Image-guided irradiation safely intensifies HSCT regimen for refractory leukemia

 描述（由申请人提供）：复发或诱导治疗难治性急性白血病患者的5年总生存率低于20%，通常被认为是异基因造血细胞移植（HSCT）的低风险患者。City of Hope帮助开创了使用图像引导调强放射治疗技术来精确提供靶向放射治疗的先河，即全骨髓和淋巴照射（TMLI）。TMLI将辐射塑造到高风险和疾病负担的区域，允许增强对靶结构的辐射剂量，在这种情况下是骨髓和主要淋巴器官，同时减少对TBI通常所见的脱靶关键器官的辐射相关毒性。我们开发了一种高强度HSCT预处理方案，用于难治性晚期急性白血病患者，该方案将TMLI与环磷酰胺（Cy）和依托泊苷（VP 16）联合使用。我们已完成的I期临床试验证明，TMLI/Cy/VP 16预处理在1200 - 2000 cGy的TMLI剂量下耐受。本项拟定的TMLI/Cy/VP 16用于HSCT预处理的II期研究在使用2000 cGy TMLI强化患有活动性疾病的患者进入移植的HSCT方案方面具有创新性。如果有效，该方案有可能为难治性急性白血病患者提供HSCT治疗选择。City of Hope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I期试验。假设：TMLI/Cy/VP 16 HSCT预处理方案通过增强疾病控制和降低放射相关毒性，将改善活动性急性白血病患者的无进展生存率，超过基于TBI的方案的历史生存率。具体目标：在一项II期试验中，评估TMLI联合环磷酰胺和依托泊苷作为难治性急性白血病患者HSCT预处理的活性。该方案的主要目的是通过2年无进展生存期（PFS）评估2000 cGy TMLI与100 mg/kg Cy和60 mg/kg VP 16组合方案的抗肿瘤活性。次要目的包括估计毒性的发生率（严重程度）、总生存期、复发/进展的累积发生率和非复发死亡率以及髓外复发的发生率（位置）。我们还将评估HSCT前疾病状态、靶向/备用区域的辐射剂量与结局之间的可能关系。环境：我们的团队非常适合执行拟议的研究。City of Hope的HSCT计划已经建立并得到了广泛的认可，自1976年以来，每年进行超过500例移植手术，其中12，000例。一个专门的多学科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。一台TomoTherapy（r）机器和PET/CT扫描仪致力于该项目。时间轴：我们将招募34名患者参加本试验，并且应该有足够的随访时间来发表 在第三年晚些时候。

 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.