Epigenetics-Associated Risk Reduction of Hematologic Neoplasms in a Nationwide Cohort Study: The Chemopreventive and Therapeutic Efficacy of Hydralazine

Bing-Heng Yang; Wei-Zhi Lin; Yu-Ting Chiang; Yeu-Chin Chen; Chi-Hsiang Chung; Wu-Chien Chien; Chia-Yang Shiau

doi:10.3389/fonc.2022.809014

Epigenetics-Associated Risk Reduction of Hematologic Neoplasms in a Nationwide Cohort Study: The Chemopreventive and Therapeutic Efficacy of Hydralazine

Front Oncol. 2022 Feb 2:12:809014. doi: 10.3389/fonc.2022.809014. eCollection 2022.

Authors

Bing-Heng Yang^{1

2}, Wei-Zhi Lin^{3

4}, Yu-Ting Chiang⁵, Yeu-Chin Chen⁶, Chi-Hsiang Chung^{7

8

9}, Wu-Chien Chien^{7

8

9}, Chia-Yang Shiau^{1

3

4}

Affiliations

¹ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
² Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan.
³ Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
⁴ Fidelity Regulation Therapeutics Inc., Taoyuan City, Taiwan.
⁵ Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.
⁶ Division of Hematology and Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
⁷ School of Public Health, National Defense Medical Center, Taipei, Taiwan.
⁸ Department of Medical Research, Tri-Service General Hospital, Taipei, Taiwan.
⁹ Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan.

Abstract

Background: Although several epigenetic drugs have been reported to have therapeutic efficacy for some hematologic neoplasms (HNs) in clinical trials, few achieved disease-free survival benefit. The traditional drug discovery pathway is costly and time-consuming, and thus, more effective strategies are required. We attempted to facilitate epigenetic drug repositioning for therapy of HNs by screening the Human Epigenetic Drug Database (HEDD) in the web, conducting a bench-work cytotoxicity test and a retrospective nationwide cohort study prior to a clinical trial.

Methods: Four FDA-approved epigenetic drugs with antitumor properties and completion of clinical phase II trials were selected from HEDD. Hydralazine (HDZ) and valproate (VAL) among the four were selected with higher cytotoxicity to HN cells, no matter whether carrying the JAK2V617F mutation or not. Both of them were chosen for a cohort study using the Longitudinal Health Insurance Database (LHID) 2000-2015 (N = 1,936,512), a subset of the National Health Insurance Research Database (NHIRD, N= 25.68 millions) in Taiwan.

Results: In the initial cohort, HDZ or VAL exposure subjects (11,049) and matching reference subjects (44,196) were enrolled according to maximal daily consumption (300/2,100 mg per day of HDZ/VAL). The HN incidence in HDZ and VAL exposure groups reduced from 4.97% to 3.90% (p <.001) and 4.45% (p = .075), respectively. A further cohort study on HDZ at a lower range of the WHO defined daily dose (<34 mg per day) and HN incidence of HDZ exposure subjects (75,612) reduced from 5.01% to 4.16% (p = 1.725 × 10 ^-18) compared to the reference subjects (302,448).

Conclusions: An association of a chronically prescribed HDZ, even prescribed low dose, with reduction of overall incidence rate and in most subgroups of HN was observed in our study. Repositioning HDZ for HN management may be feasible. This is the first nationwide cohort study of the epigenetics-associated risk evaluation of overall HN in the existing literature, showing an effective method with a wider scope to inform contemporary clinical trials of epigenetic drugs in the future.

Keywords: cohort; drug repositioning; epigenetic drug; hematologic neoplasms; hydralazine.