Objective: To investigate whether haplotype hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of pre transplant minimal residual disease (Pre-MRD) positive acute B lymphoblastic leukemia (B-ALL) compared with HLA- matched sibling donor transplantation (MSDT) . Methods: A total of 998 patients with B-ALL in complete remission pre-HSCT who either received haplo-HSCT (n=788) or underwent MSDT (n=210) were retrospectively analyzed. The pre-transplantation leukemia burden was evaluated according to Pre-MRD determinedusing multiparameter flow cytometry (MFC) . Results: Of these patients, 997 (99.9% ) achieved sustained, full donor chimerism. The 100-day cumulative incidences of neutrophil engraftment, platelet engraftment, and grades Ⅱ-Ⅳ acute graft-versus-host disease (GVHD) were 99.9% (997/998) , 95.3% (951/998) , and 26.6% (95% CI 23.8% -29.4% ) , respectively. The 3-year cumulative incidence of total chronic GVHD was 49.1% (95% CI 45.7% -52.4% ) . The 3-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) of the 998 cases were 17.3% (95% CI 15.0% -19.7% ) and 13.8% (95% CI 11.6% -16.0% ) , respectively. The 3-year probabilities of leukemia-free survival (LFS) and overall survival (OS) were 69.1% (95% CI 66.1% -72.1% ) and 73.0% (95% CI 70.2% -75.8% ) , respectively. In the total patient group, cases with positive Pre-MRD (n=282) experienced significantly higher CIR than that of subjects with negative Pre-MRD [n=716, 31.6% (95% CI 25.8% -37.5% ) vs 14.3% (95% CI 11.4% -17.2% ) , P<0.001]. For patients in the positive Pre-MRD subgroup, cases treated with haplo-HSCT (n=219) had a lower 3-year CIR than that of cases who underwent MSDT [n=63, 27.2% (95% CI 21.0% -33.4% ) vs 47.0% (95% CI 33.8% -60.2% ) , P=0.002]. The total 998 cases were classified as five subgroups, including cases with negative Pre-MRD group (n=716) , cases with Pre-MRD<0.01% group (n=46) , cases with Pre-MRD 0.01% -<0.1% group (n=117) , cases with Pre-MRD 0.1% -<1% group (n=87) , and cases with Pre-MRD≥1% group (n=32) . For subjects in the Pre-MRD<0.01% group, haplo-HSCT (n=40) had a lower CIR than that of MSDT [n=6, 10.0% (95% CI 0.4% -19.6% ) vs 32.3% (95% CI 0% -69.9% ) , P=0.017]. For patients in the Pre-MRD 0.01% -<0.1% group, haplo-HSCT (n=81) also had a lower 3-year CIR than that of MSDT [n=36, 20.4% (95% CI 10.4% -30.4% ) vs 47.0% (95% CI 29.2% -64.8% ) , P=0.004]. In the other three subgroups, the 3-year CIR was comparable between patients who underwent haplo-HSCT and those received MSDT. A subgroup analysis of patients with Pre-MRD<0.1% (n=163) was performed, the results showed that cases received haplo-HSCT (n=121) experienced lower 3-year CIR [16.0% (95% CI 9.4% -22.7% ) vs 40.5% (95% CI 25.2% -55.8% ) , P<0.001], better 3-year LFS [78.2% (95% CI 70.6% -85.8% ) vs 47.6% (95% CI 32.2% -63.0% ) , P<0.001] and OS [80.5% (95% CI 73.1% -87.9% ) vs 54.6% (95% CI 39.2% -70.0% ) , P<0.001] than those of MSDT (n=42) , but comparable in 3-year NRM [5.8% (95% CI 1.6% -10.0% ) vs 11.9% (95% CI 2.0% -21.8% ) , P=0.188]. Multivariate analysis showed that haplo-HSCT was associated with lower CIR (HR=0.248, 95% CI 0.131-0.472, P<0.001) , and superior LFS (HR=0.275, 95% CI 0.157-0.483, P<0.001) and OS (HR=0.286, 95% CI 0.159-0.513, P<0.001) . Conclusion: Haplo HSCT has a survival advantage over MSDT in the treatment of B-ALL patients with pre MRD<0.1% .
