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; Simón Méndez-Ferrer

doi:10.1038/s41467-023-43175-5

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 JainSebastian 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^*, Simón Méndez-Ferrer^*

^*Corresponding author for this work

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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.

Original language	English
Article number	7725
Number of pages	21
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-43175-5
Publication status	Published - 25 Nov 2023

Bibliographical note

Acknowledgements
We thank the patients and their families for making this study possible; the support by Blood Cancer UK under the Trials Acceleration Programme (TAP) and the Trial Steering Committee members T. Sommervaille, S. Ali and J. Lambert for study design, data collection, and analysis; C. Fielding, H. Matsubara, C. Bernardo-Castiñeira, A. Sommerschield and members of the S.M.-F. group for help and discussions; J. Carroll, B. Huntly, J. Li, and A.R. Green for critical advice and support; Cambridge NIHR BRC Cell Phenotyping Hub for technical assistance; D. Bexheti and R. Houghton (Cancer Research UK) for LC-MS/MS. Samples were provided by the Cambridge Blood and Stem Cell Biobank, which is supported by the Cambridge NIHR Biomedical Research Centre, Wellcome Trust - MRC Stem Cell Institute and the Cambridge Experimental Cancer Medicine Centre, UK. Z.F. was supported by CSC-Cambridge Trust Scholarship. T.M. was supported by NIHR Starter Grant for Clinical Lecturers (SGL018/1032). D.F. was supported by Associazione Italiana Ricerca sul Cancro (AIRC-Fellowship 20930 for Abroad) and scholarships from Società Italiana di Ematologia (SIE) and Associazione “Amici di Beat Leukemia Dr. Alessandro Cevenini ONLUS” and AIL Bologna ODV. H.R.B. and J.H. were supported by the Medical Research Council (MC_UU_00015/2). S.M.-F was supported by the National Health Service Blood and Transplant (United Kingdom). S.M.-F was supported by European Union’s Horizon 2020 research (ERC-2014-CoG-648765). S.M.-F was supported by MRC-AMED grant MR/V005421/1. S.M.-F was supported by a Programme Foundation Award (C61367/A26670) from Cancer Research UK. This research was funded in whole, or in part, by the Wellcome Trust 203151/Z/16/Z] and the UKRI Medical Research Council [MC_PC_17230]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

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Fang, Z., Corbizi Fattori, G., McKerrell, T., Boucher, R. H., Jackson, A., Fletcher, R. S., Forte, D., Martin, J.-E., Fox, S., Roberts, J., Glover, R., Harris, E., Bridges, H. R., Grassi, L., Rodriguez-Meira, A., Mead, A. J., Knapper, S., Ewing, J., Butt, N. M., ... Méndez-Ferrer, S. (2023). Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis. Nature Communications, 14(1), Article 7725. https://doi.org/10.1038/s41467-023-43175-5

@article{60e7b5f14ab44f8c831181a03f0158f6,

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

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{\textquoteright}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{\textquoteright}s A{\textquoteright}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.",

author = "Zijian Fang and {Corbizi Fattori}, Giuditta and Thomas McKerrell and Boucher, {Rebecca H.} and Aimee Jackson and Fletcher, {Rachel S.} and Dorian Forte and Jose-Ezequiel Martin and Sonia Fox and James Roberts and Rachel Glover and Erica Harris and Bridges, {Hannah R.} and Luigi Grassi and Alba Rodriguez-Meira and Mead, {Adam J} and Steven Knapper and Joanne Ewing and Butt, {Nauman M.} and Manish Jain and Sebastian Francis and Clark, {Fiona J.} and Jason Coppell and McMullin, {Mary F.} and Frances Wadelin and Srinivasan Narayanan and Dragana Milojkovic and Drummond, {Mark W.} and Mallika Sekhar and Hesham ElDaly and Judy Hirst and Maike Paramor and Baxter, {E. Joanna} and Godfrey, {Anna L.} and Harrison, {Claire N.} and Sim{\'o}n M{\'e}ndez-Ferrer",

