TY - JOUR
T1 - Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma
AU - Wong, Jonathan
AU - Gruber, Emily
AU - Maher, Belinda
AU - Waltham, Mark
AU - Sabouri-Thompson, Zahra
AU - Jong, Ian
AU - Luong, Quinton
AU - Levy, Sidney
AU - Kumar, Beena
AU - Brasacchio, Daniella
AU - Jia, Wendy
AU - So, Joan
AU - Skinner, Hugh
AU - Lewis, Alexander
AU - Hogg, Simon J.
AU - Vervoort, Stephin
AU - DiCorleto, Carmen
AU - Uhe, Micheleine
AU - Gamgee, Jeanette
AU - Opat, Stephen
AU - Gregory, Gareth P.
AU - Polekhina, Galina
AU - Reynolds, John
AU - Hawkes, Eliza A.
AU - Kailainathan, Gajan
AU - Gasiorowski, Robin
AU - Kats, Lev M.
AU - Shortt, Jake
N1 - Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128747724&partnerID=8YFLogxK
U2 - 10.1038/s41375-022-01571-8
DO - 10.1038/s41375-022-01571-8
M3 - Article
C2 - 35459873
AN - SCOPUS:85128747724
SN - 0887-6924
VL - 36
SP - 1654
EP - 1665
JO - Leukemia
JF - Leukemia
IS - 6
ER -