The relationship between minimal residual disease on day 15 and prognosis in children with acute lymphoblastic leukemia

doi:10.3969/j.issn.1004-583X.2024.01.008

Abstract

Abstract:

Objective To analyze the relationship between minimal residual disease (MRD) on day 15 and prognosis in children with acute lymphoblastic leukemia (ALL), and to create a prediction model based on the cut-off values of MRD as 0.01%, 0.1% and 1% on day 15 to predict the prognosis of ALL in children. Methods The clinical data of 90 children with ALL from January 2016 to October 2020 in the Medical Center of Children, Affiliated Hospital of Guangdong Medical University were collected. The Cox regression model was used to analyze the independent prognostic value of each clinical feature. With 0.01%, 0.1%, and 1% of MRD on day 15 as the cut-off values, three Cox regression models were created and validated for the fitting effect via the likelihood ratio test. Results The 5-year survival of 90 children with ALL was 69.1%±5.6%. As of the last follow-up visit, the overall mortality was 25.6% (23/90). Cox multivariate regression analysis showed that MRD on day 15 was an independent risk factor for the prognosis of ALL children when MRD was 0.01% and 0.1% as positive reference values ( $P$ <0.05). The likelihood ratio test was used to evaluate the fitting effect of different prognostic models on the data. The results showed that the prediction model with 0.1% of MRD as the cut-off value had a better prediction efficacy for the clinical outcome of ALL. Conclusion On day 15, MRD is an independent risk factor for the prognosis of children with ALL, and the cut-off value of 0.1% is more valuable for clinical prediction.

Key words: precursor cell lymphoblastic leukemia-lymphoma, child, risk factors, minimal residue, prognosis

CLC Number:

R733.7

Liu Lili, Yuan Yuting, Lai Gengliang, Tian Chuan, Lan Xiang, Ye Zhonglv. The relationship between minimal residual disease on day 15 and prognosis in children with acute lymphoblastic leukemia[J]. Clinical Focus, 2024, 39(1): 47-52.

Add to citation manager EndNote|Ris|BibTeX

URL: https://huicui.hebmu.edu.cn/EN/10.3969/j.issn.1004-583X.2024.01.008

https://huicui.hebmu.edu.cn/EN/Y2024/V39/I1/47

Figures/Tables 4

Tab.1 Clinical characteristics and laboratory examination of 90 children with ALL (cases [%])

临床特征	例数(%)
性别
男	54(60.0)
女	36(40.0)
年龄
<1岁	2(2.5)
1~9岁	80(88.8)
≥10	8(8.7)
初诊WBC
<10×10⁹/L	40(44.4)
10~50×10⁹/L	32(35.6)
50~300×10⁹/L	14(15.6)
≥300×10⁹/L	4(4.4)
免疫分型
B系	79(87.8)
T系	11(12.2)
危险度分级
低危	26(28.9)
中危	36(40.0)
高危	28(31. 1)
融合基因
BCR/ABL	5(6.0)
MLL重排	3(3.6)
E2A-PBX1	4(4.8)
TEL-AML1	16(19.3)
阴性	55(66.3)
未检测	7(7.8)
泼尼松试验反应
良好	72(80.0)
不良	18(20.0)
第15天骨髓涂片
M1	76(84.5)
M2	10(11.1)
M3	4(4.4)
第15天MRD(以0.01%为参考值)
≥0.01%	60(66.7)
<0.01%	30(33.3)
第15天MRD(以0.1%为参考值)
≥0.1%	59(65.6)
<0.1%	31(34.4)
第15天MRD(以1%为参考值)
≥1%	39(43.3)
<1%	51(56.6)
髓外浸润
中枢神经系统白血病	1(1.11)
睾丸白血病	1(1.11)

Tab.2 Analysis of clinical prognostic factors in 90 children with ALL

预后因素	单因素分析			多因素分析
预后因素	$P$ 值	$R R$ 值	95% $C I$	$P$ 值	$R R$ 值	95% $C I$
性别	0.169	1.810	0.777~4.216	0.953	0.965	0.294~3.171
免疫分型	0.278	0.439	0.099~1.943
年龄	0.482	1.049	0.917~1.201
危险度分级	0.188	3.083	0.922~10.315	0.132	2.552	0.660~9.872
初诊WBC	0.181	0.996	0.990~1.002	0.055	0.092	0.983~1.000
初诊血红蛋白	0.569	1.006	0.986~1.026
初诊血小板计数	0.296	0.997	0.993~1.002
融合基因
$T E L - A M L 1$	0.365	0.510	0.119~2.189
$B C R / A B L$	0.214	2.174	0.639~7.397
$E 2 A / P B X 1$	0.954	1.062	0.140~8.035
$M L L$ 重排	0.481	0.065	0.000~249.118
泼尼松试验	0.029	2.535	1.102~2.830	0.065	4.024	0.981~14.641
MRD1	0.078	2.996	0.886~10.133	0.039	0.070	0.006~0.871
MRD2	0.031	4.979	1.163~21.316	0.009	40.612	2.490~662.340
MRD3	0.311	1.527	0.673~3.462
中枢神经系统白血病	0.700	0.654	0.075~5.706
睾丸白血病	0.714	0.048	0.000~526218.723

