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4379 Evaluation of a Prognostic 23-Gene Expression Panel in a Set of 390 Multiethnic Hodgkin Lymphoma Patients

Program: Oral and Poster Abstracts
Session: 622. Lymphomas: Translational–Non-Genetic: Poster III
Hematology Disease Topics & Pathways:
Research, adult, Translational Research, young adult , Study Population, Human
Monday, December 11, 2023, 6:00 PM-8:00 PM

Anthony Colombo, MS1*, Jia Yin Wan, M.S.2*, Aixiang Jiang, MS3*, Jose Aparicio4*, Esther Lam, MPH5*, Tomohiro Aoki, PhD, M.D6*, Joo Y Song, MD7*, Sheeja Pullarkat, MD8*, Chun Chao, M.D9*, Juan Manuel Mejia-Arangure10*, Brenda Hernandez11*, Pamela B. Allen, MD12, Christopher R. Flowers, MD, MS13, Sophia S. Wang, PhD14*, Juanita Evans15*, Owen Chan11*, Jakub Svoboda, MD16, Anja Mottok17*, Leon Bernal-Mizrachi, MD18, Megan Lim19*, David W. Scott, MBChB, PhD20, Imran Siddiqi, MD, PhD4*, David Conti21*, Christian Steidl, MD, PhD22 and Wendy Cozen, DO, MPH23

1Department of Population and Public Health Sciences, University of Southern California, Keck School of Medicine, Los Angeles, CA
2University of California, Irvine, Irvine, CA
3Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
4Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA
5Department of Pathology and Laboratory Medicine, University of California Irvine, Orange, CA
6British Columbia Cancer, Vancouver, BC, Canada
7Department of Pathology, City of Hope National Medical Center, Duarte, CA
8Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA
9Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
10Instituto Nacional de Medicina Genomica & Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
11University of Hawai’i Cancer Center, University of Hawai'i, Honolulu, HI
12Department of Hematology, Emory University School of Medicine, Decatur, GA
13Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
14City of Hope, Duarte, CA
15Department of Pathology, Ascension Providence Southfield Hospital, Southfield, MO
16Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
17Department of Pathology, University of Giessen, University, Hesse, Germany
18Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
19Memorial Sloan Kettering Cancer Center, New York, NY
20Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada
21Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA
22Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
23Division of Hematology, Department of Medicine, University of California Irvine, Orange, CA

Classic Hodgkin lymphoma (CHL) is a curable lymphoma with unique epidemiological features, including rare neoplastic cells, and an adolescent/young adult age (AYA) incidence peak higher in females, correlated with socioeconomic status. We previously reported that RNA expression measured in formalin-fixed paraffin-embedded (FFPE) tissues using a panel of 23 immune response genes was associated with 5-year overall survival (OS) in predominantly White/European advanced staged CHL patients treated with ABVD chemotherapy (Scott et al., 2013). Here, we conducted a study to evaluate if the 23-gene expression panel predicted 5-year OS in a real-world set of FFPE tumor tissue from racially/ethnically diverse populations in the U.S. and Mexico from the Multi-Ethnic Study of Hodgkin Lymphoma (MESH).

Methods: We collected tumor blocks from 891 patients from 9 hospitals and 2 Residual Tissue Repositories in the U.S. and Mexico. Demographic and clinical data, including survival by month, age at diagnosis, birth year, race/ethnicity, sex, histology were abstracted. Patients were diagnosed from 1978 to 2018. CHL diagnoses and histological subtypes were validated by histopathology review. RNA was extracted and NanoString gene expression profiling was performed using 250-gene codeset including the published 23-gene expression (GE) panel (Scott et. al., 2013). 390 cases passed QC after applying a modified normalization protocol (Chan et.al., 2017). The multiethnic risk index was derived from a linear equation of the log2 GE in MESH multiplied by the established regression coefficients (Scott et al., 2013). Next, we examined a dichotomized score using a cut-off value at the 75th percentile. Both were tested for association with 5-year OS using a Cox proportional hazards model using R software 4.3.0 version adjusting for age as a continuous and categorical variable (15-39 and 40+ years), type of hospital that provided the samples, sex, EBV tumor status (assigned using EBER2), race/ethnicity, and histology. The 5-year OS was computed by right-censoring any patient that survived longer than 5 years. Proportionality assumptions were tested (using an alpha level of 0.05). Stratified models by categorical age and race/ethnicity were adjusted for patient demographical variables and effect heterogeneity was examined using a t-test.

