Myeloproliferative Disorders / Neoplasms Intro for the Internist Satish Shanbhag MBBS, MPH Assistant Professor of Medicine and Oncology Johns Hopkins University School of Medicine Objectives Internist focused review of the presentation, diagnostic workup, treatment and prognosis of the common myeloproliferative neoplasms
Disclosures None Stem Cell Basis of Hematopoiesis Stem cells Progenitors Blood Normal
characterized by overproduction of one or more of the formed (mature) elements of the blood Complicated by bone marrow expansion, extramedullary hematopoiesis (liver, spleen, l.n) , myelofibrosis and transformation to acute leukemia Transition between phenotypes common with latency period of decades The Big 4
Chronic Myeloid Leukemia Unregulated proliferation of myeloid cells in the bone marrow and accumulation of these cells in the blood Increased mature granulocytes (neutrophils, eosinophils and basophils) and their precursors in the blood Characteristic chromosomal translocation
called the Philadelphia chromosome Bcr-abl translocation detectable in the blood by karyotyping, FISH or PCR. Ph Chromosome bcr-abl gene Chromosome 9 q+ Chromosome 9 Philadelphia Chromosome (or 22q-) Chromosome 22
bcr-abl bcr P 210 FUSION PROTEIN WITH CONSTITUTIVE abl TYROSINE KINASE ACTIVITY Melo. Blood. 1996;88:2375. Pasternak et al. J Cancer Res Clin Oncol. 1998;124:643.
Typical presentation of chronic phase CML CML: Clinical Presentation Chronic Phase ~ 85% Accelerated Phase and Blast crisis Common symptoms:
fatigue weight loss/anorexia Early satiety asymptomatic in ~ 50% More aggressive disease with increased blasts and poorer prognosis
Common signs: palpable splenomegaly basophilia Faderl et al. Ann Intern Med. 1999;131:207. Goldman. Curr Opin Hematol. 1997;4:277. CML: Pre-Imatinib Survival Cumulative proportion surviving 1.0 0.9 0.8
0.7 CML Phase Total Dead Chronic Accelerated Blastic
2449 479 285 1043 276 219 0.6 0.5 5 mo
28 mo 71 mo 0.4 0.3 0.2 0.1 0 0
1 2 3 4 5 Years from referral
6 7 8 Imatinib Mesylate Targeted therapy in cancer BCR-Abl tyrosine kinase enzyme exists only in clonal cancer cells and not in normal patient cells
Imatinib is a Tyrosine-kinase inhibitor which prevents the BCR-Abl enzyme product from initiating the signalling cascade necessary for cancer development, thereby causing cancer cell apoptosis More POTENT TKIs Nilotinib, Bosutinib, Dasatinib, Ponatinib have subsequently been developed. Bone marrow / stem cell transplant for select patients Survival in newly diagnosed CP-CML by year of therapy.
Kantarjian H et al. Blood 2012;119:1981-1987 2012 by American Society of Hematology DASATINIB JAK2 V617F in Myeloid Disease One mutation, many phenotypes Disease JAK2 V617F Prevalence
PV ET PMF 97% 60% 60% Janus kinase 2 (JAK2), is a gene on the short
arm of chromosome 9 that encodes for a cytoplasmic tyrosine kinase A mutation in the JAK2 gene leads to constitutive tyrosine phosphorylation activity that promotes hypersensitivity to cytokines / growth factors and induces epo-independant erythrocytosis. Signal transduction lesions in the MPN JAK2 G5073770T JAK2V617F
Scott, et al Lancet 2005 JAK2V617F : phenotypes of disease JAK2V617F ET Transition between phenotypes common with latency period of decades
PV PMF Bone Marrow Biopsy Normocellular bone marrow http://serpins.med.unc.edu/~fcc/Biology134_Folder/hem_cd/Large/05/0518.jpg Bone Marrow Biopsy Hypercellularity and clustering of atypical megakaryocytes
Polycythemia Vera Why is he erythrocytotic? Polycythemia Vera Elevated totally body red cell mass; Hgb, Hct are surrogate markers
Rule out dehydration, epo driven erythrocytosis Chronic disease with median survival of > 15-20 years with current therapy Diagnostic Criteria for PV (PVSG) Major criteria Minor criteria 1. Increased red cell mass 1. Platelet count >400,000/microL
Low serum epo levels JAK 2 V617F mutation Pancytosis Bone Marrow panmyelosis Objectives of therapy 1. Symptom control prevent pruritus, 2. headaches
Prevent thromboses 1. Phlebotomy (goal Hct <45% men or <42% female ) 2. Aspirin 81 mg po qd 3. Cytoreductive agents such as hydroxyurea Essential Thrombocythemia ET secondary myelofibrosis Essential Thrombocythemia
Chronic non-reactive thrombocythemia that does not fit criteria for other MPNs Headache Syncope Atypical chest pain Livedo reticularis
Erythromelalgia (burning pain of the hands or feet associated with erythema and warmth) 60% patients positive for JAK2 V617F Treatment Young low risk patients may not need any therapy or just a baby aspirin daily Higher risk patients (those with prior h/o clots or elderly) benefit from cytoreduction with
Anagrelide or Hydroxyurea n engl j med 353;1 july 7, 2005 Thrombocytosis and Acquired VW syndrome Primary Myelofibrosis Megakaryocyte proliferation and atypia, usually accompanied by reticulin and/or collagen deposition in the marrow Demonstration of a clonal marker (eg, JAK2 or MPL)
Leukoerythroblastosis on smear does not met criteria for other MPN Splenomegaly Anemia Bone marrow in PMF Modern Pathology (2012) 25, 11931202 Blood smear in PMF http://imagebank.hematology.org/Content%5C969%5C1180%5C1180_full.JPG
PMF / secondary myelofibrosis PMF carries the worst prognosis among the MPNs, although survival is still measured in years PV and ET can show gradual progression to secondary myelofibrosis over decades Therapies for PMF
Bone marrow transplant is the only cure Ruxolitinib (JAK inhibitor) is a recently approved drug for treating symptomatic PMF that also reduces splenomegaly Hydroxyurea, Thalidomide and its derivatives have also been studied but not FDA approved Hopkins500: Natural History Diagnosis
10 years N=405 N=283 20 years ET PV PMF
AML slide courtesy Dr.Alison Moliterno N=57 Thanks Dr. Doug Smith and Dr.Alison Moliterno for sharing slides and images
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