Translational Research in Blood and Marrow Transplantation

血液和骨髓移植的转化研究

• 批准号: 10657571
• 负责人: RICHARD J JONES
• 金额: $ 14.98万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657571
• 关键词: AML/MDS; Age; Allogenic; Antineoplastic Agents; Aplastic Anemia; Area; Autoimmune Diseases; Biology; Blood; Bone Marrow Transplantation; Clinic; Clinical; Clinical Trials; Clinical Trials Network; Complication; Cyclophosphamide; Data; Development; Disease; Disease Resistance; Dose; Epigenetic Process; FLT3 gene; FLT3 inhibitor; Failure; Goals; Hematologic Neoplasms; Individual; Laboratories; Life; Lymphoma; Maintenance; Maintenance Therapy; Malignant - descriptor; Malignant Neoplasms; Morbidity - disease rate; Multicenter Trials; Non-Malignant; Patients; Phase; Procedures; Recurrent disease; Regimen; Relapse; Residual Neoplasm; Sickle Cell Anemia; Supportive care; System; Time; Toxic effect; Translational Research; Translations; Transplantation; Transplantation and Immune System; Tumor Burden; Tyrosine Kinase Inhibitor; Work; allotransplant; cancer stem cell; clinical center; disorder subtype; effective therapy; graft vs host disease; improved outcome; leukemia; mortality; novel; novel strategies; novel therapeutics; post-transplant; programs; randomized trial; relapse prevention; rituximab; success; targeted cancer therapy; targeted treatment; treatment choice; tumor; tumor heterogeneity; virtual

Project Summary Our program has focused on the translation of transplantation biology from the laboratory to the clinic to improve the outcome of blood and marrow transplantation (BMT). The development high-dose post-transplant cyclophosphamide (PTCy) to modulate GVHD is a prime example of our group’s successful translational research. Not only does PTCy allow safe haploidentical (haplo) BMT in patients up to at least age 75, but results are now similar to those seen with matched donors. Accordingly, the ability to successfully utilize mismatched donors now permits virtually anyone in need of BMT to undergo the procedure. In addition to moving allogeneic BMT into non-malignant indications, our group has been concentrating on reducing relapses after allogeneic BMT for malignancy. With the reduction in non-relapse mortality, relapse has become by far the major complication of allogeneic BMT. Emerging data suggest that a new non-tolerant and non-exhausted transplanted immune system may enhance the activity of most anticancer agents. Post-allogeneic BMT maintenance therapy is already generating encouraging results; this is perhaps best exemplified by the impressive results seen in FLT3/ITD AML patients who received allogeneic BMT and post-transplant FLT3 tyrosine kinase inhibitors, despite these agents showing limited activity in the non-transplant setting. The minimal residual disease (MRD) state post-allogeneic BMT may also optimize antitumor approaches, in that they will be utilized at lowest tumor burden as well as tumor heterogeneity. Thus, we hypothesize that post- transplant maintenance may be the best strategy for decreasing relapse rates after allogeneic BMT. However, although our group and others have had successes in piloting novel clinical post-transplant maintenance strategies, it is difficult for a single program to carry out larger trials with these promising approaches. Thus, with the rapid development of promising new therapies, a formal clinical trials network that can rapidly and efficiently conduct multi-center trials in BMT is critically important. Our specific objectives as a Core Clinical Center are to: 1) Participate in multicenter trials through the BMT CTN, and 2) Propose a phase 2, multicenter, adaptively randomized trial to screen multiple novel regimens for treating relapse after allogeneic BMT for AML/MDS. An important goal will be to match individual regimens to specific disease subtypes. The ultimate goal will be to move promising approaches into post-transplant maintenance to prevent relapse. Despite remarkable progress in hematologic malignancies with most patients now responding to initial therapy, the majority eventually relapse and die of the disease. Allogeneic blood or marrow transplantation remains the only curative option for many of these patients, but relapse remains the most common cause for failure even in this setting. Novel approaches that reduce relapse without increasing toxicity are needed.

项目概要 我们的项目重点关注移植生物学从实验室到临床的转化 改善血液和骨髓移植（BMT）的结果开发高剂量移植后。 环磷酰胺 (PTCy) 调节 GVHD 是我们小组成功转化的一个典型例子 研究表明，PTCy 不仅可以对 75 岁以下的患者进行安全的单倍体 BMT 现在的结果与匹配捐赠者的结果相似。 不匹配的捐赠者现在几乎允许任何需要 BMT 的人接受该程序。 我们的团队将同种异体 BMT 转向非恶性适应症，一直致力于减少复发 在接受同种异体骨髓移植治疗恶性肿瘤后，随着非复发死亡率的降低，复发已成为现实。 新出现的数据表明，同种异体 BMT 的主要并发症是非耐受性和非耗尽性。 移植的免疫系统可以增强大多数抗癌药物的异体移植后活性。 维持治疗已经产生了令人鼓舞的结果；这也许是最好的例证 在接受同种异体 BMT 和移植后 FLT3 的 FLT3/ITD AML 患者中看到了令人印象深刻的结果 酪氨酸激酶抑制剂，尽管这些药物在非移植环境中显示出有限的活性。 微小残留病 (MRD) 状态后同种异体 BMT 也可能优化抗肿瘤方法，因为 它们将以最低的肿瘤负荷和异质性使用，因此，我们追求这一目标。 移植维持可能是降低同种异体 BMT 后复发率的最佳策略。 尽管我们的小组和其他人在试点新型临床移植后维护方面取得了成功 策略，单个项目很难用这些有前途的方法进行更大规模的试验。 随着有前景的新疗法的快速发展，正式的临床试验网络可以快速、有效地 高效地进行 BMT 多中心试验至关重要，这是我们作为核心临床的具体目标。 各中心将： 1) 通过 BMT CTN 参与多中心试验，以及 2) 提出 2 期多中心试验， 适应性随机试验筛选多种治疗同种异体 BMT 后复发的新方案 AML/MDS 的一个重要目标是将个体治疗方案与特定的疾病亚型相匹配。 目标是将有希望的方法应用于移植后维护以防止复发。 尽管血液系统恶性肿瘤取得了显着进展，大多数患者现在对初始治疗有反应， 大多数人最终会因同种异体血液或骨髓移植而复发并死亡。 对于许多此类患者来说，这是唯一的治疗选择，但复发仍然是失败的最常见原因，即使在 需要在不增加毒性的情况下减少复发的新方法。