Iannone Robert, Casella James F, Fuchs Ephraim J, Chen Allen R, Jones Richard J, Woolfrey Ann, Amylon Michael, Sullivan Keith M, Storb Rainer F, Walters Mark C
Department of Pediatrics, Johns Hopkins Hospital and Oncology Center, Baltimore, Maryland, USA.
Biol Blood Marrow Transplant. 2003 Aug;9(8):519-28. doi: 10.1016/s1083-8791(03)00192-7.
We describe previously transfused patients with sickle cell disease (n = 6) and thalassemia (n = 1) who received nonmyeloablative hematopoietic stem cell transplantation (HCT) to induce stable (full or partial) donor engraftment. Patients were 3 to 20 years (median, 9 years) old. All 7 received pretransplantation fludarabine and 200 cGy of total body irradiation; 2 patients also received horse antithymocyte globulin. Patients received bone marrow (n = 6) or peripheral blood stem cells (n = 1) from HLA-identical siblings, followed by a combination of mycophenolate mofetil and cyclosporine or tacrolimus for postgrafting immunosuppression. After nonmyeloablative HCT, absolute neutrophil counts were <0.5 x 10(9)/L and <0.2 x 10(9)/L for a median of 5 days (range, 0-13 days) and 0 days (range 0-13 days), respectively. A median of 0 (range, 0-9) platelet transfusions were administered. No grade IV nonhematologic toxicities were observed. One patient experienced grade II acute graft-versus-host disease. Two months after transplantation, 6 of 7 patients had evidence of donor chimerism (range, 25%-85%). Independent of red blood cell transfusions, these 6 patients initially had increased total hemoglobin and hemoglobin A concentrations and a reduction of reticulocytosis and transfusion requirements. There were no complications attributable to sickle cell disease during the interval of transient mixed chimerism. However, after posttransplantation immunosuppression was tapered, there was loss of the donor graft, and all patients experienced autologous hematopoietic recovery and disease recurrence. One patient did not engraft. The duration of transient mixed chimerism ranged from 97 to 441 days after transplantation in patients 4 and 6, respectively, and persisted until immunosuppressive drugs were discontinued after transplantation. In summary, the nonmyeloablative HCT regimens described here produced minimal toxicity and resulted in transient donor engraftment in 6 of 7 patients with hemoglobinopathies. Although complications from the underlying hemoglobinopathies did not occur during the period of mixed chimerism, these results suggest that stable (full or partial) donor engraftment after nonmyeloablative HCT is more difficult to achieve among immunocompetent pediatric patients with hemoglobinopathies than among adults with hematologic malignancies, perhaps in part because recipients may have been sensitized to minor histocompatibility antigens of their donor by preceding blood transfusions.
我们描述了先前接受过输血的镰状细胞病患者（n = 6）和地中海贫血患者（n = 1），他们接受了非清髓性造血干细胞移植（HCT）以诱导稳定（完全或部分）的供体植入。患者年龄为3至20岁（中位数为9岁）。所有7例患者均接受了移植前氟达拉滨和200 cGy的全身照射；2例患者还接受了马抗胸腺细胞球蛋白治疗。患者接受了来自HLA相同同胞的骨髓（n = 6）或外周血干细胞（n = 1），随后联合使用霉酚酸酯和环孢素或他克莫司进行移植后免疫抑制。非清髓性HCT后，绝对中性粒细胞计数分别在中位数5天（范围为0 - 13天）和0天（范围为0 - 13天）时<0.5×10⁹/L和<0.2×10⁹/L。血小板输注的中位数为0（范围为0 - 9）。未观察到IV级非血液学毒性。1例患者发生了II级急性移植物抗宿主病。移植后两个月，7例患者中有6例有供体嵌合体的证据（范围为25% - 85%）。与红细胞输血无关，这6例患者最初总血红蛋白和血红蛋白A浓度增加，网织红细胞增多和输血需求减少。在短暂混合嵌合期未发生镰状细胞病相关的并发症。然而，移植后免疫抑制逐渐减量后，供体移植物丢失，所有患者均出现自体造血恢复和疾病复发。1例患者未植入。在患者4和6中，短暂混合嵌合的持续时间分别为移植后97至441天，并一直持续到移植后停用免疫抑制药物。总之，本文所述的非清髓性HCT方案毒性极小，7例血红蛋白病患者中有6例实现了短暂的供体植入。尽管在混合嵌合期未发生潜在血红蛋白病的并发症，但这些结果表明，与血液系统恶性肿瘤成人患者相比，有免疫活性的血红蛋白病儿科患者在非清髓性HCT后更难实现稳定（完全或部分）的供体植入，这可能部分是因为受者可能因先前的输血而对其供体的次要组织相容性抗原致敏。
