Hui Susanta, Brunstein Claudio, Takahashi Yutaka, DeFor Todd, Holtan Shernan G, Bachanova Veronika, Wilke Christopher, Zuro Darren, Ustun Celalettin, Weisdorf Daniel, Dusenbery Kathryn, Verneris Michael R
Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota.
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
Biol Blood Marrow Transplant. 2017 Jul;23(7):1110-1116. doi: 10.1016/j.bbmt.2017.04.002. Epub 2017 Apr 7.
Patients with refractory leukemia or minimal residual disease (MRD) at transplantation are at increased risk of relapse. Augmentation of irradiation, especially to sites of disease (ie, bone marrow) is one potential strategy for overcoming this risk. We studied the feasibility of radiation dose escalation in high-risk patients using total marrow irradiation (TMI) in a phase I dose-escalation trial. Four pediatric and 8 adult patients received conditioning with cyclophosphamide and fludarabine in conjunction with image-guided radiation to the bone marrow at 15 Gy and 18 Gy (in 3-Gy fractions), while maintaining the total body irradiation (TBI) dose to the vital organs (lungs, hearts, eyes, liver, and kidneys) at <13.2 Gy. The biologically effective dose of TMI delivered to the bone marrow was increased by 62% at 15 Gy and by 96% at 18 Gy compared with standard TBI. Although excessive dose-limiting toxicity, defined by graft failure or excessive specific organ toxicity, was not encountered, 3 of 6 patients experienced treatment-related mortality at 18 Gy. Thus, we halted enrollment at this dose level and treated an additional 4 patients at 15 Gy. The 1- year overall survival was 42% (95% confidence interval [CI], 15%-67%) and disease-free survival was 22% (95% CI, 4%-49%). The rate of relapse was 36% (95% CI, 10%-62%), and nonrelapse mortality was 42% (95% CI, 14%-70%). This study shows that TMI dose escalation to 15 Gy is feasible with acceptable toxicity in pediatric and adult patients with high-risk leukemia undergoing umbilical cord blood and sibling donor transplantation.
移植时患有难治性白血病或微小残留病（MRD）的患者复发风险增加。增加放疗剂量，尤其是对疾病部位（如骨髓）进行放疗，是克服这种风险的一种潜在策略。我们在一项I期剂量递增试验中，研究了使用全身骨髓照射（TMI）对高危患者进行放疗剂量递增的可行性。4名儿科患者和8名成年患者接受了环磷酰胺和氟达拉滨预处理，并结合图像引导下对骨髓进行15 Gy和18 Gy（3 Gy分次）的放疗，同时将对重要器官（肺、心脏、眼睛、肝脏和肾脏）的全身照射（TBI）剂量维持在<13.2 Gy。与标准TBI相比，给予骨髓的TMI生物有效剂量在15 Gy时增加了62%，在18 Gy时增加了96%。虽然未出现由移植失败或特定器官毒性过大所定义的过度剂量限制毒性，但6名患者中有3名在18 Gy时出现了与治疗相关的死亡。因此，我们在这个剂量水平停止了入组，并另外对4名患者进行了15 Gy的治疗。1年总生存率为42%（95%置信区间[CI]，15%-67%），无病生存率为22%（95%CI，4%-49%）。复发率为36%（95%CI，10%-62%），非复发死亡率为42%（95%CI，14%-70%）。这项研究表明，对于接受脐带血和同胞供体移植的高危白血病儿科和成年患者，将TMI剂量递增至15 Gy是可行的，且毒性可接受。
