Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis
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Published:2023-11-25
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Fang Zijian, Corbizi Fattori Giuditta, McKerrell ThomasORCID, Boucher Rebecca H., Jackson Aimee, Fletcher Rachel S., Forte DorianORCID, Martin Jose-EzequielORCID, Fox Sonia, Roberts James, Glover Rachel, Harris Erica, Bridges Hannah R.ORCID, Grassi Luigi, Rodriguez-Meira Alba, Mead Adam J.ORCID, Knapper StevenORCID, Ewing Joanne, Butt Nauman M., Jain Manish, Francis Sebastian, Clark Fiona J., Coppell Jason, McMullin Mary F.ORCID, Wadelin Frances, Narayanan Srinivasan, Milojkovic Dragana, Drummond Mark W., Sekhar Mallika, ElDaly Hesham, Hirst JudyORCID, Paramor MaikeORCID, Baxter E. JoannaORCID, Godfrey Anna L., Harrison Claire N., Méndez-Ferrer SimónORCID
Abstract
AbstractCurrent therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study’s A’herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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