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