1. CASE 411 Jose Gonzalez-Berjon, MD & Tariq Muzzafar, MD UT M.D. Anderson Cancer Center

2. CLINICAL PRESENTATION  50 year old gentleman  No significant past medical history  Two week history of constitutional symptoms  Diagnosed with acute myeloid leukemia  Refractory to induction chemotherapy  Presented to UT M.D. Anderson Cancer Center

3. CBC  Hgb 9.1 g/dL  WBC 4.0 K /UL  Platelet 3 K/UL  Neutrophils 28%  Lymphocytes 63%  Monocytes 2%  Eosinophils 1%  Bands 1%  Unclassified cells 5%

7. MYELOPEROXIDASE

8. BUTYRATE ESTERASE

9. CD 45 SSC FLOW CYTOMETRY

10. CD41 HLA DR CD 33 CD34 CD 117 CD 64 CD 13 CD 7 CD 9 MPO

11. Karyotype:  46,XY,del(9)(q22)[17]  46,XY,del(9)(q22)[cp2]  46,XY[1] NEGATIVE for  PML-RARA; short or long form  RUNX1T1/RUNX1 [t(8;21)]  CBFB-MYH11 [inv(16)]  FLT3 mutation (ITD or codon 835/836)  KRAS and NRAS mutations (codons 12, 13 and 61) CYTOGENETIC & MOLECULAR STUDIES

12. Submitted Diagnosis Acute megakaryoblastic leukemia (Acute myeloid leukemia not otherwise specified)

13. Panel Consensus Diagnosis Acute megakaryoblastic leukemia (Acute myeloid leukemia not otherwise specified)

14. ACUTE MEGAKARYTOBLASTIC LEUKEMIA (AMKL) per WHO  Acute myeloid leukaemia (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1  <3 years  Myeloid leukemia associated with Down syndrome  + 21  GATA mutations  Acute megakaryoblastic leukemia (acute myeloid leukemia, not otherwise specified)  Adults and children

15. AMKL (ADULTS)  Rare  WHO definition:  ≥ 20% blasts  ≥ 50% of blasts must be of megakaryocytic lineage  Morphologically:  Primitive blasts (like our case); some may be called AML with minimal differentiation  Large blasts; spectrum of forms  Megakaryocytes: small & dysplastic  Fibrosis often present

16. AMKL: BLASTS IN EXTENSIVE FIBROSIS

17. AMKL: MORPHOLOGIC SPECTRUM OF BLASTS

18. AMKL: PITFALLS Fibrosis  Aspirate blast count not reliable  Flow: not sufficient cells to analyze Solution  High index of suspicion  Immunohistochemistry on core biopsy  CD34, CD61, Factor VIII  Flow cytometry:  Blasts (subset) have CD41, CD42b, CD61, CD36  HLA-DR often negative  CD34 may be positive on megakaryoblasts

19. AMKL: BLASTS ARE CD34 +

20. AMKL: BLASTS ARE CD61 +

21. MPN AML-MRC AMKL MDS MRC: myelodysplasia related changes AMKL & OTHER MYELOID NEOPLASMS

22. AMKL: UT M.D. ANDERSON EXPERIENCE  53 cases diagnosed as AMKL (01/1994 to 08/2012)  Excluded cases < 18 years of age  Reassessed diagnosis using WHO criteria  Largest reported series

23. BCR-ABL 1 Karyotype = MDS Prior chemo / radiation AML with MRC AML with inv(3) CML; blast phase inv(3) AML; therapy related

24. 18 (34) 11 (21)) 12 (23) 3 (6) 5 (9) 4 (7) number of cases (% of cases) AMKL: 53 CASES PER WHO

25. 18 (34) 11 (21)) 12 (23) 3 (6) 5 (9) 4 (7) AMKL: 53 CASES PER WHO 4 cases: clinical information or cytogenetic results not available Classified as AMKL based solely on morphologic / immunohistochemical features

26. AMKL: 53 CASES PER WHO  Median survival: 26 weeks  Complex karyotype predicts adverse prognosis (p < 0.01)  No statistical significance:  History of chemo and / or radiation therapy  Pre - existing MDS or MPN  Blast percentage in peripheral blood

27. CONCLUSIONS  9% of cases with megakaryocytic differentiation (morphologic / immunophenotypic) classified as AMKL per WHO  Megakaryoblastic differentiation occurs in spectrum of myeloid neoplasms  Most cases of AMKL fulfill diagnostic criteria for AML with myelodysplasia-related changes per WHO  23% cases evolved from pre-existing MPN not commonly emphasized

28. BCR-ABL 1 Karyotype = MDS Prior chemo / radiation AML with MRC AML with inv(3) CML; blast phase inv(3) AML; therapy related MPN MPN; blast phase What is “Acute megakaryoblastic leukemia NOS”?

29.  18 years in busiest leukemia center on the planet  5 cases only as defined by WHO  AMKL NOS is an exceedingly rare entity

30. What is “Acute megakaryoblastic leukemia NOS”? AMKL NOS is an exceedingly rare entity per WHO Should morphology and immunophenotype determine the entity of AMKL? OR Should clinical history of a prior myeloid neoplasm and karyotype determine what gets called AMKL? What determines disease classification & nomenclature?