Induction-phase blood arsenic concentration and relapse risk in pediatric APL treated with arsenic and ATRA

Induction-phase blood arsenic concentration and relapse risk in pediatric APL treated with arsenic and ATRA | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Induction-phase blood arsenic concentration and relapse risk in pediatric APL treated with arsenic and ATRA Huyong Zheng, Qingyuan Xu, Linya Wang, Ning Liao, Mincui Zheng, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8698439/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract The application of targeted therapy with arsenic and all-trans retinoic acid (ATRA) has significantly improved outcomes in pediatric acute promyelocytic leukemia (APL), but relapse remains a major obstacle to cure. This study aimed to identify risk factors for relapse in pediatric APL and to evaluate the relationship between arsenic concentration and relapse. In this multicenter retrospective study, a total of 566 pediatric patients with newly diagnosed APL treated with the CCLG-APL 2016 or CCLG-APL 2018 protocol were enrolled. The median follow-up was 68.0 months, and 44 patients experienced relapse. The analysis showed complex karyotypes (≥ 3 additional chromosomal abnormalities) (HR = 3.238, 95% CI: 1.134–9.244, P = 0.028) and MCR ≥ 72 days (HR = 1.995, 95% CI: 1.132–3.757, P = 0.024) were independent risk factors for relapse. Logistic regression indicated that arsenic trioxide (ATO) used during induction was associated with a lower relapse risk compared to Realgar-Indigo naturalis formula (RIF) (OR = 0.310, 95% CI: 0.105–0.916, P = 0.034]. In 64 patients with arsenic monitoring, blood arsenic levels on days 7, 14, and 28 were significantly higher in ATO group than the RIF group (all P < 0.01), and were significantly lower in the relapse group compared to the non-relapse group ( P = 0.031, 0.036, 0.034, respectively). ROC analysis identified a blood arsenic cutoff of < 25.6 ng/mL after 7 days of induction as predictive of higher relapse risk. Our study confirmed risk factors for relapse in pediatric APL, and suggested that maintaining a blood arsenic concentration ≥ 25.6 ng/mL after seven days of induction may be beneficial for prognosis. Health sciences/Risk factors Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia Health sciences/Diseases/Cancer/Cancer therapy/Targeted therapies Health sciences/Health care/Paediatrics pediatric APL relapse risk factors arsenic concentration induction phase Figures Figure 1 Figure 2 Introduction Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), accounting for approximately 10% of AML cases( 1 , 2 ). Its pathogenesis is driven by the t(15;17) translocation, which generated the PML::RARA fusion gene. This oncoprotein disrupts myeloid differentiation and inhibits apoptosis, leading to the accumulation of immature promyelocytes in the bone marrow( 3 ). In recent years, the application of targeted therapy combining arsenic with all-trans retinoic acid (ATRA) has significantly improved outcomes in pediatric APL, with overall survival approaching 95% and event-free survival reaching about 90%( 4 – 6 ). Despite these advances, relapse occurs in 5% to 10% of patients( 7 ) and remains a major obstacle to cure. Under earlier treatment regimens based on ATRA plus chemotherapy, several factors have been associated with relapse, including FLT3-ITD mutations( 8 ), expression of cell surface antigens such as CD56( 9 , 10 ), and complex karyotypes( 11 ). However, the incorporation of arsenic into frontline therapy has mitigated the prognostic impact of some of these features( 12 ). Currently, the combination of arsenic and ATRA constitutes the first-line therapy for APL. Nevertheless, within this modern therapeutic framework, the risk factors for relapse in pediatric APL—particularly the role of arsenic pharmacokinetics—are not fully defined. Therefore, this study aims to investigate the relapse risk factors in pediatric APL in the era of arsenic-based therapy, with special emphasis on the relationship between induction-phase arsenic concentration and relapse. The results are expected to help refine treatment strategies, optimizing risk stratification, and ultimately improve prognosis while reducing relapse in children with APL. Methods 1 Study design and participants This study was a multicenter retrospective case-control study. Eligible participants were pediatric patients (age 0–18 years) with newly diagnosed APL, confirmed by cytogenetic detection of t(15;17) and/or molecular evidence of the PML::RARA fusion gene. All patients were treated according to either the CCLG-APL 2016 protocol (Registration No.: ChiCTR-OIN-17011227) or the CCLG-APL 2018 protocol (Registration No.: ChiCTR1800019726). Additional inclusion criteria included normal cardiac function and provision of written informed consent by patient or their legal guardians. Exclusion criteria were: ① early death within 30 days of induction therapy; ② Known allergy to arsenic-containing drugs used in the treatment; ③ Contraindications to anthracycline-based chemotherapy; ④ inability of the patient or family to comprehend or adhere to the study protocol; ⑤ any other condition deemed likely to interfere with the conduct of the study. 2 Treatment protocols The details of the CCLG-APL 2016 protocol has been published online( 5 ), and the CCLG-APL 2018 protocol treatment is provided in the supplementary materials and supplementary Fig. 1. The arsenic in both protocols could be either the Realgar-Indigo Naturalis formula (RIF) or arsenic trioxide (ATO). A comparison of the baseline characteristics of patients treated with the CCLG-APL 2016 and CCLG-APL 2018 protocols showed no significant differences in age, sex, complex karyotype, PML::RARA gene subtype, or risk stratification between the two groups (Supplementary Table 1). This indicates that the patient populations were not significantly heterogeneous, suggesting that the patients from both protocols can be combined for analysis. 3 Treatment response evaluation and arsenic concentration measurement In this study, hematologic complete remission (HCR) was defined as a normocellular bone marrow with blast and promyelocyte proportions < 5%. Molecular complete remission (MCR) was defined as undetectable PML::RARA transcripts in bone marrow by reverse transcriptase polymerase chain reaction (RT-PCR) or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), with a sensitivity of at least 1×10⁻⁴. Relapse was categorized as either hematologic or molecular. Hematologic relapse was defined as the reappearance of leukemic cells in the peripheral blood or bone marrow after prior HCR or MCR, with abnormal promyelocytes > 5% in the bone marrow. Molecular relapse was defined as reconversion to PML::RARA positivity in the peripheral blood or bone marrow after MCR, confirmed by a second positive bone marrow test for the PML::RARA two weeks later( 13 ). Relapse-free survival (RFS) was calculated from the date of first HCR until hematologic or molecular relapse, death from any cause, or last follow-up( 13 ). A complex karyotype was defined as the presence of three or more additional cytogenetic abnormalities (ACAs) besides t(15;17)( 14 , 15 ). For arsenic concentration analysis, peripheral blood and urine samples were collected in the morning prior to daily medication administration on day 7, day 14, and day 28 after starting arsenic-based therapy. Total arsenic concentrations in blood and urine were measured using atomic fluorescence spectrometry (AFS) and inductively coupled plasma mass spectrometry (ICP-MS). Previous studies have demonstrated comparable linear ranges and sensitivity between AFS and ICP-MS for arsenic speciation, with good concordance between the two methods( 16 – 18 ). 