (ages 17-48 years) who received anagrelide before 1992 • 82% of 33 responding patients remained on anagrelide for a median of 10.8 years • Of these, 66% were CRs, 34% were PRs CM Kessler
Long-term Experience with Anagrelide in Young ET Patients (Cont’d)
• All thrombohemorrhagic complications occurred at a platelet count of > 400,000/ m L • Complete normalization of platelet counts may be required to minimize residual hemorrhagic risk during therapy • Initial side effects decreased with time; long-term treatment was associated with mild to moderate anemia CM Kessler
Contraindications to Anagrelide
• Uncontrolled congestive heart failure – Aggravation by additional fluid retention • Pregnancy – Fetus at risk for transplacental drug exposure • Lactation – Infant at risk for drug ingestion RM Petitt
Anagrelide Maintenance Doses (mg/day)
6 mos.
12 mos.
18 mos.
P Vera ET CML OMPD 2.8
2.4
2.3
2.1
2.8
2.5
2.1
1.8
2.8
2.3
2.1
1.7
RM Petitt
Long-term Anagrelide Treatment
40 patients started on treatment 1985-1988: 4 nonresponders 2 lost to follow-up 9 deaths 3 blast transformation of CML 2 colon cancer 2 myocardial infarction 2 unknown 25 evaluable after 10 or more years of treatment RM Petitt
Long-term Anagrelide Treatment
25 older patients with chronic myeloproliferative disorders taking anagrelide for 15 or more years: 6 developed mild renal insufficiency (creatinines 2-3) all poorly controlled hypertensives azotemia appeared 3-11 years after starting maintenance dose decreased as creatinine rose 19 have had no change in dosage or response 34 young women treated with anagrelide for >10 years: no changes in renal function RM Petitt
Anagrelide Study 301: Overview Safety 3,660 Efficacy 1,618 2251
ET
462
P Vera (12.6%)
1409
Non-ET
954
CML, MF, OMPD
934
ET
208
P Vera (12.9%)
684
Non-ET
476
CML,MF, OMPD
SM Fruchtman
Anagrelide Study 301: Response Definitions
Complete response Platelets <600,000/ m L or 50% reduction from baseline at least 4 weeks after starting anagrelide therapy Partial response 20%-50% reduction from baseline SM Fruchtman
Anagrelide Study 301: Response (Efficacy Population)
120 100 80 60 40 20 0 100 63.7
11.5
75.7
All Patients Complete Response Partial Response Total Response
SM Fruchtman
Anagrelide Study 301: Response in Patients with Platelets
1,500,000/
m
L
n Total Response (%) Median time to response (days) (95% CI) ET Patients
116
Non-ET
158 99 (85.3) 125 (79.1) 64 (53-76) 63 (54-81) SM Fruchtman
Anagrelide Study 301: Transformation of ET Patients (n=2251)
n AL transformation Non-transformed 47 2180 †
†
22 additional patients had other transformations and 2 patients were misdiagnosed Median cumulative dose (mg) 342* 746*
*
p=0.005
SM Fruchtman
Anagrelide Study 301: Safety Conclusions
1. Essential thrombocythemia (n=2251) – Maximum F/U = 7.1 yrs – Conversion to AL/MDS = *2.1% 2. Polycythemia vera – Maximum F/U = 7.0 yrs – Conversion to AL/MDS = *2.8% 3. Patients treated with anagrelide for >3 yrs; 0% of ET and 0.26% of P Vera patients transformed *All received prior cytoreductive therapy SM Fruchtman
Anagrelide – Physicians’ Considerations
Why do I need to add anagrelide to my therapeutic armamentarium?
What is unique about anagrelide?
How effective is anagrelide?
What is anagrelide’s safety & toxicity profile?
What factors affect decision to treat?
What outcome can I expect?
