| Part Ⅰ Hypothyroidism during Induction Chemotherapy of ALL Children:A Retrospective StudyObjective:To investigate the incidence,clinical features and outcomes of hypothyroidism during induction chemotherapy in ALL children,analyze the risk factors for hypothyroidism,and evaluate the impact of hypothyroidism on the prognosis of ALL children.Methods:This is a retrospective and a single-center clinical study.The research objects were 276 newly diagnosed ALL children in the Department of Pediatric Hematology&Oncology of Union Hospital,Tongji Medical College,Huazhong University of Science and Technology from January 1,2015 to December 31,2019.Cases were divided into hypothyroidism group and non-hypothyroidism group according to thyroid function assessment.Clinical data of the two groups were collected,and the incidence,clinical features and outcomes of hypothyroidism during induction chemotherapy in ALL children were analyzed.The risk factors for hypothyroidism were analyzed by Logistic regression analysis,the Kaplan-Meier method was used to create survival curves,and the log-rank test was conducted to compare the survival time in different groups.Multivariate Cox regression analysis was used to investigate prognostic factors associated with overall survival(OS)and progression-free survival(PFS).The last follow-up was until July 1,2022.Results:1.The incidence of hypothyroidism:A total of 276 ALL children were enrolled in this study,and 184 children(66.67%,184/276)were confirmed to have hypothyroidism during the induction chemotherapy,including 35 patients(19.02%,35/184)with low free triiodothyronine(FT3),63(34.24%,63/184)with low free tetraiodothyronine(FT4),and 86(46.74%,86/184)with low FT3 and FT4.2.Clinical features of hypothyroidism:Among these patients,12 cases(6.52%,12/184)had increased serum thyroid-stimulating hormone(TSH)levels which conformed to primary hypothyroidism,82(44.57%,82/184)had normal serum TSH levels which conformed to low T3 syndrome,and 90(48.91%,90/184)had decreased TSH levels which conformed to central hypothyroidism.In addition,84 patients(84/184,45.65%)developed hypothyroidism in the 4th week over the course of induction chemotherapy.97 patients(35.14%,97/184)with hypothyroidism developed clinical manifestations,including sinus bradycardia(67 cases,36.41%),fatigue(34 cases,18.48%),abdominal distention(15 cases,8.15%),constipation(10 cases,5.43%),swelling of feet(8 cases,4.35%)and hoarseness(2 cases,1.09%).Some patients had multiple clinical manifestations.3.Outcomes of hypothyroidism:184 patients with hypothyroidism were divided into the treated group(n=116)who received replacement therapy with levothyroxine,and the non-treated group(n=68).At the end of induction chemotherapy,the recovery rate of hypothyroidism were 58.62%and 36.76%in the treated group and the non-treatment group,respectively(P=0.004).Among patients with clinical hypothyroidism,the difference of the recovery rate of hypothyroidism between the treated group and the non-treatment group was statistically significant(38/60 vs.15/37,P=0.028).Among patients with subclinical hypothyroidism,there was no significant difference of the recovery rate of hypothyroidism between the treated group and the non-treatment group(30/56 vs.10/31,P=0.056).4.The dynamics of thyroid hormone:In the treated group,the serum FT3,FT4,and TSH levels showed a significant downward trend from week 1 to week 4,bottomed out at week 4,and then slowly increased.In the non-treated group,FT4 and TSH had the same trend,although FT3 did not change significantly from week 1 to week 4,it could be observed that FT3 levels were lowest at week 4.5.Risk factors for hypothyroidism:Independent risk factors for hypothyroidism during induction chemotherapy included central nervous system(CNS)leukemia(95%CI:3.15-10.23),hypoalbuminaemia(95%CI:1.11-6.29),severe infections(grade 3,4 or 5)(95%CI:1.09-5.81),the