Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC
Jai Narendra Patel , Qing Zhang , Issam Hamadeh , Nury Steuerwald , Alicia Hamilton , Jonathan Michael Gerber , Michael Richard Grunwald , Lawrence Druhan , Jiaxian He , Belinda Rene Avalos , Edward Alan Copelan
Background: Cy is the backbone for many SCT conditioning regimens and is used post-SCT to prevent graft vs. host disease (GVHD). It has been proposed that genetic polymorphisms impact Cy exposure and clinical outcomes; however, no PGx studies have been performed in pts receiving FluCyTBI-postCy. Methods: Germline DNA from SCT pts receiving FluCyTBI-postCy was genotyped using a custom Ion AmpliSeq™ PGx Panel for polymorphisms in: ALDH1A1 (*2), ALDH3A1 (Pro329Ala), GSTA1 (135T > C), GSTM1 (null), GSTP1 (Ile105Val, Ala114Val), CYP2B6 (*2, *4, *5, *6, *18, *22), CYP2C8 (*2, *3), CYP2C9 (*2, *3, *8, *11), CYP2C19 (*2, *3, *17), CYP3A4 (*1B, *22), and CYP3A5 (*3, *6, *7). Phenotypes (poor [PM], intermediate [IM], normal [NM], and rapid metabolizers [RM]) were inferred based on literature. Cy 14.5 mg/kg IV was given on days -6 & -5 pre-SCT, and 50 mg/kg on days +3 & +4 post-SCT. Univariate logistic regression was used to investigate the association between polymorphisms and any grade cardiotoxicity, hemorrhage cystitis [HC], liver toxicity, and/or acute GVHD up to day +100. Univariate Cox proportional hazards regression was used to investigate the association between polymorphisms and overall [OS] & progression-free survival [PFS]. Results: In 59 evaluable pts, the median age was 57 (24-77), 61% were male, 73% received haploidentical SCT and 27% matched related donor SCT. The table summarizes significant findings (P < 0.05). Conclusions: Several genes involved in the activation (CYPs) and inactivation (ALDHs&GSTs) of Cy and its metabolites were associated with SCT outcomes and toxicities. Prospective studies exploring the combined effects of these genes on outcomes are needed to validate findings.
Phenotype | Gene | HR/OR | 95% CI | P-value |
---|---|---|---|---|
OS | ALDH3A1 IM v PM | 0.22 | 0.06-0.82 | 0.024 |
CYP3A5 NM v PM | 5.67 | 1.20-26.7 | 0.028 | |
CYP3A4 NM v IM RM v IM | 0.17 0.22 | 0.05-0.63 0.05-0.92 | 0.008 0.038 | |
PFS | CYP3A4 NM v IM RM v IM | 0.14 0.18 | 0.04-0.45 0.05-0.66 | 0.001 0.009 |
CYP2C8 NM v IM | 0.48 | 0.24-0.97 | 0.039 | |
Cardiotox | GSTP1 IM v PM NM v PM | 0.19 0.09 | 0.04-0.82 0.01-0.45 | 0.031 0.007 |
HC | ALDH1A1 NM v IM | 0.09 | 0.004-0.65 | 0.036 |
Liver tox | CYP2C8 NM v IM | 0.23 | 0.05-0.83 | 0.038 |
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