Tab.2 Analysis of clinical prognostic factors in 90 children with ALL

预后因素	单因素分析			多因素分析
预后因素	$P$ 值	$R R$ 值	95% $C I$	$P$ 值	$R R$ 值	95% $C I$
性别	0.169	1.810	0.777~4.216	0.953	0.965	0.294~3.171
免疫分型	0.278	0.439	0.099~1.943
年龄	0.482	1.049	0.917~1.201
危险度分级	0.188	3.083	0.922~10.315	0.132	2.552	0.660~9.872
初诊WBC	0.181	0.996	0.990~1.002	0.055	0.092	0.983~1.000
初诊血红蛋白	0.569	1.006	0.986~1.026
初诊血小板计数	0.296	0.997	0.993~1.002
融合基因
$T E L - A M L 1$	0.365	0.510	0.119~2.189
$B C R / A B L$	0.214	2.174	0.639~7.397
$E 2 A / P B X 1$	0.954	1.062	0.140~8.035
$M L L$ 重排	0.481	0.065	0.000~249.118
泼尼松试验	0.029	2.535	1.102~2.830	0.065	4.024	0.981~14.641
MRD1	0.078	2.996	0.886~10.133	0.039	0.070	0.006~0.871
MRD2	0.031	4.979	1.163~21.316	0.009	40.612	2.490~662.340
MRD3	0.311	1.527	0.673~3.462
中枢神经系统白血病	0.700	0.654	0.075~5.706
睾丸白血病	0.714	0.048	0.000~526218.723

Tab.3 Analysis of clinical prediction model

	Model 1	Model 2	Model 3
$P$ 值	0.0455	0.0074	0.6139
loglik 值	-76.955	-75.379	-78.327
concordance	0.573	0.614	0.514

Tab.3 Analysis of clinical prediction model

	Model 1	Model 2	Model 3
$P$ 值	0.0455	0.0074	0.6139
loglik 值	-76.955	-75.379	-78.327
concordance	0.573	0.614	0.514

Tab.4 Comparison of clinical characteristics between groups with different cut-off values

项目	以0.01%为临界值				以0.1%为临界值				以1%为临界值
项目	MRD<0.01% [例(%)]	MRD≥0.01% [例(%)]	χ²值	$P$ 值	MRD<0.01% [例(%)]	MRD≥0.01% [例(%)]	χ²值	$P$ 值	MRD<0.01% [例(%)]		MRD≥0.01% [例(%)]	χ²值		$P$ 值
总例数	30	60			31	59			51		39
性别
男女	20 10	34 26	0.833	0.361	20 11	34 25	0.402	0.526	32 19		22 17	0.370		0.543
年龄
<1岁	0	2			0	2			0		2
1~9岁	28	52	0.901	0.616	28	52	0.803	0.868	45		35	3.210		0.192
≥10岁	2	6			3	5			6		2
初诊WBC(×10⁹ /L)
<10	17	23			19	21			30		10
10~50	10	22	3.874	0.261	9	23	6.029	0.098	17		15	14.251		0.002
50~300	3	11			3	11			3		11
≥300	0	4			0	4			1		3
初诊血红蛋白
≤90 g/L >90 g/L	23 7	47 13	0.032	0.858	24 7	46 13	0.004	0.953	40 11		30 9	0.029		0.865
初诊血小板计数(×10⁹ /L)
≤100 >100	26 4	43 17	2.516	0.113	26 5	43 16	1.372	0.241	38 13		31 8	0.306		0.580
中枢神经系统白血病
是否	0 30	1 59	-	1.000	0 31	1 58	-	1.000	0 51		1 38	-		0.433
睾丸白血病
是否	0 30	1 59	-	1.000	0 31	1 58	-	1.000	0 51		1 38	-		0.433
危险度分型
低危	17	9			17	9			24		2
中危	5	31	18.430	0.000	7	29	15.716	0.000	18		18	20.959		0.000
高危	8	20			7	21			9		19
免疫分型
B系 T系	26 4	53 7	0.000	1.000	28 3	51 8	0.038	0.845	46 5		33 6	0.227		0.634
TEL-AML1
阳性阴性	8 22	8 52	2.432	0.119	10 21	6 53	6.783	0.009	12 39		4 35	2.664		0.103
BCR/ABL
阳性阴性	1 29	4 56	0.026	0.871	1 30	4 55	0.046	0.830	1 50		4 35	1.533		0.216
E2A/PBX1
阳性阴性	1 29	3 57	0.000	1.000	1 30	3 56	0.000	1.000	1 50		3 36	0.626		0.429
MLL重排
阳性阴性	0 30	3 57	0.388	0.533	1 30	2 57	0.000	1.000		1 50	2 37		0.056		0.813
泼尼松试验
良好不良	28 2	44 16	5.000	0.025	30 1	42 17	8.316	0.004		48 3	24 15		14.661		0.000
D15骨髓缓解状态
M1	29	47			30	46				50	26
M2	1	9	4.617	0.085	1	9	5.008	0.064		1	9		16.267		0.000
M3	0	4			0	4				0	4