HS Gilbert
Evidence-Based Clinical Data in ET
• Comparative phase III clinical trials for rare diseases such as ET are difficult to carry out • No head-to-head data in ET to compare therapeutic agents (hydroxyurea, anagrelide, IFN , etc) – Shire US initiated head-to-head trial. Discontinued due to inadequate recruitment in HU arm CM Kessler
Pairing MPD Phenotype and Therapy
MyM WBC RBC PLTS
ET
Anagrelide
HS Gilbert
Combined Agent Therapy in MPDs
Treatment of ET: ANAG + IFN-
120 ANAG 100 80 60 40 20 0 IFN-
SPL PLTSX10-4 WBC PCV Weeks
HS Gilbert
Algorithm for Treatment of Thrombocythemia
THROMBOCYTHEMIA Low Risk Age < 40 Age 40-60 Plts 600,000 - 1,000,000/
m
L Plts > 1,000,000/
m
L Age >60 Symptomatic Comorbidities Asymptomatic Other proliferation minimal Other proliferation significant ASA Anagrelide IFN-
Hydroxyurea
HS Gilbert
Treatment: Polycythemia Vera
Objectives of Treatment
• Reduce hematocrit to < 45% • Reduce platelets to < 400,000/ m L • Reduce spleen size • Eliminate monoclonal stem cells • Promote polyclonal hematopoiesis • Prevent myelofibrosis • Avoid leukemogenic therapy HS Gilbert
Risk-Based Treatment for P Vera
• Low risk – Age < 60 years – Platelets < 1,500,000/ m L – No history of thrombosis – No cardiovascular risks • Phlebotomy, target Hct < 45%, and consider low-dose aspirin HS Gilbert
Risk-Based Treatment for P Vera
• Intermediate risk – Age < 60 years – No history of thrombosis – Platelet counts > 1,500,000/ m L or – Cardiovascular risk factors HS Gilbert
Risk-Based Treatment for P Vera
• Intermediate-risk treatment – Phlebotomize to Hct <45% – Treat cardiovascular risk factors – Avoid aspirin if platelet counts > 1,500,000/ m L – Consider IFN , hydroxyurea, or anagrelide HS Gilbert
Risk-Based Treatment for P Vera
• High risk – Age 60 years or – History of thrombosis • Phlebotomy and hydroxyurea; consider low-dose aspirin, IFN , anagrelide HS Gilbert
Risk-Based Treatment for P Vera
• High risk – Age > 70 years – Phlebotomy and hydroxyurea and consider low-dose aspirin, radioactive phosphorous; busulfan can be considered HS Gilbert
Women of Childbearing Age with P Vera
• Phlebotomy, target Hct < 45% (42%) • Low-dose aspirin optional - avoid if platelets > 1,500,000/ m L • For high-risk patients, phlebotomy and IFN HS Gilbert
Phlebotomize to Normal Hct Rise in Hct to 55% Within 1 Year or 10% Rise in 3 Months Randomization Phlebotomy Prn to maintain Hct <45% 32 P 2.7 mc/m 2 IV Q 12 wks prn (limit 5 mc/dose) Phlebotomy for Hct >45% Chlorambucil 10 mg po qd x 6 wks; then qd alternate months Adjust dose for response Phlebotomy for Hct >45%
SM Fruchtman
Normal and Low Cerebral-Blood-Flow Measurements in Relation to Hematocrit
Normal CBF 2 Low CBF 3 040 1 2 3 4 045 6 7 8 9 0 50 1 2 3 4 0 55 6 7 8 9 060 1 2 0 63 4 1 1 3 2 5 4 Hematocrit
SM Fruchtman
Relationship of Cerebral Blood Flow to Hematocrit
60 50 40 30 20 10 0.45
0.50
0.55
Hematocrit 0.60
SM Fruchtman
Sequelae of Treatment
• Phlebotomy to reduce Hct is first-line therapy in P Vera. Sequela is iron deficiency that is usually well tolerated. Frequency of phlebotomy usually decreases with time.
• Low-dose ASA is often effective in preventing symptomatic platelet aggregation in thrombocythemia. Sequela is hemorrhage that is usually minor.
HS Gilbert
Some Myelosuppressive Agents Used for P Vera
Agent
Chlorambucil Busulfan 32 P Hydroxyurea
Pro
Easy to administer Easiest to administer Easy to administer Decreases thrombosis when compared to Phl alone
Con
Leukemogenic Greater megakaryocyte toxicity Pulmonary fibrosis Leukemogenic Vanishing expertise ? Long-term safety Rare toxicities (skin) SM Fruchtman
Agent
ASA
Some Pros and Cons of Agents
Hydroxyurea Anagrelide
Pro
Easy to administer Easy to administer Well tolerated Easy to administer
Con
? Efficacy ? Bleeding ? Dose ? Leukemogenic IFN 32 P ?
Intermittent administration Easiest to give (with experience) Fluid retention CHF ? Long-term safety SC route Drop-out rate ? Long-term safety Leukemogenic Vanishing expertise SM Fruchtman
ECLAP Trial (European Collaboration on Low-Dose ASA in PV) Eligibility Consent Randomization Aspirin 100 mg daily Placebo 12 Month: Follow-up Yearly Follow-up
SM Fruchtman
Collaborative Overview of Randomized Trials of Antiplatelet Therapy
1. 75-325 mg daily equivalent to 500-1500 mg daily 2. Risk of major bleeds small with <325 mg daily 3. Aspirin associated with 25% reduction (
p
<10 -5 ) in arterial vascular events in patients at increased risk for occlusive vascular disease 4. Aspirin halves the risk of deep venous thrombosis in surgical patients SM Fruchtman
Hydroxyurea
• Hydroxyurea (HU) with intermittent phlebotomy (PHL) is a highly efficacious treatment strategy in the management of polycythemia vera (P Vera).
• It is the most frequently employed regimen for patients requiring myelosuppression. (ASH Educational Program, 1992) • In addition, HU is being studied for benign hematologic disorders, such as sickle cell disease.
• Thus, it is imperative to establish its long term safety.
SM Fruchtman
Photo
HS Gilbert
IFN-
In polycythemia vera • Controls erythrocytosis, reduces spleen size, and relieves pruritis in ~76% of patients • Alternative to anagrelide or hydroxyurea in young patients SM Fruchtman
Long-term Effect of IFN-
in MPDs
TREATMENT OF P Vera: IFN IFN 140 120 100 80 60 40 20 0 WEEKS 7 37 86 145 201 267
PCV PLTS X 10-4 WBC SPL HS Gilbert
Photo
HS Gilbert
IFN Therapy of MPDs: Effect on Spleen and Blood Counts
Agnogenic myeloid metaplasia Post polycythemia myeloid metaplasia Active polycythemia with myeloid metaplasia Polycythemia vera 0 -10 -20 -30 -40 -50 -60 % change in spleen size % change in WBC % change in platelets
SM Fruchtman MPD Research Center.
Combined Agent Therapy in P Vera
1400 1200 1000 800 600 400 200 HU AGR IFN-
PHLEB WBC PLTS PCV 0 0 5 10 15 20 25 HU------------- AGRYLIN---------------- IFN--------- WEEKS 30 35 40
HS Gilbert
Pairing MPD Phenotype and Therapy
MyM WBC RBC PLTS
P Vera
Elderly or failed other agents Hydroxyurea
HS Gilbert
Leukemic Risk with Therapies for ET and P Vera
• Hydroxyurea: Risk (0%-5% in ET; 2.1%-10% in P Vera) increases when HU is combined with other agents – 14% risk of leukemic conversion with HU + 32 P, busulfan, or pipobroman in one study of 357 patients followed for median of 8 years • Busulfan: 3% with busulfan alone • Anagrelide: No evidence of leukemogenicity in patients treated for up to 10 years SM Fruchtman
Spent Phase
• Anemia • Splenomegaly • Nucleated RBC • Tear-drop forms SM Fruchtman
SM Fruchtman
Comparative Incidence of Spent Phase by Protocol and Treatment
On-study events, first 795 weeks of study
Protocol
HU-NPT (08) Phlebotomy (01) Wilcoxon X² 1 Logrank X² 1 = 2.253
= 1.137
Patients
51 134
p
=.1334
p
=.2863
All events HU-NPT (08) Phlebotomy (01) Wilcoxon X² 1 Logrank X² 1 = 1.734
= 0.778
51 134
p
=.1879
p
=.3777
PVSG 8/94.
