Dataset Information

A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.

ABSTRACT: Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day -5 (5 mg orally 3 times a week) with tacrolimus initiated on day -3 plus sirolimus on day -1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8-matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor-stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.

SUBMITTER: Perez L

PROVIDER: S-EPMC8288668 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.

Perez Lia L Fernandez Hugo H Kharfan-Dabaja Mohamed M Khimani Farhad F Betts Brian B Mishra Asmita A Ayala Ernesto E Locke Frederick L FL Ochoa-Bayona Leonel L Nieder Michael M Pidala Joseph J Achille Alex A Powers John J Sahakian Eva E Thapa Ram R Wang Xuefeng X Anasetti Claudio C

Blood advances 20210701 13

Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day -5 (5 mg orally 3 times a week) with tacrolimus initiated on day -3 plus sirolimus on day -1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8-matched donors, related (n = 13) or unrelated (n = 2 ...[more]

PMID: 34242388

Similar Datasets

Project description:IntroductionOf the more than one million global cases of breast cancer diagnosed each year, approximately fifteen percent are characterized as triple-negative, lacking the estrogen, progesterone, and Her2/neu receptors. Lack of effective therapies, younger age at onset, and early metastatic spread have contributed to the poor prognoses and outcomes associated with these malignancies. Here, we investigate the ability of the histone deacetylase inhibitor panobinostat (LBH589) to selectively target triple-negative breast cancer (TNBC) cell proliferation and survival in vitro and tumorigenesis in vivo.MethodsTNBC cell lines MDA-MB-157, MDA-MB-231, MDA-MB-468, and BT-549 were treated with nanomolar (nM) quantities of panobinostat. Relevant histone acetylation was verified by flow cytometry and immunofluorescent imaging. Assays for trypan blue viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation, and DNA fragmentation were used to evaluate overall cellular toxicity. Changes in cell cycle progression were assessed with propidium iodide flow cytometry. Additionally, qPCR arrays were used to probe MDA-MB-231 cells for panobinostat-induced changes in cancer biomarkers and signaling pathways. Orthotopic MDA-MB-231 and BT-549 mouse xenograft models were used to assess the effects of panobinostat on tumorigenesis. Lastly, flow cytometry, ELISA, and immunohistochemical staining were applied to detect changes in cadherin-1, E-cadherin (CDH1) protein expression and the results paired with confocal microscopy in order to examine changes in cell morphology.ResultsPanobinostat treatment increased histone acetylation, decreased cell proliferation and survival, and blocked cell cycle progression at G2/M with a concurrent decrease in S phase in all TNBC cell lines. Treatment also resulted in apoptosis induction at 24 hours in all lines except the MDA-MB-468 cell line. MDA-MB-231 and BT-549 tumor formation was significantly inhibited by panobinostat (10 mg/kg/day) in mice. Additionally, panobinostat up-regulated CDH1 protein in vitro and in vivo and induced cell morphology changes in MDA-MB-231 cells consistent with reversal of the mesenchymal phenotype.ConclusionsThis study revealed that panobinostat is overtly toxic to TNBC cells in vitro and decreases tumorigenesis in vivo. Additionally, treatment up-regulated anti-proliferative, tumor suppressor, and epithelial marker genes in MDA-MB-231 cells and initiated a partial reversal of the epithelial-to-mesenchymal transition. Our results demonstrate a potential therapeutic role of panobinostat in targeting aggressive triple-negative breast cancer cell types.

Dataset Information

A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.

Publications

A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets