超强预处理allo-HSCT联合GVL诱导策略治疗难治性急性淋巴细胞白血病74例

Allogeneic hematopoietic stem cell transplantation for 74 patients with refractory acute lymphoblastic leukemia following sequential intensified conditioning combined with graft-versns-leukemia induction

目的探讨超强预处理异基因造血干细胞移植（allo-HSCT）联合移植物抗白血病（GVL）诱导策略治疗难治性未缓解急性淋巴细胞白血病（ALL）的安全性和有效性。方法将2005年1月至2014年12月行allo-HSCT的74例难治性ALL患者纳入此研究。序贯超强预处理方案为氟达拉滨＋阿糖胞苷＋全身放疗＋环磷酰胺十依托泊苷。GVL诱导策略包括：移植后第30天对未发生急性移植物抗宿主病（GVHD）者给予快速递减免疫抑制剂，至第60天未发生Ⅱ度或以上急性GVHD者给予供者淋巴细胞输注（DLI）。结果除2例在移植后1周内分别死于感染和预处理相关毒性外，其他受者均在粒系重建时获得完全缓解。预处理相关致死率为1．4％（1／74）。白血病的5年复发率为（29．2±6．1）％，5年非复发死亡率为（30．4±5．6）％，5年总存活率（OS）和无病存活率（DFS）为（49．5±5．9）％和（48．2±5．9）％。B淋巴细胞ALL和T淋巴细胞ALL患者的5年复发率、OS和DFS无显著差异（P=0．929、P=0．652和P=0．691）。DLI、慢性GVHD和移植0天骨髓幼稚细胞是移植后复发和生存的独立预后因素（P=0．043、P=0．026及P〈0．001；P=0．045、P=0．029及P〈0．001）。结论序贯超强预处理allo-HSCT联合GVL诱导策略能降低难治性ALL复发率和提高受者的存活率。

Objective To explore the safety and effectiveness of sequential intensified conditioning regimen combined with graft-versus-leukemia （GVL） induction in allogeneic hematopoietic stem cell transplantation （allo-HSCT） for refractory advanced acute lymphoblastic leukemia （ALL）. Methods A total of 74 patients with refractory ALL, undergoing allo-HSCT from Jan. 2005 to Dec. 2014, were enrolled in this study. Intensified conditioning was： fludarabine ＋ cytarabine plus total body irradiation ＋ cyclophosphamide ＋ etoposide. Cyclosporine A was withdrawn rapidly in a stepwise fashion if patients did not experience acute graft-versus-host disease （aGVHD） by day ＋ 30 post-transplantation. Donor lymphocytes were infused in patients without grade II or more than grade II aGVHD by day ＋ 60 post-transplantation. Results Except for one who died of infection and one who died of regimen-related toxicity （RRT）, the remaining 72 patients achieved complete remission at the time of neutrophil reconstitution. The mortality of RRTs was 1.4% （1/74）. The 5-year cumulative incidence of relapse post-transplantation was （29. 2 ± 6. 1）%. The 5-year non-relapse mortality was （30. 4 ±5.6） %. The 5-year overall and disease-free survival was（49. 5 ± 5.9）% and （48. 2 ±5. 9）^ respectively. The 5-year leukemia relapse rate, overall and disease-free survival were similar between patients with B-cell ALL and T-cell ALL （P = 0. 929, P = 0. 652, P = 0. 691）. Multivariate analysis revealed that donor lymphocyte infusion, chronic GVHD and bone marrow blasts on day 0 were independent prognostic factors for relapse and survival （P = 0.043, P=0.026, P〈0.001; P=0.045, P=0.029, P〈0.001）. Conclusion The strategy of sequential intensified conditioning combined with GVL induction could decrease the relapse rate and improve the survival for refractory ALL.