A Study of Risk Factors for the Effect of Allogeneic Hematopoietic Stem Cell Transplantation on Thyroid Function in Patients with Acute Leukemia
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摘要:
目的 探讨急性白血病(acute leukemia,AL)患者在异基因造血干细胞移植术(allogeneic hematopoietic stem cell transplantation,allo-HSCT)治疗后导致甲状腺疾病(thyroid dysfunction,TD)的患病情况及危险因素。 方法 收集2018年1月至2023年6月于云南省第一人民医院血液内科初次行allo-HSCT的98例AL患者的临床资料进行回顾性分析。所有AL患者均予抗肿瘤药物(除免疫检查点抑制剂)和allo-HSCT治疗,根据是否发生TD分为非TD组(n = 55)和TD组(n = 43),收集患者的一般情况、实验室指标资料,分析2组间的资料是否有统计学差异,并探讨接受allo-HSCT治疗引起TD的相关危险因素。 结果 在接受allo-HSCT治疗的98例AL患者中,43例(43.8%)发生甲状腺功能异常,其中甲状腺功能减退(包括临床甲减、亚临床甲减)22例,甲状腺功能亢进(包括临床甲亢、亚临床甲亢)9例,单纯抗体升高12例。非TD组、TD组一般情况的单因素分析中发现,移植时的年龄、性别、供体与受体关系、HLA配型、供受体血型、粒细胞植入时间、PLT植入时间无统计学意义(P > 0.05),疾病类型、是否并发aGVHD差异有统计学意义(P < 0.05)。二元Logistic回归分析表明移植后并发aGVHD是发生TD的危险因素(OR=3.693,95%CI=1.166~11.699,P < 0.05);与基础疾病ALL对比,AML及其他AL发生甲状腺障碍的风险更高(P < 0.05)。 结论 甲状腺功能减退是AL患者接受allo-HSCT治疗引起TD最常见的类型,移植后急性非淋系白血病发生TD概率更高,患者并发aGVHD是TD的危险因素。 -
关键词:
- 异基因造血干细胞移植 /
- 急性白血病 /
- 甲状腺疾病
Abstract:Objective To investigate the incidence and identify risk factors associated with thyroid disease (TD) in patients diagnosed with acute leukemia (AL) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods Clinical data of 98 AL patients who underwent allo-HSCT for the first time in the Department of Hematology of the First People's Hospital of Yunnan Province from January 2018 to June 2023 were collected and retrospectively analyzed. All AL patients were treated with anti-tumor drugs (excluding immune checkpoint inhibitors) and allo-HSCT, divided into non-TD group (n = 55) and TD group (n = 43) based on whether TD occurred. We collected the patients' general information and laboratory data, analyzed whether there were statistical differences between the two groups, and explored the related risk factors for TD after allo-HSCT treatment. Results Among the 98 AL patients who underwent allo-HSCT, 43 (43.8%) exhibited abnormal thyroid function, including 22 cases of hypothyroidism (comprising clinical and subclinical hypothyroidism), 9 cases of hyperthyroidism (including clinical and subclinical hyperthyroidism), and 12 cases of elevated thyroid antibodies. Univariate analysis of the non-TD group and TD group showed no statistical significance in age, gender, donor-recipient relationship, HLA matching, donor and recipient blood type, neutrophil implantation time and PLT implantation time (P > 0.05). However, there were statistically significant differences in disease type and the presence of concurrent aGVHD (P < 0.05). The binary logistic regression analysis revealed that aGVHD was identified as a significant risk factor for the development of thyroid disorders after transplantation (OR=3.693, 95%CI=1.166~11.699, P < 0.05). Furthermore, when compared to the underlying disease ALL, AML and other AL exhibited a significantly higher susceptibility to thyroid disorders (P < 0.05). Conclusion Hypothyroidism is the most common type of TD caused by allo-HSCT treatment in AL patients, and TD is more likely to occur in acute non-lymphocytic post-transplantation, and patients with aGVHD is a risk factor for TD. -
