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694 Mixed Lineage Leukemia Rearrangements (MLL-R) Are Determinants of High Risk Disease in Homeobox A (HOXA)-deregulated T-Lineage Acute Lymphoblastic Leukemia:  A Children's Oncology Group Study

Acute Lymphoblastic Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis
Program: Oral and Poster Abstracts
Type: Oral
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis: New Genomic Discoveries in Acute Lymphoblastic Leukemia
Monday, December 7, 2015: 3:30 PM
W331, Level 3 (Orange County Convention Center)

Ksenia Matlawska-Wasowska, PhD1, Huining Kang, PhD2, Meenakshi Devidas, PhD3, Ji Wen, PhD4*, Richard C Harvey, PhD5, Christian C Nickl6*, Scott Ness, PhD7*, Michael Rusch, BA8*, Yongjin Li, PhD8*, Masahiro Onozawa, MD, PhD.9, Carmen Martinez10*, Brent L Wood, MD, PhD11, Barbara Asselin, MD12, I-Ming L Chen, DVM, MS13, Kathryn G. Roberts14, Andre Baruchel, MD15, Jean Soulier, MD16, Herve Dombret, MD, PhD, FRCP17*, Jinghui Zhang, PhD8*, Richard S. Larson, MD, PhD18, Elizabeth Raetz, MD19, William L. Carroll, MD20, Naomi J. Winick, MD21, Peter D. Aplan, MD22, Mignon L. Loh, MD23, Charles G. Mullighan, MBBS, MSc, MD24, Stephen P Hunger, MD25, Nyla A. Heerema, PhD26, Andrew J. Carroll, PhD27, Kimberly P. Dunsmore, MD28 and Stuart S. Winter, MD29

1Department of Pediatrics, Hematology/Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM
2University of New Mexico, Albuquerque
3Department of Biostatistics, Colleges of Medicine, Public Health & Health Profession, University of Florida, Gainesville, FL
4St. Jude Children’s Research Hospital, Memphis
5Pathology, University of New Mexico Cancer Center, Albuquerque, NM
6Pediatrics, University of New Meico, Albuquerque
7University of New Mexico Health Sciences Center, Albuquerque, NM
8Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN
9Genetics Branch, NIH/NCI/CCR, Bethesda, MD
10University of New Mexico, Albuuerque
11Seattle Cancer Care Alliance, Seattle, WA
12Pediatric Hematology-Oncology, University of Rochester, Rochester, NY
13Department of Pathology, The Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM
14Pathology, St. Jude Children's Research Hospital, Memphis, TN
15Dept. of Pediatric Hematology, Hopital Saint Louis, Paris, France
16Hematology Laboratory, Saint-Louis Hospital, Paris, France
17Saint-Louis Hospital, Paris, France
18The University of New Mexico Health Sciences Center, Albuquerque, NM
19Department of Pediatrics, Huntsman Cancer Institute and Primary Children's Hospital, University of Utah, Salt Lake City, UT
20Department of Pediatrics, Perlmutter Cancer Center,, New York University Medical Center, New York, NY
21University of Texas Southwestern Medical Center, Dallas, TX
22NCI/CCR/Genetics branch, National Institutes of Health, Bethesda, MD
23Department of Pediatrics, Benioff Children’s Hospital, University of California at San Francisco, San Francisco, CA
24Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
25Department of Pediatrics, Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
26Pathology, The Ohio State University, Columbus, OH
27Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
28Health Sciences Center, University of Virginia, Charlottesville, VA
29Department of Pediatrics, University of New Mexico, Albuquerque, NM

