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

Vardiman JW, et al. Blood. 2009;114:937..

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 Thrombocytosis

Primary Myelofibrosis

Polycythemia Vera

AcuteLeukemia

“Isolated Thrombocytosis”

Reprinted from Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol. 2008;19(4): 385-393, with permission from Elsevier.

Cytokine Receptors Utilizing Janus Family Kinases

Pluripotent Hematopoietic

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 (+/+) Higher Fewer 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 proliferationJAK2V617F is not present in some patients with familial polycythemia veraJAK2V617F can arise as a secondary event in clones expressing a cytogenetic abnormality or another mutationLeukemic transformation in patients with JAK2V617F-positive MPD can occur in a JAK2V617F-negative type cellBUT: 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 altitudePulmonary diseaseRight-to-left shuntsSleep apnea syndromeNeurologic disease

Renal Disease

Renal artery stenosis Focal sclerosing or membranous

glomerulonephritisRenal transplantation

Tumors

HypernephromaHepatomaCerebellar hemangioblastomaUterine fibromyomaAdrenal tumorsMeningiomaPheochromocytoma

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 therapyRecombinant erythropoietin therapyHypertensionTobacco use PheochromocytomaEthanol abuseSleep apnea

Only ~5 % of patients with absolute erythrocytosis are likely to have polycythemia vera

Major criteria

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 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 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.

Tefferi A, et al. Blood. 2007;110;1092.

Proposed Revised WHO Criteria for Polycythemia Vera

Red cell mass and plasma volume measurements

Elevated red cell mass

Tobacco useAndrogensDiureticsPheochromocytoma

Hypoxic erythrocytosisJAK2V617F

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

Spivak JL, Silver RT. Blood. 2008;12:231..

+

O2 saturationNormal 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

Spivak JL, Silver RT. Blood. 2008;112:231..

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

*Patients with MPD represent only a minority of patients with thrombocytosis in general but constitute most of those with persistent thrombocytosis in the absence of a definable cause.

Primary Myelofibrosis

MalignantAcute leukemia (lymphocytic, myelogenous, megakaryocytic)

Chronic myelogenous leukemia

Hairy cell leukemiaHodgkin diseasePrimary myelofibrosisLymphomaMultiple myelomaMyelodysplasiaMetastatic carcinomaPolycythemia veraSystemic mastocytosis

Causes of Myelofibrosis

Non-MalignantHIV infection

Hyperparathyroidism

Renal osteodystrophySystemic lupus erythematosusTuberculosisVitamin D deficiencyThorium dioxide exposureGray platelet syndromeThrombopoietin receptor

agonists

Spivak JL, Silver RT. Blood. 2008;112:231..

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)

Survival in Polycythemia Vera

Reprinted from Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004;117(10):755-761, with permission from Elsevier.

Survival curves of 396 patients with polycythemia vera compared with life expectancy of the general population

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]

a. GISP. Ann Intern Med. 1995;123:656. b. Najean Y, et al. Blood. 1997;90:3370. c. Thoennissen NH, et al. Blood. 2010;115:2882. d. Kiladjian JJ, et al. Blood. 2008;112:3065.

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%

Verstovsek S, et al. ASH 2010. Abstract 313.

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

Survival in Essential ThrombocytosisSurvival curves of 435 patients with essential thrombocythemia compared with life expectancy of the general population

Reprinted from Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004;117(10):755-761, with permission from Elsevier.

Treatment Is Not Always Required for Patients With ET

a. Alvarez-Laran A. et al. Blood. 2010;116:1205. b. Ruggeri M, et al. Br J Haematol. 1998;103:772. c. Tefferi A, et al. Blood. 2006;108:2493.

• 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%

Verstovsek S, et al. ASH 2010. Abstract 313.

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

Complications of Primary MyelofibrosisAnemia • Hypoproliferative due to folate or iron deficiency,

inflammation, autoimmune hemolysis, hemodilution, or impaired stem cell function

Thrombocytopenia • Splenic sequestration, impaired stem cell functionIncapacitating 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

Cervantes F, et al. Br J Haematol. 1998;102:684.

Survival in Primary Myelofibrosis

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.

Constitutional Symptoms in PMF

Spleen Size in PMF

Effects of Nonselective JAK2 Inhibitors

PMF = primary myelofibrosisVerstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117-1127. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

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