Dr.Mahmoodzadeh Hemathologist-Oncologist. Polycythemia vera (PV) Essential thrombocytosis (ET)...
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Transcript of Dr.Mahmoodzadeh Hemathologist-Oncologist. Polycythemia vera (PV) Essential thrombocytosis (ET)...
Dr.Mahmoodzadeh Hemathologist-Oncologist
The Chronic Myeloproliferative Disorders
MYELOPROLIFERATIVE NEOPLASMS•Chronic myeloid leukemia, BCR-ABL1-positive•Chronic neutrophilic leukemia •Polycythemia vera•Essential thrombocytosis•Primary myelofibrosis•Chronic eosinophilic leukemia, not otherwise specified•Mastocytosis•Myeloproliferative neoplasms, unclassifiable
The Revised WHO Classification of the Chronic MPDs
• These 3 disorders share in common mutations in the JAK2 and MPL genes
• There is an inherent (germline) patient proclivity to JAK2 and MPL mutations
• Constitutive signal transduction in these disorders occurs through normal signaling pathways
• Phenotypic mimicry and clinical overlap occur between these 3 disorders but not between them and the other MPNs
• Targeted therapy has been developed for PV, ET, and PMF
Rationale for Classifying PV, ET, and PMF Separately From the Myeloproliferative Neoplasms
The Phenotypic Mimicry of the Chronic Myeloproliferative Disorders
“All pathways lead to polycythemia vera”
Essential Thrombocytosi
sPrimary
Myelofibrosis
Polycythemia Vera
AcuteLeukemia
“Isolated Thrombocyt
osis”
.
Cytokine Receptors Utilizing Janus Family Kinases
Pluripotent Hematopoiet
ic Stem Cell
T LymphocytesCommon
Hematopoietic Stem Cell
B Lymphocytes
Granulocyte-MonocyteProgenitors
Erythroid Progenitors
Megakaryocytic Progenitors
JAK2V617F
Polycythemia vera is the ultimate consequence of the JAK2V617F
mutation
Hematopoietic Stem Cell Hierarchy
PV PMF ET JAK2V617F+
92% 42% 45%
JAK2V617F–
8%* 58% 55%*Some of these patients have JAK2 exon
12 mutations
JAK2V617F Expression in the Chronic Myeloproliferative Disorders
PV ET PMFAge - Older Older
Hemoglobin Higher)+/+( HigherFewer
transfusions
Leukocyte count
- Higher Higher
Thrombosis -More
(venous)
Pruritus More)+/+( - +
Transformation
Fibrosis )+/+(
PV -
Survival - - Longer)?(
Effect of JAK2V617F Expression on Clinical Phenotype
JAK2V617F Is Not the Initiating Mutation in the 3 MPDs Hematopoietic stem cells do not require JAK2 for their survival or proliferation
JAK2V617F is not present in some patients with familial polycythemia vera
JAK2V617F can arise as a secondary event in clones expressing a cytogenetic abnormality or another mutation
Leukemic transformation in patients with JAK2V617F-positive MPD can occur in a JAK2V617F-negative type
cell
BUT: JAK2 is the major final common signaling pathway in all chronic MPDs and, therefore,
whether mutated or not, is an appropriate therapeutic target
• Polycythemia vera is a chronic myeloproliferative disorder in which there is overproduction of morphologically normal red blood cells, white blood cells, and platelets in the absence of a definable stimulus
• Erythrocytosis is the feature that distinguishes polycythemia vera from the other 2 chronic myeloproliferative disorders
• There is currently no specific clonal diagnostic marker for polycythemia vera
Polycythemia Vera
Causes of Absolute Erythrocytosis
Hypoxia
Carbon monoxide intoxication (tobacco abuse, environmental)
High-affinity hemoglobinsHigh altitude
Pulmonary diseaseRight-to-left shunts
Sleep apnea syndromeNeurologic disease
Renal Disease
Renal artery stenosis Focal sclerosing or membranous
glomerulonephritisRenal transplantation
Tumors
HypernephromaHepatoma
Cerebellar hemangioblastomaUterine fibromyoma
Adrenal tumorsMeningioma
Pheochromocytoma
Drugs Androgenic steroids Recombinant erythropoietin
Familial (with normal hemoglobin function; Chuvash; EPO receptor mutations; 2,3 BPG
deficiency)
Polycythemia vera
JAK2V617F
JAK2 exon 12 mutations
Causes of Relative Erythrocytosis
Loss of Fluid From the Vascular Space
Emesis DiarrheaDiureticsSweatingPolyuriaHypodipsiaHypoalbuminemiaCapillary leak syndromes,burnsPeritonitis
Chronic Plasma Volume Contraction
Hypoxia from any causeAndrogen therapy
Recombinant erythropoietin therapy
HypertensionTobacco use
PheochromocytomaEthanol abuse
Sleep apneaOnly ~5 % of patients with absolute erythrocytosis are likely to have polycythemia vera
Major criteri
a
1. Hemoglobin > 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red blood cell volume*
2. Presence of JAK2617V > F or other functionally similar mutation such as JAK2 exon 12 mutation
Minor criteria
1 .Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent
erythroid, granulocytic, and megakaryocytic proliferation
2 .Serum erythropoietin level below the reference range for normal
3 .Endogenous erythroid colony formation in vitroDiagnosis requires the presence of both major criteria and 1 minor criterion or the presence of the first major criterion together with 2 minor criteria.*Hemoglobin or hematocrit greater than 99th percentile of method-specific reference range for age, sex, altitude of residence or hemoglobin greater than 17 g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from an individual’s baseline value that cannot be attributed to correction of iron deficiency, or elevated red blood cell mass greater than 25% above mean normal predicted value..
Proposed Revised WHO Criteria for Polycythemia Vera
A1 Raised red cell massA2 Normal O2 sats and EPOA3 Palpable spleenA4 No BCR-ABL fusionB1 Thrombocytosis >400 x 109/LB2 Neutrophilia >10 x 109/LB3 Radiological splenomegalyB4 Endogenous erythroid colonies
A1+A2+either another A or two B establishes PV
Red cell mass and plasma volume measurements
Elevated red cell mass
Tobacco useAndrogensDiureticsPheochromocytoma
Hypoxic erythrocytosis
JAK2V617F
Polycythemia vera
– Serum erythropoietin
level
Normal or lowPolycythemia veraEPO-receptor mutationRenal diseaseTumorsHigh-affinity hemoglobins
ElevatedRenal diseaseTumorsVHL mutationHigh-affinity hemoglobins
Elevated hemoglobin or hematocrit
Both normal
..
+
O2 saturation Normal red cell mass
Decreased plasma volume> 93% < 93%
Algorithm for the Diagnosis of Polycythemia Vera
•Also known as essential thrombocythemia, hemorrhagic thrombocytosis, idiopathic thrombocytosis, or primary thrombocytosis
•Disorder of unknown etiology• Principal clinical feature is the
overproduction of platelets in the absence of a definable cause
•No specific diagnostic marker
Essential Thrombocytosis
• Tissue inflammation– Collagen vascular disease, inflammatory bowel disease• Malignancy• Infection• Myeloproliferative disorders– Polycythemia vera, primary myelofibrosis, essential
thrombocytosis, chronic myelogenous leukemia• Myelodysplastic disorders– 5q-syndrome, idiopathic refractory sideroblastic anemia• Postsplenectomy or hyposplenism• Hemorrhage• Iron deficiency anemia• Surgery• Rebound – Correction of vitamin B12 or folate deficiency, post-ethanol
abuse• Hemolysis• Familial– Thrombopoietin overproduction, constitutive Mpl activation,
K39N
Causes of Thrombocytosis
Platelet count >600 x 109/L for at least 2 months
Megakaryocytic hyperplasia on bone marrow aspiration and biopsy
No cause for reactive thrombocytosis Absence of the Philadelphia chromosome Normal red blood cell (RBC) mass or a
HCT <0.48 Presence of stainable iron in a bone
marrow aspiration No evidence of myelofibrosis No evidence of MDS
Diagnostic Criteria for Essential ThrombocytosisPersistent thrombocytosis more than 400 x 109/L in the absence of a reactive cause*
