Abstract：
BACKGROUND: Dyskeratosis congenita/telomere biology disorders (DC/TBD) often manifest as bone marrow failure (BMF) or myelodysplastic syndrome (MDS). Allogeneic hematopoietic cell transplant (alloHCT) rescues hematologic complications, but radiation and alkylator-based conditioning regimens cause diffuse whole-body toxicity and may expedite DC/TBD-specific non-hematopoietic complications. Optimization of conditioning intensity in DC/TBD to allow for donor hematopoietic cell engraftment with the least amount of toxicity remains a critical goal of the alloHCT field.
OBJECTIVE: We report prospectively collected standard alloHCT outcomes from a single-center, single-arm, open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC), including alemtuzumab 1 mg/kg, fludarabine 200 mg/m2, and cyclophosphamide 50 mg/kg. A previous single-arm, open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 cGy of total body irradiation (TBI), served as a control cohort.
RESULTS: The non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared with the control TBI cohort, which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (non-TBI) compared with 2.6 (TBI) x 106/kg (P = .02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0% and 10% (non-TBI) and 8% and 17% (TBI), respectively (acute, P = .36; chronic, P = .72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (non-TBI cohort). The non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (non-TBI) and 75% (TBI; P = .78). MDS as an indication for alloHCT was uncommon but overall associated with poor outcomes. There were 3 MDS patients in the non-TBI cohort: 1 relapsed and died at day +387; 1 relapsed at day +500 and is alive 5.5 years later following salvage with a second alloHCT; 1 relapsed at day +1093 and is alive at day +100 after a second alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day +827 from a bacterial infection in the setting of immune-mediated cytopenia.
CONCLUSIONS: Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects.
OBJECTIVE: We report prospectively collected standard alloHCT outcomes from a single-center, single-arm, open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC), including alemtuzumab 1 mg/kg, fludarabine 200 mg/m2, and cyclophosphamide 50 mg/kg. A previous single-arm, open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 cGy of total body irradiation (TBI), served as a control cohort.
RESULTS: The non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared with the control TBI cohort, which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (non-TBI) compared with 2.6 (TBI) x 106/kg (P = .02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0% and 10% (non-TBI) and 8% and 17% (TBI), respectively (acute, P = .36; chronic, P = .72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (non-TBI cohort). The non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (non-TBI) and 75% (TBI; P = .78). MDS as an indication for alloHCT was uncommon but overall associated with poor outcomes. There were 3 MDS patients in the non-TBI cohort: 1 relapsed and died at day +387; 1 relapsed at day +500 and is alive 5.5 years later following salvage with a second alloHCT; 1 relapsed at day +1093 and is alive at day +100 after a second alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day +827 from a bacterial infection in the setting of immune-mediated cytopenia.
CONCLUSIONS: Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects.
