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

Autor: Wong J; Monash Haematology, Monash Health, Clayton, VIC, Australia.; Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Gruber E; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Maher B; Monash Haematology, Monash Health, Clayton, VIC, Australia.; Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Waltham M; Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Sabouri-Thompson Z; Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Jong I; Monash Health Imaging, Monash Health, Clayton, VIC, Australia.; Department of Imaging, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Luong Q; Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Levy S; Monash Health Imaging, Monash Health, Clayton, VIC, Australia.; Department of Imaging, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Kumar B; Monash Pathology, Monash Health, Clayton, VIC, Australia., Brasacchio D; Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Jia W; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., So J; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Skinner H; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Lewis A; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Hogg SJ; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Vervoort S; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., DiCorleto C; Monash Haematology, Monash Health, Clayton, VIC, Australia., Uhe M; Monash Haematology, Monash Health, Clayton, VIC, Australia., Gamgee J; Monash Haematology, Monash Health, Clayton, VIC, Australia., Opat S; Monash Haematology, Monash Health, Clayton, VIC, Australia.; Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Gregory GP; Monash Haematology, Monash Health, Clayton, VIC, Australia.; Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Polekhina G; Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia., Reynolds J; Biostatistics Consulting Platform, Monash University and Alfred Health, Prahran, VIC, Australia., Hawkes EA; Olivia Newton John Cancer Wellness and Research Centre, at Austin Health, Heidelberg, VIC, Australia.; Transfusion Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia., Kailainathan G; Haematology Department, Concord Repatriation General Hospital, Concord, NSW, Australia., Gasiorowski R; Haematology Department, Concord Repatriation General Hospital, Concord, NSW, Australia.; University of Sydney, Sydney, NSW, Australia., Kats LM; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Shortt J; Monash Haematology, Monash Health, Clayton, VIC, Australia. jake.shortt@monash.edu.; Blood Cancer Therapeutics Laboratory, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia. jake.shortt@monash.edu.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia. jake.shortt@monash.edu.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. jake.shortt@monash.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2022 Jun; Vol. 36 (6), pp. 1654-1665. Date of Electronic Publication: 2022 Apr 22.
DOI: 10.1038/s41375-022-01571-8
Abstrakt: 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. RHOA G17V 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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