Disclosure: Pathology Practice: Old Diseases New Expectations - PowerPoint PPT Presentation

5/24/2013 RC1 RC2 Leukemia: Genealogy of Disclosure: Pathology Practice: Old Diseases – New Expectations •Nothing to disclose Kathryn Foucar, MD Henry Moon Lecture: UCSF Annual kfoucar@salud.unm.edu Conference May 2013 2 How to get from Objectives/Outline 1. Appreciate key milestones in the to evaluation of leukemias 2. Define optimal strategies for leukemia and diagnosis and prognosis prediction Avoid 3. Define the changing role of becoming pathologists 3 4 1

Slide 1 RC1 2/25/13 - RC Revisions: 1. Check popins on slide 2 2. Move slides 9&10 on pg 2 to page 1 after slide 3 3. delete slide 7 popins 4. add new slide "Who was right", with popins, after slide 10 5. rename slide 22 "Case" 6. Delete titles on images slides 23 &24 7. Add text to legend on slide 24 8. Change title and delete text on slide 25 9. Add slide titled "Diagnosis?" 10. Add slide titled "CML in Stable Phase" 11. Revise original slide 31 12. Add text to legend of original slide 33 13. Add slide titled "Diagnosis?" 14. Add slide titled "Myeloid Neoplasms" 15. Delete original slide #41 16. Update original slide #56 17. Delete original slide #62 18. Change title on original slide #66 (Now last slide) Check slide numbers, font,pop-ins, and color of all slides Submit: 2.25.13 3.1.13 Revisions Slide #9 Remove text Slide #11 Check popins - good Slide #26 Remove text and center remaining text Slide #28 Add "L1" in italics Slide #36 remove letter "C" Total number of slides 69 Send electronically to KF 3.1.13 REVISIONS: UCSF requirements: add disclosure to 2nd slide

Slide 1 (Continued) re-checked numbering rc: 3.8.13 Raquel R. Calderon, 3/8/2013 Slide 2 Raquel R. Calderon, 3/8/2013 RC2

5/24/2013 Milestones in CML 1845 • 1845 First description of CML (Virchow, Bennett) Battle • 1960 Philadelphia chromosome reported by conventional between cytogenetics in pt. with CML (Nowell, Hungerford) Bennett • 1973 Exchange of genetic material between chromosomes 9 and 22 in CML (Rowley) and • 1982-85 BCR-ABL1 fusion gene and protein in CML Virchow (Baltimore, Witte, others) • 1987-1998 STI-571 targeted therapy and clinical trials • 2001 Imatinib FDA-approved 5 6 Autopsy Hepatosplenomegaly Gross Exam: Clinico-pathologic Earliest diagnostic tool in leukemia correlation diagnosis E.g. Blood thick like gruel; massive enlargement of spleen and liver Courtesy H. Sayar 7 8 2

5/24/2013 Clinico-Pathologic Correlation Blood: Buffy Coat CML: WBC > 900,000 WBC’s 9 10 Early Multi-head scope Who was right? infection A.Bennett - B. Virchow - leukemia C. Neither D.Both Unstained 12 150 years ago 130 years ago 11 3

5/24/2013 Acute myeloid leukemia Philadelphia Chromosome MPO 1960 >130 yrs > 100 yrs Morphology/Cytochemistry Nowell and Hungerford 14 13 Karyotype from 1976 1973 Ph 1 : first cytogenetic abnormal linked to neoplasm (1960) Courtesy J. Anastasi 16 15 4

5/24/2013 1980’s; different groups Ph 1 : reciprocal translocation BCR-ABL1 fusion gene 1982-1985 Translocation results in constitutive tyrosine kinase David Baltimore, 1980’s Courtesy J. Anastasi activity � CML 17 18 Therapy to Block Tyrosine Kinase Activity (1987-1998 ) Leukemogenic Effects of Constitutive Non- Receptor Tyrosine Kinase Activation Source: Kalidas, et al. NEJM 2001; 286:895-898 Source: Kalidas, et al. NEJM 2001;286:895-898 20 19 5

5/24/2013 2001-Present CML Disease Course: Pre-Imatinib CML: Impact of Imatinib Chronic phase 3-7 years • High rates of complete cytogenetic remission (95% in patients with stable phase CML; estimated > 50% 10-yr survival) Accelerated phase < 2 years • Improved progression-free survival • All patients achieving major molecular Blast phase < 1 year response alive at 5 years • Imatinib-resistance more common in patients • Disease progression inevitable in accelerated phase at presentation (rare exceptions) (additional mutations) • Imatinib not curative • Linked to additional cytogenetic 21 22 abnormalities (clonal evolution) Case Blast-Phase in CML: 1983-present 55-yr-old female swimmer with new onset fatigue CBC: WBC 349,000 Source: Hehlmann, R. How I treat CML blast crisis. Blood 2012;120:737. 24 6

5/24/2013 60b09 60b05 59b04 Blood Bone marrow core; mega size 25 26 Cytogenetics Diagnosis? A. CML in stable phase Karyotype: B. CML in accelerated phase 46,XX,t(9;22)(q34;q11.2)[20] C. CML in blast phase 27 28 7