4 Statistical analysis Continuous variables with non-normal distributions were expressed as median (P25, P75), and intergroup comparisons were performed using the Mann-Whitney U test. Categorical variables were expressed as the number of cases (percentage), and intergroup comparisons were performed using the chi-square test or, for small samples, Fisher's exact test. Relapse-free survival curves were generated using the Kaplan-Meier method, and differences between groups were assessed with the log-rank test. Multivariate Cox proportional-hazards regression was employed to identify independent risk factors for relapse. The relationship between arsenic formulation (ATO vs. RIF) and relapse at different treatment phases was evaluated using multivariate logistic regression. Receiver operating characteristic (ROC) curve analysis was performed to determine optimal cutoff values ​​for significant predictors. All statistical analysis was conducted using SPSS version 27.0 (IBM Corporation). A two-tailed P < 0.05 was considered statistically significant. Results 1 Baseline characteristics A total of 566 children with newly diagnosed APL were included in this study, with a median age of 9.0 (6.0, 11.0) years. Among them, 57.1% were male and 42.9% were female. Complex karyotype was identified in 15 patients (2.7%). The PML::RARA isoform was determined in 415 patients, with the long type being most prevalent (63.9%), followed by the short (28.9%) and variant (7.2%). Mutational analysis revealed FLT3-ITD mutation in 21.2%, WT1 in 11.5%, NRAS in 6.4%, FLT3-TKD 5.5%, TET2 in 3.5%, ASXL1 in 2.8%, and TP53 in 2.3% of patients. According to risk stratification, 330 patients (58.3%) were classified as standard risk (SR), and 236 patients (41.7%) as high risk (HR). Regarding treatment, 181 patients (32.0%) received the CCLG-APL 2016 protocol, and 385 (68.0%) the CCLG-APL 2018 protocol. Based on arsenic formulation, patients were divided into two groups: the ATO group included 377 patients (66.6%) who received arsenic trioxide at any treatment phase, and the RIF group included 189 patients (33.4%) who received the Realgar-Indigo naturalis formula throughout all phases (Table 1 ). The median time to achieve HCR for all patients was 33 (30, 38) days, and the median time to achieve MCR was 67 (56, 75) days. The median follow-up duration was 68.0 (55.0, 81.0) months. Table 1 Demographics and baseline characteristics Clinical information Total (n = 566) Relapse (n = 44) Non-relapse (n = 522) P value Age [years, M (P25, P75)] 9.0(6.0,11.0) 8.5(6.0,11.0) 9.0(6.0,11.0) 0.874 Gender [n, (%)] Male 323(57.1) 31(9.6) 292(90.4) Female 243(42.9) 13(5.3) 230(94.7) 0.062 Complex karyotype 1 [n, (%)] Yes 15(2.7) 4(26.7) 11(73.3) No 539(97.3) 40(7.4) 499(92.6) 0.025 PML::RARA isoform 2 [n, (%)] Long 265(63.9) 27(10.2) 238(89.8) Short 120(28.9) 10(8.3) 110(91.7) Variant 30(7.2) 2(6.7) 28(93.3) 0.734 Gene mutation [n, (%)] FLT3-ITD 116(21.2) 8(6.9) 108(93.1) 0.722 WT1 65(11.5) 7(10.8) 58(89.2) 0.343 NRAS 36(6.4) 4(11.1) 32(88.9) 0.657 FLT3-TKD 31(5.5) 0(0.0) 31(100.0) 0.186 TET2 20(3.5) 2(10.0) 18(90.0) 0.709 ASXL1 16(2.8) 1(6.3) 15(93.7) 0.814 TP53 13(2.3) 2(15.4) 11(84.6) 0.611 Risk stratification [n, (%)] SR 330(58.3) 22(6.7) 308(93.3) HR 236(41.7) 22(9.3) 214(90.7) 0.245 Treatment protocol [n, (%)] CCLG-APL 2016 protocol 181 (32.0) 10 (5.5) 171 (94.5) CCLG-APL 2018 protocol 385 (68.0) 34 (8.8) 351 (91.2) 0.171 Arsenic form [n, (%)] ATO group 3 377 (66.6) 12 (3.2) 365 (96.8) RIF group 4 189 (33.4) 32 (16.9) 157 (83.1) <0.001 Time to HCR [d, M (P25, P75)] 33 (30, 38) 34 (31, 38) 33 (29, 38) 0.458 Time to MCR [d, M (P25, P75)] 67 (56, 75) 73 (60, 79) 67 (55, 74) 0.019 1 Karyotype results unavailable for 12 patients. 2 PML::RARA isoform data available for 415 patients. 3 Patients receiving ATO at any treatment phase. 4 Patients receiving RIF throughout all phases. Abbreviations : SR: standard risk; HR: high risk;ATO: arsenic trioxide; RIF: realgar-indigo naturalis formula; HCR: hematologic complete remission; MCR: molecular complete remission. 2 Risk factors for pediatric APL relapse Among the 566 patients, 44 experienced relapse. Baseline comparison between relapsed and non-relapsed groups revealed no significant differences in age, sex, PML::RARA subtype, gene mutations, risk stratification, treatment protocols, or time to HCR (Table 1 ). The relapse rate was significantly higher in patients with a complex karyotype (26.7%, 4/15) compared to those without (7.4%, 40/539, P = 0.025). Kaplan-Meier analysis confirmed that the RFS was significantly shorter in patients with complex karyotypes ( P = 0.006) (Fig. 1 a). Patients who received ATO at any treatment phase (ATO group) had a relapse rate of 3.2%, which was significantly lower than that of the RIF group ( P < 0.001). Accordingly, RFS was significantly higher in the ATO group ( P < 0.001) (Fig. 1 b). The median time to MCR was longer in the relapse group [73 (IQR 60, 79) days] than in the non-relapsed group [67 (IQR 55, 74) days; P = 0.019]. ROC analysis identified 72 days as the optimal cut-off value for MCR timing. Patients achieving MCR within <72 days had significantly better RFS than those requiring ≥ 72 days ( P = 0.002) (Fig. 1 c). Multivariate Cox regression analysis (including variables with P < 0.2 in univariate analysis) demonstrated that complex karyotype (HR = 3.238, 95% CI 1.134–9.244, P = 0.028), treatment exclusively with RIF (HR = 0.189, 95% CI 0.097–0.368, P < 0.001), and MCR attainment ≥ 72 days (HR = 1.995, 95% CI 1.132–3.757, P = 0.024) were independent predictors of relapse. Genders and treatment protocols were not significantly associated with relapse risk. 3 Association between arsenic formulation across treatment phases and relapse Due to clinical practice patterns, patients initially receiving oral RIF were likely to continue RIF in later phases (Supplementary Fig. 2), introducing potential selection bias in arsenic agent assignment during consolidation and maintenance. To evaluate the phase-specific influence of arsenic formulation on relapse, multivariate logistic regression was performed, incorporating the type of arsenic used during induction, consolidation, and maintenance as independent variables. The analysis revealed that patients who received ATO during the induction phase had a significantly lower relapse risk compared to those given RIF in induction (OR = 0.310, 95% CI: 0.105–0.916, P = 0.034). In contrast, the formulation of arsenic used during consolidation and maintenance showed no statistically significant association with relapse (Table 2 ). Table 2 Multivariable logistic regression analysis of the association between the arsenic formulation at different treatment phases and APL relapse Arsenic formulation by phase (ATO vs RIF) B S.E. Wald P value OR (95% CI) induction period -1.172 0.553 4.492 0.034 0.310 (0.105–0.916) consolidation period -1.163 0.882 1.741 0.187 0.313 (0.056–1.759) maintenance period -0.136 1.010 0.018 0.893 0.873 (0.121–6.315) Abbreviations: ATO, arsenic trioxide; RIF, Realgar‑Indigo naturalis formula; B, regression coefficient; S.E., standard error; OR, odds ratio; CI, confidence interval. 4 Arsenic concentrations during induction and their association with relapse Induction-phase arsenic concentrations was measured in 64 patients, eight of whom experienced relapse. Among those, 18 patients received ATO, 44 received RIF during induction, and 2 switched from ATO to RIF during induction. The median blood arsenic concentrations in the ATO group were significantly higher than those in the RIF group at all measured time points: day 7 [40.8 (IQR 31.2–63.4) vs. 19.5 (13.8–29.7) ng/mL, P < 0.001], day 14 [52.2 (40.4–68.3) vs. 23.8 (18.0–33.5) ng/mL, P < 0.001], and day 28 [52.6 (27.8–67.0) vs. 27.7 (19.5–42.4) ng/mL, P = 0.006]. Additionally, urinary arsenic concentrations on days 7, 14, and 28 were significantly elevated in the ATO group compared to the RIF group (Table 3 ). Table 3 Comparison of arsenic concentrations between ATO and RIF groups during induction therapy Arsenic concentration [ng/mL, M (P25, P75)] Total ATO group 1 RIF group 2 P value Blood arsenic concentration D7 (n = 55) 27.3 (16.5, 39.6) 40.8 (31.2, 63.4) 19.5 (13.8, 29.7) <0.001 D14 (n = 56) 31.1 (21.0, 46.5) 52.2 (40.4, 68.3) 23.8 (18.0, 33.5) <0.001 D28 (n = 57) 32.6 (21.0, 45.3) 52.6 (27.8, 67.0) 27.7 (19.5, 42.4) 0.006 Urine arsenic concentration D7 (n = 54) 800.8 (239.7, 1605.6) 1223.7 (740.6, 2735.0) 373.9 (150.7, 1515.2) 0.03 D14 (n = 55) 1021.9 (459.3, 1952.2) 1597.5 (1069.5, 2876.8) 617.3 (277.5, 1292.7) 0.001 D28 (n = 57) 1187.9 (555.7, 2696.8) 2180.6 (969.8, 3295.5) 962.5 (432.5, 2336.5) 0.081 1 patients who received ATO during induction. 2 patients who received RIF during induction. The 64 patients with available induction-phase arsenic concentrations were categorized into relapse (n = 8) and non-relapse (n = 56) groups. Median blood arsenic level in the relapse group were significantly lower than those in the non-relapse group at each time point: day 7 [14.4 (IQR 9.2–25.5) vs. 28.8 (19.0–41.4) ng/mL, P = 0.031], day 14 [19.2 (13.5–36.1) vs. 32.9 (22.9–48.9) ng/mL, P = 0.036], and day 28 [18.5 (13.5–39.0) vs. 37.5 (24.0–48.3) ng/mL, P = 0.034] (Table 4 ). Similarly, median urinary arsenic concentrations were lower in the relapse group, aligning with the blood arsenic trend (Table 4 ). Table 4 Comparison of arsenic concentrations during induction between relapsed and non-relapsed patients Arsenic concentration [ng/mL, M (P25, P75)] Relapse group Non- relapse group P value Blood arsenic concentration D7 (n = 57) 14.4 (9.2, 25.5) 28.8 (19.0, 41.4) 0.031 D14 (n = 57) 19.2 (13.5, 36.1) 32.9 (22.9, 48.9) 0.036 D28 (n = 59) 18.5 (13.5, 39.0) 37.5 (24.0, 48.3) 0.034 Urine arsenic concentration D7 (n = 55) 256.6 (93.5, 639.1) 827.1 (294.8, 1797.0) 0.098 D14 (n = 56) 447.0 (83.2, 617.3) 1117.3 (497.1, 2178.3) 0.004 D28 (n = 59) 685.5 (384.6, 1042.9) 1271.8 (617.8, 2993.1) 0.099 After 7 days of arsenic therapy, blood arsenic concentration reached a steady state (Table 3 ). A total of 173 blood arsenic concentration measurements obtained from 64 patients beyond day 7 were included in a ROC analysis to define a prognostic threshold for relapse. The optimal cutoff was identified as 25.6 ng/mL, indicating that a blood arsenic levels below this value after one week of induction therapy are associated with an elevated