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Abstract
BackgroundAlthough 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.MethodsFour 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.ResultsIn 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).ConclusionsAn 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.
Highlights
Hematologic neoplasms (HNs) including Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), leukemia, and multiple myeloma [1] show high prevalence in many countries
A total of 64 epigenetic drugs were listed in the Human Epigenetic Drug Database (HEDD)
Four epigenetic drug candidates were selected from HEDD because they had been reported to have antitumor activity and had passed a phase II clinical trial to prove their safety
Summary
Hematologic neoplasms (HNs) including Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), leukemia, and multiple myeloma [1] show high prevalence in many countries. Chemotherapy is used as the first-line treatment for HN, but its therapeutic efficacy is limited and has various distressing side effects. Genetic instability and epigenetic instability are observed [6]. Cell activities such as cell proliferation, apoptosis, invasion, and senescence can be modulated by these modifications, and epigenetic dysregulations led to tumorigenesis [7]. Epigenetic treatment may restore chemosensitivity in relapsed/refractory patients by reversing drug resistance to chemotherapy [9,10,11,12], or trigger an innate immune response by alter the function of relevant immune cells to acquired immunity [13]. Several epigenetic drugs have been reported to have therapeutic efficacy for some hematologic neoplasms (HNs) in clinical trials, few achieved disease-free survival benefit. 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
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