Absence of iron deficiency (normal serum ferritin for sex)JAK2V617F assay (peripheral blood; expression establishes the presence of an MPD but not its type; absence does not exclude an MPD)Hemoglobin less than 16 g/dL in a man or less than 14 g/dL in a woman (hematocrit < 47% in a man or < 44% in a woman) in the absence of splenomegaly; otherwise, red blood cell mass and plasma volume determinations are mandatory if a JAK2V617F assay is positiveNegative Bcr-Abl FISH (peripheral blood) if a JAK2V617F assay is negativeIf there is anemia, macrocytosis, or leukopenia, or evidence of extramedullary hematopoiesis (ie, circulating nucleated erythrocytes, immature myelocytes, or splenomegaly), a bone marrow examination (including flow cytometry and cytogenetics) is mandatory regardless of JAK2V617F expression status
Primary Myelofibrosis
MalignantAcute leukemia
(lymphocytic, myelogenous,
megakaryocytic)
Chronic myelogenous leukemia
Hairy cell leukemia
Hodgkin disease
Primary myelofibrosis
Lymphoma
Multiple myeloma
Myelodysplasia
Metastatic carcinoma
Polycythemia vera
Systemic mastocytosis
Causes of Myelofibrosis
Non-MalignantHIV infection
Hyperparathyroidism
Renal osteodystrophy
Systemic lupus erythematosus
Tuberculosis
Vitamin D deficiency
Thorium dioxide exposure
Gray platelet syndrome
Thrombopoietin receptor agonists
Diagnostic Criteria for Primary MyelofibrosisLeukoerythroblastic blood pictureIncreased marrow reticulin in the absence of an infiltrative or granulomatous processSplenomegalyJAK2V617F assay (peripheral blood; expression establishes the presence of an MPD but not its type; PV is always a consideration; absence does not exclude an MPD)Increased circulating CD34+ cells (> 15 x 106/L) and no increase in marrow CD34+ cells by in situ immunohistochemistryCharacteristic cytogenetic abnormalities (peripheral blood: del(13q), 9p, del(20q), del(12p), partial trisomy 1q, trisomy 8, and trisomy 9)Absence of Bcr-Abl, AML, or MDS cytogenetic abnormalities by FISH (peripheral blood)
The Consequences of Polycythemia Vera
Consequence CauseThrombosis, systemic hypertension, hemorrhage
Elevated red blood cell mass, decreased von Willebrand factor multimers
Organomegaly, pulmonary hypertension
Extramedullary hematopoiesis or elevated red blood cell mass
Pruritus, acid-peptic disease Inflammatory mediators
Erythromelalgia Thrombocytosis
Hyperuricemia, gout, renal stones Increased cell turnover
Myelofibrosis Reaction to the neoplastic clone
Acute leukemia Therapy-induced or clonal evolution (“Richter syndrome”)
• In a study of 1213 patients with PV, cancer-free survival and survival analyses for death or major thrombosis were better among patients who did not receive chemotherapy[a]
• In a prospective, controlled clinical trial of 292 patients with PV, hydroxyurea did not prevent thrombosis or myelofibrosis[b]
• Hydroxyurea therapy was associated with a late (> 10 years) risk for transformation to acute leukemia[b,c]
• In a study of 40 patients with PV, pegylated interferon alfa-1a induced complete hematologic and molecular responses with low toxicity[d]
The Challenges of Treating Polycythemia Vera
The Complications of Polycythemia Vera and Their Management
• 97% achieved durable hematocrit control in the absence of phlebotomy
• 59% achieved a durable reduction in splenomegaly of at least 50%
• 88% achieved a reduction in leukocytosis to ≤ 15 x 109/L
• 92% achieved a reduction in platelet count to ≤ 600 x 109/L
• 59% achieved a complete phenotypic remission• 92% had durable relief from pruritus in 1 month• The reduction in JAK2V617F allele burden was
modest• There were 3 grade 3 adverse events: 2
thrombocytopenia and 1 neutropenia• The nonresponder rate was 3%
Effect of a JAK2 Inhibitor in 34 Patients With Established PV (Phase 2 trial data)
Complications of Essential ThrombocytosisMicrovascular ischemia
•migraine•erythromelalgia•transient ischemic attacks
Macrovascular thrombosis
•stroke•acute coronary syndrome•peripheral arterial occlusion•digital gangrene•deep venous thrombosis
Hemorrhage due to acquired von Willebrand diseaseTransformation to acute leukemia
• Asymptomatic thrombocytosis requires no therapy in the absence of a thrombotic (prior thrombosis, tobacco use) or significant hemorrhagic diathesis
• Platelet counts ≥ 1000 x 109/L can be associated with reduced von Willebrand factor, high molecular-weight multimers, and ristocetin cofactor activity
• Hemorrhage associated with thrombocytosis can be controlled with epsilon aminocaproic acid
• Aspirin is the treatment of choice for erythromelalgia unless ristocetin cofactor activity is reduced
• For platelet count reduction, particularly in patients under age 60, anagrelide or interferon, if tolerated, are preferable to hydroxyurea. The new JAK2 inhibitors may prove preferable to the above drugs
• It is not necessary to lower the platelet count to normal but only to a level that alleviates symptoms
Management of Thrombocytosis in Essential Thrombocytosis
• 49% normalized their platelet count within 2 weeks
• 82% maintained a platelet count ≤ 600 x 109/L for 9.8 months
• 93% with a platelet count ≥ 1000 x 109/L achieved a > 50% reduction
• 75% had complete resolution of splenomegaly • 49% had a complete phenotypic remission• Reduction in the JAK2V617F allele burden was
modest• There were 2 grade 3 adverse events involving
leukopenia• The nonresponder rate was 8%
Effects of a JAK2 Inhibitor in 39 Patients With Established Thrombocytosis (Phase 2 trial data)
Complications of Primary Myelofibrosis
Anemia •Hypoproliferative due to folate or iron deficiency, inflammation, autoimmune
hemolysis, hemodilution, or impaired stem cell function
Thrombocytopenia
• Splenic sequestration, impaired stem cell function
Incapacitating splenomegaly and splenic infarctionPortal hypertensionPulmonary hypertensionOrgan compromise due to extramedullary hematopoiesis
• Obstructive uropathy• Intestinal obstruction• Ascites• Pleural effusions• Hepatic failure• Fibrous tumors • Spinal or cranial compression• Bone pain due to periostitis or increased
intramedullary vascularityBone marrow failure with pancytopeniaAcute leukemia
Management of Primary Myelofibrosis
a. Rondelli D, et al. Blood. 2005;105:4115. b. Mesa RA, et al. Blood. 2003;101:2534. c. Verstovsek S, et al. N Engl J Med. 2010;363:1117.
Summary
• The chronic MPDs — PV, ET, and PMF — are distinct disease entities that share many clinical features (phenotypic mimicry) due to unregulated JAK2 signaling or a similar signaling abnormality
• Because these disorders differ with respect to their natural history and survival, diagnosis must be accurate to ensure that therapy is appropriate
• Treatment of these 3 disorders should be tailored to fit their clinical manifestations
• PV is the most common of the 3 MPDs because it is the ultimate expression of the JAK2V617F mutation
• All chemotherapeutic agents are leukemogenic in the MPDs and should be avoided whenever possible, which may now be possible with the new JAK2 inhibitors
• JAK2 inhibitors will be very useful for safely reducing splenomegaly, controlling blood counts, and alleviating constitutional symptoms, but will not eradicate these disorders
• Pegylated interferon or reduced-intensity conditioning bone marrow transplantation offer the possibility of complete molecular remission