relapse risk. Discussion While the integration of arsenic and ATRA has significantly improved the prognosis of pediatric APL, relapse remains a critical challenge. This multicenter study, based on the CCLG-APL 2016 and 2018 protocols, analyzed 566 newly diagnosed pediatric APL patients from over 40 hospitals (2016–2021). With a median follow-up of 68 months, 44 patients experienced relapse. Our analysis identified three or more additional chromosomal abnormalities (ACAs; i.e., complex karyotype) and a longer time to molecular complete remission (MCR ≥ 72 days) as independent risk factors for relapse. Furthermore, arsenic concentration during induction therapy was a significant influencing factor. Notably, within this ATRA-arsenic combined regimen framework, gene mutations such as FLT3-ITD , NRAS , and WT1 , as well as PML::RARA subtypes were not significantly associated with relapse. The prognostic role of ACAs in APL remains debated. While some reports indicate no impact on prognosis( 19 – 21 ), a large retrospective study (n = 1559) including both adult and pediatric newly diagnosed APL patients treated with ATRA combined with chemotherapy, and found a significantly higher 5-year cumulative relapse rate in patients with ≥ 3 ACAs compared to those with < 3 ACAs( 11 ). Similarly, a study of 248 adult APL patients receiving ATO-based regimens showed that ≥ 2 ACAs were associated with significantly shorter event-free survival( 22 ). Our findings align with this trend: after excluding early death, pediatric APL patients with complex karyotypes (≥ 3 ACAs) had a significantly increased risk of relapse. However, the small number of such cases in our cohort necessitates validation in larger studies. Monitoring the PML::RARA fusion transcript is essential for assessing treatment response. Persistence or re-emergences of PML::RARA positivity post-consolidation is strongly linked to hematological relapse( 23 ). A Korea multicenter study retrospectively analyzed the clinical outcomes in 286 adult patients treated with ATRA and idarubicin between 2002 and 2024, confirmed post-consolidation PML::RARA positivity as an independent risk factor for APL relapse( 8 ). In our pediatric cohort, the time to achieve MCR was significantly longer in the relapse group, and MCR ≥ 72 days emerged as an independent risk factor. Per our protocol, 72 days corresponds to the end of the first consolidation phase, reinforcing the clinical relevance of early molecular response. Arsenic is cornerstone of APL targeted therapy, available as intravenous ATO or the oral tablet RIF. RIF is a compound of traditional Chinese medicine including realgar (As4S4), Indigo naturalis, Radix salviae miltiorrhizae and Radix pseudostellariae. Clinical studies have demonstrated that the efficacy of RIF is non-inferior to ATO when combined with ATRA or chemotherapy( 6 , 24 , 25 ). Furthermore, RIF-based treatment regimens offers pharmacoeconomic advantages by reducing treatment-related costs and hospitalization( 26 ). In this study, the type of arsenic used during consolidation and maintenance therapy did not affect relapse rates in children with APL. However, patients receiving ATO during induction had a lower relapse rate than those receiving RIF. Previous studies in adult APL associated lower trough arsenic concentration with treatment failure( 27 ), and pediatric studies have shown an inverse correlation between induction-phase blood arsenic levels and post-induction PML::RARA transcript burden( 28 ). Consistently, we found that total blood and urinary arsenic concentration during induction were higher in the ATO group than in the RIF group. Moreover, relapse patients had significantly lower induction-phase blood arsenic levels. Supporting this, Huang et al. observed a trend toward lower urinary arsenic excretion in relapsed patients, implying lower systemic exposure( 6 ). Arsenic levels rise with administration and stabilize after approximately seven consecutive days( 25 , 29 ), and similar results were observed in our study. ROC curve analysis indicated that patients with blood arsenic concentrations < 25.6 ng/mL after 7 days of induction therapy was associated with a higher risk of relapse. These findings collectively establish induction-phase arsenic concentration as a key modifiable factor influencing relapse in pediatric APL treated with ATRA-arsenic regimens. Consequently, our center’s subsequent pediatric APL protocols recommend using ATO during induction therapy with therapeutic drug monitoring, while opting for oral RIF during consolidation and maintenance to balance efficacy with healthcare resource utilization. In conclusion, this study identifies complex karyotype (≥ 3 ACAs) and delayed MCR (MCR ≥ 72 days) as risk factors for relapse in pediatric APL. Critically, it highlights the importance of induction-phase arsenic exposure, suggesting that maintaining a blood arsenic concentration ≥ 25.6 ng/mL after seven days of treatment may be beneficial. Limitations Our findings are constrained by the limited sample size for certain subgroups, such as patients with complex karyotypes, which may affect the robustness of these associations. Additionally, while two methods for arsenic detection were used and prior studies suggest their comparability, a potential influence of methodological variation on the concentration analysis cannot be entirely ruled out. Nonetheless, given the rarity of pediatric APL relapse, these insights remain valuable. Further prospective studies with larger cohorts are warranted to confirm these results. Declarations Acknowledgments ： We sincerely thank the patients who participated in this study, his family who actively cooperated, and the health care professionals who treated and cared for the patient in the clinical setting. Funding Sources ： This work was supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special “Yang Fan” Grant (No. ZLRK202328). Author Contributions : H.Z. designed the study. Q.X., L.W. collected and analyzed the data. Q.X. and H.Z. wrote the paper. Y.P. provided statistical support. All authors treated the patients. All authors reviewed the paper and gave final approval. Conflict of Interest Disclosures : No potential conflicts of interest are reported by any of the authors. Data Availability Statement : The data that support the findings of this study are available from the corresponding author upon reasonable request (Email： [email protected] ). Ethics Approval and Consent to Participate ： The treatment was approved by the Institutional Ethics Committee of Beijing Children’s Hospital (CCLG-APL 2016 protocol approval No.: 2016-k-30; CCLG-APL 2018 protocol approval No.: 2018-174). Informed consent was obtained from all individual participants included in the study. References Anna Maria T, Andrea P, Daniela D, David G, Brenda G, Amilcar Cardoso dA, et al. Risk-adapted treatment of acute promyelocytic leukemia: results from the International Consortium for Childhood APL. Blood. 2018;132(4):405–12. Yasuhisa Y. Risk factors and remaining challenges in the treatment of acute promyelocytic leukemia. 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Additional cytogenetic changes do not influence the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with an ATRA plus anthracyclin based protocol. A report of the Spanish group PETHEMA. Haematologica. 2001;86(8):807–13. Yinjun L, Shanshan S, Hongyan T, Xingnong Y, Yungui W, Zhimei C, et al. Characteristics and prognosis analysis of additional chromosome abnormalities in newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide as the front-line therapy. Leuk Res. 2013;37(11):1451–6. Zachary D E-P, Andriy D, Susan G, Krzysztof M, Jessica K, Jae H P, et al. Effect of additional cytogenetic abnormalities on survival in arsenic trioxide-treated acute promyelocytic leukemia. Blood Adv. 2022;6(11):3433–9. Laura C, Pierre F, Hagop K, Martin T, Miguel A S, Francesco L-C. Molecular remission as a therapeutic objective in acute promyelocytic leukemia. Leukemia. 2018;32(8):1671–8. Hong-Hu Z, De-Pei W, Jie J, Jian-Yong L, Jun M, Jian-Xiang W, et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol. 2013;31(33):4215–21. Lixian C, Ju G, Xiaoying L, Yingyi H, Shuquan Z, Chunhuai L, et al. A multicenter single-arm clinical study of Chinese children's cancer group-acute promyelocytic leukemia-2017 (CCCG-APL-2017) protocol. Signal Transduct Target Ther. 2025;10(1):267. Hao J, Gong-Wen L, Xiao-Jun H, Qian J, Sheng H, Lu-Wen S, et al. Reduced medical costs and hospital days when using oral arsenic plus ATRA as the first-line treatment of acute promyelocytic leukemia. Leuk Res. 2015;39(12):1319–24. Meihua G, Jin Z, Shengjin F, Limin L, Hongzhu C, Liwang L, et al. Characteristics and clinical influence factors of arsenic species in plasma and their role of arsenic species as predictors for clinical efficacy in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide. Expert Rev Clin Pharmacol. 