1. Case 297 Guilin Tang and Sa A. Wang Department of Hematopathology UT MD Anderson Cancer Center

2. 65- year-old woman Diagnosed with invasive breast cancer in 02/2009, Had lumpectomy and left axillary LN dissection in 03/2009. LN metastasis. 05/2009: weekly Taxol for 12 weeks, three cycles of FAC (5-fluorouracil, doxorubicin, and cyclophosphamide) chemotherapy, and radiation therapy. Completed in early 2010. Present History

3. Felt weakness and fatigue in 08/2010 8/16/2010: WBC 236x10^9/L, Hb 9.4 g/dl, platelets 38x10^9/L, and 51% of blasts. Physical exam: unremarkable Present History (cont’s)

4. Bone Marrow Biopsy

5. Bone Marrow Aspirate Blasts 94%, (MPO-) granulocytes 1%, erythroblasts 3%, lymphocytes 2%.

6. Flow Cytometry CD45 CD19 CD22 CD19 TdT CD20 CD10 SSC

7. Flow Cytometry Immunophenotyping Summary Positive for: CD19, CD22, CD38, CD79a, cIgM, HLA-DR, TdT (small subset) Negative for: CD10, CD15, CD20, CD25, CD34, surface light chains, myeloid markers (CD13, CD33, CD117, MPO) and T cell markers (cCD3, CD5, CD7) Pro-B-ALL immunophenotype

8. 46,XX,t(4;11)(q21;q23)[19] 47,XX,+X,t(4;11)(q21;q23),-7,+8[1] Cytogenetics

9. MLL Dual Color B.A.P Probe MLL rearrangement in 91% cells

10. Diagnosis Therapy-related B-acute lymphoblastic leukemia with t(4;11)(q21;q23)

11. 1.What are the features of t-ALL? 2.How is it different from de novo B-ALL? 3.Is it analogous to t-AML? Questions

12. t-ALL is a uncommon disease Patients with t-ALL were older than those with p-ALL Gender distribution: similar Immunophenotype: Similar to p-ALL within the cytogenetics group. Pagano et al. Leuk Lymphoma 2000 (11/901, 1.2%) Ishizawa et al Leukemia 2003 (4/152, 2.6% ) Abdulwahab et al. Cancer 2012 (23/335, 6.9%) Tang et al. Haematologica 2012 (30/457, 6.2%)

13. t-ALL (n=30) p-ALL (n=413) P Abnormal karyotype25 (83%)319 (75%)0.161 t(4;11) (AF4/MLL) 7 (24%)18 (5%)<0.001 t(9;22) (BCR/ABL1) 7 (24%)129 (34%)0.102 t(1;19) (E2A/PBX1)09 (2%) Hyperdiploidy2 (7%)22 (6%)0.125 Hypodiploidy6 (21%)19 (5%)0.009 -5, -77 (24%)27 (7.2%)0.009 -17, del(17p)6 (21%)17 (4.5%)0.005 Cytogenetic Features Tang et al. Haematologica 2012

14. KaryotypeCase# Prior Cytotoxic Therapies T+AAPR Normal5 (17%) 1112 t(4;11) (MLL)7 (24%) 7 t(9;22) (Ph+)7 (24%) 2113 Hyperdiploidy2 (7%) 11 Hypodiploidy6 (21%) 33 -5, -77 (24%) 311 -17 or del(17p)6 (21%) 321 T: topoisomerase II inhibitors; A: Alkylating agents; P: Purine analog; R: Radiation Correlation of Cytogenetics and Cytotoxic Therapies Tang et al. Haematologica 2012

15. t-ALL (n=30) p-ALL (n=413) *P Treatment  Complete remission 18 (60%)370(93%)<0.001  Relapse 13 (43%)182(46%)0.179 3-year event free survival4 (13%)127(32%)0.008 Response to Therapy and Survival

16. Univariate analysis: Overall Survival Tang et al. Haematologica 2012

17. Variables Hazard ratio (95% CI) *p t-ALL vs. p-ALL1.48 (0.85 – 2.58)0.163 Cytogenetics t(4;11)2.35 (1.14 – 4.85)0.021 t(9;22)1.67 (1.05 – 2.65)0.031 Hypodiploidy2.31 (1.21 – 4.42)0.012 Age: ≥ 50 vs <50 years1.20 (0.84 – 1.71)0.307 Multivariate hazard analysis for OS Patients with the same cytogenetic abnormality showed a very similar OS, regardless of prior cytotoxic therapy

18. Older: median age 64 vs. 40 Higher frequency of t(4;11), hypodiploidy, -5, -7, - 17 or del(17p); correlated with cytotoxic therapies. Lower CR rate, shorter OS, and lower 3-year EFS. Similar IP within the same cytogenetics group. Summary: Compare to de novo ALL

19. Contrast in: Less frequent than t-AML Shorter latency: 27 vs. 52 months No significant dysplasia Not preceded by cytopenia Compare to t-AML Similar in: Higher frequency of t(v;11q23), -5, -7 Chromosomal abnormalities correlated with prior cytotoxic exposures Inferior outcome Pagano et al. Hematol J 2000 Tang et al. Haematologica 2012

20. Modified hyper-CVAD. 6 courses of Induction/Consolidation at MDACC, CR SCT in San Antonio in 02/2011 Has been in CR Follow-up

22. Father died of lung cancer at age 52 (smoker) Grandfather died of lung cancer (age?, smoker) Daughter diagnosed with ovarian cancer at 35. Family History