Mixed Chimerism in the Treatment of Leukemias

混合嵌合现象在白血病治疗中的应用

• 批准号: 6989533
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 11.1万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989533
• 关键词: T lymphocyte; acute lymphocytic leukemia; acute myelogenous leukemia; artificial immunosuppression; chronic lymphocytic leukemia; clinical trial phase II; clinical trial phase III; combination cancer therapy; fludarabine; hematopoietic tissue transplantation; human subject; human therapy evaluation; leukemia; neoplasm /cancer immunotherapy; patient oriented research; renal cell carcinoma; tissue mosaicism; transplantation immunology

Based on preclinical canine studies, we have developed novel clinical protocols for allogeneic hematopoietic cell transplantation (HCT) using 200 cGy total body irradiation (TBI) before and immunosuppression with mycophenolate mofetil and cyclosporine after HCT for control of both engraftment and graft-versus-host disease (GVHD). We have far exceeded the projected 5-year accrual of 40 patients with chronic myelogenous leukemia or B-cell malignancies, in part because trials have been joined by several other academic centers and, in part, because we have extended the range of candidate diseases. During the first 3 1/2 years of the grant, 439 patients have been treated who were either too old or too ill to be candidates for conventional HCT. Impressive antitumor responses have been seen in almost all the disease categories studied. For example, 50% of patients who presented with measurable disease at HCT achieved complete and 17% partial remissions. An initially observed 18% non-fatal graft rejection rate was obviated by adding fludarabine to the 200 cGy TBI (Flu/TBI), though retrospective data analysis suggested worse survival for Flu/TBI patients due to increased non-relapse mortality. Four Specific Aims are proposed in this renewal application. Aim 1 will evaluate disease-specific Phase II protocols for patients with acute myeloid leukemia (1st CR), acute lymphocytic leukemia (CR), chronic lymphocytic leukemia, and renal cell carcinoma. We anticipate that these will lead to Phase III studies in later grant years. Aim 2 proposes a randomized Phase III study comparing TBI vs. Flu/TBI in heavily pretreated patients at low risk for rejection. Donor lymphocyte infusion (DLI), initially an integral part of each protocol, was found not to be needed for most patients because of spontaneous conversion from mixed to all donor chimerism, though DLI was effective in some patients with disease relapse/progression. Aim 3 proposes to evaluate DLI prospectively as adoptive immunotherapy for progression/relapse and for preventing graft rejection in patients with decreasing donor chimerism. While GVHD is seen less frequently than after conventional HCT, better prevention of this complication remains an important research objective. Aim 4 proposes a randomized prospective trial evaluating the duration of postgrafting cyclosporine.

基于临床前犬研究，我们开发了用于同种异体造血细胞移植（HCT）的新型临床方案（HCT），使用200 CGY全身照射（TBI），并在HCT后使用HCT进行免疫抑制，以控制植入和GRAFT-verseptriment and Graft-verse-verse-verseation（GVHD）。我们远远超过了40例慢性粒细胞性白血病或B细胞恶性肿瘤患者预计的5年应计，部分原因是其他几个学术中心也加入了试验，部分原因是我们扩大了候选疾病的范围。在该赠款的前3年1/2年中，已经对439名患者进行了治疗，这些患者年龄太大或太病了，无法成为常规HCT的候选人。在几乎所有疾病类别中都看到了令人印象深刻的抗肿瘤反应 研究。例如，在HCT时出现可测量疾病的患者中有50％的患者已完成，部分减少了17％。最初观察到的18％非致命的移植排斥率通过在200 CGY TBI（FLU/TBI）中添加氟达拉滨（Fludarabine）来消除，尽管回顾性数据分析表明，由于非透露率死亡率增加，流感/TBI患者的存活率较差。在此续签应用中提出了四个具体目标。 AIM 1将评估急性髓样白血病（1st CR），急性淋巴细胞性白血病（CR），慢性淋巴细胞性白血病和肾细胞癌患者的疾病特异性II期方案。我们预计这些将导致后来的授予年份进行III期研究。 AIM 2提出了一项随机的III期研究，比较了对拒绝风险低的经过预处理的患者的TBI与流感/TBI的比较。供体淋巴细胞 由于从混合到所有供体嵌合体的自发转化，因此发现大多数患者不需要输注（DLI），这是每种方案中不可或缺的一部分，尽管DLI在某些患有疾病复发/进展的患者中有效。 AIM 3建议将DLI预期评估为采用免疫疗法，以进行进展/复发，并防止供体嵌合体降低患者的移植物排斥。尽管GVHD的频率低于常规HCT之后，但更好地预防这种并发症仍然是一个重要的研究目标。 AIM 4提出了一项随机前瞻性试验，以评估围墙后环孢素的持续时间。