2021;14(4):503–12. Zhong F, Liang-Chun Y, Yi-Qiao C, Wu-Qing W, Dun-Hua Z, Hui-Rong M, et al. Prognostic significance of MRD and its correlation with arsenic concentration in pediatric acute promyelocytic leukemia: a retrospective study by SCCLG-APL group. Ther Adv Hematol. 2025;16(0):20406207241311774. Liu-Hua L, Yi-Qiao C, Dan-Ping H, Li-Na W, Zhong-Lu Y, Li-Hua Y, et al. The comparison of plasma arsenic concentration and urinary arsenic excretion during treatment with Realgar-Indigo naturalis formula and arsenic trioxide in children with acute promyelocytic leukemia. Cancer Chemother Pharmacol. 2022;90(1):45–52. Additional Declarations There is NO conflict of interest to disclose. Supplementary Files Supplementarymaterials.docx Supplementary materials Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 04 Mar, 2026 Review # 2 received at journal 02 Mar, 2026 Review # 3 received at journal 26 Feb, 2026 Reviewer # 3 agreed at journal 26 Feb, 2026 Review # 1 received at journal 17 Feb, 2026 Reviewer # 2 agreed at journal 13 Feb, 2026 Reviewer # 1 agreed at journal 02 Feb, 2026 Reviewers invited by journal 27 Jan, 2026 Editor assigned by journal 27 Jan, 2026 Submission checks completed at journal 27 Jan, 2026 First submitted to journal 26 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8698439","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":581226904,"identity":"9a97542f-9e5b-4fd2-96f3-c1dfe6a3a9f1","order_by":0,"name":"Huyong 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Health","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Lin","suffix":""},{"id":581226921,"identity":"55f44601-580a-4cc0-b817-f7b53a6a3645","order_by":17,"name":"Peijing Qi","email":"","orcid":"","institution":"Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health","correspondingAuthor":false,"prefix":"","firstName":"Peijing","middleName":"","lastName":"Qi","suffix":""},{"id":581226922,"identity":"493652aa-64a6-4fac-9239-c4ef332ac7b7","order_by":18,"name":"Jia Fan","email":"","orcid":"","institution":"Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Fan","suffix":""},{"id":581226923,"identity":"9f21c371-fbe6-452c-bb7e-18208e2de35f","order_by":19,"name":"Rui-Dong Zhang","email":"","orcid":"","institution":"Beijing Children's Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Rui-Dong","middleName":"","lastName":"Zhang","suffix":""},{"id":581226924,"identity":"e9c049ae-ff17-48f9-afa1-8c1f7cac3000","order_by":20,"name":"Yaguang Peng","email":"","orcid":"","institution":"Beijing Children's Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yaguang","middleName":"","lastName":"Peng","suffix":""}],"badges":[],"createdAt":"2026-01-26 09:05:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8698439/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8698439/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101438744,"identity":"f1074637-3846-4523-85d8-5a515b385f3c","added_by":"auto","created_at":"2026-01-29 16:40:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":331181,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier survival analysis of risk factors for relapse in pediatric APL.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u003c/em\u003e ATO: arsenic trioxide; RIF: realgar-indigo naturalis formula; MCR: molecular complete remission.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8698439/v1/8c0ca89df681abc2876756b4.png"},{"id":101438727,"identity":"449211dd-7098-48e3-b2c8-923f29997fa4","added_by":"auto","created_at":"2026-01-29 16:40:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":207327,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMultivariable Cox regression analysis of risk factors for relapse in pediatric APL.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u003c/em\u003e ATO: arsenic trioxide; RIF: realgar-indigo naturalis formula; MCR: molecular complete remission.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8698439/v1/60f74dbe081cf44617aa5287.png"},{"id":101438975,"identity":"4018fa9c-919a-487f-a446-6a250bcd7458","added_by":"auto","created_at":"2026-01-29 16:41:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1367820,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8698439/v1/cea31cd5-a496-485c-bc32-0506701c5fdc.pdf"},{"id":101438782,"identity":"3250184f-04f2-47df-b345-87d2a613c3d9","added_by":"auto","created_at":"2026-01-29 16:41:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":131022,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary materials\u003c/p\u003e","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-8698439/v1/3278821fc2cd57ac68e9ecb1.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Induction-phase blood arsenic concentration and relapse risk in pediatric APL treated with arsenic and ATRA","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), accounting for approximately 10% of AML cases(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Its pathogenesis is driven by the t(15;17) translocation, which generated the \u003cem\u003ePML::RARA\u003c/em\u003e fusion gene. This oncoprotein disrupts myeloid differentiation and inhibits apoptosis, leading to the accumulation of immature promyelocytes in the bone marrow(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). In recent years, the application of targeted therapy combining arsenic with all-trans retinoic acid (ATRA) has significantly improved outcomes in pediatric APL, with overall survival approaching 95% and event-free survival reaching about 90%(\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Despite these advances, relapse occurs in 5% to 10% of patients(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and remains a major obstacle to cure. Under earlier treatment regimens based on ATRA plus chemotherapy, several factors have been associated with relapse, including \u003cem\u003eFLT3-ITD\u003c/em\u003e mutations(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), expression of cell surface antigens such as CD56(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), and complex karyotypes(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, the incorporation of arsenic into frontline therapy has mitigated the prognostic impact of some of these features(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Currently, the combination of arsenic and ATRA constitutes the first-line therapy for APL. Nevertheless, within this modern therapeutic framework, the risk factors for relapse in pediatric APL\u0026mdash;particularly the role of arsenic pharmacokinetics\u0026mdash;are not fully defined. Therefore, this study aims to investigate the relapse risk factors in pediatric APL in the era of arsenic-based therapy, with special emphasis on the relationship between induction-phase arsenic concentration and relapse. The results are expected to help refine treatment strategies, optimizing risk stratification, and ultimately improve prognosis while reducing relapse in children with APL.\u003c/p\u003e"},{"header":"Methods","content":"\n\u003ch3\u003e1 Study design and participants\u003c/h3\u003e\n\u003cp\u003eThis study was a multicenter retrospective case-control study. Eligible participants were pediatric patients (age 0\u0026ndash;18 years) with newly diagnosed APL, confirmed by cytogenetic detection of t(15;17) and/or molecular evidence of the \u003cem\u003ePML::RARA\u003c/em\u003e fusion gene. All patients were treated according to either the CCLG-APL 2016 protocol (Registration No.: ChiCTR-OIN-17011227) or the CCLG-APL 2018 protocol (Registration No.: ChiCTR1800019726). Additional inclusion criteria included normal cardiac function and provision of written informed consent by patient or their legal guardians. Exclusion criteria were: ① early death within 30 days of induction therapy; ② Known allergy to arsenic-containing drugs used in the treatment; ③ Contraindications to anthracycline-based chemotherapy; ④ inability of the patient or family to comprehend or adhere to the study protocol; ⑤ any other condition deemed likely to interfere with the conduct of the study.\u003c/p\u003e\n\u003ch3\u003e2 Treatment protocols\u003c/h3\u003e\n\u003cp\u003eThe details of the CCLG-APL 2016 protocol has been published online(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), and the CCLG-APL 2018 protocol treatment is provided in the supplementary materials and supplementary Fig.\u0026nbsp;1. The arsenic in both protocols could be either the Realgar-Indigo Naturalis formula (RIF) or arsenic trioxide (ATO). A comparison of the baseline characteristics of patients treated with the CCLG-APL 2016 and CCLG-APL 2018 protocols showed no significant differences in age, sex, complex karyotype, \u003cem\u003ePML::RARA\u003c/em\u003e gene subtype, or risk stratification between the two groups (Supplementary Table\u0026nbsp;1). This indicates that the patient populations were not significantly heterogeneous, suggesting that the patients from both protocols can be combined for analysis.