Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis

Zijian Fang, Giuditta Corbizi Fattori, Thomas McKerrell, Rebecca H. Boucher, Aimee Jackson, Rachel S. Fletcher, Dorian Forte, Jose-Ezequiel Martin, Sonia Fox, James Roberts, Rachel Glover, Erica Harris, Hannah R. Bridges, Luigi Grassi, Alba Rodriguez-Meira, Adam J. Mead, Steven Knapper, Joanne Ewing, Nauman M. Butt, Manish Jain, Sebastian Francis, Fiona J. Clark, Jason Coppell, Mary F. McMullin, Frances Wadelin, Srinivasan Narayanan, Dragana Milojkovic, Mark W. Drummond, Mallika Sekhar, Hesham ElDaly, Judy Hirst, Maike Paramor, E. Joanna Baxter, Anna L. Godfrey, Claire N. Harrison () and Simón Méndez-Ferrer ()
Additional contact information
Zijian Fang: Wellcome-MRC Cambridge Stem Cell Institute
Giuditta Corbizi Fattori: Wellcome-MRC Cambridge Stem Cell Institute
Thomas McKerrell: Wellcome-MRC Cambridge Stem Cell Institute
Rebecca H. Boucher: Cancer Research UK Clinical Trials Unit, University of Birmingham
Aimee Jackson: Cancer Research UK Clinical Trials Unit, University of Birmingham
Rachel S. Fletcher: Cancer Research UK Clinical Trials Unit, University of Birmingham
Dorian Forte: Wellcome-MRC Cambridge Stem Cell Institute
Jose-Ezequiel Martin: University of Cambridge
Sonia Fox: Cancer Research UK Clinical Trials Unit, University of Birmingham
James Roberts: University of Cambridge
Rachel Glover: University of Cambridge
Erica Harris: University of Cambridge
Hannah R. Bridges: University of Cambridge
Luigi Grassi: University of Cambridge
Alba Rodriguez-Meira: University of Oxford
Adam J. Mead: University of Oxford
Steven Knapper: School of Medicine, Cardiff University
Joanne Ewing: University Hospitals Birmingham NHS Foundation Trust
Nauman M. Butt: The Clatterbridge Cancer Centre NHS Foundation Trust
Manish Jain: St James University Hospital
Sebastian Francis: Sheffield Teaching Hospitals NHS Trust
Fiona J. Clark: University Hospitals Birmingham NHS Foundation Trust
Jason Coppell: Royal Devon and Exeter Hospital
Mary F. McMullin: Queens University
Frances Wadelin: Nottingham University Hospital
Srinivasan Narayanan: University Hospital Southampton NHSFT
Dragana Milojkovic: Imperial College Healthcare NHS Trust
Mark W. Drummond: Beatson West of Scotland Cancer Centre
Mallika Sekhar: University College Hospital London
Hesham ElDaly: Cambridge University Hospitals NHS Foundation Trust
Judy Hirst: University of Cambridge
Maike Paramor: Wellcome-MRC Cambridge Stem Cell Institute
E. Joanna Baxter: University of Cambridge
Anna L. Godfrey: Cambridge University Hospitals NHS Foundation Trust
Claire N. Harrison: Guy’s and Saint Thomas’ NHS Foundation Trust
Simón Méndez-Ferrer: Wellcome-MRC Cambridge Stem Cell Institute

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Current 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.

Date: 2023
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DOI: 10.1038/s41467-023-43175-5

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