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Chronic Eosinophilia Leukemia (CEL), Keganasan PMN
- 1. Myeloproliferative disorders • Clonalhematopoiesis (stem cell disorder) • Marrow hypercellularity • Overproduction of one or more cell lines (effective hematopoiesis) – Exception: myelofibrosis • Differentiation nearly normal
- 2. The “common” bcr-ablnegative myeloproliferative disorders • Polycythemia vera • Essential thrombocythemia • Myelofibrosis/myeloid metaplasia
- 3. Less common conditions •Undifferentiated myeloproliferative disorder • Mast cell disease • Hypereosinophilic syndrome • Chronic neutrophilic leukemia • Myelodysplastic/myeloproliferative disorders – CMML – Atypical CML (BCR-ABL negative) – Juvenile CML – “Unclassifiable” MDS/MPD
- 4. JAK-2 • Tyrosine kinaseinvolved in signaling pathways initiated by EPO, TPO, G-CSF and other growth factors • V617F mutations in most cases of PV, ET, MF – Other JAK-2 mutations (exon 12, etc) in a minority of PV cases (almost all cases of PV have a JAK-2 mutation of some type) – Some cases of ET, MF lack JAK-2 mutation • Mutation releases cells from dependence on growth factors • Homozygosity for mutation seen mainly in P vera, associated with disease progression • Specific inhibitors of the kinase now in clinical trials
- 5. Structure-function relationships in theJAK2 receptor Science 2014; 344:703
- 6. In Panel A,in the absence of ligand, the erythropoietin receptor (EPOR) binds JAK2 as an inactive dimer. In cells with wild-type JAK2 protein, the binding of erythropoietin (Epo) to its receptor induces conformational changes in the receptor, resulting in phosphorylation (P) of JAK2 and the cytoplasmic tail of the receptor. This leads to signaling through pathways made up of Janus kinases and signal transducers and activators of transcription (JAK–STAT), phosphatidylinositol 3 kinase (PI3K), and RAS and mitogen-activated protein kinase (RAS–MAPK). In cells with the V617F mutation, the signaling is constitutively increased, even in the absence of erythropoietin. In Panel B, the JAK2 protein binds to multiple cytokine receptors — EPOR, thrombopoietin receptor (MPL), granulocyte colony-stimulating factor receptor (G-CSFR), and probably others — that are important for hematopoietic stem-cell biology and differentiation. Therefore, the JAK2 protein with the V617F mutation exerts its effects at various stages of differentiation and in various lineages. In Panel C, the development of homozygosity for the V617F mutation is a two-step process, with the initial point mutation followed by mitotic recombination of chromosome 9p between the JAK2 locus and the centromere. This results in the loss of heterozygosity but a diploid DNA copy number. NEJM 2006; 355:2452
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- 9. Polycythemia vera • ElevatedRBC mass, typically high platelets and WBC – Some patients present with thrombocytosis and develop erythrocytosis subsequently • Hypercellular marrow with variable degree of reticulin fibrosis – Morphology fairly normal, some clustering and dysmorphism of megas • Splenomegaly in 70%, constitutional sx, increased risk of arterial & venous thrombosis (esp portal vein), microvascular disease (erythromelalgia, pruritus, headache, etc), hypermetabolic sx & gout
- 10. Differential diagnosis oferythrocytosis • H&P – COPD or other possible causes of hypoxemia? – Smoker? – Splenomegaly, pruritus, erythromelalgia? • Concomitant thrombocytosis and/or leukocytosis? • Serum EPO • JAK-2 mutation testing
- 11. Polycythemia Vera Natural History •Life expectancy decreased (3 deaths/100 pts/yr) • Cardiovascular mortality increased 1.4x • Major thrombosis in 3/100pts/yr • Risk of death from leukemia increased 36- fold • Progressive myelofibrosis
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- 14. Oxygen delivery vsHematocrit 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 Hct Oxygen Transport J Clin Invest 1963;42:1150
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- 16. Thrombosis in myeloproliferativedisorders • 41% of deaths in PV from cardiovascular causes – 15% coronary dz – 8% CHF – 8% non hemorrhagic stroke – 8% PE • Complex pathophysiology – Abnormal RBC/WBC/plt function – Activated PMNs/cytokines affect vascular endothelium – Prothrombotic microparticle release – Increased whole blood viscosity
- 17. Risk factors forthrombosis in myeloproliferative disorders • Hx of thrombosis • Disease category (PV > ET, MF) • Cardiovascular risk factors (lipids, blood pressure, smoking, diabetes) • Age • OCP therapy (splanchnic vein clots) • JAK2 mutation status/allele burden • High hematocrit (PV) & WBC – Extreme thrombocytosis increases bleeding risk • Thrombophilic genetic traits?
