Experience with Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Hematopoietic Cell Transplantation in Patients with Nonmalignant Diseases Reveals Good Outcomes and That the Risk of Mixed Chimerism Depends on Underlying Disease, Stem Cell Source, and Alemtuzumab Regimen.
Experience with Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Hematopoietic Cell Transplantation in Patients with Nonmalignant Diseases Reveals Good Outcomes and That the Risk of Mixed Chimerism Depends on Underlying Disease, Stem Cell Source, and Alemtuzumab Regimen.
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DOI：
10.1016/j.bbmt.2015.04.009
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发表时间：
2015-08
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影响因子：
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通讯作者：
Davies SM
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作者：
Marsh RA;Rao MB;Gefen A;Bellman D;Mehta PA;Khandelwal P;Chandra S;Jodele S;Myers KC;Grimley M;Dandoy C;El-Bietar J;Kumar AR;Leemhuis T;Zhang K;Bleesing JJ;Jordan MB;Filipovich AH;Davies SM
阿仑单抗、氟达拉滨和美法兰降低强度调节（RIC）方案越来越多地用于患有非恶性疾病的儿科和年轻成人患者的造血细胞移植（HCT）。早期经验表明，这些方案与良好的生存率相关，但混合嵌合的发生率高，我们之前已经证明混合嵌合受阿仑单抗方案的影响。我们假设潜在的诊断和供体移植物来源也会影响混合嵌合的发展，并且大多数患者在RIC HCT中存活而没有移植物损失。为了验证这一点，我们对206名患有代谢性疾病、非范可尼贫血、骨髓衰竭和原发性免疫缺陷的患者进行了回顾性研究，这些患者在辛辛那提儿童医院连续接受了210次RIC HCT手术。97%的患者进行了移植。46%的患者出现了混合供体和受体嵌合现象。骨髓衰竭患者混合嵌合的风险较低(风险比[HR]， .208； 95%可信区间[CI]，。061至0.709；P = .012)。接受脐带血移植的患者发生混合嵌合的风险较高（HR, 3.122; 95% CI, 1.236 ~ 7.888; P = 0.016）。正如预期的那样，接受每公斤阿仑单抗近剂量或更高剂量的患者也经历了更高的混合嵌合率（所有HR bbb 2，所有P < 0.05）。在最后一次随访时（中位654天，范围13至3337天），超过75%的患者有超过90%的全血捐献者嵌合。5%的患者进行了第二次移植。接受hla匹配的兄弟姐妹供体移植的患者三年无再移植生存率为84% （95% CI, 71% - 98%）。缺乏匹配的相关供体、年龄增加以及III级和IV级急性移植物抗宿主病的发展对无再次移植的生存产生负面影响。我们得出结论，阿仑单抗、氟达拉滨和美法兰对许多患者的RIC HCT效果良好，发生混合嵌合的风险受到潜在诊断、移植物来源和阿仑单抗剂量的影响。
Alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens are increasingly used for the hematopoietic cell transplantation (HCT) of pediatric and young adult patients with nonmalignant diseases. Early experience suggests that these regimens are associated with good survival but a high incidence of mixed chimerism, which we have previously shown to be influenced by the alemtuzumab schedule. We hypothesized that the underlying diagnosis and donor graft source would also affect the development of mixed chimerism and that the majority of patients would survive RIC HCT without graft loss. To examine this, we conducted a retrospective study of 206 patients with metabolic diseases, non-Fanconi anemia marrow failure disorders, and primary immune deficiencies who underwent 210 consecutive RIC HCT procedures at Cincinnati Children’s Hospital. Ninety-seven percent of the patients engrafted. Mixed donor and recipient chimerism developed in 46% of patients. Patients with marrow failure had a low risk of mixed chimerism (hazard ratio [HR], .208; 95% confidence interval [CI], .061 to .709; P = .012). The risk of mixed chimerism was high in patients who received a cord blood graft (HR, 3.122; 95% CI, 1.236 to 7.888; P = .016). As expected, patients who received a proximal or higher dose per kilogram of alemtuzumab schedule also experienced higher rates of mixed chimerism (all HR > 2, all P < .05). At the time of last follow-up (median, 654 days; range, 13 to 3337), over 75% of patients had greater than 90% whole blood donor chimerism. A second transplantation was performed in 5% of patients. Three-year survival without retransplantation was 84% (95% CI, 71% to 98%) for patients who underwent transplantation with an HLA-matched sibling donor. Survival without retransplantation was negatively affected by lack of a matched related donor, increasing age, and development of grades III and IV acute graft-versus-host disease. We conclude that alemtuzumab, fludarabine, and melphalan RIC HCT offers good results for many patients and that the risk of developing mixed chimerism is influenced by underlying diagnosis, graft source, and alemtuzumab dosing.