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

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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

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SLIDE 1

5/24/2013 1

Leukemia: Genealogy of Pathology Practice: Old Diseases – New Expectations

Kathryn Foucar, MD kfoucar@salud.unm.edu May 2013 Henry Moon Lecture: UCSF Annual Conference

RC1

Disclosure:

  • Nothing to disclose

2 RC2

How to get from

3

to

and Avoid becoming

Objectives/Outline

  • 1. Appreciate key milestones in the

evaluation of leukemias

  • 2. Define optimal strategies for leukemia

diagnosis and prognosis prediction

  • 3. Define the changing role of

pathologists

4

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SLIDE 2

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

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SLIDE 3

Slide 1 (Continued) re-checked numbering rc: 3.8.13

Raquel R. Calderon, 3/8/2013

Slide 2 RC2

Raquel R. Calderon, 3/8/2013

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5/24/2013 2

Milestones in CML

  • 1845 First description of CML (Virchow, Bennett)
  • 1960 Philadelphia chromosome reported by conventional

cytogenetics in pt. with CML (Nowell, Hungerford)

  • 1973 Exchange of genetic material between chromosomes

9 and 22 in CML (Rowley)

  • 1982-85 BCR-ABL1 fusion gene and protein in CML

(Baltimore, Witte, others)

  • 1987-1998 STI-571 targeted therapy and clinical trials
  • 2001 Imatinib FDA-approved

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1845

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Battle between Bennett and Virchow

Hepatosplenomegaly Clinico-pathologic correlation

Courtesy H. Sayar

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Autopsy

Gross Exam:

Earliest diagnostic tool in leukemia diagnosis E.g. Blood thick like gruel; massive enlargement of spleen and liver

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SLIDE 5

5/24/2013 3 Clinico-Pathologic Correlation Blood: Buffy Coat CML: WBC > 900,000

WBC’s

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Early Multi-head scope

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Unstained

130 years ago 150 years ago

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Who was right?

A.Bennett

  • B. Virchow -
  • C. Neither

D.Both

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infection leukemia

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SLIDE 6

5/24/2013 4

MPO

Acute myeloid leukemia Morphology/Cytochemistry

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>130 yrs > 100 yrs

1960

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Nowell and Hungerford

Philadelphia Chromosome

Ph1: first cytogenetic abnormal linked to neoplasm (1960)

Karyotype from 1976

15 16

Courtesy J. Anastasi

1973

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SLIDE 7

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17

Courtesy J. Anastasi

David Baltimore, 1980’s

1980’s; different groups

Ph1: reciprocal translocation BCR-ABL1 fusion gene 1982-1985

Translocation results in constitutive tyrosine kinase activity CML

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Source: Kalidas, et al. NEJM 2001; 286:895-898

Leukemogenic Effects of Constitutive Non- Receptor Tyrosine Kinase Activation

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Source: Kalidas, et al. NEJM 2001;286:895-898

Therapy to Block Tyrosine Kinase Activity (1987-1998 )

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CML Disease Course: Pre-Imatinib

Chronic phase 3-7 years Accelerated phase < 2 years Blast phase < 1 year

  • Disease progression inevitable

(rare exceptions)

  • Linked to additional cytogenetic

abnormalities (clonal evolution)

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CML: Impact of Imatinib

  • High rates of complete cytogenetic remission

(95% in patients with stable phase CML; estimated > 50% 10-yr survival)

  • Improved progression-free survival
  • All patients achieving major molecular

response alive at 5 years

  • Imatinib-resistance more common in patients

in accelerated phase at presentation (additional mutations)

  • Imatinib not curative

22

2001-Present

Blast-Phase in CML: 1983-present

Source: Hehlmann, R. How I treat CML blast crisis. Blood 2012;120:737.

55-yr-old female swimmer with new onset fatigue CBC: WBC 349,000

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Case

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60b05

Blood

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59b04

Bone marrow core; mega size

60b09

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Cytogenetics

Karyotype:

46,XX,t(9;22)(q34;q11.2)[20]

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Diagnosis?

  • A. CML in stable phase
  • B. CML in accelerated phase
  • C. CML in blast phase

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CML in Stable Phase

  • Complete cytogenetic

response to imatinib

  • Ongoing therapy with regular

quantitative BCR-ABL1 assessment

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CML: Accelerated Phase

32-year-old female with splenomegaly and leukocytosis (negative history)

CBC: WBC 24,300, Hgb 8.4, Hct 28%, Plt 701,000 BM: Dry tap

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CML:AP 10% blasts, 20% basos, anemia

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CML:AP blast, baso, mega fragment, anemia

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CML: accelerated phase, fibrosis

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CML:AP sheets, hypolobated megakaryocytes

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CML: Accelerated Phase

  • Increase in blasts (< 20%)
  • Cytopenias/dysplasia
  • Increase in basophils
  • Additional cytogenetic

abnormalities

  • Imatinib resistance

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New Approach to Myeloproliferative Neoplasms

1st breakthrough: Delineation of mechanism of BCR-ABL1- related leukemias 1st step: CML vs “non-CML” Rx: Imatinib for BCR-ABL-1-related disease

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New Approach to MPN

2nd breakthrough: Identification of activating (gain of function) mutation of JAK2 resulting in constitutive tyrosine kinase activity in majority of other MPN (PV, ET, PMF)

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Janus Kinases in Cytokine Signal Transduction

Source: Goldman, J. NEJM 352;17,2005

Receptor tyrosine kinase negative transmembrane receptors include EPO, TPO, G-CSF receptors