Tab.4 Comparison of clinical characteristics between groups with different cut-off values

项目	以0.01%为临界值				以0.1%为临界值				以1%为临界值
项目	MRD<0.01% [例(%)]	MRD≥0.01% [例(%)]	χ²值	$P$ 值	MRD<0.01% [例(%)]	MRD≥0.01% [例(%)]	χ²值	$P$ 值	MRD<0.01% [例(%)]		MRD≥0.01% [例(%)]	χ²值		$P$ 值
总例数	30	60			31	59			51		39
性别
男女	20 10	34 26	0.833	0.361	20 11	34 25	0.402	0.526	32 19		22 17	0.370		0.543
年龄
<1岁	0	2			0	2			0		2
1~9岁	28	52	0.901	0.616	28	52	0.803	0.868	45		35	3.210		0.192
≥10岁	2	6			3	5			6		2
初诊WBC(×10⁹ /L)
<10	17	23			19	21			30		10
10~50	10	22	3.874	0.261	9	23	6.029	0.098	17		15	14.251		0.002
50~300	3	11			3	11			3		11
≥300	0	4			0	4			1		3
初诊血红蛋白
≤90 g/L >90 g/L	23 7	47 13	0.032	0.858	24 7	46 13	0.004	0.953	40 11		30 9	0.029		0.865
初诊血小板计数(×10⁹ /L)
≤100 >100	26 4	43 17	2.516	0.113	26 5	43 16	1.372	0.241	38 13		31 8	0.306		0.580
中枢神经系统白血病
是否	0 30	1 59	-	1.000	0 31	1 58	-	1.000	0 51		1 38	-		0.433
睾丸白血病
是否	0 30	1 59	-	1.000	0 31	1 58	-	1.000	0 51		1 38	-		0.433
危险度分型
低危	17	9			17	9			24		2
中危	5	31	18.430	0.000	7	29	15.716	0.000	18		18	20.959		0.000
高危	8	20			7	21			9		19
免疫分型
B系 T系	26 4	53 7	0.000	1.000	28 3	51 8	0.038	0.845	46 5		33 6	0.227		0.634
TEL-AML1
阳性阴性	8 22	8 52	2.432	0.119	10 21	6 53	6.783	0.009	12 39		4 35	2.664		0.103
BCR/ABL
阳性阴性	1 29	4 56	0.026	0.871	1 30	4 55	0.046	0.830	1 50		4 35	1.533		0.216
E2A/PBX1
阳性阴性	1 29	3 57	0.000	1.000	1 30	3 56	0.000	1.000	1 50		3 36	0.626		0.429
MLL重排
阳性阴性	0 30	3 57	0.388	0.533	1 30	2 57	0.000	1.000		1 50	2 37		0.056		0.813
泼尼松试验
良好不良	28 2	44 16	5.000	0.025	30 1	42 17	8.316	0.004		48 3	24 15		14.661		0.000
D15骨髓缓解状态
M1	29	47			30	46				50	26
M2	1	9	4.617	0.085	1	9	5.008	0.064		1	9		16.267		0.000
M3	0	4			0	4				0	4