- 18. Prothrombotic effects oferythrocytosis Barbui et al. Blood 2013;122:2176-2184
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- 20. Hematology 2005:201 Recommendations fortreatment of patients with polycythemia vera • Keep Hct < 45 (plebotomy) • Low dose ASA unless contraindicated • Manage reversible risk factors (BP, lipids, smoking) • Consider cytoreduction if: – Intolerant to phlebotomy – Thrombocytosis or substantial leukocytosis – Symptomatic splenomegaly • Choice of cytoreductive therapy: – Age < 40: Interferon-alpha – Age > 40: hydroxyurea – Anagrelide or busulfan for patients intolerant of, or not responsive to, above choices
- 22. Aspirin vs placeboin P vera
- 23. Essential thrombocytosis • Thrombocytosis(typically > 600K) with variable leukocytosis, normal RBC count • About 50% have JAK2 mutation • Normal to mildly hypercellular marrow with marked increase in megakaryocytes, often with clustering • Minimal reticulin fibrosis • Splenomegaly in about 50% • Many patients asymptomatic at diagnosis • Increased risk of arterial and venous thrombosis as well as hemorrhage
- 24. Thrombocytosis Differential diagnosis • Essentialthrombocythemia • Other MPD P vera Myelofibrosis CML • Myelodysplasia (5q- et al) • Reactive Inflammation Surgery/trauma Non-myeloid malignancy Iron deficiency Hemolysis Acute blood loss Absence of spleen Rebound following thrombocytopenia
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- 26. Essential Thrombocytosis Natural History •1-2 cases/100,000/yr • Most patients >50, but occurs in young adults • Woman more often affected than men • Life expectancy normal to slightly decreased • Patients > 60, or with prior thrombosis, at increased risk for thrombotic events • Very high platelet counts (>1.5 million) increase risk of bleeding, not thrombosis • Risk of myelofibrosis about 8% at 10 years • Risk of AML about 1% overall
- 27. Essential Thrombocytosis Treatment • Low-riskpatients (young, no vascular risk factors) may not require treatment • Aspirin decreases thrombotic events • Hydroxyurea • Anagrelide • Interferon • Other: busulfan (leukemogenic)
- 28. Hematology 2005:201 Recommendations fortreatment of patients with essential thrombocytosis • Manage reversible risk factors (BP, lipids, smoking) • If hx of thrombosis, or age >60, or plts > 1.5 million: – Hydroxyurea – Low dose ASA unless for plts > 1.5 m – 2nd line: Anagrelide or interferon-alpha • Age < 60, no other risk factors: – Low dose ASA
- 30. Myelofibrosis • 0.5-1.5 cases/100,000/yr •Most patients >60 • Marrow fibrosis with extramedullary hematopoiesis in spleen, liver, many other tissues – “Prefibrotic” stage with hypercellular marrow & abnormal megakaryocytes • Peripheral leukoerythroblastosis, teardrop cells, often with anemia. WBC and platelet counts may be high, normal or low • Splenomegaly, constitutional symptoms • Poor prognosis: marrow failure, AML in 5-30%
- 31. Improving survival inMF Median survival 6.5 yrs Median survival 4.5 yrs J Clin Oncol 2012;30:2981
