Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Biol Blood Marrow Transplant. 2019 Nov;25(11):2297-2302. doi: 10.1016/j.bbmt.2019.07.017. Epub 2019 Jul 17.
The prognosis of steroid-refractory acute graft-versus-host disease (aGVHD) is poor, and predictors of response and survival are unclear. In an exploratory analysis of 203 steroid-refractory aGVHD patients with prospectively collected GVHD data who received antithymocyte globulin, etanercept, or mycophenolate mofetil (MMF) as second-line treatment, we determined the predictors of day 28 response, 2-year overall survival, and 2-year nonrelapse mortality (NRM). To minimize the risk of finding false-positive results, we used least absolute shrinkage and selection operator regression, aggressively eliminating variables that are unlikely to be associated with outcome. Day 28 response to second-line therapy was 38% (complete response, 23%), with a 2-year overall survival of 25% and a 2-year NRM of 62%. Factors associated with response were GVHD prophylaxis, organ involvement, and initial aGVHD to steroid-refractory aGVHD interval. Specifically, compared with cyclosporine/MMF as GVHD prophylaxis, the odds ratio (OR) for calcineurin inhibitor/methotrexate was .8 and for cyclosporine/prednisone .6. The OR for aGVHD to steroid-refractory aGVHD interval ≥ 14 versus <14 days was 1.3. The ORs for skin only involvement and gut or liver only involvement when compared with multiorgan involvement were 1.4 and 1.2, respectively. The only variable associated with worse survival was age, with a hazard ratio (HR) per decade of 1.04 for overall mortality. Similarly, age was the only variable associated with NRM (HR per decade, 1.02). When compared with complete response, no response at day 28 increased the risk of death (HR, 2.4; 95% confidence interval, 1.5 to 3.7). In conclusion, by means of an underused statistical technique in the field of transplantation, we identified predictors of response and survival in steroid-refractory aGVHD. Our results highlight the importance of developing novel treatment strategies because current treatments yield poor outcomes.
激素难治性急性移植物抗宿主病（aGVHD）的预后较差，且对反应和生存的预测因素尚不清楚。在一项对 203 例接受抗胸腺细胞球蛋白、依那西普或霉酚酸酯（MMF）二线治疗的激素难治性 aGVHD 患者前瞻性采集 GVHD 数据的探索性分析中，我们确定了 28 天反应、2 年总生存率和 2 年非复发死亡率（NRM）的预测因素。为了最大程度地降低假阳性结果的风险，我们使用最小绝对收缩和选择算子回归，积极消除与结果不太可能相关的变量。二线治疗的 28 天反应率为 38%（完全缓解率为 23%），2 年总生存率为 25%，2 年 NRM 为 62%。与反应相关的因素包括 GVHD 预防、器官受累和初始 aGVHD 至激素难治性 aGVHD 的间隔。具体而言，与环孢素/MMF 作为 GVHD 预防相比，钙调神经磷酸酶抑制剂/甲氨蝶呤的比值比（OR）为.8，环孢素/泼尼松的 OR 为.6。GVHD 至激素难治性 aGVHD 的间隔≥14 天与<14 天的 OR 为 1.3。与多器官受累相比，皮肤受累和胃肠道或肝脏受累的 OR 分别为 1.4 和 1.2。唯一与生存较差相关的变量是年龄，总死亡率每增加十年的风险比（HR）为 1.04。同样，年龄是唯一与 NRM 相关的变量（每十年 HR，1.02）。与 28 天完全缓解相比，28 天无反应增加了死亡风险（HR，2.4；95%置信区间，1.5 至 3.7）。总之，通过在移植领域中使用一种未充分利用的统计技术，我们确定了激素难治性 aGVHD 反应和生存的预测因素。我们的研究结果强调了开发新治疗策略的重要性，因为目前的治疗方法效果不佳。
