Case 089: Therapy Related t(8;21)(q22;q22) AML and

Transcription

1 Case 089: Therapy Related t(8;21)(q22;q22) AML and SM-AHNMD ST Pullarkat 1, V Pullarkat 2, SH Kroft 3, CS Wilson 4, M Thein 5, WW Grody 1, and RK Brynes 5 1 UCLA, 2 City of Hope National Med Ctr, 3 Med College of Wisconsin, 4 Univ of New Mexico, and 5 USC

2 History 54 y.o. woman with h/o breast carcinoma Adriamycin (Topo II inhibitor), Ara C, Taxol, Arimidex, and involved field radiation 1 year later, developed t(8;21)(q22;q22) AML Induction: Daunorubicin, Ara C CR Consolidation: 3 cycles of high dose Ara C

3 History Bone marrow study following cycle #3: Recurrent AML and numerous mast cells. Review of the pre-induction marrow and CD25 and CD117 immunostaining showed no evidence of increased mast cells. Reinduction: : Mitoxantrone, Etoposide, and Ara C was unsuccessful and she died 8 months after diagnosis of AML.

4 Microscopic Pathology Blood and Bone Marrow at Presentation

5 Initial PB

6 Initial PB

7 Initial BM Asp.

8 Initial Bx

9 Flow Cytometry Blasts expressed: CD33 dim, CD34, CD45 dim, CD117 dim, and HLA-DR Blasts negative for: CD7, CD11b, CD13, CD14, CD15, CD19, and CD20.

10 Cytogenetic Results 46,XX,t(8;21)(q22;q22)

11 Microscopic Pathology Bone Marrow Following Consolidation Cycle #3

12 Post-Rx Bone Marrow Asp.

13 Post-Rx Bone Marrow Asp.

14 Post-Rx Bone Marrow Asp.

15 Post-Rx Bone Marrow Asp.

16 Post-Rx Bone Marrow Bx.

17 CD117 on Post-Rx Bone Marrow Bx.

18 CD117 on Post-Rx Bone Marrow Bx.

19 CD117 on Post-Rx Bone Marrow Bx.

20 CD25 on Post-Rx Bone Marrow Bx.

21 CD25 on Post-Rx Bone Marrow Bx.

22 Molecular Analysis KIT exon 17 mutation analysis: D816V A814S

23 Interesting Features This case represents the 6 th case of AML-SM that we have studied. 5 of 6 carried t(8;21) 5 of 6 had KIT D816 mutations 1 (current case) was therapy-related related

24 t(8;21) AML with SM Case # Age/Sex 29/M 54/F 43/F 51/F 30/M 29/M Hx De novo Rx- linked De novo De novo De novo De novo Outcome DOD DOD DOD A&W p allo- SCT DOD CR but with MC infilt Cyto- genetics t(8;21) t(8;21) t(8;21) t(8;21), del(9),-x -2, 2,-5, 5,-7, -13, 13,-17, 17, -21 t(8;21) del(9) Codon 816 D816H D816V WT D816Y D816H D816Y

25 Interesting Features Effect of prior Topo II inhibitor therapy Relationship of KIT mutations to t(8;21) AML Relationship of KIT mutations to t(8;21) AML with Systemic Mastocytosis

26 Effect of Prior Therapy De novo t(8;21) one of the most frequent AML translocations. Topo II inhibitor-associated AMLs exhibit balanced translocations RUNX1 and MLL translocations common De novo and therapy-associated associated t(8;21) AMLs exhibit RUNX1 and ETO breakpoint cluster regions corresponding to topoisomerase II DNA cleavage sites and DNase I hypersensitivity sites. Zhang Y et al PNAS 2002;99:3070 Zhang Y, Rowley JD DNA Repair 2006;5: Slovak ML et al, Genes Chromosomes Cancer 2002;33:

27 Zhang Y et al PNAS 2002;99:3070 Zhang Y, Rowley JD DNA Repair 2006;5:

28 Zhang Y et al PNAS 2002;99:3070 Zhang Y, Rowley JD. DNA Repair 2006;5:

29 Effect of Prior Therapy Topo II inhibitors trap Topo II in DNA- cleavable complexes Result in DNA double strand breaks Zhang Y, Rowley JD. DNA Repair 2006;5:

30 Relationship of KIT Mutations to t(8;21) AML 20-50% of t(8;21) AMLs have KIT mutations. Most in the Tryosine Kinase-2 2 domain D816 N822 Unlikely that chemotherapy affects KIT mutation status since most t(8;21) AMLs are not therapy-associated. associated. Wang YY PNAS 2005;102:1104-9

31 KIT (CD117) Receptor Stem Cell Factor Extracellular domain } Ligand binding Exon 8 Exon 9 Exon 11 Exon 13 ATP binding domain } Dimerization Cell Membrane Juxtamemb. domain 1st catalytic domain } } Exon17: Tyrosine Kinase (Phosphotransferase) domain TK } 2nd catalytic domain

32 KIT Point Mutations } Ligand binding Exon 8: AML (codon 419) Exon 9: GIST (dupl ) Exon 11: (codon 560) GIST, MCD Exon 13:GIST Exon 17: (codon 816) AML, MCD, Seminoma TK } Dimerization Cell Membrane Juxtamemb. domain } } 1st catalytic domain } 2nd catalytic domain

33 Relationship of KIT Mutations to t(8;21) AML Most leukemic blasts exhibit both KIT mutations and t(8;21) at diagnosis KIT mutations are likely subsequent events t(8;21) but not KIT found after therapy Induced RUNX1/ETO expression in U937 cells up-regulates KIT mrna and protein levels. Wang YY PNAS 2005;102:1104-9

34 Relationship of KIT Mutations to t(8;21) AML Activating KIT mutations are associated with poor prognosis in adults and children with t(8;21) AML. Higher WBC, increased incidences of extramedullary disease and relapse. Shorter overall, and disease-free survivals. Cairoli R et al. Blood 2006;107: Shimada A et al. Blood 2006;107: Paschka P et al. J Clin Oncol 2006;24:

35 Relationship of KIT Mutations to t(8;21) AML-SM t(8;21) AMLs with KIT mutations are a common form of AML in SM-AHNMD Mutation targets pluripotent stem cell Relative frequency of t(8;21) AML with KIT mutations and lack of SM in most cases suggests multi-step oncogenesis for SM. *Garcia-Montero AC et al. Blood 2006;108:

36 Summary t(8;21) is well described in AMLs following Topo II inhibitor therapy. KIT mutations in t(8;21) AML confer a poor prognosis. Screening for mutations should be considered in CBF AMLs. t(8;21) AML appears to be the most common acute leukemia in SM-AHNMD

37 Summary Only a small subset of t(8;21) AMLs with KIT mutations progresses to SM and oncogenesis is unclear. Additional mutations probable: Promote mast cell proliferation Block mast cell proliferation