Acute leukemias are the most commonly occurring cancers among children, adolescents and young adults. Approximately 15% of newly-diagnosed patients present with T-lineage acute lymphoblastic leukemia (T-ALL). In contrast to B-precursor ALL, molecular lesions that deregulate homeobox (HOX) genes appear to be widely prevalent in T-ALL, but their impact on outcome is unclear. We hypothesized that the molecular lesions associated with HOXA-deregulated T-ALL might identify patients with high-risk disease. We performed gene expression profiling (GEP) on a cohort of 213 T-ALL diagnostic samples obtained from children and young adults enrolled on Children’s Oncology Group (COG) treatment studies 9404 (n=50) and AALL0434 (n=163). We identified a cluster of 54 cases (25%) characterized by increased expression of HOXA3, 5, 7, 9, and 10 (FDR ≤ 0.05; fold change cut off 3). We screened our database for the presence of MLL-R, AF10-R (MLLT10) and other HOXA deregulating lesions using an analysis of cytogenetics, FISH, LDI-PCR and RNA sequencing.  We identified 15 cases with MLL-R, including MLL-AF6 (n = 5), del3’MLL (n = 3), MLL-ENL (n = 5), MLL-AF17 (n = 1), and PICALM-MLL (n = 1). Five cases were confirmed to have PICALM-AF10 fusions and two cases showed DDX3X-AF10 lesions. Two cases harbored NUP98 fusions, two cases had inv(7)(p15q34), and one case each was identified for HOXA10-(3’UTR)TRBC, STAG2-LMO2, LOC338817-CCDC91. We could not identify fusion transcripts in 3 cases, but MLL-R and AF10-R were confidently excluded with RNA sequencing. Almost 90% of cases identified to have MLL-R or AF10-R had ≥ 8-fold over-expression of HOXA9/10. Because HOXA-deregulated T-ALL is characterized by a high degree of molecular heterogeneity, we hypothesized that subset analyses might identify lesions that were more likely to be associated with an inferior outcome. We found that chromosomal abnormalities involving the MLL gene, but not AF10, were associated with induction failure (IF) in T-ALL (P = 0.02, OR = 5.34). Since MLL- and AF10-R leukemias also demonstrate features of undifferentiated leukemias, we discriminated early T-cell precursor (ETP) from non-ETP cases using a GEP developed by Coustan-Smith et al. (Lancet Oncol, 2009). Among the 26 cases that showed ETP features, eleven (42%) also co-expressed HOXA9/10 (≥ 8-fold increase over the median).  We found an association between ETP-ALL and early treatment failure (P = 0.01, OR = 4.37), and next assessed whether ETP cases are enriched with translocations harboring MLL or AF10 genes.  We found overlap between MLL-R and the ETP cases (P = 0.03, OR = 4.14).  We confirmed that ETP-ALL and MLL-R are risk features for IF (P = 0.026, OR = 4.37), and that cases with MLL-R (n = 11) had an inferior EFS compared to those that did not (N = 89) (P = 0.0158).  We extended these observations to assess the impact of ETP/MLL-R (n = 6 vs. non-MLL/non-ETP, n = 69) on EFS, and found a significant association with treatment failure (P = 0.0007). For T-ALL, MRD has emerged as a prognostic indicator of high-risk disease. While MLL-ENL (n = 5) cases did not fail therapy regardless of Day 29 MRD levels, all patients with Day 29 MRD > 0.1 and MLL-AF6 (n = 5) or FISH-identified del3’MLL (n = 3) either failed induction or relapsed. Patients with AF10-R (N = 7) have been reported to have inferior EFS, but we observed that only patients with Day 29 MRD ≥10% failed treatment. Our findings show a heterogeneity of outcomes related to MLL-R, but those with MLL-AF6 and del3’MLL should be considered high-risk. We propose that cytogenetic testing including specific FISH should be performed on all T-ALL patients at diagnosis and relapse. The current development of epigenetic modifying therapies targeted against HOXA-deregulating lesions warrants further study in T-ALL.

Disclosures: Aplan: NIH Office of Technology Transfer: Patents & Royalties . Mullighan: Amgen: Honoraria , Speakers Bureau ; Cancer Science Institute: Membership on an entity’s Board of Directors or advisory committees ; Incyte: Consultancy , Honoraria ; Loxo Oncology: Research Funding . Hunger: Merck: Equity Ownership ; Sigma Tau: Consultancy ; Jazz Pharmaceuticals: Consultancy ; Spectrum Pharmaceuticals: Consultancy .

*signifies non-member of ASH