References 20

[1]	Kuhlen M, Klusmann JH, Hoell JI. Molecular approaches to treating pediatric leukemias[J]. Front pediatr, 2019, 7:368. doi: 10.3389/fped.2019.00368 pmid: 31555628
[2]	Wyatt KD, Bram RJ. Immunotherapy in pediatric B-cell acute lymphoblastic leukemia[J]. Hum Immunol, 2019, 80(6):400-408. doi: S0198-8859(18)31188-1 pmid: 30716352
[3]	Della Starza I, Chiaretti S, De Propris MS, et al. Minimal residual disease in acute lymphoblastic leukemia: Technical and clinical advances[J]. Front Oncol, 2019, 9:726. doi: 10.3389/fonc.2019.00726 pmid: 31448230
[4]	Kruse A, Abdel-Azim N, Kim HN, et al. Minimal residual disease detection in acute lymphoblastic leukemia[J]. Int J Mol Sci, 2020, 21(3):1054. doi: 10.3390/ijms21031054 URL
[5]	Henze G, Langermann HJ, Brämswig J, et al. The BFM 76/79 acute lymphoblastic leukemia therapy study (author's transl)[J]. Klin Padiatr, 1981, 193(3): 145-154. pmid: 6943387
[6]	秘营昌, 卞寿庚. 急性淋巴细胞白血病[M]. 3版. 北京: 科学出版社,2007:116-121.
[7]	Pui CH, Yang JJ, Bhakta N, et al. Global efforts toward the cure of childhood acute lymphoblastic leukaemia[J]. Lancet Child Adolesc Health, 2018, 2(6):440-454. doi: 10.1016/S2352-4642(18)30066-X URL
[8]	Pieters R, de Groot-Kruseman H, Van der Velden V, et al. Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: Study ALL10 from the dutch childhood oncology group[J]. J Clin Oncol, 2016, 34(22):2591-2601. doi: 10.1200/JCO.2015.64.6364 pmid: 27269950
[9]	吴敏媛, 李志刚, 崔蕾. 儿童急性淋巴细胞白血病诊疗建议(第四次修订)[J]. 中华儿科杂志, 2014, 52(9):641-644.
[10]	Zhu YP, Yang R, Cai JY, et al. Septicemia after chemotherapy for childhood acute lymphoblastic leukemia in China: A multicenter study CCCG-ALL-2015[J]. Cancer Med, 2020, 9(6):2113-2121. doi: 10.1002/cam4.v9.6 URL
[11]	Cui L, Li ZG, Chai YH, et al. Outcome of children with newly diagnosed acute lymphoblastic leukemia treated with CCLG-ALL 2008: The first nation-wide prospective multicenter study in China[J]. Am J Hematol, 2018, 93(7):913-920. doi: 10.1002/ajh.25124 pmid: 29675840
[12]	Lee SHR, Li Z, Tai ST, et al. Genetic alterations in childhood acute lymphoblastic leukemia: Interactions with clinical features and treatment response[J]. Cancers, 2021, 13(16):4068. doi: 10.3390/cancers13164068 URL
[13]	Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia[J]. Haematologica, 2020, 105(11):2524-2539. doi: 10.3324/haematol.2020.247031 pmid: 33054110
[14]	Gao J, Liu WJ. Prognostic value of the response to prednisone for children with acute lymphoblastic leukemia: A meta-analysis[J]. Eur Rev Med Pharmacol Sci, 2018, 22(22): 7858-7866.
[15]	Qiu KY, Xu HG, Luo XQ, et al. Prognostic value and outcome for ETV6/RUNX1-positive pediatric acute lymphoblastic leukemia: A report from the south china children's leukemia group[J]. Front Oncol, 2021, 11:797194. doi: 10.3389/fonc.2021.797194 URL
[16]	Mao R, Hu SX, Zhang YC, et al. Prognostic nomogram for childhood acute lymphoblastic leukemia: A comprehensive analysis of 673 patients[J]. Front Oncol, 2020, 10:1673. doi: 10.3389/fonc.2020.01673 pmid: 33014835
[17]	Xue YJ, Wang Y, Jia YP, et al. The role of minimal residual disease in specific subtypes of pediatric acute lymphoblastic leukemia[J]. Int J Hematol, 2021, 113(4):547-555. doi: 10.1007/s12185-020-03063-w
[18]	Eckert C, Hagedorn N, Sramkova L, et al. Monitoring minimal residual disease in children with high-risk relapses of acute lymphoblastic leukemia: Prognostic relevance of early and late assessment[J]. Leukemia, 2015, 29(8):1648-1655. doi: 10.1038/leu.2015.59 pmid: 25748682
[19]	Farkas T, Müller J, Erdelyi DJ, et al. Absolute lymphocyte count (ALC) after induction treatment predicts survival of pediatric patients with acute lymphoblastic leukemia[J]. Pathol Oncol Res., 2017, 23(4): 889-897. doi: 10.1007/s12253-017-0192-8 pmid: 28138921
[20]	Marshall GM, Haber M, Kwan E, et al. Importance of minimal residual disease testing during the secong year of therapy for children with acute lymphoblastic leukemia[J]. J Chin Oncol, 2013, 31( 4) :704-709.