L-18 Myeloproliferative Disorders

Introduction to Myeloproliferative Neoplasms (MPNs)

• MPNs are a group of clonal stem cell disorders characterized by excessive proliferation of myeloid cells.
• MPNs can be classified based on their molecular drivers.

Major Categories of MPNs

• BCR/ABL+ CML (Chronic Myeloid Leukemia) is a major category of MPNs.
• BCR/ABL- Classical MPNs including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF) form a major category of MPNs.
• Other MPNs include Chronic Neutrophilic Leukemia (CNL) and Chronic Eosinophilic Leukemia (CEL).

MPNs Key Clinical Features

• High symptom burden impacts quality of life.
• Increased thrombotic risk is a key clinical feature.
• Extramedullary hematopoiesis (EMH) leads to Hepatosplenomegaly.
• There is a risk of bone marrow fibrosis, which can progress to acute myeloid leukemia (AML).

Molecular Pathogenesis

• Classical MPNs are often driven by JAK-STAT pathway activation.
• Common mutations linked to molecular pathogenesis: JAK2, CALR, MPL
• Rare cases are triple-negative for common mutations.
• WHO classifies MPNs as clonal neoplastic disorders.
• Diagnosis requires a combination of molecular, clinical, and histological findings.

Somatic Mutations Present in MPNs

• JAK2 V617F mutations associated with JAK/stat signaling are seen in 95-97% of PV cases, 50-60% of ET cases, and 50-60% of MF cases.
• JAK 2 exon 12 mutations related to JAK/stat signaling are seen in 1-2% of PV cases, and are not observed in ET or MF.
• CALR mutations involving JAK/stat signaling are absent in PV, present in 25% of ET, and in 30% of MF cases.
• MPL mutations associated with JAK/STAT signaling are not seen in PV, observed in 3-5% of ET, and 5-10% of MF cases.
• CBL mutations related to JAK/STAT signaling are rare in ET and MF.

JAK Negative Disease

• In the absence of JAK2, CALR, and MPL mutations, the presence of another clonal marker is included as a major diagnostic criterion for PMF.
• Additional mutations in ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 genes are noted to be of use in determining the clonal nature of the disease.

MPNs Symptoms

• Fatigue presents in 81% of cases.
• Pruritus presents in 52% of cases.
• Night Sweats presents in 49% of cases.
• Bone Pain presents in 44% of cases.
• Fever presents in 14% of cases.
• Weight loss presents in 13% of cases.
• Early satiety presents in > 50% of cases.

Polycythemia Vera (PV): Diagnosis and Clinical Features

• PV is the most common myeloproliferative neoplasm (MPN) in the U.S.
• The annual incidence of PV is ~1.1 cases per 100,000 persons.
• There is a slight male predominance, with a median age at diagnosis in the ~ seventh decade.
• ~5% of PV cases occur in patients under 40 years old.
• Potential risk factors include radiation exposure, and environmental or toxic factors.

Hallmark Features of PV

• Increased red blood cell production.
• Thromboses.
• Constitutional symptoms such as fatigue, weight loss, and night sweats.
• Microvascular symptoms such as headache, dizziness, erythromelalgia.
• Splenomegaly is a hallmark feature.
• Potential progression to post-PV myelofibrosis (MF) or transformation to MPN-blast phase (MPN-BP).

Diagnosis of PV

• Requires differentiation from other causes of erythrocytosis.
• Diagnosis of PV includes elevated hematocrit.
• Absolute erythrocytosis involves increased total red cell mass.
• Relative erythrocytosis involves decreased plasma volume (e.g., dehydration).
• JAK2 V617F mutation present in ~95% of PV cases.

Differential Diagnosis of Erythrocytosis

• Primary causes include Polycythemia vera (PV).
• Relative causes include Intravascular volume depletion (e.g., diuretics, diarrhea).
• Secondary causes include Excess erythropoietin (EPO) production (e.g., tumors, renal disease).
• Hypoxia-driven erythrocytosis (e.g., lung disease, sleep apnea, smoking) can be a secondary cause.
• Androgen therapy or abuse can be a secondary cause.

