Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.
Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.
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DOI：
10.1038/s41467-023-43175-5
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发表时间：
2023-11-25
影响因子：
16.6
通讯作者：
Méndez-Ferrer S
中科院分区：
文献类型：
--
作者：
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
目前骨髓增生性肿瘤（MPN）的治疗可改善症状，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（HSPC）的正常凋亡。TAMARIN II期、多中心、单组临床试验评估了他莫昔芬在MPN稳定、既往无血栓形成事件且突变JAK 2 V617 F、CALRins 5或CALRdel 52外周血等位基因负荷≥20%的患者中的安全性和活性（EudraCT 2015-005497-38）。38例患者在112周内招募，32例完成24周治疗。由于在3/38例患者中观察到主要结局（24周时突变等位基因负荷降低≥ 50%），因此符合研究的A 'herns成功标准。次要结局包括24周时降低≥25%（5/38）、12周时降低≥50%（0/38）、血栓形成事件（2/38）、毒性、血液学缓解、各IWG-MRT缓解类别和ELN缓解标准中的患者比例。作为探索性结局，HSPC转录组的基线分析将应答者和非应答者分开，表明具有预测性特征。在应答者HSPC中，纵向分析显示JAK-STAT信号传导和氧化磷酸化基因的高基线表达，其被他莫昔芬下调。我们在临床前研究中进一步证明，在JAK 2 V617 F+细胞中，4-羟基他莫昔芬抑制线粒体复合物-I，激活整合的应激反应并降低致病性JAK 2信号传导。这些结果需要进一步研究他莫昔芬在MPN中的作用，并仔细考虑血栓形成的风险。临床前研究表明骨髓增生性肿瘤（MPN）可能对雌激素受体调节剂他莫昔芬敏感。在这里，作者提出了一个II期临床试验报告的疗效，他莫昔芬在MPN和外周造血干细胞的分析，以确定潜在的预测签名的反应。
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. Preclinical studies indicate that myeloproliferative neoplasms (MPN) may be sensitive to the estrogen receptor modulator, tamoxifen. Here, the authors present a phase II clinical trial reporting the efficacy of tamoxifen in MPN and analysis of peripheral haematopoietic stem cells to identify potential predictive signatures of responders.
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影响因子：
11.4
作者：
Klinge, Carolyn M.
通讯作者：
Klinge, Carolyn M.
影响因子：
20.3
作者：
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作者：
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Kralovics, Robert
影响因子：
11.4
作者：
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通讯作者：
Barbui T