Total # events
4 15 4 17
%
7.8
11.2
7.8
12.7
SM Fruchtman
Comparative Incidence of Spent Phase/Acute Leukemia by Protocol and Treatment
On-study events, first 795 weeks of study
Protocol
HU-NPT (08) Phlebotomy (01) Wilcoxon X² 1 Logrank X² 1 = 0.119
= 0.045
Patients
51 134
p
=.7301
p
=.8329
Total # events
7 16*
%
13.7
11.9
All events HU-NPT (08) Phlebotomy (01) Wilcoxon X² 1 Logrank X² 1 = 0.196
= 0.235
51 134
p
=.6581
p
=.6277
9 19** 17.6
14.2
*One case has both spent phase and acute leukemia.
**Three cases have both spent phase and acute leukemia.
PVSG 8/94.
SM Fruchtman
Medical Management of Spent Phase P Vera
1.
2.
Transfusion support Others: – Androgens – Low-dose splenic R.T.
– Interferons – anagrelide – erythropoietin – hydroxyurea – research protocols (thalidomide, CSA transplantation) 3.
Splenectomy SM Fruchtman
Treatment: Idiopathic Myelofibrosis
(Myelofibrosis with Myeloid Metaplasia; Agnogenic Myeloid Metaplasia)
Underlying Propensity to Develop Myelofibrosis
• Myelofibrosis is a reactive phenomenon to the abnormality of the pluripotent hematopoietic stem cell. • The fibroblast is not part of the malignant clone. • This in contrast to acute malignant myelofibrosis.
• The fibroblast may be part of the malignant clone.
• Seen in patients with acute leukemic condition.
HS Gilbert
Medical Management of IMF
• Transfusional support • Others: – Androgens – Hydroxyurea – Low-dose splenic RT – Erythropoietin – Interferons – Anagrelide • Splenectomy SM Fruchtman
Splenectomy in IMF
(Tefferi ASH 1998 vs Barosi, Blood 91:3630,1998)
• Mayo data (223 cases) – Median age, 65 years – Mortality, 9%; morb., 31% – Symptoms improved in >90% – Anemia improved in 30% – Thrombocytopenia in 25% – Leukemia in 16% at 2-yr follow-up – Hepatomegaly in 16% – Thrombocytosis in 20% – Median postop survival 2 yrs – Platelet count <50k is risky • Italian multicenter (87 cases) – Compared to 462 non splenectomized cases – Leukemia—26% vs 12% – Leukemia at 12 years after diagnosis —55% vs 27% – Disease presentation with blasts or low platelets is a risk factor for leukemia – HU therapy was not a risk factor – PPMM and PTMM excluded SM Fruchtman
Interference with Collagen Metabolism
Target
Hydroxylation Secretion
Mechanism
Substrate modification Microtubules Microfilaments
Agent
Hydroxyproline analogues Colchicine Vinblastine Cytochalasin B Polymerization Complexing chains Cleaving cross links Lysyl oxidase inhibition D-Penicillamine Potaba p-aminoproprionitrile Degradation Increase collagenase Colchicine SM Fruchtman
We NEED Antifibrosing Therapies
• Marrow • Lung • Liver • Skin • Penis SM Fruchtman
Acute Leukemia and IMF in PVSG-01
Treatment
Phlebotomy Chlorambucil 32 P Total
MM/MF
No Yes No Yes No Yes No Yes
Cases
120 14 127 14 140 16 387 44
Acute Leukemia Cases
1 1 14 5 12 4 27 10
Percent
0.8
7.1
11.0
36.0
8.6
25.0
7.0
23.0
SM Fruchtman
Effect of IFN-
on Splenomegaly
40 35 30 25 20 15 10 5 0 PRE Rx POST Rx 1 2 3 4 POST- P Vera IMF 5 6
HS Gilbert
Effect of IFN-
on Splenomegaly
40 35 30 25 20 15 10 5 0 1 2 3 4 5 6 7 8 IMF 9 10 11 12 13 14 PRE Rx POST Rx
HS Gilbert
Effect of Therapy on Control of Proliferation
MyM WBC RBC PLTS Anagrelide IFN Hydroxyurea