note = "Acknowledgements We thank the patients and their families for making this study possible; the support by Blood Cancer UK under the Trials Acceleration Programme (TAP) and the Trial Steering Committee members T. Sommervaille, S. Ali and J. Lambert for study design, data collection, and analysis; C. Fielding, H. Matsubara, C. Bernardo-Casti{\~n}eira, A. Sommerschield and members of the S.M.-F. group for help and discussions; J. Carroll, B. Huntly, J. Li, and A.R. Green for critical advice and support; Cambridge NIHR BRC Cell Phenotyping Hub for technical assistance; D. Bexheti and R. Houghton (Cancer Research UK) for LC-MS/MS. Samples were provided by the Cambridge Blood and Stem Cell Biobank, which is supported by the Cambridge NIHR Biomedical Research Centre, Wellcome Trust - MRC Stem Cell Institute and the Cambridge Experimental Cancer Medicine Centre, UK. Z.F. was supported by CSC-Cambridge Trust Scholarship. T.M. was supported by NIHR Starter Grant for Clinical Lecturers (SGL018/1032). D.F. was supported by Associazione Italiana Ricerca sul Cancro (AIRC-Fellowship 20930 for Abroad) and scholarships from Societ{\`a} Italiana di Ematologia (SIE) and Associazione “Amici di Beat Leukemia Dr. Alessandro Cevenini ONLUS” and AIL Bologna ODV. H.R.B. and J.H. were supported by the Medical Research Council (MC_UU_00015/2). S.M.-F was supported by the National Health Service Blood and Transplant (United Kingdom). S.M.-F was supported by European Union{\textquoteright}s Horizon 2020 research (ERC-2014-CoG-648765). S.M.-F was supported by MRC-AMED grant MR/V005421/1. S.M.-F was supported by a Programme Foundation Award (C61367/A26670) from Cancer Research UK. This research was funded in whole, or in part, by the Wellcome Trust 203151/Z/16/Z] and the UKRI Medical Research Council [MC_PC_17230]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.",

year = "2023",

month = nov,

day = "25",

doi = "10.1038/s41467-023-43175-5",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

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number = "1",

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Fang, Z, Corbizi Fattori, G, McKerrell, T, Boucher, RH , Jackson, A, Fletcher, RS, Forte, D, Martin, J-E, 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 2023, 'Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis', Nature Communications, vol. 14, no. 1, 7725. https://doi.org/10.1038/s41467-023-43175-5

TY - JOUR

T1 - Tamoxifen for the treatment of myeloproliferative neoplasms

T2 - A Phase II clinical trial and exploratory analysis

AU - Fang, Zijian

AU - Corbizi Fattori, Giuditta

AU - McKerrell, Thomas

AU - Boucher, Rebecca H.

AU - Jackson, Aimee

AU - Fletcher, Rachel S.

AU - Forte, Dorian

AU - Martin, Jose-Ezequiel

AU - Fox, Sonia

AU - Roberts, James

AU - Glover, Rachel

AU - Harris, Erica

AU - Bridges, Hannah R.

AU - Grassi, Luigi

AU - Rodriguez-Meira, Alba

AU - Mead, Adam J

AU - Knapper, Steven

AU - Ewing, Joanne

AU - Butt, Nauman M.

AU - Jain, Manish

AU - Francis, Sebastian

AU - Clark, Fiona J.

AU - Coppell, Jason

AU - McMullin, Mary F.

AU - Wadelin, Frances

AU - Narayanan, Srinivasan

AU - Milojkovic, Dragana

AU - Drummond, Mark W.

AU - Sekhar, Mallika

AU - ElDaly, Hesham

AU - Hirst, Judy

AU - Paramor, Maike

AU - Baxter, E. Joanna

AU - Godfrey, Anna L.

AU - Harrison, Claire N.

AU - Méndez-Ferrer, Simón

N1 - Acknowledgements We thank the patients and their families for making this study possible; the support by Blood Cancer UK under the Trials Acceleration Programme (TAP) and the Trial Steering Committee members T. Sommervaille, S. Ali and J. Lambert for study design, data collection, and analysis; C. Fielding, H. Matsubara, C. Bernardo-Castiñeira, A. Sommerschield and members of the S.M.-F. group for help and discussions; J. Carroll, B. Huntly, J. Li, and A.R. Green for critical advice and support; Cambridge NIHR BRC Cell Phenotyping Hub for technical assistance; D. Bexheti and R. Houghton (Cancer Research UK) for LC-MS/MS. Samples were provided by the Cambridge Blood and Stem Cell Biobank, which is supported by the Cambridge NIHR Biomedical Research Centre, Wellcome Trust - MRC Stem Cell Institute and the Cambridge Experimental Cancer Medicine Centre, UK. Z.F. was supported by CSC-Cambridge Trust Scholarship. T.M. was supported by NIHR Starter Grant for Clinical Lecturers (SGL018/1032). D.F. was supported by Associazione Italiana Ricerca sul Cancro (AIRC-Fellowship 20930 for Abroad) and scholarships from Società Italiana di Ematologia (SIE) and Associazione “Amici di Beat Leukemia Dr. Alessandro Cevenini ONLUS” and AIL Bologna ODV. H.R.B. and J.H. were supported by the Medical Research Council (MC_UU_00015/2). S.M.-F was supported by the National Health Service Blood and Transplant (United Kingdom). S.M.-F was supported by European Union’s Horizon 2020 research (ERC-2014-CoG-648765). S.M.-F was supported by MRC-AMED grant MR/V005421/1. S.M.-F was supported by a Programme Foundation Award (C61367/A26670) from Cancer Research UK. This research was funded in whole, or in part, by the Wellcome Trust 203151/Z/16/Z] and the UKRI Medical Research Council [MC_PC_17230]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

PY - 2023/11/25

Y1 - 2023/11/25

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-023-43175-5

DO - 10.1038/s41467-023-43175-5

M3 - Article

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7725

ER -

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

Abstract

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