表 1 接受allo-HSCT治疗患者的基本情况 [($\bar x \pm s $)/n(%)]
Table 1. Basic condition of patients receiving allo-HSCT [($\bar x \pm s $)/n(%)]
项目 基本情况 年龄(岁) 31.36±11.05 性别 男 57(58.2) 女 41(41.8) 急性白血病类型 AML 50(51.0) ALL 35(35.7) 其他(MLA/MDS转化等) 13(13.3) TD发生情况 临床甲状腺功能减退 6(6.1) 亚临床甲状腺功能减退 16(16.3) 临床甲状腺功能亢进 1(1.0) 亚临床甲状腺功能亢进 8(8.2) 单纯抗体升高 12(12.2) 表 2 非TD组、TD组一般情况的单因素分析 [n(%)/M(P25,P75)]
Table 2. Univariate analysis of the general data of the non-TD group and TD group [n(%)/M(P25,P75]
基本信息 非TD组(n=55) TD组(n=43) Z/χ2 P 移植时年龄(岁) <35 38(58.5) 27(62.8) 0.429 0.513 ≥35 17(51.5) 16(37.2) 性别 男 29(52.7) 28(65.1) 1.522 0.217 女 26(47.3) 15(34.9) AL类型 AML 25(45.5) 25(58.1) 12.806 0.002* ALL 27(49.1) 8(18.6) 其他(MAL等) 3(5.5) 10(23.3) 是否并发aGVHD 是 34(61.8) 36(83.7) 5.673 0.017* 否 21(38.2) 7(16.3) 供体与受体关系 亲缘 52(94.5) 43(100) 0.931 0.335 非亲缘 3(5.5) 0(0) HLA匹配 全相合 25(44.6) 19(44.2) 0.002 0.964 半相合 31(55.4) 24(55.8) 供体与受体血型 相同 33(60.0) 32(48.8) 0.765 0.382 不同 22(40.0) 21(51.2) 粒细胞植入时间(d) 12.00(11.00,13.00) 12.00(11.00,15.00) 0.845 0.398 PLT植入时间(d) 13.00(12.00,15.00) 14.00(12.00,15.00) 1.594 0.111 *P < 0.05。 表 3 非TD组、TD组实验室指标的单因素分析 [n(%)/($\bar x \pm s $)/M(P25,P75)]
Table 3. Univariate analysis of laboratory indicators in the non-TD group and TD group [n(%)/($\bar x \pm s $)/M(P25,P75)]
项目 非TD组(n=55) TD组(n=43) t/Z P 移植前TSH(mIU/L) 2.25±0.90 2.36±1.07 0.561 0.576 移植前T4(nmol/L) 88.94(81.70,106.00) 83.90(78.90,93.73) 1.661 0.097 移植前T3(nmol/L) 1.90(1.66,2.16) 1.81(1.44,2.01) 2.016 0.044* 移植前FT4(pmol/L) 14.46(12.89,16.90) 13.93(12.40,15.50) 0.992 0.321 移植前FT3(pmol/L) 5.13(4.58,5.88) 4.93(4.01,5.29) 2.137 0.033* WBC(×109/L) 4.64(3.31,7.05) 5.52(3.63,6.78) 0.291 0.771 RBC(×109/L) 3.42±0.87 3.23±0.83 1.091 0.278 HGB(g/L) 109.87±23.32 104±26.86 0.150 0.253 PLT(×109/L) 145.00(82.00,174.00) 103.00(52.75,164.00) 1.842 0.065 G(mmol/L) 5.00(4.65,5.65) 5.10(4.70,5.95) 0.943 0.346 LDH(U/L) 239.00(185.50,300.00) 254.00(206.50,319.25) 1.027 0.305 ASL(U/L) 25.50(20.00,30.00) 24.00(20.00,39.00) 0.432 0.665 ALT(U/L) 22.50(14.00,39.00) 16.00(11.00,38.00) 1.170 0.242 CHOL(mmol/L) 4.41(3.65,5.16) 3.98(3.09,4.88) 1.552 0.121 TG(mmol/L) 1.82(1.15,2.41) 2.01(1.46,2.81) 1.642 0.104 BUN(mmol/L) 4.30(3.40,6.50) 4.80(4.00,6.90) 0.931 0.352 CR(µmol/L) 63.00(56.00,77.00) 67.00(59.00,81.00) 1.296 0.195 UA(µmol/L) 331.00(287.00,418.00) 351.00(252.00,422.00) 0.039 0.969 *P < 0.05。 -
[1] Sharma R,Jani C. Mapping incidence and mortality of leukemia and its subtypes in 21 world regions in last three decades and projections to 2030[J]. Annals of Hematology,2022,101(7):1523-1534. doi: 10.1007/s00277-022-04843-6 [2] Zheng R,Zhang S,Zeng H,et al. Cancer incidence and mortality in China,2016[J]. Journal of the National Cancer Center,2022,2(1):1-9. doi: 10.1016/j.jncc.2022.02.002 [3] Tang L,Huang Z,Mei H,et al. Immunotherapy in hematologic malignancies: Achievements,challenges and future prospects[J]. Signal Transduction and Targeted Therapy,2023,8(9):4043-4081. doi: 10.1038/s41392-023-01521-5 [4] Inamoto Y,Lee S J. Late effects of blood and marrow transplantation[J]. Haematologica,2017,102(4):614-625. doi: 10.3324/haematol.2016.150250 [5] Lawitschka A,Peters C. Long-term effects of myeloablative allogeneic hematopoietic stem cell transplantation in pediatric patients with acute lymphoblastic leukemia[J]. Current Oncology Reports,2018,20(9):1-10. doi: 10.1007/s11912-018-0719-5 [6] 中华医学会血液学分会干细胞应用学组. 中国异基因造血干细胞移植治疗血液系统疾病专家共识(Ⅰ)——适应证、预处理方案及供者选择(2014年版)[J]. 中华血液学杂志,2014,35(8):775-780. doi: 10.3760/cma.j.issn.0253-2727.2014.08.029 [7] 中华医学会血液学分会干细胞应用学组. 中国异基因造血干细胞移植治疗血液系统疾病专家共识(Ⅲ)——急性移植物抗宿主病(2020年版)[J]. 中华血液学杂志,2020,41(7):529-536. doi: 10.3760/cma.j.issn.0253-2727.2020.07.001 [8] Medinger M,Zeiter D,Heim D,et al. Hypothyroidism following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia[J]. Leukemia Research,2017,58:43-47. doi: 10.1016/j.leukres.2017.04.003 [9] Felicetti F,Gatti F,Faraci D,et al. Impact of allogeneic stem cell transplantation on thyroid function[J]. Journal of Endocrinological Investigation,2023,46(9):1825-1834. doi: 10.1007/s40618-023-02039-x [10] 中华医学会内分泌学分会,《中国甲状腺疾病诊治指南》编写组. 中国甲状腺疾病诊治指南——甲状腺疾病的实验室及辅助检查[J]. 中华内科杂志,2007,46(8):697-702. [11] Taylor P N,Albrecht D,Scholz A,et al. Global epidemiology of hyperthyroidism and hypothyroidism[J]. Nature Reviews. Endocrinology,2018,14(5):301-316. doi: 10.1038/nrendo.2018.18 [12] Li Y,Teng D,Ba J,et al. Efficacy and safety of long-term universal salt iodization on thyroid disorders: Epidemiological evidence from 31 provinces of mainland China[J]. Thyroid®,2020,30(4):568-579. [13] Wang W,Wang S,Zhang K,et al. Hypothyroidism is associated with clinical outcomes in patients with acute myocardial infarction: Subgroup analysis of China PEACE Study[J]. Endocrine,2021,74(1):128-137. doi: 10.1007/s12020-021-02742-w [14] Brenta G,Nepote A,Barreto A,et al. Low glomerular filtration rate values are associated with higher TSH in an elderly population at high cardiovascular disease risk[J]. Frontiers in Endocrinology,2023,14:1162626. doi: 10.3389/fendo.2023.1162626 [15] 张鹏程,罗琴,杨芳. 血清甲状腺激素和25-(OH)D_3对急性白血病患儿化疗疗效的影响[J]. 中国处方药,2019,17(6):164-165. doi: 10.3969/j.issn.1671-945X.2019.06.102 [16] Paviglianiti A. Endocrine and metabolic disorders after hematopoietic cell transplantation[J]. Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology,2020,37(2):111-115. [17] Bhatia S,Armenian S H,Landier W. How i monitor long-term and late effects after blood or marrow transplantation[J]. Blood,2017,130(11):1302-1314. doi: 10.1182/blood-2017-03-725671 [18] Muller I,Moran C,Lecumberri B,et al. 2019 European Thyroid Association Guidelines on the management of thyroid dysfunction following immune reconstitution therapy[J]. European Thyroid Journal,2019,8(4):173-185. doi: 10.1159/000500881 [19] Akiyama M,Inamoto K,Katayanagi N,et al. [Clinical features of thyroid