Acute leukemias and myeloproliferative neoplasms GERGELY SZOMBATH SEMMELWEIS UNIVERSITY OF MEDICINE IIIRD. DEPARTMENT OF INTERNAL MEDICINE
Basics of acute leukemia Neoplastic disease Cell of origin is an immature myeloid or lymphoid precursor cell
Basics of acute leukemia Demography
Symptoms Acute onset of symptoms Bleeding (petechiae, gum, hematuria, hematochesia, melaena) Fever (from blast activity, from neutropenic infection) Fatigue (anaemia) Neurologic symptoms (intracranial bleeding, hyperviscosity) Bone pain
3 pillars of diagnosis Morphology Immunchemistry, immunophenotyping Cytogenetics, molecular biology
AML Cells of origin
Flow cytometry
Flow cytometry Dot-plot
Flow cytometry Dot-plot
Cytogenetics Karyogram, FISH
Diagnostic criteria 20% blasts in the bone marrow or in the peripheral blood OR Caracteristic genetic abnormality OR Accumulation of blasts in an extramedullary site
Classification Morphologic: FAB Cytogenetic, morphologic: WHO 2008
AML classification WHO 2008 Acute myeloid leukemia with recurrent genetic abnormalities AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 APL with t(15;17)(q22;q12); PML-RARA AML with t(9;11)(p22;q23); MLLT3-MLL AML with t(6;9)(p23;q34); DEK-NUP214 AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1 Provisional entity: AML with mutated NPM1 Provisional entity: AML with mutated CEBPA Acute myeloid leukemia with myelodysplasia-related changes Therapy-related myeloid neoplasms Acute myeloid leukemia, not otherwise specified AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic/monocytic leukemia Acute erythroid leukemia Pure erythroid leukemia Erythroleukemia, erythroid/myeloid Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma
AML morphology and underlying genetics
Precursor lymphoid neoplasms B lymphoblastic leukemia/lymphoma B lymphoblastic leukemia/lymphoma, NOS B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities ALL classification WHO 2008 B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2);bcr-abl 1 B lymphoblastic leukemia/lymphoma with t(v;11q23);mll rearranged B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) TEL-AML1 (ETV6-RUNX1) B lymphoblastic leukemia/lymphoma with hyperdiploidy B lymphoblastic leukemia/lymphoma with hypodiploidy B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) IL3-IGH B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);tcf3-pbx1 T lymphoblastic leukemia/lymphoma
AML Prognosis based on cytogenetics Favorable: t(8;21), inv(16)(p13;q22), t(16;16)(p13;q22), t(15;17)(q24.1;q21.1) Intermediate: Abnormalities not described in favorable or unfavorable Adverse: del (5q); add (5q); del (7q); add (7q); monosomies 5 or 7; inv(3)(q21q26); t(3;3)(q21;q26); t(6;11)(q27;q23); t(10;11)(p11-13;q23); t(9;22)(q34;q11); 17p abnormalities or monosomy 17; complex aberrant karyotypes described as at least 4 unrelated abnormalities; 11q23 abnormalities excluding t(9;11)(p21;q23) and excluding t(11;19)(q23;p13); or abnormalities of 3q excluding t(3;5)(q21-25;q31-35).
AML cytonegetics and survival Distinct subgroups
AML Prognosis based on molecular genetics FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3- ITD)or less frequently point mutation Nucleophosmin (NPM) CCAAT/enhancer binding protein alpha (CEBPA) isocitrate dehydrogenase (IDH)
AML prognosis based on mutational status
Genetic group Subset AML Integrated prognostic groups European LeukaemiaNet Favorable Intermediate-I Intermediate-II t(8;21)(q22;q22); RUNX1-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB- MYH11 Mutated NPM1 without FLT3-ITD (normal karyotype) Mutated CEBPA (normal karyotype) Mutated NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 without FLT3-ITD (normal karyotype) t(9;11)(p22;q23); MLLT3-MLL Cytogenetic abnormalities not classified as favorable or adverse inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 Adverse t(6;9)(p23;q34); DEK-NUP214 t(v;11)(v;q23); MLL rearranged 5 or del(5q); 7; abnl(17p); complex karyotype
Charateristics Kantarjian 2004 Hoelzer 1988 Rowe 2005 and Lazarus 2006 Le 2006 Age, y >60 >35 >35 Higher vs lower ALL Unfavorable risk factors Cancer 2010 WBC, 10 9 /L >5 >30 >30 Higher vs lower LDH NA NA NA Higher vs lower Time to CR >1 Course >4 Wk Immunophenotype B Pro-B, early and mature T T lineage Karyotype t(9;22) t(9;22) t(9;22); Misc vs normal Molecular BCR-ABL BCR-ABL; ALL1- AF4 NA NA CNS involvement Yes NA Yes NA Minimal residual disease NA Persistent NA NA
Prognosis Prognosis is always valid for certain treatment modalities only!!!!
Complications during evaluation and treatment DIC Infection Bleeding and transfusion complications Consequences of anaemia Hyperviscosity
Treatment options and the choices to be made Curative or palliative care (need to reach complete remission)? If curative stem cell tansplantation candidate? If palliative cytoreduction or supportation only? Minimal residual disease Response to initial therapy
ALL Differencies in treatment strategies Pediatric vs adult
Effect of age on AML survival
Effect of CR on AML survival
Importance of MRD in AML
Treatment and MRD
Myeloid neoplasms Former name: chronic myeloproliferative disorders
What entities are in this group? Chronic myelogenous leukemia (CML) Polycythemia rubra vera (PV) Essential thrombocythemia (ET) Primary myelofibrosis (MF)
When to think of myeloid neoplasms? Mid- or older aged patient Frequently an incidental laboratory finding (scrrening blood count) Sometimes the first symptom is abdominal discomfort (splenomegaly) In some cases neurologícal symptoms got the attention (stroke, hyperviscosity)
How to build up the diagnosis? Prove clonality Typical mutations (BCR/ABL, JAK2, CALR, MPL) Supressed EPO Rule out secondary causes No erythroid proliferation stimuli (normal EPO, normal SpO 2 ) Other Typical bone marrow histology (e.g. accumulation of fibers)
Characteristics - CML Philadelphia chromosome or BCR/ABL fusion In chronic phase all stages of WBC maturation are present In accelerated and blast phase elevated amounts of myeloblasts Splenomegaly
Characteristics - PV JAK2 mutation present in 95% Splenomegaly Pruritus, erythromelalgia Mostly erythroid proliferation
Characteristics - ET JAK2 mutation in the 50% of the cases Mostly thrombocytosis Recurrant thrombotic events
Characteristics - MF JAK2 mutation in the 50% of the cases After a proliferative phase cytopenias are dominant Significant hepatosplenomegaly (extramedullary hemopoiesis) Dacryocytes present