Hyperbaric oxygen to improve blood count recovery in Auto-HCT for myeloma

大剂量化疗联合自体造血细胞移植（Auto-HCT） 被认为是多发性骨髓瘤（MM）患者的标准治疗。大剂量化疗 导致粘膜损伤、粘膜炎和骨髓（BM）消融，导致中性粒细胞减少、血小板减少、 发热和感染，这可能导致移植后发病率和潜在死亡率。因此，我们认为， 有必要采取干预措施缩短Auto-HCT后的中性粒细胞减少，以减少这种移植相关的 死亡率和发病率，并降低Auto-HCT的总成本。这些干预措施应侧重于 改善造血干/祖细胞（HSPC）BM归巢，如HSPC移植到循环中 必须穿过血液/BM内皮屏障，并在产生前停留在BM隔室中（归巢） 成熟和功能性造血细胞（植入）。我们以前已经证明，HSPC 暴露于促红细胞生成素（EPO）抑制脐带血（UCB）-HSPC的体外迁移。为了 为了改善HSPC归巢，我们研究了在HSPC移植之前降低EPO的高压条件。中 初步临床试验，我们已经表明，高压氧治疗，作为一个单一的治疗之前，脐带血移植， 耐受性良好，导致EPO水平较基线显著降低， 中性粒细胞和血小板恢复的中位时间。高压氧治疗被证明是非常好的耐受性，在一个 随后的Auto-HCT初步研究。当比较我们的HBO队列患者与我们的历史对照组时， 初步数据表明中性粒细胞和血小板计数恢复的时间显著减少。此外，HBO 患者的粘膜炎明显较少，需要的输血也较少。从生物学上讲，我们观察到 HBO介导的EPO减少与我们的HBO队列中中性粒细胞恢复时间之间的相关性。早期 绝对淋巴细胞计数（ALC）恢复，历史上归因于IL-15刺激的NK细胞恢复， 在76%的HBO患者中观察到，而历史上约为50%。根据初步数据，我们 假设HBO治疗显著降低了移植后EPO，结果改善了HSPC 移植，如接受骨髓移植的MM患者中中性粒细胞和血小板恢复时间改善所证明 高剂量治疗和Auto-HCT。我们还假设HBO治疗在移植后上调IL-15 导致接受Auto-HCT的MM患者中NK细胞和ALC恢复增强。来测试我们 假设，我们提出了一个II期随机临床试验，其中患者将或将不接受高压氧 疗法在这项研究中，我们将检查高压氧对中性粒细胞，血小板和早期ALC恢复的影响， 其他临床终点。我们还将研究HBO对血浆EPO、IL-15和NK细胞恢复的影响， 对我们发现的一个可能的解释这项拟议试验的结果将用于计算样本 为了确定HBO对移植结果的影响， 接受高剂量治疗和Auto-HCT的骨髓瘤患者。

High-dose chemotherapy combined with autologous hematopoietic cell transplantation (Auto-HCT) is considered a standard of care treatment in patients with multiple myeloma (MM). High-dose chemotherapy results in mucosal damage, mucositis, and bone marrow (BM) ablation, leading to neutropenia, neutropenic fever and infections which can result both in post-transplant morbidity and potential mortality. Therefore, interventions shortening neutropenia following Auto-HCT are necessary to reduce such transplant-related mortality and morbidity and to reduce the overall cost of Auto-HCT. These interventions should focus on improving hematopoietic stem/progenitor cell (HSPC) BM homing, as HSPCs transplanted into the circulation must cross the blood/BM endothelium barrier and lodge in the BM compartment (homing) before producing mature and functional hematopoietic cells (engraftment). We previously have demonstrated that HSPC exposure to erythropoietin (EPO) inhibits umbilical cord blood (UCB)-HSPC in vitro transmigration. In order to improve HSPC homing, we investigated hyperbaric conditions to lower EPO prior to HSPC transplantation. In a pilot clinical trial, we have shown that HBO therapy, given as a single treatment prior to UCB transplantation, was well-tolerated, resulting in significant reduction in EPO levels from baseline, also with improvement in median time to neutrophil and platelet recoveries. HBO therapy was shown to be very well tolerated in a subsequent Auto-HCT pilot study. When comparing our HBO cohort patients with our historic controls, our preliminary data indicate a significant reduction in time to neutrophil and platelet count recoveries. Also, HBO patients had significantly less mucositis and required less transfusions. Biologically, we observed a positive correlation between HBO-mediated reduction in EPO and time to neutrophil recovery in our HBO cohort. Early absolute lymphocyte count (ALC) recovery, historically attributed to NK cell recovery stimulated by IL-15, was observed in 76% of HBO patients, compared to ~50% historically. Based on our preliminary data, we hypothesize that HBO therapy significantly reduces post-transplant EPO and, as a result, improves HSPC engraftment as evidenced by improved time to neutrophil and platelet recoveries in MM patients undergoing high-dose therapy and Auto-HCT. We also hypothesize that HBO therapy up-regulates IL-15 post-transplant resulting in enhanced NK cell and ALC recoveries in MM patients undergoing Auto-HCT. To test our hypotheses, we propose a phase II randomized clinical trial in which patients will or will not receive HBO therapy. In this study, we will examine HBO effects on neutrophil, platelet, and early ALC recovery among other clinical end points. We also will examine HBO effects on plasma EPO, IL-15, and on NK cell recovery as a potential explanation for our findings. Results from this proposed trial will be used to calculate the sample size and power for a future III trial designed in order to determine HBO effects on transplant outcomes in myeloma patients undergoing high-dose therapy and Auto-HCT.