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847 Gene Expression Profiling Reveals Two Overarching Types of Anaplastic Large Cell Lymphoma with Distinct Targetable Biology: An L.L.M.P.P. StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 621. Lymphomas: Translational – Molecular and Genetic: Insights into Lymphoma: Unraveling the Molecular Complexity for Precision Diagnostics and Therapeutics
Hematology Disease Topics & Pathways:
Lymphomas, T Cell lymphoma, Diseases, Lymphoid Malignancies
Monday, December 11, 2023: 2:45 PM

Andrew L. Feldman, MD1, Surendra Dasari, PhD2*, Lisa M. Rimsza, MD3, David W. Scott, MBChB, PhD4, Naoki Oishi5*, Catalina Amador, MD6*, Elias Campo, MD, PhD7, Wing C. Chan, MD8, James R. Cook, MD, PhD9, Jan Delabie, MD, PhD10*, Pedro Farinha, MD, PhD4, Kai Fu, MD, PhD11, Timothy C. Greiner, MS, MD12*, Giorgio Inghirami, MD13*, Javeed Iqbal, PhD, MSc12*, Elaine S. Jaffe, MD14, Sarah L. Ondrejka, DO9, German Ott, MD15*, Stefania Pittaluga, MD, PhD16*, Phil Raess, MD, PhD17*, Andreas Rosenwald, MD18*, Kerry J. Savage, MD, MSc, BSc19, Graham Slack, MD4*, Susan L. Slager, PhD2, Joo Y. Song, MD8, Louis M. Staudt, MD, PhD20, George Wright21*, Hao-Wei Wang, MD, PhD22*, Yu Zeng23*, Tadashi Yoshino, MD, PhD24*, Xiaojun Wu, MD, PhD25*, Ryan A. Wilcox, MD26, Xueju Wang27*, Akira Satou28*, Anamarija M. Perry, MD29, Roberto Miranda, MD30*, L. Jeffrey Medeiros, MD31, Matthew J. Maurer, DrMed2*, Eric Mou, MD32*, Young Hyeh Ko, MD33*, Kennosuke Karube, MD, PhD34*, Brad S. Kahl, MD35, Liuyan Jiang, MD36*, David L Jaye, MD37, Laurence de Leval, MD, PhD38, Weina Chen39*, Jennifer R. Chapman-Fredricks, MD6*, James R. Cerhan, MD, PhD2, Carlos Barrionuevo, MD40*, Stephen M Ansell, MD, PhD41 and Ahmed Aljudi, MD42*

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

Background: Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell lymphomas that share pathologic features but differ in clinical presentation, outcome, and molecular features. The World Health Organization (WHO) and International Consensus Classification (ICC) classify ALCLs by presence or absence of ALK rearrangements (R) and clinical presentation (systemic, cutaneous [c], or breast implant-associated [BIA]). ICC, but not WHO, recognizes DUSP22-R as defining a new genetic subtype of ALK- ALCL. The classifications otherwise do not reflect additional molecular heterogeneity in genetics (e.g., TP63-R) or therapeutic vulnerabilities (e.g., JAK-STAT3 pathway activation).

Methods: ALCLs (N=689) underwent expert consensus review (WHO/ICC) through the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). All cases also underwent genetic subtyping (ALK, DUSP22, TP63, and triple-negative [TN]) using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), as well as IHC for phospho-STAT3Tyr705 (pSTAT3). RNAseq was performed and evaluable in 393 cases; the remaining cases had insufficient tissue, tumor content, RNA yield or quality, and/or sequencing data quality. Sequenced and non-sequenced sub-cohorts had similar demographics and subtype distribution.