dysfunction in adult Japanese after allogeneic hematopoietic stem cell transplantation][J/OL]. [Rinsho ketsueki] The Japanese journal of clinical Hematology,2022,63(8): 876-879. [20] Cherian K E,Kapoor N,Devasia A J,et al. Endocrine challenges and metabolic profile in recipients of allogeneic haematopoietic stem cell transplant: A cross-sectional study from Southern India[J]. Indian Journal of Hematology & Blood Transfusion,2020,36(3):484-490. [21] Cima L N,Martin S C,Lambrescu I M,et al. Long-term thyroid disorders in pediatric survivors of hematopoietic stem cell transplantation after chemotherapy-only conditioning[J]. Journal of Pediatric Endocrinology & Metabolism: JPEM,2018,31(8): 869–878. [22] Zubarovskaya N,Bauer D,Ronceray L,et al. To Lighten the burden of cure: Thyroid disease in long-term survivors after TBI conditioning for paediatric ALL[J]. Frontiers in Pediatrics,2021,9:798974. [23] Lebbink C A,Bresters D,Tersteeg J P B,et al. Changes in thyroid function parameters 3 months after allogeneic and autologous hematopoietic stem cell transplantation in children[J]. European Journal of Endocrinology,2023,188(6):503-509. doi: 10.1093/ejendo/lvad058 [24] Lee Y J,Lee H Y,Ahn M B,et al. Thyroid dysfunction in children with leukemia over the first year after hematopoietic stem cell transplantation[J]. Journal of Pediatric Endocrinology & Metabolism: JPEM,2018,31(11):1241-1247. [25] 冯秋,夏宁,梁瑜祯. TH1/TH2/TH17细胞因子与造血干细胞移植术后甲状腺功能的相关性研究[J]. 重庆医学,2021,50(11):1834-1838. doi: 10.3969/j.issn.1671-8348.2021.11.008 [26] Farhadfar N,Stan M N,Shah P,et al. Thyroid dysfunction in adult hematopoietic cell transplant survivors: Risks and outcomes[J]. Bone Marrow Transplantation,2018,53(8):977-982. doi: 10.1038/s41409-018-0109-5 [27] Wang Y,Wu D P,Liu Q F,et al. Donor and recipient age,gender and ABO incompatibility regardless of donor source: Validated criteria for donor selection for haematopoietic transplants[J]. Leukemia,2018,32(2):492-498. doi: 10.1038/leu.2017.199 [28] Srinivasan A,Raffa E,Wall D A,et al. Outcome of haploidentical peripheral blood allografts using post-transplantation cyclophosphamide compared to matched sibling and unrelated donor bone marrow allografts in pediatric patients with hematologic malignancies: A single-center analysis[J]. Transplantation and Cellular Therapy,2022,28(3): 158. e1-158. e9. [29] Ataca Atilla P,Akkus E,Atilla E,et al. Thyroid dysfunctions in adult patients after allogeneic hematopoietic stem cell transplantation[J]. Clinical Transplantation,2020,34(10):1-10. doi: 10.1111/ctr.14049 [30] Milenković T,Vujić D,Vuković R,et al. Subclinical hypothyroidism in children and adolescents after hematopoietic stem cells transplantation without irradiation[J]. Vojnosanitetski Pregled,2014,71(12):1123-1127. doi: 10.2298/VSP1412123M [31] Pan B,Zhang Y,Sun Y,et al. Deviated balance between Th1 and Th17 cells exacerbates acute graft-versus-host disease in mice[J]. Cytokine,2014,68(2):69-75. doi: 10.1016/j.cyto.2014.04.002 -