Kurtzberg Joanne, Prockop Susan, Chaudhury Sonali, Horn Biljana, Nemecek Eneida, Prasad Vinod, Satwani Prakash, Teira Pierre, Hayes Jack, Burke Elizabeth
Duke University Medical Center, Durham, North Carolina.
MSK Kids Memorial Sloan Kettering Cancer Center, New York, New York.
Biol Blood Marrow Transplant. 2020 May;26(5):855-864. doi: 10.1016/j.bbmt.2020.01.026. Epub 2020 Feb 7.
Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor, with a high mortality rate and limited therapeutic options. Here we report our updated investigational experience with mesenchymal stromal cell (MSC) therapy with remestemcel-L in a multicenter expanded access protocol (ClinicalTrials.gov identifier NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies. A total of 241 children with grade B-D SR-aGVHD were enrolled at 50 sites in 8 countries and received 8 biweekly i.v. infusions of human MSCs, 2 × 10 per kg for 4 weeks, with an option for an additional 4 weekly infusions after day +28 for subjects who achieved either a partial response (PR) or mixed response. The mean age of the subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease, and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response (OR; the sum of complete response [CR] and PR) at day +28. Across all subjects, a 28-day OR was observed in 157 patients (65.1%), with 34 (14.1%) achieving CR and 123 (51.3%) achieving PR. Stratified by aGVHD grade at baseline, the OR rate at day +28 was 72.9% for patients with aGVHD grade B, 67.1% for those with aGVHD grade C, and 60.8% for those with aGVHD grade D. Survival through day +100, a secondary endpoint of the study, was 66.9% (n = 160 of 239). Importantly, survival through day +100 was significantly greater in subjects who achieved a day +28 OR compared with nonresponders (82.1% versus 38.6%; P < .001, log-rank test). Remestemcel-L safety was generally well tolerated, with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L expanded access program confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options.
类固醇难治性急性移植物抗宿主病（SR-aGVHD）患儿的临床结局通常较差，死亡率高且治疗选择有限。在此，我们报告了在一项多中心扩大准入方案（ClinicalTrials.gov标识符NCT00759018）中，使用remestemcel-L进行间充质基质细胞（MSC）治疗的最新研究经验，该方案纳入了241例对类固醇治疗无反应（无论是否接受其他二线和三线免疫抑制治疗）的aGVHD患儿。共有241例B-D级SR-aGVHD患儿在8个国家的50个地点入组，接受了8次每两周一次的静脉注射人MSC，剂量为每千克2×10，共4周，对于达到部分缓解（PR）或混合反应的受试者，在第+28天之后可选择再进行4次每周一次的输注。受试者的平均年龄为9.6岁；39%为女性，60%为白人。大多数受试者患有C级（30%）或D级（50%）疾病，并且在大多数情况下，受试者在类固醇治疗失败后对其他免疫抑制剂也无反应。主要终点是第+28天的总体缓解率（OR；完全缓解[CR]和PR的总和）。在所有受试者中，157例患者（65.1%）观察到28天OR，34例（14.1%）达到CR，123例（51.3%）达到PR。根据基线时的aGVHD分级进行分层，B级aGVHD患者在第+28天的OR率为72.9%，C级患者为67.1%，D级患者为60.8%。研究的次要终点即第+100天的生存率为66.9%（239例中的160例）。重要的是，与无反应者相比，在第+28天达到OR的受试者中第+100天的生存率显著更高（82.1%对38.6%；P <.001，对数秩检验）。Remestemcel-L的安全性总体上耐受性良好，没有输注毒性，也没有发现安全问题。总之，remestemcel-L扩大准入计划的这一更新证实了remestemcel-L治疗对用尽所有传统治疗选择的aGVHD患儿所报告的临床和生存益处。