5/24/2013 CML in Stable Phase CML: Accelerated Phase 32-year-old female with splenomegaly •Complete cytogenetic and leukocytosis (negative history) response to imatinib •Ongoing therapy with regular CBC : WBC 24,300, Hgb 8.4, quantitative BCR-ABL1 Hct 28%, Plt 701,000 assessment 29 30 BM: Dry tap CML:AP 10% blasts, 20% basos, anemia CML:AP blast, baso, mega fragment, anemia 32 31 8

5/24/2013 CML: accelerated phase, fibrosis CML:AP sheets, hypolobated megakaryocytes 33 34 New Approach to CML: Accelerated Phase Myeloproliferative Neoplasms • Increase in blasts (< 20%) 1 st breakthrough: • Cytopenias/dysplasia Delineation of mechanism of BCR-ABL1- • Increase in basophils related leukemias • Additional cytogenetic 1st step: CML vs “non-CML” abnormalities Rx: Imatinib for BCR-ABL-1- related • Imatinib resistance 35 36 disease 9

5/24/2013 Janus Kinases in Cytokine Signal Transduction New Approach to MPN 2nd breakthrough: Receptor tyrosine Identification of activating (gain of kinase negative function) mutation of JAK2 resulting in transmembrane constitutive tyrosine kinase activity in receptors include EPO, TPO, G-CSF majority of other MPN (PV, ET, PMF) receptors Source: Goldman, J. NEJM 352;17,2005 37 38 Why Does Excess, Unregulated Cell JAK 2 Mutations in MPN Production Occur? • Acquired point mutation in JAK2 (9p) results in CML constitutive cytoplasmic tyrosine kinase activity , Ph 1 t(9;22) results in BCR-ABL1 fusion gene confers to HP precursor cells: with constitutive tyrosine kinase activity – growth factor independence – other proliferative/survival advantages • V617F (phenylalanine substituted for valine from Other MPN G � T transversion) Point mutation in regulatory region of JAK2 • > 80% PV, > 50% ET, > 50% CIMF (PMF) results in constitutive tyrosine kinase activity Sources: Nature, Cancer Cell, NEJM, Lancet 2005 39 40 10

5/24/2013 74 yr-old female 74 yr-old female Hgb 17 Hgb 17 Hct 51% Hct 51% Plt 950,000 Plt 950,000 Erythrocytosis, thrombocytosis, JAK2 + BM aspirate: ↑ cell, ↑ megakaryocytes 41 42 74 yr-old female Diagnosis? Hgb 17 Hct 51% Plt 950,000 A. Essential thrombocythemia B. Polycythemia vera C. Cellular phase of primary myelofibrosis BM biopsy: ↑ megs, dilated sinuses, EMH 44 43 11

5/24/2013 Essential Thrombocythemia Myeloid Neoplasms 1.7 million plts • > 50 categories •Blast percentage •59a36 •Many other features •MDS, MPN, MDS/MPN, AML BM: hyperlobulated megas; Bld: ↑ ↑ plts 45 46 MDS MPN AML MDS CML AML Comparison of blood features Comparison of bone marrow features 48 47 12

5/24/2013 AML, Auer rod Established Techniques HP Dx • Morphology (cytochemical stains) • Immunohistochemistry (>100 antibodies) • Flow cytometric IP All are complementary and somewhat overlapping modalities to determine lineage and stage of maturation. 49 Morphology: >100yr s 50 Acute myeloid leukemia AML: Morphologic and IP Subclassifications • Pathologists very good at applying criteria • Morphologic subclassification does not predict outcome (Exception - APL) CD 34 Immunophenotype: 30yrs 52 51 13

5/24/2013 AML: Cytogenetic Prognostic AML: Morphologic Classification * Groups* Favorable: t(8;21), t(15;17), inv(16), t(16;16), other Intermediate: Normal karyotype, +8, -4, +6 Poor: -5/del(5q) , -7/del(7q) , t(11q23), other, complex karyotype ( ≥ 3 Years from Start of Therapy abnormalities) * Source: J Clin Oncol 21:256, 2003 53 54 AML: Overall Survival by Karyotype* Molecular Genetic Testing • Highly relevant prognostic information • Determination of clonality P < 0.0001 • Progressive integration into primary diagnosis • Potential to replace “established” Years from Start of Therapy diagnostic techniques *Source: J Clin Oncol 21:256, 2003 56 55 14

5/24/2013 AML Classification: Biologic Groups AML: Overall Survival 2001 2008 AML with 4 types 9 types recurrent genetic t(1;22), NPM1, CEBPA , abnormalities inv(3), t(6;9) AML with MDS- AML after MDS AML after MDS, MDS/MPN related changes AML with multi. dysplasia AML with MDS karyotypes Therapy-related Alkylating Agent T-AML, MDS, MPN Source: Grimwade, Hematology 2009 57 AML Topo II inhibitor T-AML with balanced tx AML: Class I and Class II Mutations Class I Mutations Class II Mutations (Proliferation) (Impaired differentiation) FLT3 PML-RARA KIT RUNX1-RUNX1T1 RAS CBFB-MYH11 59 60 PTPN11 MLL fusions 15