PDF(Pubmed)
Abstract：
Graft-versus-host disease (GVHD) has remained the main cause of post-transplantation mortality and morbidity after allogeneic hematopoietic cell transplantation (alloHCT), adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GVHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have tested a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplantation cyclophosphamide (PTCy) for patients with acute myeloid leukemia in first or second CR, to attenuate the risk of chronic GVHD by using PTCy, while using escalated targeted radiation conditioning before allografting to offset the possible increased risk of relapse. The primary objective was to evaluate the safety/feasibility of combining a TMLI transplantation conditioning regimen with a PTCy-based GVHD prophylaxis strategy, through the assessment of adverse events in terms of type, frequency, severity, attribution, time course, duration, and complications, including acute GVHD, infection, and delayed neutrophil/platelet engraftment. Secondary objectives included estimation of non-relapse mortality (NRM), overall survival (OS), relapse-free survival, acute and chronic GVHD, and GVHD-relapse-free survival (GRFS). A patient safety lead-in was first conducted to ensure there were no unexpected toxicities and was expanded on the basis of lack of dose-limiting toxicities. The patient safety lead-in segment followed 3 + 3 dose expansion/(de-)escalation rules based on observed toxicity through day 30; the starting dose of TMLI was 2000 cGy, and a de-escalation to 1800 cGy was considered. After the safety lead-in segment, an expansion cohort of up to 12 additional patients was to be studied. TMLI was administered on days -4 to 0, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Cyclophosphamide was given on days 3 and 4 after alloHCT, 50 mg/kg each day for GVHD prevention; tacrolimus was given until day 90 and then tapered. Among 18 patients with a median age of 40 years (range 19-56), the highest grade toxicities were grade 2 Bearman bladder toxicity and stomatitis. No grade 3 or 4 Bearman toxicities or toxicity-related deaths were observed. The cumulative incidence of acute GVHD grade 2 to 4 and moderate-to-severe chronic GVHD were 11.1% and 11.9%, respectively. At a median follow up of 24.5 months, two-year estimates of OS and relapse-free survival were 86.7% and 83.3%, respectively. Disease relapse at 2 years was 16.7%. The estimates of NRM at 2 years was 0%. The GVHD/GRFS rate at 2 years was 59.3% (95% confidence interval, 28.8-80.3). This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe, with no NRM. Preliminary results suggest an improved GRFS rate.
摘要：
移植物抗宿主病（GVHD）仍然是异基因造血细胞移植（alloHCT）后移植后死亡率和发病率的主要原因，增加了巨大的经济负担，影响了生活质量。希望在不增加复发风险的情况下降低完全缓解(CR)患者的GVHD发生率。在这项研究中,我们已经在2000cGy测试了一种新的全骨髓和淋巴照射（TMLI）的预处理方案，联合移植后环磷酰胺（PTCy）治疗急性髓系白血病患者的第一次或第二次CR，通过使用PTCy降低慢性GVHD的风险，同时在同种异体移植前使用逐步升级的靶向放射调节来抵消可能增加的复发风险。主要目的是评估TMLI移植预处理方案与基于PTCy的GVHD预防策略相结合的安全性/可行性。通过对不良事件类型的评估，频率,严重程度,归因,时间进程,持续时间,和并发症，包括急性GVHD,感染,和中性粒细胞/血小板移植延迟。次要目标包括非复发死亡率(NRM)的估计，总生存期（OS），无复发生存，急性和慢性GVHD，和GVHD无复发生存期（GRFS）。首先进行了患者安全导入，以确保没有意外的毒性，并在缺乏剂量限制性毒性的基础上进行了扩展。根据第30天观察到的毒性，患者安全导入段遵循3+3剂量扩大/（降低）递增规则；TMLI的起始剂量为2000cGy，并考虑降级到1800cGy。在安全导入段之后，本研究将对多达12例患者的扩展队列进行研究.在第-4天至第0天施用TMLI,每天两次以200cGy级分递送。递送至肝脏和大脑的辐射剂量保持在1200cGy。在alloHCT后第3天和第4天给予环磷酰胺，每天50mg/kg用于GVHD的预防;给予他克莫司直至第90天,然后逐渐减量。在18名中位年龄为40岁（范围19-56）的患者中，最高的毒性是2级Bearman膀胱毒性和口腔炎。未观察到3级或4级Bearman毒性或毒性相关死亡。急性GVHD2-4级和中重度慢性GVHD的累计发病率分别为11.1%和11.9%,分别。在中位随访24.5个月时，两年的OS和无复发生存率估计分别为86.7%和83.3%，分别。2年时疾病复发率为16.7%。两年的NRM估计为0%。2年的GVHD/GRFS率为59.3%(95%置信区间，28.8-80.3)。这种无化疗的预处理方案，连同PTCy和他克莫司,是安全的,没有NRM。初步结果表明提高了GRFS率。
