Recurrent PD-L1 Structural Rearrangements in Natural Killer/T Cell Lymphoma Patients with Complete Response to PD-1 Blockade Therapy
Burton Kuan Hui Chia,
Da Chuan Huang,
Wan Lu Pang,
Daryl Ming Zhe Cheah,
Cedric Chuan Young Ng,
Qi Chun Cai,
Nicholas Francis Grigoropoulos,
Yeow Tee Goh,
Chee Leong Cheng,
Yuh Shan Lee,
Thomas Sau-Yan Chan,
Bin Tean Teh,
Chiea Chuen Khor,
ICGC Blood Cancer T-cell and NK-cell lymphoma group,
Soon Thye Lim,
Choon Kiat Ong
Posted 19 Jul 2018
bioRxiv DOI: 10.1101/372383
Posted 19 Jul 2018
Natural killer/ T-cell lymphoma (NKTL) patients failing L-asparaginase regimens have extremely poor treatment outcomes. Previous case series showed promising activity when relapsed or refractory NKTL patients were treated with anti-programmed death 1 (PD1) inhibitors. Here, we continue to unravel the molecular profiles with whole-genome sequencing (WGS) on an extended cohort of 11 pembrolizumab-treated patients (median age at diagnosis, 42 years; range, 27-66 years) with a median follow-up of 11 months (range, 2 - 25 months) since starting anti-PD1 therapy. Seven patients achieved complete response (CR) and four patients had progressive disease (PD). Using WGS, we found structural rearrangements of the PD-L1 gene, JAK3-activating mutations and ARID1B homozygous insertion in four, two and one of the CR patient's tumors, respectively. Interesting, these alterations, especially PD-L1 rearrangements, were absent in the four PD cases. Expression of PD1 ligand (PD-L1) was strong in nine patients (5 CR and 4 PD cases) and weak in two patients (both CR). PD1 blockade with pembrolizumab was a potent strategy for NKTL patients and genomic screening could potentially accompany PD-L1 immunohistochemical screening to better select patients for anti-PD1 therapy.
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