Primary Familial and Congenital Erythrocytosis

• Primary Familial and Congenital Erythrocytosis presents via Autosomal-dominant inheritance.
• Low serum EPO levels are present.
• Genetic Causes include EPO receptor mutations (constitutive activation).
• VHL mutations (Chuvash-type polycythemia).
• HIF2A mutations (oxygen-sensing defect).
• PHD2 mutations (HIF2A degradation impairment).
• High-affinity hemoglobins (low P50 value on oxygen affinity testing).

Chuvash-Type Congenital Polycythemia

• Autosomal-recessive disorder first identified in Russia.
• Presents a High thrombotic and hemorrhagic risk.
• Mutations in von Hippel-Lindau (VHL) gene.
• Features Defective HIF1 degradation leading to upregulated EPO expression.

Differentiating PV from Secondary Erythrocytosis

• PV features JAK2 mutation (~95% cases).
• PV presents Low serum EPO levels.
• PV presents Risk of leukemic transformation and fibrosis.
• Secondary Polycythemia features High or normal EPO levels.
• Secondary Polycythemia has No risk of leukemic transformation.
• Secondary Polycythemia features Usually hypoxia-driven or EPO-producing tumor.

Clinical Management of PV

• Phlebotomy (goal hematocrit < 45%) is first-line therapy.
• Low-dose aspirin (to reduce thrombosis risk) is first-line therapy.
• Hydroxyurea is applied as Cytoreductive therapy for high-risk patients.
• Ruxolitinib (JAK2 inhibitor) is applied as Cytoreductive therapy for high-risk patients.
• Management of symptoms involves Antihistamines for pruritus.
• Cytoreduction for symptomatic splenomegaly is part of symptom management.

Management of Secondary Erythrocytosis

• Identify and treat underlying cause.
• Phlebotomy is only applied when necessary for symptomatic hyperviscosity.
• There is No established hematocrit goal.
• Avoid unnecessary phlebotomy in cases of compensatory erythrocytosis.

Summary PCV

• PV is a clonal MPN with increased red blood cell production.
• Differentiation from secondary erythrocytosis is essential.
• JAK2 mutation testing plays a key role in diagnosis.
• Treatment includes phlebotomy, aspirin, and cytoreduction in high-risk cases.
• Prognosis varies; there is a risk of progression to myelofibrosis or acute leukemia.

PCV WHO Diagnostic Criteria (2016)

• Major Criteria: Hemoglobin >16.5 g/dL (men) or > 16 g/dL (women) OR Hematocrit >49% (men) or >48% (women).
• Presence of JAK2 V617F or JAK2 exon-12 mutation.
• Bone marrow biopsy showing hypercellularity, panmyelosis, and increased pleomorphic megakaryocytes.
• Minor Criterion: Subnormal serum erythropoietin (EPO) levels.
• Diagnosis requires all 3 major criteria or the first 2 major criteria plus the minor criterion.

2017 WHO Diagnostic Criteria for Polycythemia Vera

• Hemoglobin >16.5 g/dL in men, >16.0 g/dL in women or Hematocrit >49% in men, >48% in women or Increased red cell mass are all Major criteria.
• Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes.
• Presence of JAK2 V617F or JAK2 exon 12 mutation is a major diagnostic criteria.
• Subnormal serum EPO level represents a minor criteria for diagnosis.

Differential Diagnosis of Polycythemia Vera

• Primary causes include PV.
• Secondary causes includes Hypoxia-driven or pathologic EPO production.
• Relative causes includes Dehydration, diuretics, and plasma volume contraction.
• An Evaluation includes JAK2 testing, EPO levels, and bone marrow biopsy.

Disease Course and Prognosis of Polycythemia Vera

• Early Phase includes Increased hematocrit, risk of thrombosis, and vasomotor symptoms.
• Progression includes Possible evolution to myelofibrosis or acute leukemia.
• Prognostic Factors include Age, leukocytosis, thrombosis history, JAK2 allelic burden, and additional mutations (ASXL1, IDH, SRSF2).
• Life expectancy ranges from 11 to 28 years depending on risk stratification.

