Mixed Chimerism in the Treatment of Leukemias

基于临床前犬类研究，我们开发了异体造血细胞移植（HCT）的新临床方案，在HCT前使用200 cGy的全身照射（TBI），在HCT后使用霉酚酸酯和环孢素进行免疫抑制，以控制移植物和移植物抗宿主病（GVHD）。我们已经远远超过了预计的5年累计治疗40名慢性骨髓性白血病或b细胞恶性肿瘤患者的目标，部分原因是其他几个学术中心已经加入了试验，部分原因是我们扩大了候选疾病的范围。在拨款的前3年半期间，439名患者接受了治疗，这些患者要么太老，要么病得太重，不适合接受常规HCT。令人印象深刻的抗肿瘤反应已经在几乎所有的疾病类别中被观察到

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.