目的： 探讨单倍型造血干细胞移植（haplo-HSCT）治疗移植前微小残留病（Pre-MRD）阳性急性B淋巴细胞白血病（B-ALL）是否较全相合同胞造血干细胞移植（MSDT）具有生存优势，以及该作用是否受Pre-MRD的影响。 方法： 对2009年6月至2018年6月在北京大学血液病研究所接受异基因造血干细胞移植（allo-HSCT）的998例移植前处于完全缓解（CR）的B-ALL患者进行回顾性分析，其中haplo-HSCT组788例、MSDT组210例，移植前用多参数流式细胞术（MFC）检测MRD水平。 结果： ①全部998例B-ALL患者中，997例获得持续的完全供者嵌合状态，移植后100 d中性粒细胞、血小板植入率分别为99.9%（997/998）、95.3%（951/998），Ⅱ~Ⅳ度急性移植物抗宿主病（GVHD）发生率为26.6%（95%CI 23.8%~29.4%），3年慢性GVHD累积发生率为49.1%（95%CI 45.7%~52.4%），移植后3年白血病累积复发率（CIR）为17.3%（95%CI 15.0%~19.7%），非复发死亡率（NRM）为13.8%（95% CI 11.6%~16.0%），移植后3年无白血病生存（LFS）率、总生存（OS）率分别为69.1%（95%CI 66.1%~72.1%）、73.0%（95%CI 70.2%~75.8%）。②Pre-MRD阳性组（282例）患者移植后3年CIR高于Pre-MRD阴性组（716例）[31.6%（95%CI 25.8%~37.5%）对14.3%（95%CI 11.4%~17.2%），P<0.001]。③在Pre-MRD阳性组中，haplo-HSCT患者（219例）移植后3年CIR低于MSDT患者（63例）[27.2%（95%CI 21.0%~33.4%）对47.0%（95%CI 33.8%~60.2%），P＝0.002]。④全部998例患者按照Pre-MRD结果分为阴性组（716例）、<0.01%组（46例）、0.01%~<0.1%组（117组）、0.1%~<1%组（87例）、≥1%组（32例）；5组患者中，<0.01%组haplo-HSCT患者（40例）移植后3年CIR低于MSDT患者（6例）[10.0%（95%CI 0.4%~19.6%）对32.3%（95%CI 0%~69.9%），P＝0.017]，0.01%~<0.1%组haplo-HSCT患者（81例）移植后3年CIR也低于MSDT患者（36例）[20.4%（95%CI 10.4%~30.4%）对47.0%（95%CI 29.2%~64.8%），P＝0.004]；其他三组中，haplo-HSCT和MSDT患者移植后3年CIR差异无统计学意义。⑤在Pre-MRD<0.1%组（163例）中，haplo-HSCT患者（121例）移植后3年CIR低于MSDT患者（42例）[16.0%（95%CI 9.4%~22.7%）对40.5%（95% CI 25.2%~55.8%），P<0.001]，3年LFS率、OS率均高于MSDT组[78.2%（95%CI 70.6%~85.8%）对47.6%（95%CI 32.2%~63.0%），P<0.001；80.5%（95%CI 73.1%~87.9%）对54.6%（95%CI 39.2%~70.0%），P<0.001]，两组3年NRM差异无统计学意义[5.8%（95%CI 1.6%~10.0%）对11.9%（95%CI 2.0%~21.8%），P＝0.188]。多因素分析显示，haplo-HSCT是Pre-MRD<0.1%组移植后低CIR（HR＝0.248，95%CI 0.131~0.472，P<0.001）、高LFS率（HR＝0.275，95%CI 0.157~0.483，P<0.001）和高OS率（HR＝0.286，95%CI 0.159~0.513，P<0.001）的独立影响因素。 结论： haplo-HSCT治疗Pre-MRD<0.1%的B-ALL患者较MSDT具有生存优势。.
Keywords: Haploidentical stem cell transplantation; Human leukocyte antigen-matched sibling donor transplantation; Minimal residual disease; Relapse.