Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Mayo Clinic, Phoenix, Arizona.
Biol Blood Marrow Transplant. 2020 Jan;26(1):94-106. doi: 10.1016/j.bbmt.2019.08.018. Epub 2019 Sep 4.
Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.
同种异体血液或骨髓移植（BMT）是原发性免疫缺陷（PID）患者潜在的治愈性治疗方法。需要安全有效的低强度预处理（RIC）方法，这些方法毒性低，使用替代供体，并能提供良好的免疫重建，以推进该领域的发展。20 名年龄在 4 岁至 58 岁之间的 PID 患者接受了一种新型、无辐射和无血清治疗的 RIC、T 细胞丰富的 BMT 前瞻性临床试验治疗，该方法使用喷司他丁、低剂量环磷酰胺和白消安进行预处理，并在移植后使用环磷酰胺为基础的移植物抗宿主病（GVHD）预防方案。这是一个高危队列，造血细胞移植合并症指数中位数为 3。在幸存者的中位随访 1.9 年后，1 年总生存率为 90%，无 III 至 IV 级急性 GVHD-无移植物衰竭生存率为 80%，在第 180 天。移植失败发生率为 10%。在 BMT 后早期经常观察到嵌合体分裂，供体 T 细胞的比例较低，在第 60 天逐渐增加。II 级至 IV 级和 III 级至 IV 级急性 GVHD（aGVHD）的累积发生率分别为 15%和 5%。所有 aGVHD 对类固醇均有反应。没有患者发生慢性 GVHD。观察到的器官毒性较少。所有植入患者都观察到表型逆转的证据，即使是那些具有明显混合嵌合体（n=2）或未知潜在遗传缺陷（n=3）的患者。所有 6 名患有 BMT 前恶性肿瘤或淋巴增殖性疾病的患者均处于缓解状态。大多数患者已停止免疫球蛋白替代治疗。所有幸存者均停止免疫抑制治疗以预防或治疗 GVHD。对于 PID 患者，这种新型 RIC BMT 方法取得了令人鼓舞的结果，即使是高危患者也是如此。