- 32. DDx of MarrowFibrosis • Myeloproliferative disorders • MF > > P vera, ET, CML • Other heme neoplasm • Megakaryocytic leukemia • Hodgkins • Hairy cell leukemia • Non-heme cancer • Non-malignant conditions • Renal osteodystrophy • Autoimmune disease • Vitamin D deficiency
- 33. SPLENOMEGALY IN MYELOFIBROSIS MayoClin Proc 2004;79:503
- 34. Myelofibrosis Treatment • Supportive care –Transfusions – Splenectomy • Thalidomide/lenalidomide (low dose) – Reduce transfusion requirements, reduce spleen size • Chemotherapy (limited data; myelosuppression often dose-limiting) – Cladribine – Azacytidine/decitabine – Low dose cytarabine • Marrow transplant in selected patients • JAK inhibitor therapy: Ruxolitinib (inhibits JAK-1 and JAK-2)
- 35. Ruxolitinib treatment ofmyelofibrosis Spleens shrink Symptoms improve Better survival NEJM 2012;366:799
- 36. Eosinophilia • Non-clonal/secondary (common) •Clonal • Idiopathic hypereosinophilic syndrome • Familial (very rare) Mild: AEC 500-1500 Moderate: AEC 1500-5000 Severe: AEC > 5000
- 37. Hypereosinophilia (AEC > 5000) •Parasitic infection • Drug reaction • Allergic gastroenteritis • Eosinophilic fasciitis • Churg-Strauss syndrome • Pulmonary eosinophilia • Eosinophilia-myalgia syndrome • IL-2 therapy • Hyper-IgE syndrome • AML • Eosinophilic leukemia • Hypereosinophilic syndrome
- 38. Clinical manifestations of hypereosinophilia •Skin: pruritus, angioedema, ulcers, papular or nodular lesions • Heart: endocardial fibrosis, valvular disease, mural thrombi, cardiomyopathy, incr troponin • Lungs: infiltrates, nodules, pleural effusion • Neurologic: poly- or mononeuropathy, transverse myelitis, optic neuritis, CNS vasculitis • GI: hepatosplenomegaly, gastroenteritis, sclerosing cholangitis • Heme: marrow fibrosis, cytopenias • Kidney: thrombotic microangiopathy
- 39. Secondary Eosinophilia • Infection –Usually parasitic • Allergy – Asthma, allergic rhinitis, dermatitis, urticaria/angioedema, drug reaction • Autoimmune/inflammatory disorders (many) • Paraneoplastic – Solid tumors, lymphomas (Hodgkin>NHL) • Endocrinopathy – Adrenal insufficiency, growth hormone deficiency • Clonal T-cell disorder (→ IL-5) Most cases with IL-5 overproduction
- 40. Clonal Eosinophilia • Acuteleukemia (AML>ALL) • Chronic myeloid disorders – CML (bcr-abl) – Systemic mastocytosis (c-Kit) – 8p11 myeloproliferative disorder (FGFR-1) – PDGFRA and PDGFRB mutations – “Classic” MPD (JAK-2) – MDS – Chronic eosinophilic leukemia
- 41. Clonal eosinophilic disorderscaused by mutations in tyrosine kinase genes • PDGFRA, PDGFRB – May be cytogenetically silent→ FISH testing for dx – Marrow fibrosis, incr mast cells, elevated tryptase → variant of mast cell dz? – Male predominance – Imatinib-responsive (100-400 mg/d) • FGFR1 – Associated with 8p11 translocations – Stem cell disorder → aggressive MPD associated with T-lymphoblastic lymphoma – High dose chemotherapy + allo-HSCT
- 42. Chronic eosinophilic leukemia WHOdiagnostic criteria • Eosinophil count > 1500 • No Ph chromosome or BCR-ABL fusion • No PDGFRB, PDGFRA or FGFR1 rearrangement • Blast count in blood and marrow < 20% • No inv (16) or other variant characteristic of AML • Presence of clonal cytogenetic or molecular abnormality OR blasts >2% in blood or >5% in marrow
