The Chronic Myeloproliferative Disorders

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The Chronic Myeloproliferative Disorders

• Dr.Mahmoodzadeh
• Hemathologist-Oncologist

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The Chronic Myeloproliferative Disorders

• Polycythemia vera (PV)
• Essential thrombocytosis (ET)
• Primary myelofibrosis (PMF)
• All 3 are clonal stem cell disorders in which
  there is
• Overproduction of 1 or more of the formed
  elements of the blood
• Splenomegaly due to extramedullary hematopoiesis
• Myelofibrosis
• Transformation to acute leukemia at variable but
  low rates
• The 3 disorders were recently reclassified by the
  WHO as myeloproliferative neoplasms

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The Revised WHO Classification of the Chronic
MPDs

• 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

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Rationale for Classifying PV, ET, and PMF
Separately From the Myeloproliferative Neoplasms

• 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

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The Phenotypic Mimicry of the Chronic
Myeloproliferative Disorders
Essential Thrombocytosis
Primary Myelofibrosis
Acute Leukemia
Isolated Thrombocytosis
Polycythemia Vera
All pathways lead to polycythemia vera
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Cytokine Receptors Utilizing Janus Family Kinases
.
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Hematopoietic Stem Cell Hierarchy
Pluripotent Hematopoietic Stem Cell
Common Hematopoietic Stem Cell
T Lymphocytes
B Lymphocytes
Erythroid Progenitors
Granulocyte-Monocyte Progenitors
Megakaryocytic Progenitors
JAK2V617F
Polycythemia vera is the ultimate consequence of
the JAK2V617F mutation
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JAK2V617F Expression in the Chronic
Myeloproliferative Disorders
PV PMF ET
JAK2V617F 92 42 45
JAK2V617F 8 58 55
Some of these patients have JAK2 exon 12
mutations
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Effect of JAK2V617F Expression on Clinical
Phenotype
PV ET PMF
Age - Older Older
Hemoglobin Higher (/) Higher Fewer transfusions
Leukocyte count - Higher Higher
Thrombosis - More (venous)
Pruritus More (/) -
Transformation Fibrosis (/) PV -
Survival - - Longer(?)
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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
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Polycythemia Vera

• 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

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Causes of Absolute Erythrocytosis Causes of Absolute Erythrocytosis
Hypoxia Carbon monoxide intoxication (tobacco abuse, environmental) High-affinity hemoglobins High altitude Pulmonary disease Right-to-left shunts Sleep apnea syndrome Neurologic disease
Renal Disease Renal artery stenosis Focal sclerosing or membranous glomerulonephritis Renal transplantation
Tumors Hypernephroma Hepatoma Cerebellar hemangioblastoma Uterine fibromyoma Adrenal tumors Meningioma Pheochromocytoma
Drugs Androgenic steroids Recombinant erythropoietin
Familial (with normal hemoglobin function Chuvash EPO receptor mutations 2,3 BPG deficiency) Familial (with normal hemoglobin function Chuvash EPO receptor mutations 2,3 BPG deficiency)
Polycythemia vera Polycythemia vera
JAK2V617F JAK2V617F
JAK2 exon 12 mutations JAK2 exon 12 mutations
Causes of Relative Erythrocytosis Causes of Relative Erythrocytosis
Loss of Fluid From the Vascular Space Emesis Diarrhea Diuretics Sweating Polyuria Hypodipsia Hypoalbuminemia Capillary leak syndromes, burns Peritonitis
Chronic Plasma Volume Contraction Hypoxia from any cause Androgen therapy Recombinant erythropoietin therapy Hypertension Tobacco use Pheochromocytoma Ethanol abuse Sleep apnea
Only 5 of patients with absolute
erythrocytosis are likely to have polycythemia
vera
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Proposed Revised WHO Criteria for Polycythemia
Vera

Major criteria 1. Hemoglobin gt 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 gt 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 vitro
Diagnosis 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
individuals 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.
.
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Diagnostic Criteria

• A1 Raised red cell mass
• A2 Normal O2 sats and EPO
• A3 Palpable spleen
• A4 No BCR-ABL fusion
• B1 Thrombocytosis gt400 x 109/L
• B2 Neutrophilia gt10 x 109/L
• B3 Radiological splenomegaly
• B4 Endogenous erythroid colonies
• A1A2either another A or two B establishes PV

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Algorithm for the Diagnosis of Polycythemia Vera
Elevated hemoglobin or hematocrit
Red cell mass and plasma volume measurements
Elevated red cell mass
Both normal
O2 saturation
Normal red cell mass Decreased plasma volume
gt 93
lt 93
JAK2V617F
Tobacco use Androgens Diuretics Pheochromocytoma
Hypoxic erythrocytosis


Polycythemia vera
Serum erythropoietin level
Normal or low Polycythemia vera EPO-receptor
mutation Renal disease Tumors High-affinity
hemoglobins
Elevated Renal disease Tumors VHL
mutation High-affinity hemoglobins
..
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Essential Thrombocytosis

• 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

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Causes of 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

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Diagnostic criteria for ET

• Platelet count gt600 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 lt0.48
• Presence of stainable iron in a bone marrow
  aspiration
• No evidence of myelofibrosis
• No evidence of MDS

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Therapy of ET based on the risk of thrombosis
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Diagnostic Criteria for Essential Thrombocytosis
Persistent 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 lt 47 in a man or lt 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 positive
Negative Bcr-Abl FISH (peripheral blood) if a JAK2V617F assay is negative
If 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
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Primary Myelofibrosis