\u003c/p\u003e\n\u003ch3\u003e3 Treatment response evaluation and arsenic concentration measurement\u003c/h3\u003e\n\u003cp\u003eIn this study, hematologic complete remission (HCR) was defined as a normocellular bone marrow with blast and promyelocyte proportions\u0026thinsp;\u0026lt;\u0026thinsp;5%. Molecular complete remission (MCR) was defined as undetectable \u003cem\u003ePML::RARA\u003c/em\u003e transcripts in bone marrow by reverse transcriptase polymerase chain reaction (RT-PCR) or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), with a sensitivity of at least 1\u0026times;10⁻⁴. Relapse was categorized as either hematologic or molecular. Hematologic relapse was defined as the reappearance of leukemic cells in the peripheral blood or bone marrow after prior HCR or MCR, with abnormal promyelocytes\u0026thinsp;\u0026gt;\u0026thinsp;5% in the bone marrow. Molecular relapse was defined as reconversion to \u003cem\u003ePML::RARA\u003c/em\u003e positivity in the peripheral blood or bone marrow after MCR, confirmed by a second positive bone marrow test for the \u003cem\u003ePML::RARA\u003c/em\u003e two weeks later(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Relapse-free survival (RFS) was calculated from the date of first HCR until hematologic or molecular relapse, death from any cause, or last follow-up(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). A complex karyotype was defined as the presence of three or more additional cytogenetic abnormalities (ACAs) besides t(15;17)(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFor arsenic concentration analysis, peripheral blood and urine samples were collected in the morning prior to daily medication administration on day 7, day 14, and day 28 after starting arsenic-based therapy. Total arsenic concentrations in blood and urine were measured using atomic fluorescence spectrometry (AFS) and inductively coupled plasma mass spectrometry (ICP-MS). Previous studies have demonstrated comparable linear ranges and sensitivity between AFS and ICP-MS for arsenic speciation, with good concordance between the two methods(\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003e4 Statistical analysis\u003c/h3\u003e\n\u003cp\u003eContinuous variables with non-normal distributions were expressed as median (P25, P75), and intergroup comparisons were performed using the Mann-Whitney U test. Categorical variables were expressed as the number of cases (percentage), and intergroup comparisons were performed using the chi-square test or, for small samples, Fisher's exact test. Relapse-free survival curves were generated using the Kaplan-Meier method, and differences between groups were assessed with the log-rank test. Multivariate Cox proportional-hazards regression was employed to identify independent risk factors for relapse. The relationship between arsenic formulation (ATO vs. RIF) and relapse at different treatment phases was evaluated using multivariate logistic regression. Receiver operating characteristic (ROC) curve analysis was performed to determine optimal cutoff values ​​for significant predictors. All statistical analysis was conducted using SPSS version 27.0 (IBM Corporation). A two-tailed \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\n\u003ch3\u003e1 Baseline characteristics\u003c/h3\u003e\n\u003cp\u003eA total of 566 children with newly diagnosed APL were included in this study, with a median age of 9.0 (6.0, 11.0) years. Among them, 57.1% were male and 42.9% were female. Complex karyotype was identified in 15 patients (2.7%). The \u003cem\u003ePML::RARA\u003c/em\u003e isoform was determined in 415 patients, with the long type being most prevalent (63.9%), followed by the short (28.9%) and variant (7.2%). Mutational analysis revealed \u003cem\u003eFLT3-ITD\u003c/em\u003e mutation in 21.2%, \u003cem\u003eWT1\u003c/em\u003e in 11.5%, \u003cem\u003eNRAS\u003c/em\u003e in 6.4%, \u003cem\u003eFLT3-TKD\u003c/em\u003e 5.5%, \u003cem\u003eTET2\u003c/em\u003e in 3.5%, \u003cem\u003eASXL1\u003c/em\u003e in 2.8%, and \u003cem\u003eTP53\u003c/em\u003e in 2.3% of patients. According to risk stratification, 330 patients (58.3%) were classified as standard risk (SR), and 236 patients (41.7%) as high risk (HR). Regarding treatment, 181 patients (32.0%) received the CCLG-APL 2016 protocol, and 385 (68.0%) the CCLG-APL 2018 protocol. Based on arsenic formulation, patients were divided into two groups: the ATO group included 377 patients (66.6%) who received arsenic trioxide at any treatment phase, and the RIF group included 189 patients (33.4%) who received the Realgar-Indigo naturalis formula throughout all phases (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median time to achieve HCR for all patients was 33 (30, 38) days, and the median time to achieve MCR was 67 (56, 75) days. The median follow-up duration was 68.0 (55.0, 81.0) months.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographics and baseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical information\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;566)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRelapse (n\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-relapse (n\u0026thinsp;=\u0026thinsp;522)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge [years, M (P25, P75)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.0(6.0,11.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5(6.0,11.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.0(6.0,11.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.874\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender [n, (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e323(57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31(9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e292(90.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e243(42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e230(94.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplex karyotype\u003csup\u003e1\u003c/sup\u003e [n, (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11(73.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e539(97.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40(7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e499(92.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePML::RARA\u003c/em\u003e isoform\u003csup\u003e2\u003c/sup\u003e [n, (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e265(63.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27(10.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e238(89.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120(28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e110(91.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30(7.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28(93.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.734\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene mutation [n, (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eFLT3-ITD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e116(21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108(93.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.722\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eWT1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65(11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58(89.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.343\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eNRAS\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36(6.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32(88.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.657\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eFLT3-TKD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31(5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31(100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.186\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTET2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18(90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.709\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eASXL1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15(93.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.814\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTP53\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13(2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11(84.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.611\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisk stratification [n, (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e330(58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e308(93.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e236(41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e214(90.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.245\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment protocol [n, (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCLG-APL 2016 protocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e181 (32.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e171 (94.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCLG-APL 2018 protocol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e385 (68.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (8.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e351 (91.