Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK.
Department of Haematology, University of Cambridge, Cambridge, UK.
Nat Commun. 2023 Nov 25;14(1):7725. doi: 10.1038/s41467-023-43175-5.
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, CALR or CALR 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.
目前治疗骨髓增殖性肿瘤（MPN）的方法可以改善症状，但对肿瘤大小的影响有限。在临床前研究中，他莫昔芬恢复了突变造血干/祖细胞（HSPCs）中的正常凋亡。TAMARIN 二期、多中心、单臂临床试验评估了他莫昔芬在稳定 MPN、无血栓事件史和突变 JAK2、CALR 或 CALR 外周血等位基因负担≥20%的患者中的安全性和活性（EudraCT 2015-005497-38）。在 112 周内招募了 38 名患者，其中 32 名患者完成了 24 周的治疗。主要终点（在 24 周时突变等位基因负担降低≥50%）达到研究 A'herns 成功标准，38 名患者中有 3 名观察到该标准。次要终点包括在 24 周时降低≥25%（5/38）、在 12 周时降低≥50%（0/38）、血栓事件（2/38）、毒性、血液学反应、每个 IWG-MRT 反应类别和 ELN 反应标准中的患者比例。作为探索性终点，对 HSPC 转录组的基线分析将应答者和无应答者区分开来，提示存在一个预测性特征。在应答者的 HSPCs 中，纵向分析显示 JAK-STAT 信号和氧化磷酸化基因的基线表达较高，他莫昔芬可下调这些基因。我们进一步在临床前研究中表明，在 JAK2V617F+细胞中，4-羟基他莫昔芬抑制线粒体复合物-I，激活综合应激反应，降低致病的 JAK2 信号。这些结果证明了他莫昔芬在 MPN 中的进一步研究是合理的，需要仔细考虑血栓形成的风险。
