Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.
Author
Fang, ZijianCorbizi Fattori, Giuditta
McKerrell, Thomas
Boucher, Rebecca H
Jackson, Aimee
Fletcher, Rachel S
Forte, Dorian
Martin, Jose-Ezequiel
Fox, Sonia
Roberts, James
Glover, Rachel
Harris, Erica
Bridges, Hannah R
Grassi, Luigi
Rodriguez-Meira, Alba
Mead, Adam J
Knapper, Steven
Ewing, Joanne
Butt, Nauman M
Jain, Manish
Francis, Sebastian
Clark, Fiona J
Coppell, Jason
McMullin, Mary F
Wadelin, Frances
Narayanan, Srinivasan
Milojkovic, Dragana
Drummond, Mark W
Sekhar, Mallika
ElDaly, Hesham
Hirst, Judy
Paramor, Maike
Baxter, E Joanna
Godfrey, Anna L
Harrison, Claire N
Méndez-Ferrer, Simón
Publication date
2023-11-25
Metadata
Show full item recordAbstract
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.Citation
Fang Z, Corbizi Fattori G, McKerrell T, Boucher RH, Jackson A, Fletcher RS, Forte D, Martin JE, Fox S, Roberts J, Glover R, Harris E, Bridges HR, Grassi L, Rodriguez-Meira A, Mead AJ, Knapper S, Ewing J, Butt NM, Jain M, Francis S, Clark FJ, Coppell J, McMullin MF, Wadelin F, Narayanan S, Milojkovic D, Drummond MW, Sekhar M, ElDaly H, Hirst J, Paramor M, Baxter EJ, Godfrey AL, Harrison CN, Méndez-Ferrer S. Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis. Nat Commun. 2023 Nov 25;14(1):7725. doi: 10.1038/s41467-023-43175-5. PMID: 38001082; PMCID: PMC10673935.Type
ArticlePMID
38001082Journal
Nature CommunicationsPublisher
Nature Publishing Groupae974a485f413a2113503eed53cd6c53
10.1038/s41467-023-43175-5