• Also known as agnogenic myeloid metaplasia,
  idiopathic myelofibrosis, myelofibrosis and
  myeloid metaplasia, or primary osteomyelofibrosis
• Clonal stem cell disorder involving a pluripotent
  hematopoietic stem cell resulting in disordered
  blood cell production, marrow fibrosis, and
  extramedullary hematopoiesis, most prominently
  involving the spleen, with eventual bone marrow
  failure or transformation to acute leukemia in
  some patients

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Causes of Myelofibrosis
Malignant
Acute leukemia (lymphocytic, myelogenous, megakaryocytic)
Chronic myelogenous leukemia
Hairy cell leukemia
Hodgkin disease
Primary myelofibrosis
Lymphoma
Multiple myeloma
Myelodysplasia
Metastatic carcinoma
Polycythemia vera
Systemic mastocytosis
Non-Malignant
HIV infection
Hyperparathyroidism
Renal osteodystrophy
Systemic lupus erythematosus
Tuberculosis
Vitamin D deficiency
Thorium dioxide exposure
Gray platelet syndrome
Thrombopoietin receptor agonists
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Diagnostic Criteria for Primary Myelofibrosis
Leukoerythroblastic blood picture
Increased marrow reticulin in the absence of an infiltrative or granulomatous process
Splenomegaly
JAK2V617F 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 (gt 15 x 106/L) and no increase in marrow CD34 cells by in situ immunohistochemistry
Characteristic 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)
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The Consequences of Polycythemia Vera
Consequence Cause
Thrombosis, 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)
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The Challenges of Treating Polycythemia Vera

• 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 chemotherapya
• In a prospective, controlled clinical trial of
  292 patients with PV, hydroxyurea did not prevent
  thrombosis or myelofibrosisb
• Hydroxyurea therapy was associated with a late (gt
  10 years) risk for transformation to acute
  leukemiab,c
• In a study of 40 patients with PV, pegylated
  interferon alfa-1a induced complete hematologic
  and molecular responses with low toxicityd

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The Complications of Polycythemia Vera and Their
Management
Complications Management
Erythrocytosis Phlebotomy (new JAK2 inhibitors)
Pruritus Antihistamines (new JAK2 inhibitors) pegylated interferon psoralens and ultraviolet-A light hydroxyurea
Erythromelalgia ocular migraine Aspirin anagrelide (new JAK2 inhibitors) pegylated interferon hydroxyurea
Thrombosis (arterial venous) Phlebotomy aspirin coumadin hydroxyurea (transient ischemic attack only)
Thrombocytosis (new JAK2 inhibitors) anagrelide pegylated interferon hydroxyurea
Hemorrhage Epsilon aminocaproic acid
Leukocytosis (new JAK2 inhibitors) pegylated interferon hydroxyurea
Hyperuricemia Allopurinol (uric acid 10 mg )
Splenomegaly (new JAK2 inhibitors) pegylated interferon thalidomide hydroxyurea imatinib splenectomy
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Effect of a JAK2 Inhibitor in 34 Patients With
Established PV (Phase 2 trial data)

• 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

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Complications of Essential Thrombocytosis Complications of Essential Thrombocytosis
Microvascular 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 disease Hemorrhage due to acquired von Willebrand disease
Transformation to acute leukemia Transformation to acute leukemia
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Treatment Is Not Always Required for Patients
With ET

• Thrombosis and hemorrhage are infrequent in
  patients with low-risk ET and the thrombosis rate
  was not different than normala,b
• Thrombosis in patients with ET reaches a plateau
  after 9 yearsa
• Cytoreduction did not change the complication
  rate of extreme thrombocytosisc
• The transformation of ET to high risk does not
  have an impact on overall survivala

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Management of Thrombocytosis in Essential
Thrombocytosis

• 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

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Effects of a JAK2 Inhibitor in 39 Patients With
Established Thrombocytosis (Phase 2 trial data)

• 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 gt 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

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Complications of Primary Myelofibrosis 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 infarction Incapacitating splenomegaly and splenic infarction
Portal hypertension Portal hypertension
Pulmonary hypertension Pulmonary hypertension
Organ 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 vascularity
Bone marrow failure with pancytopenia Bone marrow failure with pancytopenia
Acute leukemia Acute leukemia
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Management of Primary Myelofibrosis

• Low-risk patients under age 45 should be
  considered for marrow transplantation if a
  matched sibling donor is available
• High-risk patients up to age 65 may benefit from
  reduced-intensity conditioning marrow
  transplantationa
• Symptomatic anemia may respond to
  corticosteroids, recombinant erythropoietin,
  folate, danazol, or low-dose thalidomide, or
  possibly targeted JAK2 inhibitionb
• Constitutional symptoms respond to targeted JAK2
  inhibitionc
• Splenomegaly may respond to targeted JAK2
  inhibition, low-dose interferon, low-dose
  thalidomide and prednisone, or hydroxyureac
• Splenic irradiation is only palliative and
  temporary and is associated with severe
  neutropenia and infection
• Splenectomy is only palliative and can lead to
  exuberant hepatic extramedullary hematopoiesis or
  splanchnic vein thrombosis

a. Rondelli D, et al. Blood. 20051054115. b.
Mesa RA, et al. Blood. 20031012534. c.
Verstovsek S, et al. N Engl J Med. 20103631117.
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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