dosages of prednisone(95%CI:1.74-18.45)and the dosages of L-Asparaginase(L-Asp)(95%CI:0.69-4.78).6.The impact of hypothyroidism on survival:The median follow-up times were 3.01 ± 1.23 years and 2.89±1.65 years in the hypothyroidism group and the non-hypothyroidism group,respectively.The difference was statistically significant for the probability of 5-year OS between the hypothyroidism group(79.45%± 1.37%)and the non-hypothyroidism group(85.27%± 1.02%,P=0.042).Comparing the PFS of patients,the median follow-up times were 2.79± 1.49 years and 2.56± 1.28 years in the hypothyroidism group and the non-hypothyroidism group respectively.The probability of 5-year PFS in the hypothyroidism group was 74.24%±2.61%,and that of patients in the non-hypothyroidism group was 81.43%±2.16%,the difference was statistically significant(P=0.023).In the subgroup analysis,the median follow-up time was significantly shorter for patients with simultaneous reductions in FT3 and FT4 than for those with decreased FT3 alone(OS:2.65± 1.63 years vs.2.98± 1.49 years,P=0.034;PFS:1.94± 1.72 years vs.2.35± 1.35 years,P=0.012)and those with decreased FT4 alone(OS:2.65± 1.63 years vs.2.87± 1.41 years,P=0.038;PFS:1.94± 1.72 years vs.2.18± 1.46 years,P=0.013).7.Hypothyroidism was a predictor for poor PFS:The independent factors associated with inferior OS of children with ALL were male sex(P=0.021,95%CI:1.1-3.1),leukocyte count(WBC)≥50×109/L(P=0.025,95%CI:1.3-5.8),CNS2 or CNS3 status(P=0.015,95%CI:1.2-5.6),T-ALL(P=0.006,95%CI:1.5-6.8),BCR-ABL1 fusion(P=0.008,95%CI:1.3-5.3),MLL rearrangement(P=0.016,95%CI:1.5-4.2),hypodiploidy<44(P=0.015,95%CI:0.9-2.5),and the presence of MRD≥0.01%at Day 46(P=0.001,95%CI:2.0-6.5).The significant predictors for lower PFS were WBC≥50 ×109/L(P=0.012,95%CI:1.9-4.8),CNS2 or CNS3 status(P=0.026,95%CI:0.8-3.9),T-ALL(P=0.001,95%CI:2.4-10.2),BCR-ABL1 fusion(P<0.001,95%CI:2.4-10.3),MLL rearrangement(P=0.003,95%CI:1.2-5.2),hypodiploidy<44(P=0.025,95%CI:0.6-2.7),the presence of MRD≥0.01%at Day 46(P<0.001,95%CI:4.0-12.9),and hypothyroidism(P=0.024,95%CI:1.1-4.1).Conclusions:1.The incidence of hypothyroidism during induction chemotherapy in ALL children was high,reaching 66.67%,which often occurred 1 month after induction chemotherapy.2.Hypothyroidism during induction chemotherapy in ALL children mainly included functional central hypothyroidism and low T3 syndrome,presented with sinus bradycardia,fatigue,abdominal distention,constipation,swelling of feet,hoarseness and other non-specific symptoms.3.Hypothyroidism was closely associated with CNS leukemia,hypoproteinemia,severe infections,and the use of chemotherapy drugs including glucocorticoids and L-Asp.4.Hypothyroidism had an effect on survival of ALL children.Patients with hypothyroidism,especially with simultaneous reductions in FT3 and FT4,had a worse prognosis than those without hypothyroidism.5.Hypothyroidism was a predictor for poor PFS in ALL children.Part Ⅱ Hypothyroidism during Induction Chemotherapy of ALL Children:A Prospective StudyObjective:To analyze the effect of induction chemotherapy on the neuroendocrine function in ALL children,and evaluate the clinical efficacy of levothyroxine replacement therapy.Methods:In this study,children with ALL newly diagnosed in the Department of Pediatric Hematology&Oncology of Union Hospital,Tongji Medical College,Huazhong University of Science and Technology were enrolled from June 1,2022 to December 31,2022.Serum concentrations of adrenocorticotropic hormone(ACTH),aldosterone(ALD),prolactin(PRL),growth hormone(GH),luteinizing hormone(LH),follicle-stimulating hormone(FSH),progesterone(PROG),estradiol(E2)and testosterone(TESTO)were measured before induction chemotherapy and at week 4.Thyroid function(FT3,FT4,TSH,thyroglobulin antibodies(TgAb),thyroid peroxidase antibodies(TPOAb))was assessed before chemotherapy and monitored dynamically during induction