HS Gilbert
Pairing MPD Phenotype and Therapy
MyM
MyM WBC RBC PLTS
P Vera
IFN
HS Gilbert
Combined Agent Therapy in MPDs
MyM
IFN Anagrelide Hydroxyurea
P Vera ET
HS Gilbert
Three Classes of Drugs Used for Treatment of Thrombocythemia in MPDs
DRUG ANAGRELIDE HYDROXYUREA IFN α CLASS OF DRUG MECHANISM OF ACTION EFFECT ON CLONAL vs NORMAL PHPC EFFECT ON MEGAKARYOCYTES Prostaglandin synthetase inhibitor Inhibitor of megakaryocyte maturation and platelet budding None; targets megakaryocytes Prevents maturation and budding Ribonucleoside diphosphate reductase inhibitor Biological response modifier DNA synthesis inhibitor; myelosuppressive Myelosuppressive Immunomodulatory Nonselective Selective; reduces and/or changes MPD clone Decreases by inhibiting proliferation of PHPC Decreases by inhibiting proliferation of PHPC
HS Gilbert
Three Classes of Drugs Used for Treatment of Thrombocythemia in MPDs
DRUG ANAGRELIDE HYDROXYUREA IFN α REDUCTION AND MAINTENANCE OF PLATELETS TO <400,000/ µL Achieved by titration; Gradual reduction; Steady maintenance while on drug.
Difficult to achieve; Difficult to maintain; Requires continuous drug for maintenance.
REDUCTION OF SPLENOMEGALY/ MYELOID METAPLASIA None PREVENTION OR REVERSAL OF FIBROSIS Potentially by effect on megakaryocytes.
ACUTE LEUKEMIA OR MDS TRANS FORMATION Unlikely Unknown None None Increased 5%-10% Achieved by titration; Gradual reduction; Steady maintenance that persists after drug stopped.
Spleen shrinks beginning at 2 mos, continues during 6-12 mos, and persists after drug stopped.
Potentially by changing MPD clone and marrow milieu.
Unlikely Unknown
HS Gilbert
Three Classes of Drugs Used for Treatment of Thrombocythemia in MPDs
DRUG ANAGRELIDE HYDROXYUREA IFN α Good STABILITY OF RESPONSE DURING TREATMENT Good Short without rebound DURATION OF EFFECT AFTER STOPPING TREATMENT SIDE EFFECTS USE DURING PREGNANCY COST ACUTE LEUKEMIA/MDS TRANSFORMATION 2-3+ No $5.00/capsule Unknown Unlikely Fair Short with rebound 1-2+ No $1.00/capsule 5%-10% Long without rebound 2-4+ Acceptable $8.00/MU Unknown Unlikely
HS Gilbert
Three Classes of Drugs Used for Treatment of Thrombocythemia in MPDs
DRUG ANAGRELIDE HYDROXYUREA IFN α Good STABILITY OF RESPONSE DURING TREATMENT Good Fair Short without rebound Short with rebound DURATION OF EFFECT AFTER STOPPING TREATMENT SIDE EFFECTS USE DURING PREGNANCY COST ACUTE LEUKEMIA/MDS TRANSFORMATION 2-3+ No $5.00/capsule Unknown Unlikely 1-2+ No $1.00/capsule 5%-10% Long without rebound 2-4+ Acceptable $8.00/MU Unknown Unlikely
HS Gilbert
ANAGRELIDE
Side Effects of Therapy
HYDROXYUREA IFN α Prostaglandin Inhibition Vasodilator: Headache Dizziness Inotrope: “Palpitations” Renal blood flow: Fluid retention Lactose vehicle Bloating, diarrhea Nausea, vomiting CHF, PULMONARY EDEMA Antimetabolite Myelosuppression: Neutropenia Anemia Dermal: Mucositis Hyperpigmentation Ulceration Gastrointestinal: Nausea, vomiting Bloating, diarrhea Liver damage Systemic: Headache, nausea, Asthenia Biologic Response Modifier Systemic: Fever, chills Myalgia, fatigue Anorexia Cytoreductive: Alopecia Diarrhea Myelosuppression: Neutropenia Anemia Neurologic: Headache, depression Neuropathy Immunomodulator: Hypothyroidism LEUKEMOGENIC MUTAGENIC