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JAK 2 Mutations in MPN

  • Acquired point mutation in JAK2 (9p) results in

constitutive cytoplasmic tyrosine kinase activity, confers to HP precursor cells: – growth factor independence – other proliferative/survival advantages

  • V617F (phenylalanine substituted for valine from

G T transversion)

  • > 80% PV, > 50% ET, > 50% CIMF (PMF)

Sources: Nature, Cancer Cell, NEJM, Lancet 2005

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Why Does Excess, Unregulated Cell Production Occur? CML

Ph1 t(9;22) results in BCR-ABL1 fusion gene with constitutive tyrosine kinase activity

40

Other MPN

Point mutation in regulatory region of JAK2 results in constitutive tyrosine kinase activity

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41

Erythrocytosis, thrombocytosis, JAK2+

74 yr-old female Hgb 17 Hct 51% Plt 950,000

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BM aspirate: ↑ cell, ↑ megakaryocytes

74 yr-old female Hgb 17 Hct 51% Plt 950,000

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BM biopsy: ↑ megs, dilated sinuses, EMH

74 yr-old female Hgb 17 Hct 51% Plt 950,000

Diagnosis?

  • A. Essential thrombocythemia
  • B. Polycythemia vera
  • C. Cellular phase of primary

myelofibrosis

44

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45

  • 59a36

BM: hyperlobulated megas; Bld: ↑ ↑ plts

Essential Thrombocythemia

1.7 million plts

Myeloid Neoplasms

  • > 50 categories
  • Blast percentage
  • Many other features
  • MDS, MPN, MDS/MPN,

AML

46

Comparison of blood features

MDS MPN AML

47

MDS CML AML

Comparison of bone marrow features

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Established Techniques HP Dx

  • Morphology (cytochemical stains)
  • Immunohistochemistry (>100 antibodies)
  • Flow cytometric IP

All are complementary and somewhat

  • verlapping modalities to determine

lineage and stage of maturation.

49 50

AML, Auer rod Morphology: >100yrs

Acute myeloid leukemia

Immunophenotype: 30yrs

51

CD 34

AML: Morphologic and IP Subclassifications

  • Pathologists very good at applying

criteria

  • Morphologic subclassification does

not predict outcome (Exception - APL)

52

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53

AML: Morphologic Classification*

*Source: J Clin Oncol 21:256, 2003

Years from Start of Therapy

AML: Cytogenetic Prognostic 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),
  • ther, complex karyotype (≥ 3

abnormalities)

54 55

AML: Overall Survival by Karyotype*

Years from Start of Therapy

*Source: J Clin Oncol 21:256, 2003

P < 0.0001

Molecular Genetic Testing

  • Highly relevant prognostic

information

  • Determination of clonality
  • Progressive integration into primary

diagnosis

  • Potential to replace “established”

diagnostic techniques

56

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AML Classification: Biologic Groups

2001 2008 AML with recurrent genetic abnormalities 4 types 9 types t(1;22), NPM1, CEBPA, inv(3), t(6;9) AML with MDS- related changes AML after MDS AML after MDS, MDS/MPN AML with multi. dysplasia AML with MDS karyotypes Therapy-related AML Alkylating Agent Topo II inhibitor T-AML, MDS, MPN T-AML with balanced tx

57

AML: Overall Survival

Source: Grimwade, Hematology 2009

59

AML: Class I and Class II Mutations

Class I Mutations (Proliferation) Class II Mutations (Impaired differentiation) FLT3 PML-RARA KIT RUNX1-RUNX1T1 RAS CBFB-MYH11 PTPN11 MLL fusions

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61

Source: NEJM 366(12):1079-89, 2012

400 cases; patients <60 massive parallel sequencing

Acute Myeloid Leukemia

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Source: Patel, et al. NEJM 366:1079, 2012

Gene Overall Frequency (%) FLT3 (ITD, TKD) 37 (30, 7) NPM1 29 DNMT3A 23 NRAS 10 CEBPA 9 TET2 8 WT1 8 IDH2 8 IDH1 7 KIT 6 RUNX1 5 MLL-PTD 5 ASXL1 3 PHF6 3

A Total Cohort

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Source: Patel, et al. NEJM 366:1079, 2012

64

Source: NEJM 366(12):1079-89, 2012

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65

Source: NEJM 366(12):1079-89, 2012

66

New Focus

  • n

Prediction Therapy-Related Leukemia ‡ :

Extrinsic events: Type of therapy, combination therapy (with radiation), total dosage, dosing regimen (genotoxic stress) Intrinsic events: Patient’s genetic makeup; genes involved in DNA repair, genes involved in drug metabolism

‡ Rund, et al. Leukemia 19;1919, 2005.

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Role Change

  • Dramatic change in the role of the

pathologist

  • Old days: Confirm diagnosis of advanced

disease

  • Current: Predict development of disease,

early detection, identify minimal residual disease, predict response to specific therapy, predict risk of drug toxicity

  • Still: Maintain Morph/IP skillset

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Practice Changes

  • More rapid implementation of more

complex technology into “routine” practice

  • Whole new array of diagnostic

pitfalls, more rigid specimen requirements, more splitting up (subspecialization) of diagnostic work-up

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New Challenges

  • Stay “state of the art” but be “evidence-

based”

  • Pathology must take the lead in test

selection and development, reporting, and integration

  • Pathologist must be leaders in cost-

effective testing strategies

  • A higher level of expertise will be

required for routine practice

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