Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma

Jonathan Wong, Emily Gruber, Belinda Maher, Mark Waltham, Zahra Sabouri-Thompson, Ian Jong, Quinton Luong, Sidney Levy, Beena Kumar, Daniella Brasacchio, Wendy Jia, Joan So, Hugh Skinner, Alexander Lewis, Simon J. Hogg, Stephin Vervoort, Carmen DiCorleto, Micheleine Uhe, Jeanette Gamgee, Stephen OpatGareth P. Gregory, Galina Polekhina, John Reynolds, Eliza A. Hawkes, Gajan Kailainathan, Robin Gasiorowski, Lev M. Kats, Jake Shortt

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1–5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.

Original languageEnglish
Number of pages12
JournalLeukemia
DOIs
Publication statusAccepted/In press - 2022

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