HS Gilbert
Treatment: Stem Cell Transplant
Experimental
• Therapies for idiopathic myelofibrosis • Allogeneic stem cells • Autologous stem cells SM Fruchtman
Allogeneic Bone Marrow Transplantation
DONOR usually HLA matched sibling c 750 ml bone marrow aspirated from iliac crest High-dose chemotherapy ± total body irradiation bone marrow graft: donor marrow infused intravenously RECIPIENT ± T cell depletion by monoclonal antibodies Intensive support therapy, e.g. red cells & ± platelets, antibiotics attempts to prevent GVHD, e.g. cyclosporin ± methotrexate
SM Fruchtman
The Sheffield Schema for Predicting Survival
Age (yrs)
<68
Hb (g/dL)
10 >10
Karyotype
N A N A
Median survival
54 22 180 72 >68 10 >10 N A N A 44 16 70 78 N=normal, A=abnormal SM Fruchtman
The LILLE Scoring System for Predicting Survival
No. of adverse prognostic factors
0
Risk group
Low
Cases (%)
47
Median survival (months)
93 1 Intermediate 45 26 2 High 8 Adverse prognostic factors; Hb <10g/dL, WBC <4 or >30 x 10 9 /L 13 SM Fruchtman
Diagnosis
P Vera
Age
44 P Vera 31
Gender
F
Time from DX to transplant (months)
156 F 144 ET ET ET
P Vera, ET, and Allogeneic BMT
18 49 31 F M F 60 37 180
Medical RX
Hydrea, Phl Hydrea, ASA ASA, Persantin Hydrea Epo, Hydrea
Spleen size
Resected Mildly enlarged Mildly enlarged Mildly enlarged Mildly enlarged SM Fruchtman
Hematologic Parameters
Diagnosis
P Vera
WBC*
5.9
Blasts
<1
Platelet*
879
HCT%
38.2
Grade of fibrosis
3
Cytogenetics
Normal P Vera ET 13.8
11.7
<1 1 ET 14.8
ET *x10 9 cells/L 5.5
1 0 966 1,256 40.2
38.4
252 554 38.6
34.0
1 2-3 2 2-3 Normal Normal Normal Normal SM Fruchtman
Transplantation Characteristics and Outcome
Diagnosis
P Vera P Vera
Donor
HLA ID VUD HLA ID SIB
GVHD
GR 1 Acute Chronic extensive GR 2 Acute Chronic extensive ET ET ET HLA ID SIB HLA ID SIB HLA ID SIB None Grade 3 Acute None Prep Regimen BU/Cy GVHD Prophylaxis CSA/MTX
Comments
On immunosuppression Alive (2.1 yrs) 100% Performance On immunosuppression Alive (1.7 yrs) 80% Performance Alive (7.1 yrs) 100% Performance Alive (1.4 yrs) 100% Performance Alive (1.2 yrs) 80% Performance SM Fruchtman
Cost-effectiveness
Treatment Model: ET
• Treatment in ET: based on high-risk patients • Treatment options include Hydroxyurea (HU), anagrelide and interferon alpha.
• Controversy regarding best choice of agent.
CL Bennett
Available Evidence
• Comparative phase III clinical trials for rare diseases such as ET are difficult to carry out • No head to head comparison data are available for choosing best therapeutic agent in ET CL Bennett
Complications of Untreated ET
• Angina/MI 4.3% /year • TIA/Stroke 3.6% /year • GI or other hemorrhage 0.2% /year • Venous/Arterial thrombosis 2.9% /year CL Bennett
Hydroxyurea
• Typical effective dose 1g/day; – Cost: $142/month • Response rate: 80%-89% • Often used as first-line therapy for ET • Concerns: long-term tolerability and leukemogenicity CL Bennett
Anagrelide
• Maintenance Dose 2.5mg daily; • Cost: $520/month • Adverse effects: Palpitations, (10%-27%), tachycardia & other arrhythmias (< 10%), CHF exacerbation (<2%).
