Allogeneic HCT for Hematologic Malignancies: Immune Manipulations

项目3：血液系统恶性肿瘤的同种异体红细胞移植：免疫调控 我们已经将异基因造血细胞移植(HCT)的一种新方法转化为临床 治疗恶性血液病患者。该方法使用2Gy全身照射(TBI)或 之前未使用氟达拉滨(Flu；90 mg/m2)，并使用霉酚酸酯和 HCT后应用环孢素A(CSP)控制植入和移植物抗宿主病(GVHD)。使用 这种方法，将根除肿瘤的负担从常规的大剂量细胞毒转移到了 调节HCT供者的免疫细胞(移植物抗肿瘤效应)。令人印象深刻的抗肿瘤药物 在几乎所有研究的疾病类别中都看到了反应。然而，疾病的复发 仍然是导致高危患者预后不佳的主要因素。捐献者自然杀手的节奏 HCT后(NK)细胞恢复似乎与复发风险相关。这一发现影响了 特定目的的试验1建议捐献者输注NK细胞以减少复发。受到人类白细胞抗原研究结果的鼓舞- 血缘和非血缘关系相匹配的血细胞移植，我们扩大了捐献库以包括人类白细胞抗原半相合 捐赠者。这与NK细胞输注相结合，应该可以提供GVT效应。具体目标2 无复发死亡率(NRM)问题。接受流感治疗的患者NRM增加的回顾性研究结果是 正在进行一项III期试验，以确定是否需要在2GyTBI的基础上再进行流感治疗 经过大量预治疗的病人。移植物抗宿主病及其免疫抑制药物的延长治疗也会导致 NRM。为了减少移植物抗宿主病，他克莫司已经在第二阶段研究中取代了CSP，早期 结果看起来很有希望。对于急性髓细胞白血病，老年患者和 合并症与接受清髓剂同时移植的年轻患者没有什么不同 调理养生法。基于这些发现，我们已经启动了一项III期研究，比较清髓剂 和非清髓性条件作用于年轻的髓系恶性肿瘤患者(特定目标3)。在.期间 在上一次赠款期间，我们评估了合并症对生存和治愈的影响。在最初使用 Charlson共病指数，我们开发了一种造血细胞移植特异性指数(HCT-CL)， 似乎具有较高的辨别能力。为了验证HCT-CL，我们建议解决以下问题 多中心问题，以及未来研究中评价者之间的可重复性(具体目标4)。公共卫生 这个项目的好处是，患有各种恶性血液疾病的患者本来可以 因年龄和合并症而被排除的患者受益于同种异体血细胞移植治疗。在……里面 此外，人类白细胞抗原半相合捐献者的使用将使更多的患者可以选择接受HCT， 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.