NCCN Guidelines Version 1.2024 Myeloproliferative Neoplasms

• Polycythemia Vera Advanced age (ie, >60 years) and history of thrombosis are the most consistent risk factors associated with thrombosis risk.
• In an ECLAP trial cohort of 1638 patients with PV, age >65 years and a previous history of thrombosis were the two most important prognostic factors associated with an increased risk of cardiovascular events, resulting in three risk groups.
• Low-risk is composed of patients <65 years and no prior history of thrombosis.
• Intermediate-risk is composed of patients <65 years with prior thrombosis or age ≥65 years without prior thrombosis.
• High-risk is composed of patients ≥65 years with prior thrombosis.
• Use of age ≥60 years or history of thrombosis is agreed upon as prognostic factors for thrombosis risk.

Risk Stratification for patients with Polycythemia Vera

• Thrombosis History equates to 1 risk point.
• Leukocyte count greater than 15 equates to 1 risk point.
• Age greater than 67 equates to 2 risk point.
• Adverse mutations (SRSF2) equates to 3 risk points.

Risk Stratification for patients with Polycythemia Vera (Categories)

• Low: 0-1 points.
• Intermediate: 2-3 points.
• High: >4 points.

Thrombotic and Hemorrhagic Risks

• Thrombosis is a major cause of morbidity/mortality.
• There are 5.5 thrombosis events per 100 patients per year (ECLAP study).
• Risk factors for thrombosis include age >65, prior thrombosis, and cardiovascular comorbidities.
• Arterial incidents (strokes, MI) are greater than Venous incidents (DVT, PE).
• Bleeding Risk is lower than thrombosis but multifactorial.
• Extreme thrombocytosis may lead to acquired von Willebrand disease.
• Anticoagulants/antiplatelets may increase bleeding risk.

Post-PV Myelofibrosis (Post-PV MF)

• Develops in long-standing disease (>10 years).
• Signs include Anemia, thrombocytopenia, splenomegaly, and worsening symptoms.
• Risk factors include Leukocytosis, high JAK2 burden, bone marrow fibrosis, and additional mutations.

MPN-Blast Phase (MPN-BP)

• Defined as >20% blasts in bone marrow or peripheral blood.
• Transformation occurs in 1-3% of patients.
• There is a Higher risk with alkylating agents, phosphorus-32 therapy.
• Associated with additional somatic mutations (ASXL1, IDH1/2, SRSF2).

Hematocrit Control

• Phlebotomy is first-line therapy, goal Hematocrit <45% (CYTO-PV study).
• Over-phlebotomy may lead to iron deficiency and reactive thrombocytosis.
• Cytoreductive therapy is considered in high-risk patients (age >60, thrombosis history).

Antiplatelet Therapy

• Low-dose aspirin (100 mg/day) reduces thrombosis and cardiovascular death (ECLAP study).
• Higher doses (>500 mg/day) increase bleeding risk without additional benefit.
• Clopidogrel and newer agents are not well-studied in PV.

Cytoreductive Therapy

• Cytoreductive Therapy is Indicated for high-risk patients or those intolerant to phlebotomy.
• Hydroxyurea (HU) is a first-line cytoreductive agent that reduces thrombosis risk.
• Interferon-alpha is considered for younger patients, pregnancy, or HU intolerance.
• JAK inhibitors (e.g., ruxolitinib) are used in refractory cases with symptomatic splenomegaly.

Hydroxyurea

• Hydroxyurea lowers lowers thrombosis rates compared to phlebotomy alone.
• Lower risk of secondary leukemia vs. chlorambucil and 32P.
• Utilized in conditions like polycythemia vera (PV) and sickle cell disease.
• Potential mutagenic and leukemogenic effects.
• AML/MDS risk lower than other cytoreductive agents.
• Avoided in younger adults due to long-term risks.

Interferons as an Alternative Therapy

• Recommended for younger patients needing cytoreduction.
• Control erythrocytosis, leukocytosis, and thrombocytosis.
• Pegylated IFNa shows clinical and molecular remission.
• IFNa is safe in pregnancy.

JAK2

• Intracellular signaling linked to the cell surface domain leads to the removal of inhibition in kinase domain regions.
• Removal of inhibition of kinase domain regions causes the proliferation of white blood cells (WBC), hemoglobin (HGB), and platelets (PLT).