• Response rate: 90% CL Bennett
IFN-
• Typical effective dose 30 MU/week; Cost (including injection supplies) $1860/month • Withdrawal secondary to adverse effects: 25% 1 st year; 25% additional in 2 nd year • Response rate: 80% CL Bennett
Methods
• A Markov model was used to derive life expectancy and lifetime risk of sequelae of ET and treatments.
• Data derived from the Markov model was then used in a decision tree to compare relative benefits and life-time costs of treatment and treatment-related sequelae of HU, anagrelide and IFN . CL Bennett
Costs of Complications
• Stroke • MI • GI bleed • TIA • Venous thrombosis • Acute Leukemia $30,000 $30,000 $5,000 $4,700 $3,200 $245,000 CL Bennett
Assumptions of Model
• Leukemia risk modeled as part of sensitivity analysis (baseline risk of 10%) • Markov model allows for only one complication in any one cycle.
• It takes three months to evaluate efficacy of drug.
• Treatment of leukemia results in cure of ET (if survive).
CL Bennett
Markov Model
CL Bennett
Estimated Cost/Effectiveness of Cytoreductive Therapy
Drug Cost [C] Effectiveness [E] (years of life) Marginal C/E [$/LYS] HU $78,000 20.677
$93,073 Anagre lide $132,000 IFN $148,000 21.266
21.229
(Dominated) Costs and cost-effectiveness estimates for a 40 year old individual with ET who is treated with HU, anagrelide, or IFN.
CL Bennett
Cost effectiveness Results (Cont’d)
• $75,000 to $100,000 per life year gained is used as threshold for "cost-effective" • For younger high-risk patients, anagrelide is clinically effective and in the range of options that are considered cost-effective • Hydroxyurea is a cost-effective option for older individuals • IFN is never cost-effective CL Bennett
Limitations
• No reliable estimate of leukemic risk CL Bennett
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 CL Bennett
Conclusions
A New Treatment Dynamic?
• Reduce platelets to low normal range • Is IFN underutilized? Does it affect the clone more than other approaches?
• Is ASA warranted in all cases? Prescreen with platelet aggregation studies?
• Reserve hydroxyurea for refractory cases?
• Begin treatment earlier – Thrombotic complications are not uncommon in young patients. Early, more aggressive treatment may reduce future complications CM Kessler
Conclusion —P Vera, ET
1. Hydroxyurea has become an old friend (? Enemy).
2. It is an excellent choice for older patients and those at risk for thrombosis.
3. No myelosuppressive therapy is an excellent option for young patients and those at low thrombotic risk.
4. Medium-dose aspirin (75-325 mg daily). The risk/benefit ratio remains to be determined.
SM Fruchtman
Modern Therapeutic Options in MPD
Essential Thrombocythemia Hydroxyurea Anagrelide ASA 32 P IFN-
Plateletpheresis
SM Fruchtman
Take-Home Messages
• Diagnose ET earlier – Be more suspicious – Criteria now permit diagnosis at platelet count of 400,000/ m 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/ m L RM Petitt
Future Directions for MPD
• Anagrelide – Sustained release ?
– Congeners • IFN – Pegylated IFN – now on market – Albumin-bound IFN – coming • Marrow curettage + autologous CD34 infusion – Better results after splenectomy?
• Angiogenesis inhibitors – Thalidomide – Over 40 others in various phases of evaluation • Other biologic response modifiers RM Petitt
References
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Tefferi A, Silverstein MN, Hoagland HC. Primary thrombocythemia. Sem Onc 1995, 22:334-340. Gilbert HS. Diagnosis and treatment of polycythemia vera, agnogenic myeloid metaplasia, and essential thrombocythemia. In Neoplastic Diseases of the Blood. Wiernik PH, Canellos GP, Kyle RA, Schiffer CA, (eds): New York: Churchill Livingstone, 1991, p 123.
Hachulla E, Rose C, Trillot N, Caulier-Leleu MT, Pasturel-Michon U. [What vascular events suggest a myeloproliferative disorder]?
J Mal Vasc 2000, 25(5):382-387.
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