Leukemia/Lymphoma/Hematologic

SS 35 - Hematologic 3 -?Translating Better Technology to Improved Outcome in Primary and Relapsed Disease

253 - Exploring Host Germline Genetics to Help Identify Patients With Early Stage Lymphoma Who Might Benefit From the Addition of Radiation Therapy

Wednesday, October 24
8:05 AM - 8:15 AM
Location: Room 007 A/B

Exploring Host Germline Genetics to Help Identify Patients With Early Stage Lymphoma Who Might Benefit From the Addition of Radiation Therapy
S. C. Lester1, K. Taparra2, D. M. Routman1, M. J. Maurer3, S. M. Ansell4, A. L. Feldman5, B. K. Link6, B. J. Stish1, J. A. Martenson1, S. L. Slager3, S. L. Stafford1, T. M. Habermann4, and J. R. Cerhan3; 1Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 2Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN, 3Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 4Division of Hematology, Mayo Clinic, Rochester, MN, 5Department of Pathology, Mayo Clinic, Rochester, MN, 6Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA

Purpose/Objective(s): Radiation therapy (RT) improves event-free survival (EFS) for a subset of patients after systemic therapy for early stage classical Hodgkin (HL) and diffuse large B-cell lymphoma (DLBCL); however it is poorly understood which patients are most likely to benefit from the addition of RT. Host genetic background in immune function or chemotherapy metabolism genes may interact with treatment to impact outcome. In an exploratory study, we assessed whether single nucleotide polymorphisms (SNPs) from 27 candidate immune function and 20 chemotherapy metabolism genes predicted EFS in patients treated with chemotherapy (CT) alone , and for those SNPs associated with inferior EFS, whether this association was observed in patients treated with CT + RT.

Materials/Methods: We used a prospective cohort study of patients with Stage I/II HL or DLBCL. Event-free survival (EFS) was defined as time from diagnosis to disease progression, retreatment, or death. 265 SNPs from our candidate genes were selected from HapMap using a standard tagging approach (r2 ≥0.80 and minor allele frequency ≥0.05) and included SNPs 5kb upstream and downstream from the gene. Genotyping was conducted using a custom panel. The most prevalent homozygous genotype was used as the reference, and each SNP was modeled as having a log-additive effect in a Cox regression model adjusted for age and lymphoma subtype. In Stage 1, we identified SNPs that were associated with inferior EFS (p<0.05) in patients treated with CT alone. In stage 2, SNPs found to be associated with inferior EFS in Stage 1 were analyzed for an association with EFS in patients treated with CT+RT.

Results: 348 patients (138 HL; 210 DLBCL) were included in the analysis. The mean age was 54.5 years (range, 18-92) and 54% were male. Patients treated with CT only (n = 190) compared to CT+RT (n = 158) were more likely to have DLBCL (72 vs. 46%) and thus older (56 vs 45 years), but were similar on sex, performance status, and IPI/IPS risk grouping. In the CT only cohort, there were 80 events, while in the CT+RT cohort there were 29 events. In stage 1, 10 SNPs within the 7 candidate immune function genes and no chemotherapy metabolism genes were associated with inferior EFS in patients treated with CT only. In Stage 2, 7 of 10 SNPs associated with inferior EFS in Stage 1 were not associated with inferior EFS for patients treated with CT+RT, as displayed in the Table.

Conclusion: In this preliminary analysis, germline variation in 5 immune function genes was associated with differing EFS for patients treated with CT alone vs those treated with CT+RT. Further exploration is needed to determine if the addition of radiation could mitigate inferior outcomes associated with these genes.
Stage 1 CT only Stage 2 CT+RT
Gene SNP HR p-value HR p-value
BCL2 rs9955190 1.68 0.005 0.98 0.946
TBX21 rs16947058 1.55 0.008 1.00 0.995
rs2074190 1.45 0.040 0.88 0.663
PTPN6 rs10744724 2.27 0.008 0.24 0.143
C4BPA rs4844573 1.56 0.010 0.86 0.587
rs4571969 1.45 0.055 0.69 0.285
PRF1 rs10999423 2.44 0.036 0.93 0.906

Author Disclosure: S.C. Lester: Employee; Mayo Clinic. K. Taparra: None. D.M. Routman: Employee; Mayo Clinic. M.J. Maurer: None. A.L. Feldman: None. B.K. Link: None. J.A. Martenson: None. S.L. Stafford: Employee; Mayo Clinic.

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