Translational Research in Blood and Marrow Transplantation

血液和骨髓移植的转化研究

• 批准号: 10429934
• 负责人: RICHARD J JONES
• 金额: $ 14.92万
• 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/10429934
• 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; Donor person; 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; base; cancer stem cell; clinical center; disorder subtype; effective therapy; graft vs host disease; improved outcome; leukemia; mortality; novel; novel strategies; novel therapeutics; post-transplant; prevent; programs; randomized trial; rituximab; success; targeted cancer therapy; targeted treatment; treatment choice; 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.

项目摘要 我们的计划集中于从实验室到诊所的移植生物学翻译到 改善血液和骨髓移植（BMT）的结果。开发高剂量后移植物 环磷酰胺（PTCY）调节GVHD是我们小组成功翻译的一个很好的例子 研究。 PTCY不仅允许至少75岁以下的患者使用Safe HaploIdential（Haplo）BMT 现在，结果与匹配捐助者看到的结果相似。彼此之间，成功利用的能力 现在，不匹配的捐助者允许几乎需要BMT的任何人接受该程序。此外 将同种异体BMT移动到非机敏的指示中，我们的组一直集中于减少继电器 同种异体BMT发生恶性肿瘤后。随着非释放死亡率的降低，救济已成为迄今为止 同种异体BMT的主要并发症。新兴的数据表明，一种新的不耐受性和无精神肠性 移植的免疫系统可以增强大多数抗癌药的活性。合成后BMT 维护疗法已经在产生令人鼓舞的结果。这可能最好用 在接受同种异体BMT和移植后FLT3的FLT3/ITD AML患者中看到的令人印象深刻的结果 酪氨酸激酶抑制剂，dospite这些药物在非移植环境中表现出有限的活性。这 最小残留疾病（MRD）州后同种性BMT也可能优化抗肿瘤方法，因为 它们将在最低的肿瘤燃烧以及肿瘤异质性下使用。这，我们假设这是 移植维护可能是同种异体BMT后降低继电器率的最佳策略。然而， 尽管我们的小组和其他人在试播新型临床移植后维护方面取得了成功 策略，单个程序很难采用这些有前途的方法进行更大的试验。那， 随着Promise New Therapies的快速发展，正式的临床试验网络可以迅速而又 有效地在BMT中进行多中心试验至关重要。我们作为核心临床的特定目标 中心为：1）通过BMT CTN参加多中心试验，以及2）提出一个阶段2，多中心， 适应随机试验以筛选多种新型方案，用于治疗同种异体BMT后的浮雕 AML/MDS。一个重要的目标是将单个方案与特定疾病亚型相匹配。最终 目标是将承诺转移到移植后维护中，以防止退休。 尽管血液系统恶性肿瘤取得了显着进展，但大多数患者现在都对初始疗法做出反应，但 大多数人最终将这种疾病传达和死亡。同种异体血液或骨髓移植仍然是 对于许多患者而言，仅是治愈性的选择，但接力赛仍然是失败的最常见原因 此设置。需要减少浮雕而无需增加毒性的新方法。