Mixed Chimerism in the Treatment of Leukemias

基于临床前犬研究，我们已经开发了新的临床方案，用于异基因造血细胞移植（HCT），使用200 cGy的全身照射（TBI）前和免疫抑制与吗替麦考酚酯和环孢素HCT后的植入和移植物抗宿主病（GVHD）的控制。我们已经远远超过了40例慢性粒细胞白血病或B细胞恶性肿瘤患者的预期5年累积，部分原因是其他几个学术中心加入了试验，部分原因是我们扩大了候选疾病的范围。在赠款的前3年半中，439名患者接受了治疗，他们要么年龄太大，要么病情太重，不能接受常规HCT。在几乎所有的疾病类别中都看到了令人印象深刻的抗肿瘤反应 研究了例如，在HCT时出现可测量疾病的患者中，50%实现了完全缓解，17%实现了部分缓解。通过在200 cGy TBI（Flu/TBI）中添加氟达拉滨，避免了最初观察到的18%的非致命性移植物排斥率，但回顾性数据分析表明，由于非复发死亡率增加，Flu/TBI患者的生存率更差。本续期申请提出四项具体目标。目的1将评估急性髓性白血病（首次CR）、急性淋巴细胞白血病（CR）、慢性淋巴细胞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III期研究在以后的赠款年。目的2提出了一项随机III期研究，比较TBI与流感/TBI在重度预治疗患者中的低排斥风险。供者淋巴细胞 输注（DLI），最初是每个协议的组成部分，被发现是不需要的，因为从混合到所有供体嵌合体的自发转换，大多数患者，虽然DLI是有效的，在一些患者的疾病复发/进展。目的3提出前瞻性评估DLI作为过继免疫治疗的进展/复发和预防供体嵌合体减少患者的移植排斥反应。虽然GVHD的发生率低于常规HCT，但更好地预防这种并发症仍然是一个重要的研究目标。目的4提出了一个随机前瞻性试验评估移植后环孢素的持续时间。

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.