Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis PMID: 38001082

ADC Targets in Oncology

2026-04-10

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.

Zijian Fang ¹ ² ³ , Giuditta Corbizi Fattori ^# ¹ ² ³ , Thomas McKerrell ^# ¹ ³ ⁴ , Rebecca H Boucher ⁵ , Aimee Jackson ⁵ , Rachel S Fletcher ⁵ , Dorian Forte ¹ ² ³ , Jose-Ezequiel Martin ⁶ , Sonia Fox ⁵ , James Roberts ² , Rachel Glover ² , Erica Harris ² , Hannah R Bridges ⁷ , Luigi Grassi ² , Alba Rodriguez-Meira ⁸ , Adam J Mead ⁸ , Steven Knapper ⁹ , Joanne Ewing ¹⁰ , Nauman M Butt ¹¹ , Manish Jain ¹² , Sebastian Francis ¹³ , Fiona J Clark ¹⁰ , Jason Coppell ¹⁴ , Mary F McMullin ¹⁵ , Frances Wadelin ¹⁶ , Srinivasan Narayanan ¹⁷ , Dragana Milojkovic ¹⁸ , Mark W Drummond ¹⁹ , Mallika Sekhar ²⁰ , Hesham ElDaly ⁴ , Judy Hirst ⁷ , Maike Paramor ¹ , E Joanna Baxter ² , Anna L Godfrey ⁴ , Claire N Harrison ²¹ , Simón Méndez-Ferrer ²² ²³ ²⁴

Affiliations

1. Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK.
2. Department of Haematology, University of Cambridge, Cambridge, UK.
3. NHS Blood and Transplant, Cambridge, UK.
4. Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
5. Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
6. Cancer Molecular Diagnostic Laboratory, Department of Oncology, University of Cambridge, Cambridge, UK.
7. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
8. NIHR Biomedical Research Centre and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
9. School of Medicine, Cardiff University, Cardiff, UK.
10. University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
11. The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK.
12. St James University Hospital, Leeds, UK.
13. Sheffield Teaching Hospitals NHS Trust, Sheffield, UK.
14. Royal Devon and Exeter Hospital, Exeter, UK.
15. Queens University, Belfast, UK.
16. Nottingham University Hospital, Nottingham, UK.
17. University Hospital Southampton NHSFT, Southampton, UK.
18. Imperial College Healthcare NHS Trust, London, UK.
19. Beatson West of Scotland Cancer Centre, Glasgow, UK.
20. University College Hospital London, London, UK.
21. Guy's and Saint Thomas' NHS Foundation Trust, London, UK. [email protected].
22. Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK. [email protected].
23. Department of Haematology, University of Cambridge, Cambridge, UK. [email protected].
24. NHS Blood and Transplant, Cambridge, UK. [email protected].
# Contributed equally.

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 JAK2^V617F, CALR^ins5 or CALR^del52 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.