JAK Inhibition (Ruxolitinib)

• Used for HU-resistant or intolerant patients.
• The RESPONSE trial showed improved spleen volume reduction & hematocrit control.
• Adverse effects can include weight gain, increased cholesterol, skin cancer risk, and infections (zoster).

Essential Thrombocythemia (ET)

• Essential Thrombocythemia has a prevalence similar to PV (~150,000 cases in the U.S.).
• There are ~0.5 to 1.5 cases per 100,000 persons annually.
• Median age at diagnosis: mid-seventies, but broad distribution.
• Predominantly affects women.
• Main complications: thrombotic, vasomotor, and hemorrhagic.
• There is a Long-term risk of progression to post-ET myelofibrosis (MF) or MPN blast phase.

Diagnosis of ET

• Primary vs. secondary thrombocytosis must be investigated.
• Common secondary causes include Iron deficiency, infection, inflammation, malignancy as well as Surgery, trauma, and infarction.
• ET must be distinguished from other myeloproliferative neoplasms (MPNs) such as Occult PV, PMF, CML, MDS with thrombocytosis , and Hereditary thrombocytosis from germline MPL, and JAK2 mutations.

WHO 2016 Diagnostic Criteria for ET

• Sustained platelet count ≥450 × 10^9/L.
• Bone marrow biopsy findings include proliferation of megakaryocytes with hyperlobulated nuclei and minimal reticulin fibrosis.
• Exclusion of PV, PMF, CML, MDS, or another myeloid neoplasm.
• Presence of JAK2 V617F, CALR, or MPL mutation.
• The presence of a clonal marker or exclusion of reactive thrombocytosis.
• Diagnosis requires all four major criteria or the first three major criteria plus the minor criteria.

Blood & Bone Marrow Findings in ET

• Peripheral Blood Smear analysis shows large/giant platelets, occasional eosinophils, basophils, or megakaryocyte fragments.
• Bone Marrow Features: Increased clusters of large megakaryocytes with hyperploid nuclei.
• Normocellular or mildly hypercellular marrow can be expected
• Minimal or absent reticulin and collagen fibrosis can be observed.
• Presence of >15% ring sideroblasts suggests MDS/MPN RS-T rather than ET.

Essential Thrombocythemia: Disease Course and Prognosis

• Essential thrombocythemia (ET) presents a broad spectrum of disease progression.
• While some patients experience near-normal life expectancy, others suffer from significant morbidity due to vascular complications or disease transformation.
• ET is often mistakenly thought to be asymptomatic; patients experience vascular, vasomotor, and cytokine-related symptoms affecting their quality of life
• Up to 30% of ET patients experience a thrombotic event before or at the time of diagnosis.
• Risk of thrombosis is significantly elevated in ET compared to the general population, particularly in the first five years post-diagnosis.
• Risk factors include older age, history of thrombosis, cardiovascular comorbidities, and JAK2 mutation.
• Risk stratification using the revised IPSET-thrombosis score helps predict thrombotic risk.

Essential Thrombocythemia Disease Progression

• Approximately 10% of ET patients develop post-ET MF within 15 years.
• Indicators of progression include increasing spleen size, development of anemia, Elevated LDH levels, and Bone marrow fibrosis.
• Mutations in CALR, SH2B3, SF3B1, U2AF1, TP53, IDH2, or EZH2 increase the risk of MF progression.
• Direct progression to MPN-BP without an intervening MF phase is rare (~2% at 15 years).
• Risk factors include adverse mutations (TP53, IDH2, EZH2, etc.).

Survival in ET

• Predictors of survival include age, leukocytosis, and history of vascular events.
• While life expectancy is reduced compared to age-matched controls, median survival is approximately 20 years.
• Driver mutations do not significantly impact survival, but adverse variants correlate with worse prognosis

Management of ET

• Symptom relief.
• Thrombosis and hemorrhage prevention.
• Delay or prevent disease transformation (currently not achievable with medical therapy) can be a goal.
• Aspirin is selectively used based on vascular risk factors and symptoms.
• CALR-mutant ET patients may have increased bleeding risk with aspirin.
• Extreme thrombocytosis (>1500 × 10^9/L) raises concern for acquired von Willebrand disease, requiring caution with aspirin use.
• Cytoreduction Therapy is Recommended for high-risk patients or those with significant ET-related symptoms.
• Hydroxyurea (HU): First-line therapy in high-risk patients, reducing thrombotic events.
• Anagrelide is an alternative cytoreductive agent, with varying recommendations for frontline vs. second-line use.
• Interferons (IFN-a, pegylated IFN): Effective in hematologic and molecular response, considered safe in pregnancy.
• JAK inhibitors (Ruxolitinib): Showed symptomatic benefits but no significant impact on thrombosis or disease progression.

