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2974 The Fusion Landscape of Anaplastic Large Cell Lymphoma: An L.L.M.P.P. Study

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster II
Hematology Disease Topics & Pathways:
Lymphomas, T Cell lymphoma, Diseases, Lymphoid Malignancies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Andrew L. Feldman, MD1, Guangzhen Hu, PhD1*, Surendra Dasari, PhD2*, Lisa M. Rimsza, MD3*, David W. Scott, MBChB, PhD4, Jimena B. Gimenez, MD1*, Farah M. Salama1*, Min Shi, MD, PhD1*, Elías Campo5, Wing Chung Chan, MD6, James R. Cook, MD, PhD7, Giorgio Inghirami, MD8*, Elaine S. Jaffe, MD9*, Ryan Morin, PhD10, Phillipp W. Raess, MD, PhD11*, Andreas Rosenwald12*, Kerry J. Savage, MD, MSc13, Louis M. Staudt, MD, PhD14, George W. Wright, PhD15*, Catalina Amador, MD16*, Jan Delabie, MD, PhD17*, Timothy C. Greiner, MS, MD18*, Javeed Iqbal, PhD, MSc18*, Laura K. Hilton, PhD19*, Sarah L. Ondrejka, DO7, German Ott, MD20*, Stefania Pittaluga, MD, PhD21*, Graham W. Slack, MD19*, Susan L. Slager, PhD22, Joo Y. Song, MD6*, Hao-Wei Wang, MD, PhD23*, Ahmed A. Aljudi, MD24*, Stephen M. Ansell, MD, PhD22, Carlos Barrionuevo, MD25*, James R. Cerhan, MD, PhD26, Jennifer R. Chapman-Fredricks, MD27*, Weina Chen, MD, PhD28*, Laurence de Leval, MD, PhD29, Alejandro A. Gru, MD30*, David L. Jaye, MD31, Liuyan Jiang, MD32*, Brad S. Kahl, MD33, Kennosuke Karube, MD, PhD34*, Young Hyeh Ko, MD35*, Eric Mou, MD36*, Matthew J. Maurer, DSc2*, L. Jeffrey Medeiros, MD37, Roberto N. Miranda, MD37*, Naoki Oishi, MD, PhD38*, Perry M. Anamarija, MD39*, Akira Satou, MD40*, Xueju Wang, MD, PhD41*, Ryan A. Wilcox, MD, PhD42*, Xiaojun Wu, MD, PhD43*, Tadashi Yoshino, MD, PhD44* and Yu Zeng, MD, PhD45*

1Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN
2Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
3Department of Pathology and Laboratory Medicine, University of Arizona College of Medicine and Science, Tucson, AZ
4Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
5Universitat de Barcelona (UB), Barcelona, Spain
6Department of Pathology, City of Hope National Medical Center, Duarte, CA
7Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH
8Weill Cornell Medicine, New York, NY
9Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
10Simon Fraser University, Burnaby, BC, Canada
11Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR
12Institute of Pathology, University Hospital of Wuerzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany
13Division of Medical Oncology, University of British Columbia, Vancouver, BC, Canada
14Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
15Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
16Division of Hematopathology, University of Miami, Miami, FL
17Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
18Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
19Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
20Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
21Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
22Division of Hematology, Mayo Clinic, Rochester, MN
23Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD
24Department of Pathology, Childrens Healthcare of Atlanta, Atlanta, GA
25Departamento de Patología, Instituto Nacional de Enfermedades Neoplásicas, Lima, PER
26Division of Epidemiology / Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
27Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL
28Department of Pathology, UT Southwestern Medical Center, Dallas, TX
29Hôpital Universitaire de Lausanne, Lausanne, Switzerland
30Dermatopathology Section, Columbia University Irving Medical Center/New York Presbyterian, New York, NY
31Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA
32Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Jacksonville
33Department of Medicine, Washington University School of Medicine, St. Louis, MO
34Department of Pathology and Laboratory Medicine, Nagoya University, Nagoya, Japan
35Department of Pathology, Korea University College of Medicine, Seoul, Korea, Republic of (South)
36Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa, Iowa City, IA
37Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
38Department of Pathology, University of Yamanashi, Chuo, JPN
39Department of Pathology, University of Michigan, Ann Arbor, MI
40Aichi Medical University School of Medicine, Aichi, JPN
41Jilin University, Changchun, CHN
42Division of Hematology/Oncology, University of Michigan Cancer Center, Ann Arbor, MI
43Department of Pathology, Johns Hopkins Medicine, Baltimore, MD
44Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
45Department of Pathology, Tongji University School of Medicine, Shanghai, China

Background: Anaplastic large cell lymphomas (ALCLs) represent a heterogeneous group of T-cell lymphomas that currently are classified by the presence or absence of ALK tyrosine kinase (TK) fusion genes (ALK+ or ALK−) and clinical presentation (systemic, cutaneous, or breast implant-associated). Two overarching molecular types of ALCL recently were discovered, defined by the presence (Type I) or absence (Type II) of a gene expression signature highly enriched for JAK-STAT3 activation. Fusions involving non-ALK TK genes occur in some ALK− cases, but the fusion landscape of ALCL remains incompletely characterized.

