1. Case 251: Clinical Information Raymond E Felgar, MD, PhD University of Pittsburgh, Pittsburgh, PA 45-year-old man with recent history of shingles, night sweats and gum swelling. Hematologic testing showed the following: WBC 69,300 / Hgb 23.5 / Platelets = 114,000 Leukocyte Differential 55.5% Blasts. Bone marrow examination performed.

2. Case 251: Blood Smear Findings

3. Bone Marrow Aspirate Differential

4. Bone Marrow Aspirate, Wright-Giemsa, 1,000x

5. Biopsy, H&E, 1,000x

6. Flow Cytometry

7. Case 251: Flow Summary Two prominent cell populations: 1) 41% CD34+ myeloblasts marking as follows: CD34+, dim CD45+, CD13/33+, CD14-, CD36 (partial+), CD64+, CD117+, CD15 (partial+), HLA- DR+, CD33+, CD56-, CD13+, CD11b (partial+), partial MPO+. 2) 37% CD14+ monocytes marking as follows: CD34-, bright CD45+, CD13/33+, CD14+, CD36+, CD64+, CD117-, CD15+, HLA-DR+, bright CD33+, CD56-, CD13 (partial+), CD11b+, probable partial MPO+.

8. Myeloperoxidase Cytochemistry

9. Double Esterase: Black = a-naphthyl acetate esterase Red = Chloroacetate esterase

10. Cytogenetics: 46, XY, t(6:11)(q27;q23)

11. FISH: Cell with One Intact MLL (Red Arrow), One Rearranged (Split Signal, Yellow Arrows)

12. Case 251: Other Data FLT3 ITD Positive, D835 Negative NPM1 Unmutated

13. Case 251: Diagnosis Submitted Diagnosis: Acute myeloid leukemia with t(6;11)(q27;q23) and MLL gene rearrangement. Consensus Diagnosis: Acute myeloid leukemia with t(6;11)(q27;q23).

14. Case 251: Clinical Course -Induction chemotherapy with achieval of remission status. -In Jan 2013, received matched unrelated stem cell transplant. -Mild graft vs. host disease, now apparently resolved. -Most recent marrow (April 2013) indicated both morphologic and cytogenetic remission (FISH negative for MLL rearrangement.)

15. Case 251: Discussion Should we include AML with t(6;11)(q27;q23) amongst cases with defined translocations? Should t(6;11) be considered a leukemia defining translocation, regardless of blast percentage?

16. Case 251: Discussion SUMMARY POINTS 6q27 gene partner: MLLT4 RAS pathway activation Worse prognostically Associated with AML-M4 or M5 morphology

17. Case 251: AML with t(6;11)(q27;q23): Clinical and Laboratory Studies Supporting Recognition as Specific Disease Martineau M et al. Leukemia 1998;12:788-91. Blum W et al. Cancer 2004;101:1420-7. Grimwade D et al. Blood 2010;116:354-365.

18. Case 251: AML with t(6;11)(q27;q23): Clinical and Laboratory Studies Martineau M et al. Leukemia 1998;12:788-91. 30 cases (5.5% of cases studies as part of an EU Concerted Action Workshop on 11q23 in haematological malignancy). 22 of 30 (73%) had M4, M4/5, or M5 morphology –3 M1, 2 M2, 3 ALL (2 B, one T lineage) Median survival = 12 months, with median event free survival of 7.8 month.

19. Case 251: AML with t(6;11)(q27;q23): Clinical and Laboratory Studies Blum W et al. Cancer 2004;101:1420-7. CALGB study of 2667 AML cytogenetic database –16 patients (0.6% of database) with additional review of 33 adult cases. –81% had M4 or M5 morphology –Frequent gingival involvement (31% cases) –CR in 69%, CR duration (median, 9 mos), –2 Year OS of 13%, literature 15%. –2 long term survivors, both after allogeneic hematopoietic stem cell transplant.

20. Case 251: AML with t(6;11)(q27;q23): Clinical and Laboratory Studies Grimwade D et al. Blood 2010;116:354-365. Outcome data of 5876 patients in UK Medical Research Council Trials (ages 16-59 yrs). –Focussed on outcomes in less common abnormalities, each with incidence <2%. –Identified t(6;11) as poor prognostic group –Survival curve (grouped with “other 11q23”) slightly better than AML with MDS related cytogenetic changes (i.e. cases with -7, del(7q), -5, del(5q), or other MDS- related).

21. Conclusions? AML with t(6;11)(q27;q23) in poor prognostic group. Although not common, probably should be recognized as separate disease. Should we define cases with <20% blasts as AML? –Not sure, but probably? (Limited data regarding translocation behavior in low blast count setting.)