- 43. Idiopathic Hypereosinophilic Syndrome •Persistent moderate or severe eosinophilia (AEC > 1500) with end-organ damage • Other causes of eosinophilia ruled out • Male predominance • Can evolve into overt myeloid or lymphoid neoplasm • Potentially fatal – 10 yr survival < 50% • Treatment – Asymptomatic: corticosteroids vs watchful waiting – Symptomatic patients: corticosteroids, IFNα, hydroxyurea, imatinib, various myelosuppressive agents
- 44. Laboratory evaluation of hypereosinophilia •Marrow biopsy with cytogenetics • FISH for PDGFR mutations • Serum tryptase • T-cell immunophenotyping and gene rearrangement study • Serum IL-5 • Serum IgE • Screen for organ damage – Echo, troponin level – CXR, PFTs
- 45. Classification of MastCell Disease WHO classification and frequency in Mayo Clinic series • Indolent – often limited to skin (urticaria pigmentosa (46%) • Associated with myeloproliferative disorder (40%) • “Aggressive” mastocytosis – with lymphadenopathy & eosinophilia (12%) • Mast cell leukemia (1%) Blood 2009;113:5727
- 46. WHO Diagnostic Criteria forMast Cell Disease • Major: multifocal dense infiltrates of mast cells (15+) in marrow or other extracutaneous organs • Minor – >25% spindle shaped or otherwise atypical MC – c-KIT codon 816 mutation – MC in marrow or other extracutaneous organ express CD2 and/or CD25 – Serum tryptase persistently >20 ng/ml in the absence of another clonal myeloid disorder Diagnosis requires major + 1 minor criterion or at least 3 minor criteria
- 47. Stuff in mastcell granules that could make you sick Metcalfe, Blood 2008;112:946
- 48. Clinical & laboratoryfeatures of mast cell disease • Skin: Urticaria pigmentosa, Darier sign (dermatographism), telangiectasias • Lymphadenopathy • Hepatosplenomegaly • Constitutional symptoms • Recurrent anaphylaxis • GI symptoms (N/V, diarrhea, abd pain, peptic ulcer) • Elevated serum/urinary histamine levels • Elevated serum tryptase (96%) • Cytopenias • Eosinophilia • Coagulopathy (heparin in mast cells) – rare • Lytic or blastic bone lesions
- 49. Blood 2009; 113:5727 ISM: Indolent MCD SM-ANMD: associated with clonal non-mast cell lineage disease ASM: Aggressive MCD MCL: Mast cell leukemia
- 50. Mastocytosis in bonemarrow H&E Tryptase
- 51. Mastocytosis in bonemarrow
- 52. Skin findings inmast cell disease Dermatographism Telangiectasia macularis eruptiva perstans Urticaria pigmentosa
- 53. Molecular biology ofmast cell disease • A majority of patients have D816V mutation in c-KIT tyrosine kinase gene (imatinib-insensitive) – A minority have other mutations, may be imatinib-sensitive – Occasionally found together with JAK2 V617F • Some patients have eosinophilia & PDGFRA mutation (imatinib-responsive)
- 54. Treatment of mastcell disease • Antihistamines, PPIs • Vit D/Calcium, bisphosphonates • Glucocorticoids • Epinephrine (for anaphyactic reactions) • For aggressive disease: – Interferon – Imatinib (if there is an imatinib-sensitive mutation) • Other TKIs (dasatinib, nilotinib)? – Cladribine – Combination chemotheapy – Allo-HSCT
- 55. Survival of patientswith MCD Blood 2009; 113: 5727