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Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia

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Abstract

Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy and safety of PD-1 inhibitor with DNA hypomethylating agent (HMA) + CAG regimen in patients who had failed prior AML therapy. In this phase 2, single-arm study, r/r AML patients received azacitidine or decitabine plus CAG regimen with tislelizumab. Primary endpoints were efficacy (objective response rate [ORR]) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). Statistical analyses were performed using Stata 14.0 and SPSS 20.0 software where P < 0.05 denoted significance. Twenty-seven patients were enrolled patients and completed 1 cycle, and 14 (51.9%) and 4 (14.8%) patients completed 2 and 3 cycles, respectively. ORR was 63% (14: complete remission [CR]/CR with incomplete hematologic recovery [CRi], 3: partial remission (PR), 10: no response [NR]). Median OS (mOS) and EFS were 9.7 and 9.2 months, respectively. With a median follow-up of 8.2 months (1.1–26.9), the mOS was not reached in responders (CR/CRi/PR) while it was 2.4 months (0.0–5.4) in nonresponders (P = 0.002). Grade 2–3 immune-related adverse events (irAEs) were observed in 4 (14.8%) patients and 3 nonresponders died of lung infection after treatment. Tislelizumab + HMA + CAG regimen showed improved outcomes in r/r AML patients with lower pretherapy leukemia burden. irAEs were mild and low-grade and higher pretherapy bone marrow CD4+ CD127+ PD-1+ T cells might serve as a predictor of treatment response.

ClinicalTrials.gov identifier NCT04541277.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the National Natural Science Foundation of China for the partial funding support provided to conduct the study.

Funding

This work was partially supported by grants from the National Natural Science Foundation of China (82070149 to X-N G).

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  1. **ao-Ning Gao, Yong-Feng Su, Meng-yue Li and Yu **g have contributed equally to this work.

Authors and Affiliations

  1. Senior Department of Hematology, The Fifth Medical Center, Chinese PLA General Hospital, 8 East Main Street, Bei**g, 100071, China

    **ao-Ning Gao, Yong-Feng Su, Meng-yue Li, Jun Wang, Lei Xu, An Wang, Yi-Zhi Wang, Xuan Zheng & Dai-Hong Liu

  2. Department of Hematology, The First Medical Center, Chinese PLA General Hospital, Bei**g, 100853, China

    Yu **g, Lin-Lin Zhang & Yan-Fen Li

  3. Graduate School, Chinese PLA General Hospital, Bei**g, 100853, China

    Meng-yue Li

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Contributions

XNG was involved in conceptualization, funding acquisition, investigations, data curation, data analysis and manuscript writing. YFS was responsible for patient enrollment, investigation and data curation. MYL contributed to patient follow-up and data analysis. YJ, JW, LX, LLZ, AW, YZW, XZ and YFL participated in patient enrollment and data curation. DHL took part in conceptualization, supervision, resources and project administration.

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Correspondence to **ao-Ning Gao or Dai-Hong Liu.

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All the authors declare no financial or other conflicts of interest.

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The study protocol was approved by the Ethics Committee of Chinese PLA General Hospital and investigators abided by Good Clinical Practice, as described in the International Council for Harmonization guideline E6 and in accordance with the general ethical principles as outlined in the Declaration of Helsinki.

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Signed informed consent was obtained from all patients or respective guardians prior to treatment.

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Gao, XN., Su, YF., Li, My. et al. Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia. Cancer Immunol Immunother 72, 2769–2782 (2023). https://doi.org/10.1007/s00262-023-03454-y

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