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.
Introduction
Myeloproliferative neoplasms (MPN) arise from mutations acquired by HSPCs, most frequently affecting the genes encoding the kinase JAK21,2,3,4 or the multi-functional protein CALR5,6. Currently JAK1/2 inhibitors can improve disease-related symptoms and overall survival but have a limited impact on clone size7,8, likely because they cannot discriminate between mutant and wild-type JAK2 or due to the acquisition of pharmacological resistance9,10,11. Allogeneic HSC transplantation remains the only curative treatment for MPN but can only be performed in a minority of patients due to its toxicity12, warranting investigation of new therapies.
Men exhibit a higher prevalence of myeloid neoplasia compared with women13,14. Furthermore, MPN subtypes with poorer prognosis (primary myelofibrosis and polycythemia vera, compared with essential thrombocythemia) have a higher prevalence in males than in females15,16,17. Additionally, the risk of secondary myelofibrosis, which worsens the outcomes of PV/ET, is higher for men than for women, regardless of their age17,18,19. However, the reasons underlying this gender difference are unclear. It is possible that sex-chromosome genes and gender-dependent differences in epigenetic regulation, metabolism or immune response partly account for sexual dimorphism in cancer20. Another explanation might be the loss of sex chromosomes with age, which preferentially occurs in males, perhaps suggesting a higher genomic instability in men21.
However, one key determinant of gender disparities in cancer might be the effect of sex hormones20. Estrogens regulate the self-renewal, proliferation, and apoptosis of mouse hematopoietic stem and progenitor cells (HSPCs)22,23. Estrogen receptors (ERs) are differentially expressed in mouse HSPC subsets22. ERα activation induces proliferation of mouse long-term HSCs22,23 and protects them from proteotoxic stress through the modulation of UPR24. The selective ER modulator (SERM) tamoxifen induces apoptosis of multipotent hematopoietic progenitors but spares normal HSCs22. In MPN mouse models, tamoxifen restores the physiological apoptosis levels in mutant HSCs and selectively eliminates these cells, but not their non-mutated counterparts22. Based on these preclinical studies, we conducted a Phase II, multicenter, single-arm A’herns design clinical trial assessing tamoxifen’s safety and activity in reducing molecular markers of disease burden in MPN (TAMARIN). Here we report the results of the TAMARIN study. In addition, we describe an exploratory analysis of HSPCs from study patients and associated laboratory research investigating the mechanism of action of tamoxifen in human MPN.