Mielcarek Marco, Furlong Terry, O'Donnell Paul V, Storer Barry E, McCune Jeannine S, Storb Rainer, Carpenter Paul A, Flowers Mary E D, Appelbaum Frederick R, Martin Paul J
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; and Department of Medicine.
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA; and.
Blood. 2016 Mar 17;127(11):1502-8. doi: 10.1182/blood-2015-10-672071. Epub 2016 Jan 13.
The cumulative incidence of National Institutes of Health (NIH)-defined chronic graft-versus-host disease (GVHD) requiring systemic treatment is ∼35% at 1 year after transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized blood cells from HLA-matched related or unrelated donors. We hypothesized that high-dose cyclophosphamide given after G-CSF-mobilized blood cell transplantation would reduce the cumulative 1-year incidence of chronic GVHD to 15% or less. Forty-three patients with high-risk hematologic malignancies (median age, 43 years) were enrolled between December 2011 and September 2013. Twelve (28%) received grafts from related donors, and 31 (72%) received grafts from unrelated donors. Pretransplant conditioning consisted of fludarabine and targeted busulfan (n = 25) or total body irradiation (≥12 Gy; n = 18). Cyclophosphamide was given at 50 mg/kg per day on days 3 and 4 after transplantation, followed by cyclosporine starting on day 5. The cumulative 1-year incidence of NIH-defined chronic GVHD was 16% (95% confidence interval, 5-28%). The cumulative incidence estimates of grades 2-4 and 3-4 acute GVHD were 77% and 0%, respectively. At 2 years, the cumulative incidence estimates of nonrelapse mortality and recurrent malignancy were 14% and 17%, respectively, and overall survival was projected at 70%. Of the 42 patients followed for ≥1 year, 21 (50%) were relapse-free and alive without systemic immunosuppression at 1 year after transplantation. Thus, myeloablative pretransplant conditioning can be safely combined with high-dose cyclophosphamide after transplantation, and the risk of chronic GVHD associated with HLA-matched mobilized blood cell grafts can be substantially reduced. This trial was registered at www.clinicaltrials.gov as #NCT01427881.
接受来自 HLA 匹配的相关或无关供者的粒细胞集落刺激因子（G-CSF）动员血细胞移植后 1 年，美国国立卫生研究院（NIH）定义的需要全身治疗的慢性移植物抗宿主病（GVHD）的累积发病率约为 35%。我们假设，在 G-CSF 动员血细胞移植后给予大剂量环磷酰胺可将慢性 GVHD 的 1 年累积发病率降低至 15%或更低。2011 年 12 月至 2013 年 9 月期间，纳入了 43 例高危血液系统恶性肿瘤患者（中位年龄 43 岁）。12 例（28%）接受了来自相关供者的移植物，31 例（72%）接受了来自无关供者的移植物。移植前预处理包括氟达拉滨和靶向白消安（n = 25）或全身照射（≥12 Gy；n = 18）。移植后第 3 天和第 4 天给予环磷酰胺 50 mg/kg/天，随后从第 5 天开始给予环孢素。NIH 定义的慢性 GVHD 的 1 年累积发病率为 16%（95%置信区间，5-28%）。2-4 级和 3-4 级急性 GVHD 的累积发病率估计分别为 77%和 0%。2 年时，非复发死亡率和复发恶性肿瘤的累积发病率估计分别为 14%和 17%，预计总生存率为 70%。在 42 例随访≥1 年的患者中，21 例（50%）在移植后 1 年无疾病复发且存活，无需全身免疫抑制。因此，移植前清髓性预处理可安全地与移植后大剂量环磷酰胺联合使用，与 HLA 匹配的动员血细胞移植物相关的慢性 GVHD 风险可大幅降低。该试验已在 www.clinicaltrials.gov 注册，注册号为 #NCT01427881。
