Novel Intervention Approaches to Alleviate Allogeneic Transplant-Related Morbidity and Mortality

项目总结/摘要 背景：血液恶性肿瘤（HM）是一种罕见的影响血液和淋巴系统的癌症 并且只能通过移植供体干细胞即异基因造血细胞来治愈 移植（HCT）。虽然进步改善了年轻人和其他健康人的结果， HCT对老年人的健康相关生活质量（HRQOL）具有破坏性影响， 医学上虚弱（脆弱）的HM患者。我们是第一个开发HCT特异性合并症指数的 （HCT-CI），特别表明那些得分高的人可能会遭受严重的损害， 与合并症较低的患者相比，HCT后HRQOL和发病率及死亡率较高 成绩.在我们和其他人的初步研究的指导下，我们在这里建议将这些脆弱的患者随机化 支持性和姑息治疗，针对特定合并症的临床管理，两种方法 联合治疗与标准治疗（SOC）比较，以观察哪种干预可以改善这些患者的HRQOL， HCT。步骤：（1）在随机II期研究中评估四种方法的有效性 （2）确定上述方法在改善同种异体HCT易感受者第90天HRQOL方面的作用; III期研究II期的赢家组是否明确改善了HRQOL与SOC;以及（3）比较 关于生存率、其他患者报告结局和资源使用的干预措施。 方法：我们将在5例大型移植患者中开展一项多中心无缝II/III期随机临床试验， 中心.无缝特征意味着在II期分析中使用的患者将被纳入III期分析。 但只有在第二阶段产生的干预措施明显优于SOC的情况下，才会发生这种情况。 1，我们将入组300例年龄≥65岁、HCT-CI评分≥3和/或步行速度缓慢的患者 作为虚弱的指示，在他们开始异基因HCT之前两周。每个干预组将 在HCT前2周和HCT后8周的10周内实施，以实现最大获益， 为患者准备HCT并指导他们完成手术的早期阶段。患者将 随机分配到上述四个臂中的一个。如果第二阶段有一个干预机构， 改善HRQOL，那么我们将继续在III期研究中仅针对SOC测试该臂。我们只会 第三阶段需要增加300名脆弱患者（第二/三阶段总共需要600名）。在目标3中，我们将看看是否有 干预措施的有效性可以改善生存率、其他患者报告的结局和/或资源的使用。 患者结局：该提案首次比较了易受影响的患者的这些围移植期干预措施。 HM患者给予HCT。结果可以最大限度地减少痛苦，如果可能的话，延长类似患者的生命 在未来和世界范围内。研究结果还可以鼓励医生为更脆弱的人提供移植手术 目前，由于担心其发病率和死亡率风险，这些患者被拒绝接受手术。最后 为了其他病人的利益，可以改善国家对保健资源的总体利用。

Project Summary/Abstract BACKGROUND: Hematological malignancies (HM) are rare cancers that affect the blood and lymph system and can only be cured with transplantation of donor stem cells; namely allogeneic hematopoietic cell transplantation (HCT). While advancements have improved outcomes for younger and otherwise healthy patients, HCT can have devastating effects on the health-related quality of life (HRQOL) for older and medically infirm (vulnerable) patients with HM. We were the first to develop an HCT-specific comorbidity index (HCT-CI) that specifically showed that those with high scores can suffer from significant impairments in HRQOL and higher rates of morbidity and mortality after HCT compared to patients with lower comorbidity scores. Guided by our and others’ preliminary studies, we propose here to randomize those vulnerable patients between supportive and palliative care, clinical management targeting specific comorbidities, both approaches combined, vs. standard of care (SOC) to see which intervention can improve HRQOL of those patients after HCT. OBJECTIVES: (1) Evaluate in a randomized phase II study the effectiveness of the four approaches mentioned above in improving day-90 HRQOL for vulnerable recipients of allogeneic HCT; (2) determine in a phase III study whether the winner arm from phase II definitively improves HRQOL vs. SOC; and (3) compare the interventions with respect to survival, additional patient-reported outcomes, and the use of resources. METHODS: We will conduct a multi-center seamless phase II/III randomized clinical trial in five large transplant centers. The seamless feature means patients used in the phase II analysis will be included in the phase III analysis but that will only happen if phase II produces an intervention with a clear advantage over SOC. In Aim 1, we will enroll 300 patients who either have age of ≥65 years, HCT-CI scores of ≥3, and/or slow walk speed as indication of frailty, two weeks before they start their allogeneic HCT. Each intervention arm will be implemented over 10 weeks period, 2 weeks before and 8 weeks after HCT, to achieve the maximum benefit in preparing patients for HCT and guiding them through the early phases of the procedure. Patients will be randomly assigned to one of the four arms described above. If there is an intervention arm from phase II that improves HRQOL, then we will continue to test that arm only against SOC in a phase III study. We will only need an additional 300 vulnerable patients for phase III (total of 600 for phase II/III). In Aim 3, we will see if any of the interventions can improve survival, other patient-reported outcomes, and/or the use of resources. PATIENT OUTCOMES: This proposal is the first to compare these peri-transplant interventions in vulnerable HM patients given HCT. Results can minimize the suffering and, if possible, prolong the lives of similar patients in the future and world-wide. Results could also encourage physicians to offer transplants to more vulnerable patients, who are currently being denied the procedure for fear of its morbidity and mortality risks. Finally, the national overall use of healthcare resources could be improved for the benefit of other patients.