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.171\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArsenic form [n, (%)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATO group\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e377 (66.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e365 (96.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRIF group\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e189 (33.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e157 (83.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to HCR [d, M (P25, P75)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (30, 38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (31, 38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (29, 38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.458\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime to MCR [d, M (P25, P75)]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (56, 75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73 (60, 79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67 (55, 74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e1\u003c/sup\u003e Karyotype results unavailable for 12 patients. \u003csup\u003e2\u003c/sup\u003e \u003cem\u003ePML::RARA\u003c/em\u003e isoform data available for 415 patients. \u003csup\u003e3\u003c/sup\u003e Patients receiving ATO at any treatment phase. \u003csup\u003e4\u003c/sup\u003e Patients receiving RIF throughout all phases.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eAbbreviations\u003c/em\u003e: SR: standard risk; HR: high risk;ATO: arsenic trioxide; RIF: realgar-indigo naturalis formula; HCR: hematologic complete remission; MCR: molecular complete remission.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003e2 Risk factors for pediatric APL relapse\u003c/h3\u003e\n\u003cp\u003eAmong the 566 patients, 44 experienced relapse. Baseline comparison between relapsed and non-relapsed groups revealed no significant differences in age, sex, \u003cem\u003ePML::RARA\u003c/em\u003e subtype, gene mutations, risk stratification, treatment protocols, or time to HCR (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The relapse rate was significantly higher in patients with a complex karyotype (26.7%, 4/15) compared to those without (7.4%, 40/539, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025). Kaplan-Meier analysis confirmed that the RFS was significantly shorter in patients with complex karyotypes (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Patients who received ATO at any treatment phase (ATO group) had a relapse rate of 3.2%, which was significantly lower than that of the RIF group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Accordingly, RFS was significantly higher in the ATO group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). The median time to MCR was longer in the relapse group [73 (IQR 60, 79) days] than in the non-relapsed group [67 (IQR 55, 74) days; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019]. ROC analysis identified 72 days as the optimal cut-off value for MCR timing. Patients achieving MCR within \u0026lt;72 days had significantly better RFS than those requiring\u0026thinsp;\u0026ge;\u0026thinsp;72 days (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMultivariate Cox regression analysis (including variables with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.2 in univariate analysis) demonstrated that complex karyotype (HR\u0026thinsp;=\u0026thinsp;3.238, 95% CI 1.134\u0026ndash;9.244, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028), treatment exclusively with RIF (HR\u0026thinsp;=\u0026thinsp;0.189, 95% CI 0.097\u0026ndash;0.368, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and MCR attainment\u0026thinsp;\u0026ge;\u0026thinsp;72 days (HR\u0026thinsp;=\u0026thinsp;1.995, 95% CI 1.132\u0026ndash;3.757, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) were independent predictors of relapse. Genders and treatment protocols were not significantly associated with relapse risk.\u003c/p\u003e\n\u003ch3\u003e3 Association between arsenic formulation across treatment phases and relapse\u003c/h3\u003e\n\u003cp\u003e Due to clinical practice patterns, patients initially receiving oral RIF were likely to continue RIF in later phases (Supplementary Fig.\u0026nbsp;2), introducing potential selection bias in arsenic agent assignment during consolidation and maintenance. To evaluate the phase-specific influence of arsenic formulation on relapse, multivariate logistic regression was performed, incorporating the type of arsenic used during induction, consolidation, and maintenance as independent variables. The analysis revealed that patients who received ATO during the induction phase had a significantly lower relapse risk compared to those given RIF in induction (OR\u0026thinsp;=\u0026thinsp;0.310, 95% CI: 0.105\u0026ndash;0.916, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034). In contrast, the formulation of arsenic used during consolidation and maintenance showed no statistically significant association with relapse (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable logistic regression analysis of the association between the arsenic formulation at different treatment phases and APL relapse\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArsenic formulation by phase (ATO vs RIF)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS.E.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWald\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003einduction period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-1.172\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.492\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.310 (0.105\u0026ndash;0.916)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003econsolidation period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-1.163\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.882\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.741\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.313 (0.056\u0026ndash;1.759)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emaintenance period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.893\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.873 (0.121\u0026ndash;6.315)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\u003cp\u003e\u003cem\u003eAbbreviations:\u003c/em\u003e ATO, arsenic trioxide; RIF, Realgar‑Indigo naturalis formula; B, regression coefficient; S.E., standard error; OR, odds ratio; CI, confidence interval.\u003c/p\u003e\n\u003ch3\u003e4 Arsenic concentrations during induction and their association with relapse\u003c/h3\u003e\n\u003cp\u003eInduction-phase arsenic concentrations was measured in 64 patients, eight of whom experienced relapse. Among those, 18 patients received ATO, 44 received RIF during induction, and 2 switched from ATO to RIF during induction. The median blood arsenic concentrations in the ATO group were significantly higher than those in the RIF group at all measured time points: day 7 [40.8 (IQR 31.2\u0026ndash;63.4) vs. 19.5 (13.8\u0026ndash;29.7) ng/mL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001], day 14 [52.2 (40.4\u0026ndash;68.3) vs. 23.8 (18.0\u0026ndash;33.5) ng/mL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001], and day 28 [52.6 (27.8\u0026ndash;67.0) vs. 27.7 (19.5\u0026ndash;42.4) ng/mL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006]. Additionally, urinary arsenic concentrations on days 7, 14, and 28 were significantly elevated in the ATO group compared to the RIF group (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of arsenic concentrations between ATO and RIF groups during induction therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArsenic concentration [ng/mL, M (P25, P75)]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eATO group\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRIF group\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood arsenic concentration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD7 (n\u0026thinsp;=\u0026thinsp;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27.3 (16.5, 39.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40.8 (31.2, 63.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.5 (13.8, 29.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD14 (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31.1 (21.0, 46.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52.2 (40.4, 68.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.8 (18.0, 33.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD28 (n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32.6 (21.0, 45.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52.6 (27.8, 67.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27.7 (19.5, 42.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine arsenic concentration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD7 (n\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e800.8 (239.7, 1605.