摘要： 目的·分析混合谱系白血病（mixed linage leukemia，
MLL）基因重排（
MLL rearrangement，
MLL-r）阳性的儿童急性白血病（acute leukemia，AL）患者的临床特点及预后情况。方法·回顾性分析2009年1月1日至2019 年12月31日上海交通大学附属儿童医院收治的
MLL-r AL患儿45例。采用荧光原位杂交和/或实时荧光定量PCR检测
MLL-r。Kaplan-Meier法评估患儿生存情况，Log-rank检验比较各组生存率。对性别、年龄、白细胞数等影响生存的指标进行单因素和多因素分析。结果·AL患儿
MLL-r的检出率为7.1%；在急性淋巴细胞白血病（acute lymphoblastic leukemia，ALL）和急性髓细胞性白血病（acute myeloid leukemia，AML）中
MLL-r的检出率分别为5.4%和13.3%，二者差异有统计学意义（
P=0.002）；2组患儿的年龄（>1岁和≤1岁）和初发时白细胞数（≥50×10
9/L和<50×10
9/L）比较，差异均有统计学意义（
P=0.032和
P=0.021）。
MLL-r ALL患儿的免疫分型以早期前体B-ALL为主，占79.2%；
MLL-r AML患儿以M
5为主，占77.8%。
MLL伙伴基因分析，ALL患儿
MLL/
AF4占59.2%（16/27），其中小于1岁的患儿占68.7%（11/16），与非
MLL/
AF4组小于1岁的患儿数相比差异有统计学意义（
P=0.034）；AML患儿以
MLL/
AF9为主，占33.3%。42例患儿可进行疗效分析，完全缓解率为97.6%（41/42），中位随访时间26个月（2~138个月），中位无事件生存（event-free survival，EFS）和总生存（overall survival，OS）时间分别为21个月和24.5个月，3年EFS和OS率分别为（41.8±9.4）%和（60.9±9.3）%。
MLL-r ALL患儿中位EFS和OS时间分别为21.5个月和28个月，3年EFS和OS率分别为（44.3±11.7）%和（58.2±12.1）%。
MLL-r AML患儿中位EFS和OS时间分别为16个月和23个月，2年EFS和OS率分别为（36.5±15.8）%和（64.7±14.5）%。ALL患儿复发8例，中位复发时间20个月（2~36个月）；AML患儿复发7例，中位复发时间16个月（5~38个月）；二者累积复发率分别为48.4%和63.9%，差异无统计学意义（
P=0.398）。单因素分析显示，
MLL-r ALL患儿年龄>1岁与≤1岁组、白细胞数≥50×10
9/L与<50×10
9/L组、血小板数>30×10
9/L与≤30×10
9/L组EFS率比较差异均有统计学意义，
P值分别为0.028、0.024和0.027。多因素分析显示发病时的白细胞数为影响
MLL-r ALL患儿EFS的独立预后因素（
RR=6.113，95%
CI 0.017~1.050，
P=0.013）结论·AML患儿
MLL-r的发生率比ALL患儿高。
MLL-r ALL患儿免疫分型以早期前体B-ALL为主，
MLL-r AML患儿多见于M
5型。
MLL-r阳性儿童白血病患者化学治疗的缓解率尚可，但复发率高。发病时的白细胞数≥50×10
9/L是
MLL-r ALL患儿的不良预后因素。
关键词: 白血病, 混合谱系白血病基因, 儿童, 预后分析 Abstract: Objective·To analyze the clinical characteristics and prognosis of pediatric acute leukemia (AL) patients with positive mixed linage leukemia (MLL) gene rearrangement (MLL-r).
Methods·Forty-five children with MLL-r AL admitted to Shanghai Children′s Hospital, Shanghai Jiao Tong University from January 1, 2009 to December 31, 2019 were retrospectively analyzed. Fluorescence in situ hybridization and/or fluorescent real-time PCR were used to detect the MLL-r. Kaplan-Meier method was used to evaluate the survival of children. Log-rank test was used to compare the difference of survival rate. Univariate analysis and multivariate analysis were performed on the factors influencing survival, such as gender, age and the number of white blood cells.
Results·The incidence rate of MLL-r in children with AL in our center was 7.1%, and the incidence rate of MLL-r in children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were 5.4% and 13.3%, respectively. The difference between the two groups was statistically significant (P=0.002). The age of the two groups of children (>1 year and ≤1 year) and the number of white blood cells at the time of onset (≥50×109/L and <50×109/L) were compared. The differences were statistically significant (P=0.032 and 0.021). The main immunophenotype of children with MLL-r ALL was early precursor B-ALL, accounting for 79.2%. The main immunophenotype of children with MLL-r AML was M5, accounting for 77.8%. MLL partner gene analysis showed that MLL/AF4 accounted for 59.2% (16/27) of MLL-r ALL children, of which 68.7% (11/16) were children younger than 1 year old. Compared with the children younger than 1 year old in the non-MLL/AF4 group, the difference was statistically significant (P=0.034). The majority of children with MLL-r AML were MLL/AF9, accounting for 33.3%. Of the 45 patients, 42 cases were included for the prognosis analysis. The complete remission rate was 97.6% (41/42), and the median follow-up time was 26 (2?138) months. The median event-free survival (EFS) and overall survival (OS) time were 21 months and 24.5 months, respectively. The 3-year EFS and OS rates were (41.8±9.4) % and (60.9±9.3) %, respectively. The median duration of EFS and OS in children with MLL-r ALL were 21.5 months and 28 months, respectively, and the 3-year EFS and OS rates were (44.3±11.7) % and (58.2±12.1) %, respectively. The median EFS and OS time in children with MLL-r AML were 16 months and 23 months, respectively. The 2-year EFS and OS rates were (36.5±15.8) % and (64.7±14.5) %, respectively. Eight cases of ALL children relapsed, with a median recurrence time of 20 (2?36) months; 7 cases of AML children relapsed, with a median recurrence time of 16 (5?38) months, and the cumulative recurrence rates were 48.4% and 63.9%, respectively. There was no statistically significant difference between them (P=0.398). Univariate analysis showed that between the groups of MLL-r ALL children >1 year and ≤1 year, white blood cell count ≥50×109/L and <50×109/L, platelet count ≥30×109/L and <30×109/L, there were statistically significant differences in the EFS rate. The P values were 0.028, 0.024 and 0.027 respectively. Multivariate analysis showed that the number of white blood cells at onset was an independent prognostic factor affecting EFS in children with MLL-r ALL (RR=6.113, 95% CI 0.017?1.050, P=0.013).
Conclusion·The incidence of MLL-r in children with AML is higher than that in children with ALL. The main immunophenotype of MLL-r ALL is early precursor B-ALL. The main immunophenotype of MLL-r AML is M5. Conventional chemotherapy produces a high response rate, which is likely to relapse. The number of white blood cells at the onset ≥50×109/L is a poor prognostic factor for children with MLL-r ALL.
Key words: leukemia, mixed-lineage leukemia genes, children, prognostic analysis PDF全文下载地址:
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