Result: The analytic set comprised 47% females and 44% Hispanic, 24% White, 20% Black, 9% Asian, and 3% Pacific Islander/Native Hawaiians. 62% were 15-39 years and 32% 40+ years at diagnosis. The multivariate analysis, excluding age, indicated an association between the risk index and 5-year OS (HR =1.41 (1.08, 1.93), p=0.01). However, including age attenuated the association (HR=1.18 (0.89, 1.57), p=0.25). When stratified by age categories, the continuous risk index was associated with 5-year OS only in the older age group: 15-39 years (HR = 0.89 (0.54, 1.47), p=0.65), and >40 years (HR = 1.47 (1.08, 2.01), p=0.02), indicating effect heterogeneity by age groups (p=0.09). We did not observe significant effect heterogeneity by EBV status (p=0.6), race/ethnicity (p=0.72), nor sex (p=0.33). When the dichotomized score was examined, the model was attenuated after adjusting for age, but stratification analysis showed an association in the older adults (HR= 2.8 (1.42, 5.51), p<0.01) with significant effect heterogeneity across age (p=0.02) (Figure 1).

Evaluating the association between individual genes and OS, we found effect heterogeneity by age; two genes from the 23-gene panel indicated protective effects in the AYA but hazardous in older adults: B2M (peffect heterogeneity` =0.048), and APOL6 (p`=0.059). Individual genes with heterogeneity of association across race/ethnicity included RNF144B (p` =0.0021) with increased hazards in Whites compared to Blacks, whereas WDR83 (p`=0.018), PRF1 (p`=0.0018), LYZ (p`=0.0028) had higher hazards in Blacks compared to Whites, and RAPGEF2 (p`=0.036) had higher hazards in Hispanics compared to Whites.

Conclusion: The risk index and dichotomized score derived from the previously developed 23-gene panel was significantly associated with OS among >40 year age group, with evidence of age effect heterogeneity. We detected 2 genes with an association that varied by age, and five across race/ethnicity, suggesting the importance of including diverse racial/ethnic and age groups in CHL patient populations when developing predictive models.

Disclosures: Allen: Daiichi Sankyo: Consultancy; Secura Bio: Consultancy; Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Flowers: Sanofi: Research Funding; Pfizer: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; Burroghs Wellcome Fund: Research Funding; Ziopharm: Research Funding; Cellectis: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Guardant: Research Funding; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Kite: Research Funding; Takeda: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Jannsen Pharmaceuticals: Research Funding; Iovance: Research Funding; Adaptimmune: Research Funding; 4D: Research Funding; Acerta: Research Funding; Spectrum: Consultancy; SeaGen: Consultancy; Pharmacyclics Jansen: Consultancy; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Genentech Roche: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Beigene: Consultancy; Abbvie: Consultancy, Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; CPRIT Scholar in Cancer Research: Research Funding. Svoboda: Adaptive: Consultancy, Research Funding; Atara: Consultancy; ADCT: Consultancy; Incyte: Consultancy, Research Funding; Genmab: Consultancy; Astra Zeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; SEAGEN: Consultancy, Research Funding. Scott: Janssen and Roche: Research Funding; Abbvie, AstraZeneca, Incyte: Consultancy. Steidl: Seattle Genetics, AbbVie, and Bayer: Consultancy; Bristol Myers Squibb, Epizyme and Trillium Therapeutics Inc.: Research Funding.

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