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1223.7 (740.6, 2735.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e373.9 (150.7, 1515.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD14 (n\u0026thinsp;=\u0026thinsp;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1021.9 (459.3, 1952.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1597.5 (1069.5, 2876.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e617.3 (277.5, 1292.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD28 (n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1187.9 (555.7, 2696.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2180.6 (969.8, 3295.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e962.5 (432.5, 2336.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.081\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e1\u003c/sup\u003e patients who received ATO during induction.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e2\u003c/sup\u003e patients who received RIF during induction.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe 64 patients with available induction-phase arsenic concentrations were categorized into relapse (n\u0026thinsp;=\u0026thinsp;8) and non-relapse (n\u0026thinsp;=\u0026thinsp;56) groups. Median blood arsenic level in the relapse group were significantly lower than those in the non-relapse group at each time point: day 7 [14.4 (IQR 9.2\u0026ndash;25.5) vs. 28.8 (19.0\u0026ndash;41.4) ng/mL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031], day 14 [19.2 (13.5\u0026ndash;36.1) vs. 32.9 (22.9\u0026ndash;48.9) ng/mL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036], and day 28 [18.5 (13.5\u0026ndash;39.0) vs. 37.5 (24.0\u0026ndash;48.3) ng/mL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034] (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Similarly, median urinary arsenic concentrations were lower in the relapse group, aligning with the blood arsenic trend (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of arsenic concentrations during induction between relapsed and non-relapsed patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArsenic concentration [ng/mL, M (P25, P75)]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRelapse group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon- relapse group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood arsenic concentration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD7 (n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14.4 (9.2, 25.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28.8 (19.0, 41.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD14 (n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.2 (13.5, 36.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32.9 (22.9, 48.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD28 (n\u0026thinsp;=\u0026thinsp;59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18.5 (13.5, 39.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37.5 (24.0, 48.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine arsenic concentration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD7 (n\u0026thinsp;=\u0026thinsp;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e256.6 (93.5, 639.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e827.1 (294.8, 1797.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD14 (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e447.0 (83.2, 617.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1117.3 (497.1, 2178.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD28 (n\u0026thinsp;=\u0026thinsp;59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e685.5 (384.6, 1042.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1271.8 (617.8, 2993.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.099\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAfter 7 days of arsenic therapy, blood arsenic concentration reached a steady state (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A total of 173 blood arsenic concentration measurements obtained from 64 patients beyond day 7 were included in a ROC analysis to define a prognostic threshold for relapse. The optimal cutoff was identified as 25.6 ng/mL, indicating that a blood arsenic levels below this value after one week of induction therapy are associated with an elevated relapse risk.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWhile the integration of arsenic and ATRA has significantly improved the prognosis of pediatric APL, relapse remains a critical challenge. This multicenter study, based on the CCLG-APL 2016 and 2018 protocols, analyzed 566 newly diagnosed pediatric APL patients from over 40 hospitals (2016\u0026ndash;2021). With a median follow-up of 68 months, 44 patients experienced relapse. Our analysis identified three or more additional chromosomal abnormalities (ACAs; i.e., complex karyotype) and a longer time to molecular complete remission (MCR\u0026thinsp;\u0026ge;\u0026thinsp;72 days) as independent risk factors for relapse. Furthermore, arsenic concentration during induction therapy was a significant influencing factor. Notably, within this ATRA-arsenic combined regimen framework, gene mutations such as \u003cem\u003eFLT3-ITD\u003c/em\u003e, \u003cem\u003eNRAS\u003c/em\u003e, and \u003cem\u003eWT1\u003c/em\u003e, as well as \u003cem\u003ePML::RARA\u003c/em\u003e subtypes were not significantly associated with relapse.\u003c/p\u003e \u003cp\u003eThe prognostic role of ACAs in APL remains debated. While some reports indicate no impact on prognosis(\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), a large retrospective study (n\u0026thinsp;=\u0026thinsp;1559) including both adult and pediatric newly diagnosed APL patients treated with ATRA combined with chemotherapy, and found a significantly higher 5-year cumulative relapse rate in patients with \u0026ge;\u0026thinsp;3 ACAs compared to those with \u0026lt;\u0026thinsp;3 ACAs(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Similarly, a study of 248 adult APL patients receiving ATO-based regimens showed that \u0026ge;\u0026thinsp;2 ACAs were associated with significantly shorter event-free survival(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Our findings align with this trend: after excluding early death, pediatric APL patients with complex karyotypes (\u0026ge;\u0026thinsp;3 ACAs) had a significantly increased risk of relapse. However, the small number of such cases in our cohort necessitates validation in larger studies.\u003c/p\u003e \u003cp\u003eMonitoring the \u003cem\u003ePML::RARA\u003c/em\u003e fusion transcript is essential for assessing treatment response. Persistence or re-emergences of \u003cem\u003ePML::RARA\u003c/em\u003e positivity post-consolidation is strongly linked to hematological relapse(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). A Korea multicenter study retrospectively analyzed the clinical outcomes in 286 adult patients treated with ATRA and idarubicin between 2002 and 2024, confirmed post-consolidation \u003cem\u003ePML::RARA\u003c/em\u003e positivity as an independent risk factor for APL relapse(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In our pediatric cohort, the time to achieve MCR was significantly longer in the relapse group, and MCR\u0026thinsp;\u0026ge;\u0026thinsp;72 days emerged as an independent risk factor. Per our protocol, 72 days corresponds to the end of the first consolidation phase, reinforcing the clinical relevance of early molecular response.\u003c/p\u003e \u003cp\u003eArsenic is cornerstone of APL targeted therapy, available as intravenous ATO or the oral tablet RIF. RIF is a compound of traditional Chinese medicine including realgar (As4S4), Indigo naturalis, Radix salviae miltiorrhizae and Radix pseudostellariae. Clinical studies have demonstrated that the efficacy of RIF is non-inferior to ATO when combined with ATRA or chemotherapy(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Furthermore, RIF-based treatment regimens offers pharmacoeconomic advantages by reducing treatment-related costs and hospitalization(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). In this study, the type of arsenic used during consolidation and maintenance therapy did not affect relapse rates in children with APL. However, patients receiving ATO during induction had a lower relapse rate than those receiving RIF. Previous studies in adult APL associated lower trough arsenic concentration with treatment failure(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), and pediatric studies have shown an inverse correlation between induction-phase blood arsenic levels and post-induction \u003cem\u003ePML::RARA\u003c/em\u003e transcript burden(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Consistently, we found that total blood and urinary arsenic concentration during induction were higher in the ATO group than in the RIF group. Moreover, relapse patients had significantly lower induction-phase blood arsenic levels. Supporting this, Huang et al. observed a trend toward lower urinary arsenic excretion in relapsed patients, implying lower systemic exposure(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eArsenic levels rise with administration and stabilize after approximately seven consecutive days(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), and similar results were observed in our study. ROC curve analysis indicated that patients with blood arsenic concentrations\u0026thinsp;\u0026lt;\u0026thinsp;25.6 ng/mL after 7 days of induction therapy was associated with a higher risk of relapse. These findings collectively establish induction-phase arsenic concentration as a key modifiable factor influencing relapse in pediatric APL treated with ATRA-arsenic regimens. Consequently, our center\u0026rsquo;s subsequent pediatric APL protocols recommend using ATO during induction therapy with therapeutic drug monitoring, while opting for oral RIF during consolidation and maintenance to balance efficacy with healthcare resource utilization.