Circulating tumor DNA predicts response in Chinese patients with relapsed or refractory classical hodgkin lymphoma treated with sintilimab

Yuankai Shi, Hang Su, Yongping Song, Wenqi Jiang, Xiuhua Sun, Wenbin Qian, Wei Zhang, Yuhuan Gao, Zhengming Jin, Jianfeng Zhou, Chuan Jin, Liqun Zou, Lugui Qiu, Wei Li, Jianmin Yang, Ming Hou, Yan Xiong, Hui Zhou, Xinhua Du, Xiong Wang, Bo Peng, Yuankai Shi, Hang Su, Yongping Song, Wenqi Jiang, Xiuhua Sun, Wenbin Qian, Wei Zhang, Yuhuan Gao, Zhengming Jin, Jianfeng Zhou, Chuan Jin, Liqun Zou, Lugui Qiu, Wei Li, Jianmin Yang, Ming Hou, Yan Xiong, Hui Zhou, Xinhua Du, Xiong Wang, Bo Peng

Abstract

Background: Blood-based biomarker such as circulating tumor DNA (ctDNA) has emerged as a promising tool for assessment of response to immunotherapy in solid tumors; But in hematological malignances, evidences are still lacking to support its clinical utility. In current study the feasibility of ctDNA for prediction and monitoring of response to anti-PD-1 therapy in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r cHL) was assessed.

Methods: A total of 192 plasma samples from 75 patients with r/r cHL were collected at baseline and upon therapeutic evaluation. ctDNA were sequenced by targeting panels capturing frequently mutated genes in cHL and other hematological malignancies and then quantified. Analysis on: 1) Gene mutation profile and association of the gene mutations with progression-free survival; 2) Association of pre- and post-treatment ctDNA variant allelic frequencies with clinical outcome; (3) Correlation of the mutated genes with treatment resistance; were performed.

Findings: Somatic mutations were detected in 50 out of 61 patients by ctDNA genotyping. The mutations of CHD8 was significantly higher in patients with PFS ≥ 12 months. Baseline ctDNA was significantly higher in responders and a decrease of ctDNA ≥ 40% from baseline indicated superior clinical outcome. Strong agreement between ctDNA dynamic and radiographic response change during therapy was observed in majority of the patients. Furthermore, the mutations of B2M, TNFRSF14 and KDM2B were found to be associated with acquired resistance.

Interpretation: ctDNA could be an informative biomarker for anti-PD-1 immunotherapy in r/r cHL.

Funding: This work was supported by Innovent Biologics, Eli Lilly and Companyhttps://doi.org/10.13039/501100002852, China National New Drug Innovation Program (2014ZX09201041-001 and 2017ZX09304015), Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001) and National Key Scientific Program Precision Medicine Research Fund of China (2017YFC0909801). The funders had no role in study design, data collection, data analysis, interpretation or writing.

Keywords: Biomarker; Circulating tumor DNA; Classical hodgkin lymphoma; Immunotherapy; Sintilimab; anti-PD-1.

Conflict of interest statement

Declaration of Competing Interest Yan Xiong, Hui Zhou, Xiong Wang, and Bo Peng are employees of Innovent Biologics (Suzhou) Co., Ltd. Xinhua Du is an employee of Geneplus-Beijing. All other authors declare no competing interests.

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Scheme of blood samples for circulating tumor DNA (ctDNA) analysis. A flowchart showing the blood samples of participants analyzed in the study.
Fig. 2
Fig. 2
The mutation profiling in relapse/refractory classical Hodgkin lymphoma before sintilimab treatment. A comparison between the progression-free survival (PFS)

Fig. 3

Association between baseline ctDNA levels…

Fig. 3

Association between baseline ctDNA levels and clinical outcomes. (a) Baseline ctDNA VAFs in…

Fig. 3
Association between baseline ctDNA levels and clinical outcomes. (a) Baseline ctDNA VAFs in patients with complete remission (CR) + partial remission (PR) (n = 41, red) vs. stable disease (SD) + progressive disease (PD) (n = 9, blue). (b) Receiver operative curve (ROC) analysis illustrates the performance of ctDNA content in the different response group. (c) Time-to-response (TTR) analysis of patients with different ctDNA VAF at baseline. (d) Progression-free survival (PFS) analysis of patients with different ctDNA contents at baseline.

