Phase II trial of single-agent panobinostat consolidation improves responses after sub-optimal transplant outcomes in multiple myeloma.
Phase II trial of single-agent panobinostat consolidation improves responses after sub-optimal transplant outcomes in multiple myeloma.
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DOI：
10.1111/bjh.17080
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发表时间：
2021-04
影响因子：
6.5
通讯作者：
Spencer A
中科院分区：
文献类型：
--
作者：
Mithraprabhu S;Kalff A;Gartlan KH;Savvidou I;Khong T;Ramachandran M;Cooke RE;Bowen K;Hill GR;Reynolds J;Spencer A
Panobinostat是一种泛去乙酰酶抑制剂，可以调节参与肿瘤细胞生长和生存的致癌基因和免疫中介基因的表达。我们评估了帕诺比妥诱导的移植后反应，并在自体移植后未能达到完全反应的多发性骨髓瘤患者中确定了相关的生物标志物。患者在移植后8-12周开始接受Panobinostat 4500万mg每周三次(TIW)治疗，每隔一周28天为一周期。25名患者中有12名(48%)在服用帕诺比妥4·3个月(1.9-9.7)个月后，他们的反应深度有所改善。在有反应的患者中，与基线相比，在三个周期(P<0.05)和六个周期(P<0.05)和六个周期(P<0.01)的Panobinostat后，T淋巴细胞组蛋白乙酰化水平增加，无反应者没有差异。与移植前相比，无反应者的CD127+CD8+T细胞比例和CD4/CD8比率在Panobinostat治疗3个和6个周期后的下降幅度明显更大。全骨髓RNA-SEQ显示，只有在核糖体生物发生、氧化磷酸化和代谢途径相关基因基线差异的应答者中，才有广泛的转录变化。这项研究证实了潘诺比坦作为单一药物治疗多发性骨髓瘤的有效性，并确立了淋巴细胞组蛋白的乙酰化、免疫亚群的调节和转录变化作为临床受益的药效学生物标志物。
Panobinostat is a pan‐deacetylase inhibitor that modulates the expression of oncogenic and immune‐mediating genes involved in tumour cell growth and survival. We evaluated panobinostat‐induced post‐transplant responses and identified correlative biomarkers in patients with multiple myeloma who had failed to achieve a complete response after autologous transplantation. Patients received panobinostat 45 mg administered three‐times weekly (TIW) on alternate weeks of 28‐day cycles commencing 8–12 weeks post‐transplant. Twelve of 25 patients (48%) improved their depth of response after a median (range) of 4·3 (1·9–9·7) months of panobinostat. In responders, T‐lymphocyte histone acetylation increased after both three cycles (P < 0·05) and six cycles (P < 0·01) of panobinostat when compared to baseline, with no differences in non‐responders. The reduction in the proportion of CD127+CD8+ T cells and CD4:CD8 ratio was significantly greater, after three and six cycles of panobinostat compared to pre‐transplant, in non‐responders when compared to responders. Whole marrow RNA‐seq revealed widespread transcriptional changes only in responders with baseline differences in genes involved in ribosome biogenesis, oxidative phosphorylation and metabolic pathways. This study confirmed the efficacy of panobinostat as a single agent in multiple myeloma and established acetylation of lymphocyte histones, modulation of immune subsets and transcriptional changes as pharmacodynamic biomarkers of clinical benefit.
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影响因子：
56.9
作者：
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通讯作者：
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