\u003c/p\u003e \u003cp\u003eIn conclusion, this study identifies complex karyotype (\u0026ge;\u0026thinsp;3 ACAs) and delayed MCR (MCR\u0026thinsp;\u0026ge;\u0026thinsp;72 days) as risk factors for relapse in pediatric APL. Critically, it highlights the importance of induction-phase arsenic exposure, suggesting that maintaining a blood arsenic concentration\u0026thinsp;\u0026ge;\u0026thinsp;25.6 ng/mL after seven days of treatment may be beneficial.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eLimitations\u003c/strong\u003e \u003cp\u003eOur findings are constrained by the limited sample size for certain subgroups, such as patients with complex karyotypes, which may affect the robustness of these associations. Additionally, while two methods for arsenic detection were used and prior studies suggest their comparability, a potential influence of methodological variation on the concentration analysis cannot be entirely ruled out. Nonetheless, given the rarity of pediatric APL relapse, these insights remain valuable. Further prospective studies with larger cohorts are warranted to confirm these results.\u003c/p\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e：\u003c/p\u003e\n\u003cp\u003eWe sincerely thank the patients who participated in this study, his family who actively cooperated, and the health care professionals who treated and cared for the patient in the clinical setting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special \u0026ldquo;Yang Fan\u0026rdquo; Grant (No. ZLRK202328).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eH.Z. designed the study. Q.X., L.W. collected and analyzed the data. Q.X. and H.Z. wrote the paper. Y.P. provided statistical support. All authors treated the patients. All authors reviewed the paper and gave final approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eNo potential conflicts of interest are reported by any of the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request (Email：[email protected]).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e：\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe treatment was approved by the Institutional Ethics Committee of Beijing Children\u0026rsquo;s Hospital (CCLG-APL 2016 protocol approval No.: 2016-k-30; CCLG-APL 2018 protocol approval No.: 2018-174). Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAnna Maria T, Andrea P, Daniela D, David G, Brenda G, Amilcar Cardoso dA, et al. Risk-adapted treatment of acute promyelocytic leukemia: results from the International Consortium for Childhood APL. Blood. 2018;132(4):405\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYasuhisa Y. Risk factors and remaining challenges in the treatment of acute promyelocytic leukemia. Int J Hematol. 2024;120(5):548\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUgo T, Elvira P. Function of PML-RARA in Acute Promyelocytic Leukemia. Adv Exp Med Biol. 2024;1459(0):321\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatthew A K, Todd A A, Oussama A, Madhvi R, Robert B G, Yi-Cheng W, et al. 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Characteristics and clinical influence factors of arsenic species in plasma and their role of arsenic species as predictors for clinical efficacy in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide. Expert Rev Clin Pharmacol. 2021;14(4):503\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhong F, Liang-Chun Y, Yi-Qiao C, Wu-Qing W, Dun-Hua Z, Hui-Rong M, et al. Prognostic significance of MRD and its correlation with arsenic concentration in pediatric acute promyelocytic leukemia: a retrospective study by SCCLG-APL group. Ther Adv Hematol. 2025;16(0):20406207241311774.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu-Hua L, Yi-Qiao C, Dan-Ping H, Li-Na W, Zhong-Lu Y, Li-Hua Y, et al. The comparison of plasma arsenic concentration and urinary arsenic excretion during treatment with Realgar-Indigo naturalis formula and arsenic trioxide in children with acute promyelocytic leukemia. Cancer Chemother Pharmacol. 2022;90(1):45\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"pediatric APL, relapse, risk factors, arsenic concentration, induction phase","lastPublishedDoi":"10.21203/rs.3.rs-8698439/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8698439/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe application of targeted therapy with arsenic and all-trans retinoic acid (ATRA) has significantly improved outcomes in pediatric acute promyelocytic leukemia (APL), but relapse remains a major obstacle to cure. This study aimed to identify risk factors for relapse in pediatric APL and to evaluate the relationship between arsenic concentration and relapse. In this multicenter retrospective study, a total of 566 pediatric patients with newly diagnosed APL treated with the CCLG-APL 2016 or CCLG-APL 2018 protocol were enrolled. The median follow-up was 68.0 months, and 44 patients experienced relapse. The analysis showed complex karyotypes (\u0026ge;\u0026thinsp;3 additional chromosomal abnormalities) (HR\u0026thinsp;=\u0026thinsp;3.238, 95% CI: 1.134\u0026ndash;9.244, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028) and MCR\u0026thinsp;\u0026ge;\u0026thinsp;72 days (HR\u0026thinsp;=\u0026thinsp;1.995, 95% CI: 1.132\u0026ndash;3.757, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) were independent risk factors for relapse. Logistic regression indicated that arsenic trioxide (ATO) used during induction was associated with a lower relapse risk compared to Realgar-Indigo naturalis formula (RIF) (OR\u0026thinsp;=\u0026thinsp;0.310, 95% CI: 0.105\u0026ndash;0.916, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034]. In 64 patients with arsenic monitoring, blood arsenic levels on days 7, 14, and 28 were significantly higher in ATO group than the RIF group (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and were significantly lower in the relapse group compared to the non-relapse group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031, 0.036, 0.034, respectively). ROC analysis identified a blood arsenic cutoff of \u0026lt; 25.6 ng/mL after 7 days of induction as predictive of higher relapse risk. Our study confirmed risk factors for relapse in pediatric APL, and suggested that maintaining a blood arsenic concentration\u0026thinsp;\u0026ge;\u0026thinsp;25.6 ng/mL after seven days of induction may be beneficial for prognosis.\u003c/p\u003e","manuscriptTitle":"Induction-phase blood arsenic concentration and relapse risk in pediatric APL treated with arsenic and ATRA","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 16:38:57","doi":"10.21203/rs.3.rs-8698439/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-03-04T16:22:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-03-02T14:42:19+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-02-26T12:41:31+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-26T11:25:37+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-02-17T15:24:03+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-13T10:19:14+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-02-02T18:50:06+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-01-27T16:28:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-27T14:37:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-27T14:37:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"Leukemia","date":"2026-01-26T09:00:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"73f4baf4-be8d-4388-be57-5d7c3cc3a147","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61833692,"name":"Health sciences/Risk factors"},{"id":61833693,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Acute myeloid leukaemia"},{"id":61833694,"name":"Health sciences/Diseases/Cancer/Cancer therapy/Targeted therapies"},{"id":61833695,"name":"Health sciences/Health care/Paediatrics"}],"tags":[],"updatedAt":"2026-03-19T15:31:00+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-29 16:38:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8698439","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8698439","identity":"rs-8698439","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}