Results: Unsupervised gene expression profiling (GEP) identified 2 main molecular types of ALCL. Type I ALCLs predominantly included ALK+ ALCLs, BIA-ALCLs, and a subset of TN ALCLs (designated TN-I), whereas Type II ALCLs predominantly included ALCLs with DUSP22-R, TP63-R, or both (double-hit; DH), and the remaining TN ALCLs (TN-II). Type I ALCLs were strongly associated with pSTAT3 expression (74.2±26.4% positive malignant cells vs 9.9±22.7% for Type II; P<0.0001). An independently derived pSTAT3 staining threshold of 30% assigned Type I vs II with 91% accuracy. A third cluster of ALCLs, mostly cALCL, showed an epithelial GEP signature rather than a lymphoma signature; these cases were assigned to Types I or II based on pSTAT3 IHC. Distinct sub-signatures were identified for ALK+, DUSP22-R, TP63-R, and BIA ALCL (Fig. 1), but not ALK- ALCL or cALCL.

Gene set enrichment analysis showed Type I ALCLs to be enriched for JAK-STAT3 signaling genes (normalized enrichment score [NES], 2.22; FDR<0.0001) and related pathways, such as TNFα-NFκB signaling (NES, 2.21; FDR<0.0001). In contrast, Type II ALCLs were enriched for cell cycle, DNA repair, epigenetic, and metabolic pathway genes, but not for major tyrosine kinase-mediated signaling pathway genes. Enriched epigenetic pathways included chromatin modifying enzymes (NES, -1.86; FDR=0.002) and histone methylation (NES, -1.71; FDR=0.002). EZH2 was the most overexpressed gene in Type II ALCLs (fold-change, 7.74; FDR=8.84×10-306). At the protein level, EZH2 IHC H-scores were 275±45 in Type II and 168±70 in Type I ALCLs (P<0.0001); H3K27me3 H-scores were 170±81 and 76±63, respectively (P<0.001). The top metabolic gene set involved cholesterol biosynthesis (NES, -1.88; FDR=0.002).

Overall survival (OS) data were available in 257 systemic ALCL patients (145 sequenced and 112 non-sequenced; cALCL and BIA-ALCL were excluded). Non-sequenced TN ALCLs were assigned to TN-I or TN-II using pSTAT3 IHC. The results supported earlier data indicating favorable prognosis of DUSP22-R ALCL (5 y OS, 95%) and ALK+ ALCL (87%), intermediate prognosis of TN ALCL (TN-I, 52% and TN-II, 38%; P=NS), and poor prognosis of TP63-R/DH ALCL (0%)(P<0.0001; Fig. 2).

Conclusions: Two overarching molecular types of ALCL exist, predominantly associated with the presence (Type I) or absence (Type II) of the JAK-STAT3 signaling program. Distinct GEP signatures exist for ALK+ ALCL and BIA-ALCL (predominantly Type I), and DUSP22-R ALCL and TP63-R ALCL (predominantly Type II). TN ALCLs lacking ALK-R, DUSP22-R, and TP63-R can be stratified into TN-I and TN-II subtypes. pSTAT3 IHC has >90% accuracy as a surrogate for GEP-based subtyping. ALK- ALCL and cALCL cluster by molecular subtype rather than by defining GEP signatures. Type II ALCLs are enriched for targetable epigenetic and metabolic pathways, including EZH2/histone methylation and cholesterol biosynthesis. This molecular classification is diagnostically, prognostically, and potentially therapeutically relevant, and can be applied using FISH and IHC in routine practice and in the clinical trial setting.

Disclosures: Rimsza: Roche: Other: Consulting; NanoString: Other: Licensed intellectual property. Scott: Abbvie, AstraZeneca, Incyte: Consultancy; Janssen and Roche: Research Funding. Savage: Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Roche: Research Funding; Seagen: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Yoshino: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin: Honoraria. Kahl: Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; ADCT: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. de Leval: Lunaphore: Consultancy; Novartis: Consultancy; Bio Ascend: Consultancy; Bayer: Consultancy; Abb Vie: Consultancy. Cerhan: Genmab: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Protagonist: Other: Safety Monitoring Committee; NanoString: Research Funding; Genentech: Research Funding. Ansell: Regeneron Pharmaceuticals Inc: Other: Contracted Research; Pfizer, Inc: Other: Contracted Research; Bristol-Myers Squibb: Other: Contracted Research; Affirmed: Other: Contracted Research; ADC Therapeutics: Other: Contracted Research; Seagen Inc: Other: Contracted Research; Takeda Pharmaceuticals USA Inc: Other: Contracted Research.

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