Pidala Joseph, Kim Jongphil, Alsina Melissa, Ayala Ernesto, Betts Brian C, Fernandez Hugo F, Field Teresa, Jim Heather, Kharfan-Dabaja Mohamed A, Locke Frederick L, Mishra Asmita, Nishihori Taiga, Ochoa-Bayona Leonel, Perez Lia, Riches Marcie, Anasetti Claudio
Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA
Oncologic Sciences, College of Medicine at University of South Florida, USA Biostatistics, Moffitt Cancer Center; USA.
Haematologica. 2015 Jul;100(7):970-7. doi: 10.3324/haematol.2015.123588. Epub 2015 Apr 3.
Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27-60) for sirolimus/tacrolimus and 49 months (range 29-63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed.
异基因造血细胞移植中采用的有效药理学策略应预防严重的慢性移植物抗宿主病，并促进供体-受体免疫耐受。基于已证实的促耐受活性，西罗莫司（雷帕霉素）有望实现这些目标。在一项随机II期试验的长期随访分析中，比较了西罗莫司/他克莫司与甲氨蝶呤/他克莫司在匹配的同胞或无关供体移植中预防移植物抗宿主病的效果，我们研究了长期使用西罗莫司（移植后≥1年）的影响。在本次分析时，西罗莫司/他克莫司组存活患者的中位随访时间为41个月（范围27 - 60个月），甲氨蝶呤/他克莫司组为49个月（范围29 - 63个月）。西罗莫司/他克莫司组患者的美国国立卫生研究院共识定义的中度至重度慢性移植物抗宿主病显著更低（34%对65%；P = 0.004），晚期急性移植物抗宿主病也更低（20%对43%；P = 0.04）。虽然西罗莫司/他克莫司组患者的泼尼松暴露量更低，他克莫司停药更早（他克莫司停药的中位时间为368天对821天；P = 0.002），但在完全停用免疫抑制剂方面无显著差异（60个月估计值：43%对31%；P = 0.78）。长期使用西罗莫司是减轻中度至重度慢性和晚期急性移植物抗宿主病风险的可行方法。需要进一步研究成功停用免疫抑制剂的决定因素。