Methods: Expert consensus pathology review was conducted in the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). RNAseq was performed and fusions were identified using FusionCatcher. Here, we focused on recurrent in-frame coding fusions. Previously unreported fusions were validated by RT-PCR. Type I/II was assigned using a previously validated gene expression-based model. Genes with adjusted (adj) P<0.05 were considered differentially expressed. Overall survival (OS) was assessed for systemic ALCL, when available.

Results: We evaluated 379 ALCLs (229M/150F; mean age, 56 y). Of 199 candidate fusions (excluding reciprocal events), 28 were recurrent and passed quality metrics. At least 1 of these 28 fusions was present in 150 cases (40%).

ALK fusions were present in 106 ALK+ ALCLs (all Type I; P<0.0001). Of these, NPM1::ALK was seen in 68/106 (64%). Alternate partners (X::ALK) included ATIC (N=24) and CTLC, COL1A2, MSN, MYH9, RNF213, SATB1, TFH, TPM3, and TRAF1 (1-3 cases each). X::ALK was associated with older age (mean, 52 y) than NPM1::ALK (32 y; P<0.0001) and showed relative overexpression of 49 genes, including multiple activators of small GTPases such as CGNL1 (FC, 5.6; Padj=2.4×10‑6), SRGAP1, ALS2, DOCK1, and NCKAP1. ALK expression was similar in cases with NPM1::ALK and X::ALK and there was no significant difference in OS.

Non-ALK TK fusions were seen in 17/273 ALK− cases (6%), including TYK2 (N=9); JAK2 (N=6); and ROS1 (N=2). All were Type I ALCLs (P<0.0001). ALK− cases with non-ALK TK fusions overexpressed 38 genes compared to ALK− cases without TK fusions, including cytokines involved in the IL17 signaling pathway such as CXCL6 (FC, 12.5; Padj=4.2×10-3), CXCL1, and CSF3.

We then assessed the relationship between ALK− cases with non-ALK TK fusions and ALK+ cases by separately comparing each subset to ALK− cases without TK fusions. FC values for ALK− cases with non-ALK TK fusions were significantly correlated with FC values for ALK+ ALCLs over the set of expressed genes (R=0.54; P<0.0001). At a median follow-up of 32 months, 0/4 systemic ALCL patients with non-ALK TK fusions had died, while 30% of those with ALK− ALCL without TK fusions had died, but this was not statistically significant (P=0.26). The other 13 ALK− cases with non-ALK TK fusions were either localized ALCLs or did not have outcome data available.

Of 20 TP63 fusions, 17 (85%) were TBL1XR1::TP63 and 3 were X::TP63. As previously reported, TP63 fusions were associated with poor OS (median OS, 10 months; not reached for other ALK− ALCLs; P=0.007).

Four ALCLs had a novel NCL::UBTF fusion involving genes encoding the nucleolar proteins nucleolin and nucleolar (upstream binding) transcription factor-1. Four cases each had PARG::BMS1 and TNK1::GPS2 (the latter seen only in Type I ALCLs).

Conclusions: This large consortium-based analysis of coding fusions further elucidates the molecular distinction between Type I and Type II ALCLs. Both ALK and non-ALK TK fusions were seen exclusively in Type I ALCLs, which we have shown previously are enriched for JAK-STAT3 pathway genes and correlate strongly with pSTAT3Y705 positivity by immunohistochemistry. These fusions were not identified in Type II ALCLs, which previous data suggest are associated with epigenetic alterations. ALK+ ALCLs with NPM1::ALK and X::ALK showed differences in gene expression, suggesting biological differences. Furthermore, ALCLs with non-ALK TK fusions shared gene expression features with ALK+ ALCL. Clinical fusion detection could enhance molecular classification of Type I and Type II ALCLs and may guide precision therapy.

Disclosures: Feldman: Zeno Pharmaceuticals: Patents & Royalties; Seattle Genetics: Research Funding. Dasari: The Binding Site: Patents & Royalties: Intellectual Property Rights licensed to Binding Site with potential royalties. Scott: Roche: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; AstraZenenca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Veracyte: Consultancy, Honoraria; Roche/Genentech: Research Funding; Nanostring: Patents & Royalties: use of gene expresssion to subtype aggressive lymphoma. Inghirami: Daiichi Sankyo: Consultancy. Rosenwald: MorphoSys: Other: institutional research contract; Incyte: Other: Institutional research contract . Savage: Bristol Myers Squibb: Consultancy, Research Funding; Regeneron: Other: DSMC; AbbVie: Consultancy; Seagen: Consultancy, Honoraria, Research Funding. Ansell: Takeda: Research Funding; SeaGen: Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cerhan: BMS: Research Funding; GenMab: Research Funding; Protagonist Therapeutics: Other: SMC; Genentech: Research Funding. Gru: Innate-Pharma: Consultancy. Kahl: AstraZeneca: Consultancy, Research Funding; ADCT: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; BeiGene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy; AbbVie: Consultancy; Lilly: Consultancy, Honoraria.

*signifies non-member of ASH