Allogeneic HCT for Hematologic Malignancies: Immune Manipulations

项目3：血液系统恶性肿瘤的同种异体HCT：免疫操作 我们已经将异基因造血细胞移植（HCT）的新方法转化为临床， 治疗恶性血液病患者。该方法使用2戈伊全身照射（TBI）， 之前未使用氟达拉滨（Flu;90 mg/m2），并使用吗替麦考酚酯进行免疫抑制， 环孢菌素（CSP），在HCT后用于控制植入和移植物抗宿主病（GVHD）。与 这种方法，肿瘤根除的负担已经从传统的高剂量细胞毒性转移到 调节HCT供体的免疫细胞（移植物抗肿瘤[GVT]效应）。抗肿瘤效果显著 几乎在所有研究的疾病类别中都看到了反应。然而，疾病复发 仍然是高风险患者不良结局的主要原因。捐赠者自然杀手的克里思 (NK)HCT后的细胞恢复似乎与复发风险相关。这一发现影响了 具体目标1中的试验提出供体NK细胞输注以减少复发。受HLA结果的鼓舞- 匹配的相关和无关的HCT，我们扩大了供体库，包括HLA-半相合 捐助者。这与NK细胞输注相结合，应该提供GVT效应。具体目标2地址 非复发死亡率（NRM）。流感患者NRM增加的回顾性结果如下 在III期临床试验中，确定除了2戈伊TBI外，是否还需要流感来治疗 重度预治疗患者。GVHD及其免疫抑制药物的延长治疗也引起了 NRM。为了减少GVHD，他克莫司已在II期研究中取代CSP，并且早期 结果看来很有希望。对于急性髓细胞白血病，老年患者和 合并症与同时接受清髓性移植的年轻患者没有区别 调理方案。基于这些发现，我们启动了一项III期研究， 和非清髓性预处理在年轻骨髓恶性肿瘤患者中的应用（具体目标3）。期间 在最后一个资助期，我们评估了合并症对生存和治疗的影响。在最初使用 Charlson共病指数，我们开发了造血细胞移植特异性指数（HCT-Cl）， 这似乎具有更高的辨别能力。为了验证HCT-Cl，我们建议解决 多中心问题，以及未来研究中的评价者间重现性（具体目标4）。公共卫生 该项目的好处是，患有各种恶性血液病的患者， 由于年龄和合并症而被排除，从同种异体HCT治疗中获益。在 此外，HLA-半相合供体的使用将使HCT的选择扩展到更多的患者， 包括少数民族。

PROJECT 3: ALLOGENEIC HCT FORHEMATOLOGIC MALIGNANCIES: IMMUNE MANIPULATIONS We have translated a novel approach at allogeneic hematopoietic cell transplantation (HCT) into the clinic to treat patients with hematologic malignancies. The approach uses 2 Gy total body irradiation (TBI) with or without fludarabine (Flu;90 mg/m2) before and immunosuppression with mycophenolate mofetil and cyclosporine (CSP), after HCT for control of both engraftment and graft-versus-host disease (GVHD). With this approach, the burden of tumor eradication has been shifted from the conventional high-dose cytotoxic conditioning to the HCT donors' immune cells (graft-versus-tumor [GVT] effect). Impressive antitumor responses have been seen among almost all of the disease categories studied. However, relapse of disease continues to be a major contributor to poor outcomes in high risk patients. The tempo of donor natural killer (NK) cell recovery after HCT appeared correlated with relapse risk. This finding has influenced the design of trials in Specific Aim 1 proposing donor NK cell infusions to reduce relapse. Encouraged by results inHLA- matched related and unrelated HCT, we have expanded the donor pool to include HLA-haploidentical donors. This, in combination with NK cell infusions, should provide for GVT effects. Specific Aim 2 addresses the issue of nonrelapse mortality (NRM). Retrospective findings of increased NRM in patients given Flu are being addressed in a phase III trial to determine whether Flu is needed in addition to 2 Gy TBI to condition heavily pretreated patients. GVHD and its extended treatment with immunosuppressive drugs also caused NRM. In order to reduce GVHD, tacrolimus has been substituted for CSP in a phase II study, and early results look promising. For acute myelocytic leukemias, outcomes in elderly patients and those with comorbidities were not different from concurrently transplanted younger patients given myeloablative conditioning regimens. Based on these findings, we have initiated a phase III study comparing myeloablative and nonmyeloablative conditioning in younger patients with myeloid malignancies (Specific Aim 3). During the last grant period, we assessed the impact of comorbidities on survival and cure. After initially using the Charlson Co-morbidity Index, we developed a hematopoietic cell transplantation-specific index (HCT-Cl), which seemed to have higher discriminative capacity. In order to validate the HCT-Cl, we propose to address multi-center issues, as well as inter-rater reproducibility in future studies (Specific Aim 4). The public health benefits of this Project are that patients with various malignant blood disorders who otherwise would have been excluded because of age and comorbidities have benefited from treatment by allogeneic HCT. In addition, the use of HLA-haploidentical donors will extend the option of HCT to a greater number of patients, including ethnic minorities.