Effects of minimal residual disease level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia
KUANG Wen-Yong, ZHENG Min-Cui, LI Wan-Li, YANG Hai-Xia, ZHANG Ben-Shan, WU Pan
Department of Hematology, Hunan Children's Hospital, Changsha 410007, China
Abstract：Objective To study the effects of minimal residual disease (MRD) level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia (B-ALL).Methods A total of 152 children with newly-diagnosed B-ALL who had complete remission after the frst cycle of the chemotherapy and had complete follow-up information were enrolled in this study. According to the MRD detection by flow cytometry on day 33 of remission induction, they were divided into three groups:standard-risk (SR) group (MRD <10-4; n=60), intermediate-risk (IR) group (10-4 ≤ MRD < 10-2; n=55), and high-risk (HR) group (MRD ≥ 10-2; n=37). Nested RT-PCR was used to determine the IKZF1 genotype of all children before chemotherapy. The effects of MRD level on day 33 of remission induction and IKZF1 genotype on the recurrence-free survival (RFS) of children with B-ALL were analyzed.Results There were 7 common IKZF1 subtypes in all the 152 children with B-ALL:IK1, IK2/3, IK4, IK6, IK8, IK9, and IK10. Of the 152 children, 130 had functional subtypes of IKZF1 and 22 had non-functional subtypes of IKZF1. During the follow-up period, relapse occurred in 26 (17%) children, and the recurrence rate was highest in the HR group (P < 0.05). However, there was no signifcant difference in the recurrence rate between the SR group and the IR group (P > 0.05). The cumulative recurrence rate of the children with non-functional subtypes of IKZF1 was signifcantly higher than that of those with functional types of IKZF1 (P < 0.01). The predicted 5-year RFS rates in the SR, IR, and HR groups were (94.2±2.9)%, (86.7±3.8)%, and (56.2±4.5)% respectively (P < 0.05). The 5-year RFS rate of the children with functional subtypes of IKZF1 was signifcantly higher than that of those with non-functional subtypes of IKZF1 (P < 0.01). There was no significant difference in the predicted 5-year RFS rate between the children with functional subtypes of IKZF1 and those with non-functional subtypes of IKZF1 in the SR group (P > 0.05). However, the predicted 5-year RFS rate of the children with functional subtypes of IKZF1 was signifcantly higher than that of those with nonfunctional subtypes of IKZF1 in the IR group and the HR group (P < 0.05).Conclusions B-ALL children with nonfunctional subtypes of IKZF1 have a high recurrence rate, and the recurrence rate will be even higher in B-ALL children with non-functional subtypes of IKZF1 and MRD ≥ 10-4 on day 33 of chemotherapy.
KUANG Wen-Yong,ZHENG Min-Cui,LI Wan-Li et al. Effects of minimal residual disease level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia[J]. CJCP, 2018, 20(7): 538-542.
Pui CH, Pei D, Campana D, et al. A revised defnition for cure of childhood acute lymphoblastic leukemia[J]. Leukemia, 2014, 28(12):2336-2343.
[2]
Schmiegelow K, Forestier E, Hellebostad M, et al. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia[J]. Leukemia, 2010, 24(2):345-354.
[3]
Paganin M, Zecca M, Fabbri G, et al. Minimal residual disease is all important predictive factor of outcome in children with relapsed high-risk acute lymphoblastic leukemia[J]. Leukemia, 2008, 22(12):2193-2200.
[4]
Cui L, Li Z, Wu M, et al. Combined analysis of minimal residual disease at two time points and its value for risk stratification in childhood B-lineage acute lymphoblastic leukemia[J]. Leuk Res, 2010, 34(10):1314-1319.
Meleshko AN, Savva NN, Fedasenka UU, et al. Prognostic value of MRD-dynamics in childhood acute lymphoblastic leukemia treated according to the MB-2002/2008 protocols[J]. Leuk Res, 2011, 35(10):1312-1320.
[11]
Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia:a prospective study[J]. Lancet Oncol, 2015, 16(4):465-474.
[12]
Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defned by minimal residual disease (UKALL 2003):a randomised controlled trial[J]. Lancet Oncol, 2013, 14(3):199-209.
[13]
Vora A, Goulden N, Mitchell C, et al. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standardrisk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003):a randomised controlled trial[J]. Lancet Oncol, 2014, 15(8):809-818.
Marke R, Havinga J, Cloos J, et al. Tumor suppressor IKZF1 mediates glucocorticoid resistance in B-cell precursor acute lymphoblastic leukemia[J]. Leukemia, 2016, 30(7):1599-1603.
[16]
Liu P, Lin Z, Qian S, et al. Expression of dominant-negative Ikaros isoforms and associated genetic alterations in Chinese adult patients with leukemia[J]. Ann Hematol, 2012, 91(7):1039-1049.