Myelofibrosis characteristics

• Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder characterized by bone marrow fibrosis.
• Several subtypes of MF exist: Prefibrotic MF, Overt Primary MF (PMF), Post-ET MF (evolved from Essential Thrombocythemia), Post-PV MF (evolved from Polycythemia Vera).

Epidemiology of Myelofibrosis

• Incidence: 0.2 to 0.5 cases per 100,000 persons per year.
• Median Age of Diagnosis: ~65 years.
• 70% of patients are diagnosed after age 60.
• Approximately 10% of patients are diagnosed at <45 years.
• There is a Higher incidence in older populations.

Diagnostic Criteria for Myelofibrosis

• Bone Marrow Morphology is Essential for diagnosis.
• Reticulin fibrosis.
• Leukoerythroblastosis (immature blood cells).
• Driver mutations are found in ~90% of cases via Cytogenetics/Molecular Abnormalities.
• Clinical Findings include Spleen size (Hepatosplenomegaly) and Blood tests (cytopenias).

Subtypes of Myelofibrosis

• Prefibrotic MF: Early stage, may resemble other diseases, and often involves megakaryocyte atypia.
• Overt Primary MF: More advanced, with extensive fibrosis and leukoerythroblastosis and includes clonal mutations in 90% of cases.
• Post-ET and Post-PV MF: Develops after Essential Thrombocythemia or Polycythemia Vera.

Differential Diagnosis of Bone Marrow Fibrosis

• Other Diseases Leading to Fibrosis: MDS (Myelodysplastic Syndromes), Acute Leukemias, Lymphomas, Chronic Myelogenous Leukemia (CML), Multiple Myeloma, and Metastatic Carcinoma.
• Also, Infections (Tuberculosis, viral or fungal infections) and Autoimmune Diseases can feature Bone morrow fibrosis.

Myelofibrosis Manifestations

• Leukocytosis and Thrombocytosis can feature Elevated white blood cells and platelets, similar to ET and PV.
• Low Blood Cell Counts include anemia, thrombocytopenia, and/or leukopenia.
• Atypical Megakaryocytes feature Clustering and irregularly folded hyperchromatic nuclei seen in both prefibrotic and overt MF.
• Accumulation of extracellular fibers in Reticulin fibers and Collagen fibers.
• Advanced stages show complete replacement by fibroblasts, causing "dry tap" during marrow aspiration are characteristic.

Bone Marrow Fibrosis and Cytokines

• Fibrosis Mechanisms: Proliferation of fibroblasts and mesenchymal cells driven by Inflammatory cytokines and Megakaryocyte and monocyte-derived growth factors.
• Increased Cytokine Levels: IL-1 and TNF-alpha contributing to fibroblast activation.
• Egress of CD34+ Cells: Circulating CD34+ cells up to 50 times higher than in PV or ET.
• Associated with Bone Marrow Fibrosis: Higher CD34+ levels correlate with more advanced fibrosis.
• Extra-medullary Hematopoiesis (EMH) can occur in liver, spleen, and rarely in sites like vertebrae, lungs, or kidneys.

Differential Diagnosis of Myelofibrosis

• Conditions to Rule Out: Acute panmyelosis with myelofibrosis, MDS with fibrosis, and Late-stage PV, ET, CML.
• Also, Hairy cell leukemia, lymphoma, plasma cell dyscrasias, infections, multiple myeloma, and metastatic carcinoma must be ruled out.

Clinical Features and Disease Course in Myelofibrosis

• Symptoms: Fatigue, Fever, night sweats, weight loss, pruritus, bone and muscle pain, and Splenomegaly.
• Portal hypertension, ascites, and EMH-related complications may occur.
• Patients often die in chronic MF phase.
• Up to 30% may progress to MPN-BP.

