非清髓性造血干细胞移植治疗血液病预处理中ATG/ALG的应用及作用

Application and Effects of ATG/ALG in Non-myeloablative Conditioning Regimen for Hematologic Diseases

目的：探讨抗胸腺细胞球蛋白（ATG）和抗淋巴细胞球蛋白（ALG）在血液病非清髓性异基因造血干细胞移植中的作用，以及ATG/ALG的毒副作用，对移植并发症的影响。方法：以ATG／ALG为基础降低化疗剂量的非清髓性预处理方案，对16例恶性血液病、17例重型再生障碍性贫血（SAA）实施骨髓、骨髓加外周血造血干细胞或脐血造血干细胞移植；对5例恶性血液病实施逐渐增加剂量的供者淋巴细胞输注（DLI），1例S从实行供者干细胞输注（DSI）。GVHD的预防：恶性血液病采用环孢菌素A联合短程甲氨喋呤，SAA患者采用CSA联合甲泼尼龙。采用糖皮质激素和甾体类消炎药等防治ATG／ALG毒副作用和并发症。结果：3例患者在移植后早期感染死亡。其余30例患者恢复造血功能，ANC〉0．5×10^8/L和PLT〉20×10^9／l平均时间为12．2（3-35）d和20．1（5～80）d。移植后7例为供者型完全嵌合体（CC），3例无植入证据；23例为混合性嵌合体（MC），其中7例逐渐转为CC，6倒是在DLI或者DSI后实现MC向CC转变。移植后早期均无aGVHD，3～8次DLI并发Ⅰ度aGVHD1例、Ⅱ度aGVHD3例，2例皮肤局限型cGVHD、2例为广泛型cGVHD。并发严重的细菌感染3例、病毒感染4例、真菌感染5例。ATG／ALG使用过程中全部出现寒战、发热症状，大部分出现皮疹、一过性血压下降、少数出现一过性心律不齐，经积极防治不需中断治疗。结论：ATG／ALG促进异基因造血干细胞的植入，延迟和减少GVHD的发生率并降低严重程度．是否增加病毒、真菌感染的机会有待进一步观察。

Objective：To evaluate the effects of ATG/ALG in non-myeloablative stem call transplantation for patients with hematologic diseases, and its influences on transplantation complications as well as side-effects of ATG/ ALG. Methods： The protocol was designed to minimizing the intensity of conditioning regimen to the range of nonmyeloablative therapy on basis of application of ATG/ALG for 16 cases of hematological malignancies, 17 cases of severe aplastic anemia （SAA）. Hematopoietic stem cells were collected from sibling donors bone marrow and peripheral blood, or unrelated donors umbilical cord blood. Donor lymphocyte infusions （DLIs） were performed after transplantation by means of escalated T-lymphocyte dosage regimen（EDR） for patients with hematologic malignancies （n = 5） ,while donor stem cell infusion（DSI） was performed for one patient with SAA（n = 1 ）. GVHD prophy- laxis consisted of CSA and methotrexate （MTX） for patients with hematological malignancies, cyclosporin A（CSA） and methylprednisolone （MP） for patients with SAA. Glucocorticoid and steroidal anti-inflammatory drug were used for prevention of side-effects of ATG/ALG and therapy of transplantation complications. Results： Three patients could not achieve haemopoietic reconstruction and died from infection at early stage after transplantation, and other 30 patients with hematopoietic recovery. The mean time of ANC more than 0. 5 × 10^9/L and platelet count more than 20 × 10^9/L were 12.2（3-35） and 20. 1 （5-80） days respectively. Three patients had no evidence of engraftment and 7 patients achieved donor hematopoietic cell complete chimera （CC）. Twenty-three patients achieved donor -recipient hematopoietic cell mixed chimera（MC）, among them, 7 patients spontaneously converted to CC, and 6 patients gradually converted to CC from MC after receiving 3 to 8 procedures of DLI or one DSI post-transplantly. No evidence of aGVHD was proved in early stage after transplantation. After 2 or 3 dosages of DLI. Grade Ⅰ （n = 1） and Ⅱ （n = 3） aGVHD were discovered with local skin cGVHD（n = 2） and extensive cGVHD（n = 2）respectively. Infection complications included bacterial （n = 3）, viral （n = 4） and fungal（n = 5）. During use of ATG/ALG, all patients complicated with chills and fever in different degrees, most of them presented erythra and transient hypotension, and few patients presented transient arrhythmia. All of them did not need interruption of ATG/ALG after active treatment. Conclusion： ATG/ALG is safe and be tolerated in the procedure, it helps engraftment, and delay or decrease the occurance of aGVHD. Whether or not it increases the opportunity of viral and fungal infection, still need to be further investigated.