Image-guided irradiation safely intensifies HSCT regimen for refractory leukemia

 描述(申请人提供)：复发或对诱导治疗无效的急性白血病患者的5年总存活率低于20%，通常被认为是异基因造血细胞移植(HSCT)的低风险患者。希望之城帮助开创了图像引导调强放射治疗技术的先河，以精确地提供被称为全骨髓和淋巴照射(TMLI)的靶向辐射。TMLI将辐射塑造到高风险和疾病负担的区域，允许加强对目标结构的辐射剂量，在这种情况下，骨髓和主要淋巴器官，同时减少与辐射相关的毒性，对目标外的关键器官，通常在脑损伤。我们已经开发出一种用于晚期急性白血病难治性疾病患者的高强度HSCT预适应方案，该方案将TMLI与环磷酰胺(Cy)和依托泊苷(VP16)相结合。我们完成的I期临床试验表明，TMLI/Cy/VP16条件作用在TMLI剂量从1200到2000 cGy时是耐受的。这项拟议的TMLI/Cy/VP16用于HSCT调节的第二阶段研究是创新的，它使用2000cGyTMLI来强化HSCT方案，用于患有活动期疾病的进入移植的患者。这种方案，如果有效，有可能为难治性急性白血病患者提供HSCT治疗选择。希望之城的初步努力已经导致亚洲、欧洲和美国的其他中心开始自己的试点或第一阶段试验。假设：TMLI/Cy/VP16 HSCT预适应方案将通过加强疾病控制和减少放射相关毒性，提高基于TBI方案的活动期急性白血病患者的无进展存活率。具体目的：在II期试验中，评价TMLI联合环磷酰胺和依托泊苷作为造血干细胞移植预适应方案在难治性急性白血病患者中的作用。该方案的主要目的是评估2000 cGyTMLI+100 mg/kg Cy+60 mg/kg VP16方案的抗肿瘤活性，通过两年无进展生存期(PFS)进行评估。次要目标包括估计毒性的发生率(严重性)、总存活率、复发/进展的累积发生率、无复发死亡率以及髓外复发的发生率(部位)。我们还将评估HSCT前疾病状态、向目标/备用区域提供的辐射剂量和结果之间的可能关系。环境：我们的团队非常适合执行建议的研究。希望之城HSCT计划已经建立并得到了广泛的重视，自1976年以来每年进行500多例移植，自1976年以来进行了12,000例移植。一个专门的、多学科的TMLI HSCT团队已经到位，迄今已治疗了230多名TMLI患者，并完成了4项临床试验。TomoTreatment(R)机器和PET/CT扫描仪致力于这一项目。时间表：我们将有34名患者参加这项试验，并应该有足够的随访来发表 第三年晚些时候。

 DESCRIPTION (provided by applicant): Patients with acute leukemia who have relapsed or are refractory to induction therapy have 5-year overall survivals of less than 20%, and are typically considered poor risk for allogeneic hematopoietic cell transplantation (HSCT). City of Hope helped pioneer the use of image-guided intensity-modulated radiotherapy technologies to precisely deliver targeted radiation, known as total marrow and lymphoid irradiation (TMLI). TMLI sculpts the radiation to areas of high risk and disease burden, allowing intensification of radiation dose to target structures, in this case the bone marrow and major lymph organs, while decreasing the radiation-related toxicities to off-target critical organs typically seen with TBI. e have developed a high-intensity HSCT conditioning regimen for advanced acute leukemia patients with refractory disease, that combines TMLI with cyclophosphamide (Cy) and etoposide (VP16). Our completed phase I clinical trial demonstrated that TMLI/Cy/VP16 conditioning is tolerated at TMLI doses from 1200 to 2000 cGy. This proposed phase II study of TMLI/Cy/VP16 for HSCT conditioning is innovative in its use of 2000 cGy TMLI to intensify the HSCT regimen for patients entering transplant with active disease. This regimen, if effective has the potential o give patients with refractory acute leukemia an HSCT curative option. Initial efforts at City of Hope have already led to other centers in Asia, Europe and the U.S. beginning their own pilot or phase I trials. Hypothesis: The TMLI/Cy/VP16 HSCT conditioning regimen will improve progression-free survival over historical rates for TBI-based regimens in patients with active acute leukemia, through enhanced disease control and decreased radiation-related toxicity. Specific Aim: In a phase II trial, assess the activity of TMLI combined with cyclophosphamide and etoposide as conditioning for HSCT in patients with treatment refractory acute leukemia. This protocol has the primary objective of evaluating the anti-tumor activity of a regimen combining 2000 cGy TMLI with 100 mg/kg Cy and 60 mg/kg VP16, as assessed by 2-year progression-free survival (PFS). Secondary objectives include estimating incidence (severity) of toxicities, overall survival, cumulative incidence of relapse/progression, and non-relapse mortality, and incidence (location) of extramedullary relapse. We will also assess the possible relationship between pre-HSCT disease status, radiation doses delivered to targeted/spared regions, and outcomes. Environment: Our team is ideally suited to execute the proposed studies. The City of Hope HSCT program is well established and regarded, performing over 500 transplants yearly and 12,000 since 1976. A dedicated and multi-disciplinary TMLI HSCT team is already in place, with more than 230 TMLI patients treated to date and 4 clinical trials completed. A TomoTherapy(r) machine and PET/CT scanner are committed to this project. Timeline: We will accrue 34 patients to this trial, and should have sufficient follow-up to publish late in year 3.