Complications in Myelofibrosis

• Thrombosis or bleeding may occur.
• Bone Marrow Failure: Infection, anemia, and transfusion dependence.
• Transformation to MPN-BP can often prove fatal.
• Pulmonary Hypertension is often under-recognized but important.

Management and Prognosis of Myelofibrosis

• Palliation of Symptoms: Reducing the burden of fatigue, spleen-related discomfort, and other symptoms.
• Treatment Options: Targeted therapies, bone marrow transplantation, and symptom management.
• Prognosis: Chronic MF phase with management aimed at improving quality of life.

Treatment of Anemia in MF

• Lusparercept– FDA approval.
• Danazol-~30% RR.
• ΕΡΟ ~ 45-60% RR.
• Revlimid-prednisone ~34% RR.
• Pomalidomide ~34% RR.

Chronic Eosinophilic Leukemia, Not Otherwise Specified (CEL-NOS)

• A rare myeloproliferative neoplasm.
• More common in men than women.
• Peak incidence in the 4th decade, but can occur at any age, including childhood.
• Exact incidence is unknown

Clinical Features of Chronic Eosinophilic Leukemia

• Common Symptoms include Fever, fatigue, cough, pruritus, diarrhea, angioedema, and muscle pain.
• End-Organ Damage may affect the Cardiac, Nervous System, Pulmonary, Skin, and Gastrointestinal systems.

Diagnostic Criteria for CEL-NOS (WHO)

• Eosinophilia: >1.5 × 10^9/L.
• Clonal Cytogenetic/Molecular Abnormality: or Blasts >2% in peripheral blood or >5% in bone marrow.
• Exclusion Criteria: No BCR-ABL1, PDGFRA/PDGFRB, FGFR1, PCM1-JAK2 rearrangements.
• Bone marrow blasts <20%.
• Idiopathic Hypereosinophilic Syndrome (HES) must be ruled out.

Myeloproliferative Neoplasm, Unclassifiable (MPN-U)

• A diagnostic term for patients who meet the clinical, laboratory, and morphologic criteria of myeloproliferative neoplasms (MPNs) but do not fit the characteristics of any single MPN entity.
• Clinical presentation may have overlapping features of 2 or more MPNs.
• Exclusion of BCR-ABL1, PDGFRA/PDGFRB/FGFR1/PCM1-JAK2 rearrangements confirms MPN-U.
• Key Molecular Tests: BCR-ABL1 fusion excludes Chronic Myeloid Leukemia and also PDGFRA, PDGFRB, FGFR1, PCM1-JAK2 rearrangements exclusion Other specific MPNs like Chronic Eosinophilic Leukemia (CEL) or Systemic Mastocytosis.
• Cases of in MPN-U are expected to decrease as molecular diagnostic features are increasingly recognized.

Clinical Features of MPN-U

• Variable Presentations: Early Disease presents with minimal organomegaly and well-preserved peripheral blood counts.
• The disease is diagnosed by excluding presence of BCR-ABL1 or specific mutations involving PDGFRA or PDGFRB.
• Advanced Disease: Massive organomegaly, extensive myelofibrosis, and severe cytopenias can happen
• Initial Symptoms are Unexplained portal or splanchnic vein thrombosis.

Clinical Course and Prognosis of MPN-U

• Heterogeneous Course: The Early-stage disease can actively observe.
• The disease course becomes aggressive in the Later Stages.
• Prognosis: Early Stage presents with good prognosis.
• Advanced Stage presents with Poor prognosis because of aggressive clinical course and complications.

Management of MPN

• For Early Disease Management, observation is often sufficient.
• Advanced Disease Management involves treating complications like thrombosis, cytopenias, and organomegaly.
• Supportive Care involves blood transfusions and potential use of targeted therapies.

Differentiation from Other MPNs

• Chronic Myeloid Leukemia (CML) is differentiated by BCR-ABL1 fusion
• Polycythemia Vera (PV) is differentiated by JAK2 mutations.
• Essential Thrombocythemia (ET) is differentiated by JAK2, CALR, and MPL mutations.
• Myelofibrosis is differentiated by Features of fibrosis with JAK2, CALR.
• Idiopathic Hypereosinophilic Syndrome (HES) is differentiated via Exclusion of specific molecular markers.