chemotherapy.Based on thyroid function assessment,patients were divided into the hypothyroidism group and the non-hypothyroidism group,hypothyroidism patients with symptoms were treated with levothyroxine.Laboratory and clinical data were collected to analyze the changes of hormones before and after induction chemotherapy in ALL children,and the clinical efficacy of levothyroxine was evaluated.Statistical analysis of the data was performed by using the Fisher’s exact test,Chi-square test,Wilcoxon Signed Rank test,Mann-Whitney U test and t-test.Results:1.Characteristics of study population:Based on the inclusion and exclusion criteria,a total of 46 ALL children were enrolled in this study.There were 18 girls and 28 boys,with an average age of 4.36±2.67 years(range:1-14 years old)and a male-to-female ratio of 1.56:1.There were 21 cases(45.65%,21/46)with low-risk(LR)ALL,20 cases(43.78%,20/46)with intermediate-risk(IR)ALL,and 5 cases(10.87%,5/46)with high-risk(IR)ALL.2.The impact of hypothyroidism on neuroendocrine function:After one month of induction chemotherapy,the average concentration of ADL was was significantly higher than that before chemotherapy(110 ± 21.5pg/ml vs.234± 18.3pg/ml,P<0.05),while the average concentration of ACTH was significantly lower than that before chemotherapy(5.14± 1.42pg/ml vs.2.53± 1.71pg/ml,P<0.05).The average concentrations of GH,LH,FSH,PROG,E2 and TETO were lower than those before chemotherapy(GH:2.4±0.45ng/mL vs.1.8±0.73ng/mL,P<0.05;LH:0.78±0.14mIU/mL vs.0.65±0.21 mIU/mL,P>0.05;FSH:1.98±0.67mIU/mL vs.1.81±0.26mIU/mL,P>0.05;PROG:0.27±0.11nmol/L vs.0.185±0.12nmol/L,P>0.05;E2:26.6 ± 3.45pmol/L vs.22.3 ±1.81pmol/L,P>0.05;TESTO:0.73 ± 0.35nmol/L vs.0.46±0.18nmol/L,P>0.05),while the average concentration of PRL was higher than that before chemotherapy(245±87.25mIU/L vs.555±36.38mIU/L,P<0.05).The average concentrations of TSH,FT3 and FT4 were significantly lower than those before chemotherapy(TSH:4.02± 1.32mIU/L vs.1.98± 1.02mIU/L,P<0.05;FT3:4.36 ± 0.78pmol/L vs.3.78 ± 0.65pmol/L,P>0.05;FT4:15.2 ± 1.35pmol/L vs.6.9±1.82pmol/L,P<0.05).3.Clinical features of hypothyroidism:30 patients(65.22%,30/46)were confirmed to have hypothyroidism during the induction chemotherapy,including 5 cases(16.67%,3/30)with low FT3,5 cases(16.67%,3/30)with low FT4,and 20 cases(50%,20/30)with low FT3 and FT4.Among these patients with hypothyroidism,8 cases(26.67%,8/30)had normal TSH levels which conformed to low T3 syndrome,and 22 cases(73.33%,22/30)had decreased TSH levels which conformed to central hypothyroidism.15 patients(50%,15/30)with hypothyroidism developed clinical manifestations,including sinus bradycardia(12 cases,40%),abdominal distension(8 cases,26.67%),fatigue(6 cases,20%),constipation(5 cases,16.67%),and eyelid edema(2 cases,6.67%).Some patients had multiple clinical manifestations.4.Clinical efficacy of replacement therapy:At the end of induction chemotherapy,the average concentrations of FT3 and FT4 in the treated group were higher than those in the non-treated group(FT3:5.2± 1.02pmol/L vs.3.34± 1.73pmol/L,P<0.05;FT4:13.2± 1.63pmol/L vs.7.8± 1.82pmol/L,P<0.05),while the average concentrations of TSH in the two groups were close(TSH:3.89± 1.52mIU/L vs.3.76± 1.68mIU/L,P>0.05).Between the treated group and the non-treated group,the recovery rates of hypothyroidism were 66.67%and 27.67%,respectively(P=0.028);the remission rates of leukemia on day 19 were 20%and 26.67%,respectively(P>0.05);the remission rates of leukemia on day 46 were 73.33%and 60%,respectively(P>0.05).Conclusions:1.Induction chemotherapy mainly inhibited neuroendocrine function of ALL children,but serum ALD and PRL levels increased after induction chemotherapy.2.Levothyroxine replacement therapy was beneficial in eliminating the symptoms and signs associated with hypothyroidism and normalizing thyroid hormones,but could not improve early remission rates of ALL children. |
