Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, No 11 Xizhimen South Street, Beijing, 100044, China.
Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, 2019RU029, Beijing, China.
BMC Cancer. 2022 Jan 3;22(1):11. doi: 10.1186/s12885-021-09051-5.
The mixed-lineage leukemia (MLL) gene is located on chromosome 11q23. The MLL gene can be rearranged to generate partial tandem duplications (MLL-PTD), which occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation.
We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People's Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL > 0.08% was defined as MLL-PTD positive in this study.
The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7 ± 5.2, 67.8 ± 6.9, 68.1 ± 6.8 and 20.3% ± 6.1%, respectively. ROC curve showed that post-transplant MLL-PTD ≥ 1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD ≥ 1.0% and MLL-PTD < 1.0% groups (3-year CIR: 75% ± 15.3% vs. 0%, P < 0.001; 3-year OS: 25.0 ± 15.3% vs. 80.7% ± 6.6%, P < 0.001; 3-year DFS: 25.0 ± 15.3% vs. 80.7 ± 6.6%, P < 0.001; 3-year TRM: 0 vs. 19.3 ± 6.6%, P = 0.277). However, whether MLL-PTD ≥ 1% or MLL-PTD < 1% before transplantation has no significant difference on the prognosis.
Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.
混合谱系白血病（MLL）基因位于 11q23 染色体上。MLL 基因可发生部分串联重复（MLL-PTD）重排，约 5-10%的染色体核型正常的急性髓系白血病（AML）和 5-6%的骨髓增生异常综合征（MDS）患者中存在这种情况。异基因造血干细胞移植（allo-HSCT）是目前治疗伴有过量白血病细胞的 AML 和 MDS（MDS-EB）的一种根治性疗法。然而，allo-HSCT 后高水平 MLL-PTD 的患者预后如何，以及 MLL-PTD 是否可以作为移植患者微小残留病（MRD）监测的可靠指标，目前尚不清楚。本研究旨在分析移植前后 MLL-PTD 的动态变化，并确定预测移植后复发的最佳阈值。
我们回顾性收集了北京大学人民医院接受 allo-HSCT 的 MLL-PTD AML 或 MDS-EB 患者的临床资料。采用实时定量聚合酶链反应（RQ-PCR）在诊断时、移植前和移植后固定时间点检测 MLL-PTD。本研究中，检测到的 MLL-PTD/ABL>0.08%定义为 MLL-PTD 阳性。
48 例患者中包括 33 例 AML 患者和 15 例 MDS-EB 患者。HSCT 后中位随访时间为 26（0.7-56）个月。AML 患者中，7 例（21.2%）因治疗相关死亡（TRM）死亡，6 例（18.2%）发生血液学复发并最终死亡。15 例 MDS-EB 患者中，2 例（13.3%）因感染死亡。3 年累积复发率（CIR）、总生存率（OS）、无病生存率（DFS）和 TRM 分别为 13.7±5.2%、67.8±6.9%、68.1±6.8%和 20.3%±6.1%。ROC 曲线显示，移植后 MLL-PTD≥1.0%是预测 allo-HSCT 后血液学复发的最佳截断值。移植后 MLL-PTD≥1.0%和 MLL-PTD<1.0%两组之间存在统计学差异（3 年 CIR：75%±15.3%vs.0%，P<0.001；3 年 OS：25.0±15.3%vs.80.7%±6.6%，P<0.001；3 年 DFS：25.0±15.3%vs.80.7%±6.6%，P<0.001；3 年 TRM：0%vs.19.3%±6.6%，P=0.277）。然而，移植前 MLL-PTD≥1%或 MLL-PTD<1%对预后无显著影响。
本研究表明，MLL-PTD 具有一定的稳定性，可以有效反映肿瘤负荷的变化。移植后 MLL-PTD 的表达水平可作为预测复发的有效指标。