Fig. 4

Agreement between ctDNA response and…

Fig. 4

Agreement between ctDNA response and best radiographic response after two treatment cycles. (a)…

Fig. 4
Agreement between ctDNA response and best radiographic response after two treatment cycles. (a) Agreement of ctDNA VAF change and best radiographic response. Dotted lines indicate a decrease of ctDNA at 40% after two treatment cycles. (b) The maximum change of tumor area (mm2) post-treatment from baseline. Red outline indicates patients who achieved a ctDNA decrease ≥ 40%. (c) Time-to-response (TTR) analysis of patients with a ctDNA decrease ≥ 40% vs. patients with a ctDNA decrease < 40%. (d) Percentage change in ctDNA VAF from baseline during the first 8 treatment cycles of immunotherapy among patients with a ≥ 60% decrease (n = 17) or a <60% decrease (n = 17) in tumor burden defined by PET/CT scan.

Fig. 5

Correlation of ctDNA response to…

Fig. 5

Correlation of ctDNA response to radiographic response during sintilimab therapy. Plasma levels of…

Fig. 5
Correlation of ctDNA response to radiographic response during sintilimab therapy. Plasma levels of ctDNA (red line) and measurements of radiographic tumor area (mm2) (blue line) are plotted for three representative patients. (a) Patient 7002, a 36-year-old woman achieved persistent ctDNA response and radiographic response after treatment. (b) Patient 3018, a 33-year-old man who achieved ctDNA and radiographic response after 2 treatment cycles, and then progressed after 12 cycles. (c) Patient 21,003, a 26-year-old woman who showed an increase of ctDNA VAF and radiographic progression after 2 cycles, showed ctDNA decrease with radiographic responses after 8 cycles. ctDNA and radiographic measurements for the remaining 31 patients in the study are presented in Supplementary Table 6.
Fig. 3
Fig. 3
Association between baseline ctDNA levels and clinical outcomes. (a) Baseline ctDNA VAFs in patients with complete remission (CR) + partial remission (PR) (n = 41, red) vs. stable disease (SD) + progressive disease (PD) (n = 9, blue). (b) Receiver operative curve (ROC) analysis illustrates the performance of ctDNA content in the different response group. (c) Time-to-response (TTR) analysis of patients with different ctDNA VAF at baseline. (d) Progression-free survival (PFS) analysis of patients with different ctDNA contents at baseline.
Fig. 4
Fig. 4
Agreement between ctDNA response and best radiographic response after two treatment cycles. (a) Agreement of ctDNA VAF change and best radiographic response. Dotted lines indicate a decrease of ctDNA at 40% after two treatment cycles. (b) The maximum change of tumor area (mm2) post-treatment from baseline. Red outline indicates patients who achieved a ctDNA decrease ≥ 40%. (c) Time-to-response (TTR) analysis of patients with a ctDNA decrease ≥ 40% vs. patients with a ctDNA decrease < 40%. (d) Percentage change in ctDNA VAF from baseline during the first 8 treatment cycles of immunotherapy among patients with a ≥ 60% decrease (n = 17) or a <60% decrease (n = 17) in tumor burden defined by PET/CT scan.
Fig. 5
Fig. 5
Correlation of ctDNA response to radiographic response during sintilimab therapy. Plasma levels of ctDNA (red line) and measurements of radiographic tumor area (mm2) (blue line) are plotted for three representative patients. (a) Patient 7002, a 36-year-old woman achieved persistent ctDNA response and radiographic response after treatment. (b) Patient 3018, a 33-year-old man who achieved ctDNA and radiographic response after 2 treatment cycles, and then progressed after 12 cycles. (c) Patient 21,003, a 26-year-old woman who showed an increase of ctDNA VAF and radiographic progression after 2 cycles, showed ctDNA decrease with radiographic responses after 8 cycles. ctDNA and radiographic measurements for the remaining 31 patients in the study are presented in Supplementary Table 6.

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