减低预处理剂量异基因造血干细胞移植后的白血病复发

Influence of allogenic hematopoietic stem cell transplantation on leukemic recurrence after reduced intensity conditioning

目的：减低预处理剂量异基因造血干细胞移植预处理方案剂量强度弱于清髓性移植且又强于真正的非清髓移植，期望在降低毒副反应的同时能够减少复发。评价减低预处理剂量的异基因造血干细胞移植后白血病的复发情况及主要影响因素。方法：①对象：选取2003—03／2005—06厦门大学附属中山医院血液科收治的23例白血病患者，急性粒细胞白血病6例，急性淋巴细胞白血病7例，慢性粒细胞白血病10例。供者同胞HLA全相合10例，同胞或亲缘供者不全相合12例，非血缘1例。供受者对治疗均签署知情同意书，实验经医院医学伦理委员会批准。②实验方法：23例白血病患者均采用减低预处理剂量方案，马利兰4mg/（kg·d），2-3d；环磷酰胺50mg／（kg·d），2d。其中19例患者在上述方案的基础上加用氟达拉滨30mg／（m^2·d），3-5d；10例患者同时加用阿糖胞苷（1．0～2．0）g／（m^2·d），1～3d。供受者HLA位点不合时用兔抗胸腺细胞球蛋白（3．0～5．0）mg/（kg·d），3-5d。异基因造血干细胞移植前行供者外周血干细胞动员，4-5d后连续采集2次，23例白血病患者输入CD34^＋细胞中位数为4．02×10^6／kg。采用骁悉＋环孢素＋短程甲氨喋呤方案预防移植物抗宿主病。③实验评估：采用STR—PCR方法检测异基因造血干细胞植入证据。结果：①造血功能重建检测：23例患者均顺利完成造血功能重建，无一例发生预处理相关死亡。经预处理后外周血白细胞最低值为（0．01～0．30）×10^9L^-1，血小板最低值为（5～20）×10^9L^-1；中性粒细胞恢复到0．5×10^9L^-1的中位时间为术后11d，血小板恢复到30×10^9L^-1的中位时间为术后12d。术后30d经STR—PCR检测22例患者为完全供者型，骨髓象均完全缓解，剩余1例复发患者未行STR—PCR检测。②移植物抗宿主病发生情况：23例患者中，9例（39．1％）发生急性移植物抗宿主病，19例（82．6％）发生慢性移植物抗宿主病。③术后复发及生存情况：随访截止至2007—06—30，共5例患者复发，复发率21．7％，复发时间为移植后1～24个月；其中急性淋巴细胞白血病2例，急性粒细胞白血病2例，慢性粒细胞白血病1例，后3例移植前处于复发状态。移植前处于缓解期的患者其复发率为10％。结论：①急、慢性粒细胞白血病缓解期患者采用减低预处理剂量的异基因造血干细胞移植方式，其术后复发率并未高于清髓性异基因造血干细胞移植，且预处理相关死亡率低。②疾病类型的选择、移植时的疾病状态、适当的预处理强度以及移植物抗宿主病是影响术后复发的重要因素。

AIM： Reduced intensity conditioning allogenic hematopoietic stem cell transplantation （RIC-HSCT）, the pre-conditional regimen of which is less intensive compared to myeloablative allogenic stem cell transplantation, but greater compared to truly non-myeloablative allogenic stem cell transplantation, is expected to overcome regimen-related toxicity and reduce relapse of leukemia. This study was designed to evaluate recurrence of leukemia and to ientify factors related to relapse after RIC-HSCT. METHODS： ①Twenty-three patients with acute myeloblastic leukemia （AML, n=6）, acute lymphoblastic leukemia （ALL, n=7） or chronic myeloblastic leukemia （CML, n=10） were selected from the Department of Hematology in Zhongshan Hospital of Xiamen University from March 2003 to June 2005. There were 10 HLA-identical sibling donors, 12 family partially mismatched donors and 1 unrelated donor. They all signed the informed consent, and the Hospital Ethics Committee permitted the experiment.②The RIC regimen including busulfan 4 mg/（kg · d）, 2-3 days and cyclophosphamide 50 mg/（kg · d）, 2 days were used in all the patients, and fludarabine 30 mg/（m^2·d）, 3-5 days was added in 19 patients and Ara-c 1-2 g/m^2·d, 1-3 days in 10 patients. Rabbit anti-T-lymphocyte globulin 3.0-5.0 mg/（kg · d）, 3-5 days was used in the HLA-mismatched patients. Peripheral stem cells of donors were mobilized before transplantation, and harvested at days 4 and 5. The median of CD34^＋cells infused was 4.02× 10^6/kg in all patients. Cyclosporine, methotrexate and mycophenolate mofetil were used for the prophylaxis of graft-versus-host disease （GVHD）. ③Short tandem repeat polymerase chain reaction （STR-PCR） was used to detect evidence of donor cell engraftment. RESULTS： ①All 23 patients achieved successful hemopoiesis reconstitution. No patient died of side effects related to the pre-conditional regimen. After RIC, the lowest counts of peripheral white cells and platelets were （0.01-0.03）× 10^9 L^-1 and （5-20）× 10^9 L^-1, respectively. The duration for granulocytes to exceed 0.5 × 10^9 L^-1 was 11 days and platelets to exceed 30× 10^9 L^-1 was 12 days. In 22 patients, STR-PCR confirmed that the donor cell was fully implanted 30 days after RIC-HSCT, and the bone marrow showed complete remission. One case was not tested by STR-PCR because of leukemia relapse.②Acute GVHD occurred in 9 patients （39.1%） and 19 patients （82.6%） developed chronic GVHD.③All 23 patients were followed up until June 30th 2007. Five patients （21.7%） got recurrence, of which two patients with AML and one patient with CML were recurrent before transplantation and other two were patients with ALL. The recurrence rate was 10% in the patients who were in complete remission before the transplantation. The recurrence time was from 1 to 24 months after the transplantation. CONCLUSION： ①In the patients with AML and CML in complete remission before the transplantation, the recurrence rate after RIC-HSCT is not higher than that in myeloablative allogenic stem cell transplantation, and is accompanied by a lower mortality related pre-conditioning regimen.②Type of disease, the disease status at the time of transplantation, intensity of pre-conditional regimen and GVHD are important factors for recurrence of leukemia after RIC-HSCT.