Myeloproliferative Disorders / Neoplasms Intro for the Internist Satish Shanbhag MBBS, MPH Assistant Professor of Medicine and Oncology Johns Hopkins University School of Medicine.download report
Transcript Myeloproliferative Disorders / Neoplasms Intro for the Internist Satish Shanbhag MBBS, MPH Assistant Professor of Medicine and Oncology Johns Hopkins University School of Medicine.
Myeloproliferative Disorders / Neoplasms Intro for the Internist
Satish Shanbhag MBBS, MPH Assistant Professor of Medicine and Oncology Johns Hopkins University School of Medicine
Internist focused review of the presentation, diagnostic workup, treatment and prognosis of the common myeloproliferative neoplasms
Stem Cell Basis of Hematopoiesis
Stem cells Progenitors Blood Normal Myeloproliferative disease
The Chronic Myeloproliferative Disorders
• • • Acquired hematopoietic stem cell disorders 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 Polycythemia vera Essential thrombocythemia Primary myelofibrosis • • Chronic Eosinophilic leukemia Systemic Mastocytosis
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
P 210 FUSION PROTEIN WITH CONSTITUTIVE 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%
• Common symptoms: – fatigue – weight loss/anorexia – Early satiety – asymptomatic in ~ 50% • Common signs: – palpable splenomegaly – basophilia •
Accelerated Phase and Blast crisis
More aggressive disease with increased blasts and poorer prognosis
Faderl et al. Ann Intern Med. 1999;131:207. Goldman. Curr Opin Hematol. 1997;4:277.
CML: Pre-Imatinib Survival
0 0 1 5 mo 28 mo CML Phase Chronic Accelerated Blastic Total 2449 479 285 Dead 1043 276 219 2 3 4 5 Years from referral 6 71 mo 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
JAK2 V617F in Myeloid Disease One mutation, many phenotypes
PV ET PMF
JAK2 V617F Prevalence
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
Signal transduction lesions in the MPN JAK2 G5073770T JAK2 V617F
Scott, et al Lancet 2005
JAK2 V617F : phenotypes of disease JAK2V617F ET Transition between phenotypes common with latency period of decades PMF PV
Bone Marrow Biopsy Normocellular bone marrow
Bone Marrow Biopsy Hypercellularity and clustering of atypical megakaryocytes
Why is he erythrocytotic?
• • • 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
1. Increased red cell mass Males: ≥36 mL/kg Females: ≥32 mL/kg 2. Arterial oxygen saturation ≥92 % 3. Splenomegaly
1. Platelet count >400,000/microL 2. White blood cell count >12,000/microL* 3. Serum vitamin B12 >900 pg/mL
Low serum epo levels JAK 2 V617F mutation Pancytosis Bone Marrow panmyelosis
Objectives of therapy
Symptom control – prevent pruritus, headaches 2.
Prevent thromboses 1.
Phlebotomy (goal Hct <45% men or <42% female ) Aspirin 81 mg po qd Cytoreductive agents such as hydroxyurea
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
• 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
• 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, 1193 –1202
Blood smear in PMF
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
ET PV PMF AML Hopkins500: Natural History Diagnosis 10 years 20 years N=405 N=283 slide courtesy Dr.Alison Moliterno N=57
• Dr. Doug Smith and Dr.Alison Moliterno for sharing slides and images