摘要：
背景：先天性角化不良/端粒生物学障碍（DC/TBD）通常表现为骨髓衰竭（BMF）或骨髓增生异常综合征（MDS）。异基因造血细胞移植（alloHCT）挽救血液学并发症，但辐射和基于烷化剂的预处理方案会引起弥漫性全身毒性,并可能加速DC/TBD特异性非造血系统并发症.优化DC/TBD中的调节强度以允许供体造血细胞以最小的毒性植入仍然是alloHCT领域的关键目标。
目的：我们报告前瞻性收集了一项单中心单臂开放标记的骨髓或外周血干细胞alloHCT治疗DC/TBD相关BMF或MDS的标准alloHCT结果。调节强度降低（RIC），包括阿仑珠单抗1mg/kg，氟达拉滨200mg/m2，环磷酰胺50mg/kg。先前在同一中心针对同一患者人群进行的单臂开放标签II期临床试验，不同之处仅在于包含200厘格的全身照射(TBI)，作为对照组。
结果：非TBI队列包括10名患者（年龄1.7-65.9岁，中位随访3.9年），与包括12例患者（年龄2.2-52.2岁，中位随访10.5年)。基线特征仅在接受的总CD34+细胞中有所不同，中位数为5.6（非TBI），而中位数为2.6（TBI）×106/kg（p=0.02；总有核细胞无差异）。第100天的II-IV级急性和4年慢性移植物抗宿主病（GvHD）的累积发病率较低，分别为0％和10％（非TBI）和8％和17％（TBI），分别(急性，p=0.36；慢性，p=0.72）。没有原发性移植物失败。继发性非中性粒细胞减少性移植物衰竭发生在一个(非TBI队列)中。非TBI队列显示完全供体嵌合的延迟实现，但淋巴细胞恢复优越。在80%(非TBI)和75%(TBI;p=0.78)的4年总生存率没有差异。MDS作为alloHCT的指征并不常见，但总体上与不良结果相关。非TBI队列中有3名MDS患者：1名复发并在第387天死亡；1名在第500天复发，在第二次alloHCT抢救后存活5.5年；1名在第1093天复发，在第二次alloHCT后第100天存活。TBI队列中有1名MDS患者实现了100%供体骨髓植入而没有复发,但在免疫介导的血细胞减少的情况下在第+827天死于细菌感染。
结论：从DC/TBD的RIC方案中消除TBI与移植物失败率的显著变化无关。GvHD,和总生存率，但与延迟实现完全供体嵌合和改善淋巴细胞重建有关。对于DC/TBD相关的BMF,TBI似乎是可有可无的。DC/TBD相关MDS的最佳方法仍不清楚。需要更大的队列来更好地评估TBI和供体CD34+细胞剂量的独特贡献。需要更长时间的随访来评估DC/TBD并发症和晚期效应的差异。
目的：我们报告前瞻性收集了一项单中心单臂开放标记的骨髓或外周血干细胞alloHCT治疗DC/TBD相关BMF或MDS的标准alloHCT结果。调节强度降低（RIC），包括阿仑珠单抗1mg/kg，氟达拉滨200mg/m2，环磷酰胺50mg/kg。先前在同一中心针对同一患者人群进行的单臂开放标签II期临床试验，不同之处仅在于包含200厘格的全身照射(TBI)，作为对照组。
结果：非TBI队列包括10名患者（年龄1.7-65.9岁，中位随访3.9年），与包括12例患者（年龄2.2-52.2岁，中位随访10.5年)。基线特征仅在接受的总CD34+细胞中有所不同，中位数为5.6（非TBI），而中位数为2.6（TBI）×106/kg（p=0.02；总有核细胞无差异）。第100天的II-IV级急性和4年慢性移植物抗宿主病（GvHD）的累积发病率较低，分别为0％和10％（非TBI）和8％和17％（TBI），分别(急性，p=0.36；慢性，p=0.72）。没有原发性移植物失败。继发性非中性粒细胞减少性移植物衰竭发生在一个(非TBI队列)中。非TBI队列显示完全供体嵌合的延迟实现，但淋巴细胞恢复优越。在80%(非TBI)和75%(TBI;p=0.78)的4年总生存率没有差异。MDS作为alloHCT的指征并不常见，但总体上与不良结果相关。非TBI队列中有3名MDS患者：1名复发并在第387天死亡；1名在第500天复发，在第二次alloHCT抢救后存活5.5年；1名在第1093天复发，在第二次alloHCT后第100天存活。TBI队列中有1名MDS患者实现了100%供体骨髓植入而没有复发,但在免疫介导的血细胞减少的情况下在第+827天死于细菌感染。
结论：从DC/TBD的RIC方案中消除TBI与移植物失败率的显著变化无关。GvHD,和总生存率，但与延迟实现完全供体嵌合和改善淋巴细胞重建有关。对于DC/TBD相关的BMF,TBI似乎是可有可无的。DC/TBD相关MDS的最佳方法仍不清楚。需要更大的队列来更好地评估TBI和供体CD34+细胞剂量的独特贡献。需要更长时间的随访来评估DC/TBD并发症和晚期效应的差异。
