左旋门冬酰胺酶、培门冬酶对急性淋巴细胞白血病患儿的治疗效果比较

Comparison of therapeutic effects of L-asparaginase and pegaspargase on children with acute lymphoblastic leukemia

摘要

目的 对比左旋门冬酰胺酶、培门冬酶对急性淋巴细胞白血病(ALL)患儿的治疗效果。方法 回顾性收集2016年6月至2022年9月无锡市儿童医院收治的所有ALL患儿临床资料,根据治疗方法不同随机选取左旋门冬酰胺酶组和培门冬酶组,例数各37例。两组均进行常规基础治疗,在此基础上,左旋门冬酰胺酶组采用左旋门冬酰胺酶进行治疗,培门冬酶组采用培门冬酶进行治疗,两组均治疗46天,并随访3个月。统计两组治疗46天的临床疗效及治疗期间不良反应发生情况,比较两组治疗前、治疗21天、46天后、随访3个月后糖脂代谢指标及治疗前、治疗21天、46天后细胞因子、凝血功能、肝功能。结果 治疗46天后,与左旋门冬酰胺酶组比较,培门冬酶组总缓解率差异无统计学意义(P＞0.05),而完全缓解率更高(χ²＝4.874,P＜0.05)。治疗前及治疗21天、46天后、随访3个月后,两组血清胰岛素、C肽水平呈降低趋势,不同时间点比较,差异具有统计学意义(P＜0.05);治疗21天后,培门冬酶组高于左旋门冬酰胺酶组(t＝3.372、3.704,P＜0.05)。治疗46天后、随访3个月后,两组血清甘油三酯(TG)水平较治疗前、治疗21天后升高,培门冬酶组高于左旋门冬酰胺酶组(t＝7.181、5.635,P＜0.05)。治疗前、治疗21天、46天后,两组血清肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)、白介素-8(IL-8)、白介素-10(IL-10)、干扰素-γ(IFN-γ)、铁蛋白(SF)水平呈先升高后降低趋势,不同时间点比较,差异具有统计学意义(P＜0.05);治疗21天后培门冬酶组高于左旋门冬酰胺酶组(t值介于3.785~7.921之间,均P＜0.05);治疗46天后培门冬酶组低于左旋门冬酰胺酶组(t值介于2.983~7.000之间,均P＜0.05)。两组凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)时长呈先升高后降低趋势,培门冬酶组治疗21天后长于左旋门冬酰胺酶组(t＝2.985,P＜0.05);两组血浆纤维蛋白原(FIB)水平呈先降低后升高趋势,培门冬酶组治疗21天后低于左旋门冬酰胺酶组(t＝5.711,P＜0.05);两组血清D-二聚体(D-D)、纤维蛋白原降解产物(FDP)、丙氨酸氨基转移酶(ALT)、总胆汁酸(TBil)水平呈先升高后降低趋势,培门冬酶组治疗21天、46天后高于左旋门冬酰胺酶组(t值介于3.566~40.745之间,均P＜0.05)。治疗期间,培门冬酶组总不良反应发生率高于左旋门冬酰胺酶组(χ²＝7.341,P＜0.05)。结论 与左旋门冬酰胺酶相比,采用培门冬酶治疗ALL患儿对患儿胰岛功能和肝功能、凝血功能影响较大,安全性相对较差,但其在降低患者机体炎症反应方面应用效果更好,同时疗效更好,临床可根据患儿具体情况选取合适的药物进行治疗。

Abstract

Objective To compare the therapeutic effects of L-asparaginase and pegaspargase on children with acute lymphoblastic leukemia (ALL). Methods The clinical data of ALL children admitted to Wuxi Children's Hospital from June 2016 to September 2022 were retrospectively collected. According to different treatment methods, 37 cases were randomly selected for the L-asparaginase group and the perasparagase group, respectively. Both groups received conventional basic treatment. On this basis, the L-asparaginase group was treated with L-asparaginase, and the perasparagase group was treated with perasparagase. Both groups were treated for 46 days and followed up for 3 months. The clinical efficacy and adverse reactions during the 46-day treatment period in both groups were analyzed. The lipid and glucose metabolism indicators before treatment, at 21 days, and after 46 days, as well as cytokines, coagulation function, and liver function before treatment, at 21 days, and after 46 days, were compared between the two groups. Results After 46 days of treatment, there was no statistically significant difference in the total remission rate between the perasparagase group and the L-asparaginase group (P＞0.05). However, the complete remission rate of the perasparagase group was higher than that of the L-asparaginase (χ²＝4.874, P＜0.05). Before treatment, after 21 and 46 days of treatment, and 3 months of follow-up, levels of serum insulin and C-peptide of the two groups showed a decreased trend, and the difference was statistically significant at different time points (P＜0.05). After 21 days of treatment, the perasparagase group was higher than the L-asparaginase group (t＝3.372, 3.704, P＜0.05). After 46 days of treatment and 3 months of follow-up, the serum triglyceride (TG) levels in two groups were higher than that before treatment and after 21 days of treatment, with the perasparagase group higher than that in the L-asparaginase group (t＝7.181, 5.635, P＜0.05). Before treatment, 21 days and 46 days after treatment, the levels of serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interferon-γ (IFN-γ) and ferritin (SF) in two groups were firstly increased and then decreased. The differences at different time points were statistically significant (P＜0.05). After 21 days of treatment, the perasparagase group was higher than the L-asparaginase group (t＝3.785-7.921, all P＜0.05), and after 46 days of treatment, the perasparagase group was lower than the L-asparaginase group (t＝2.983-7.000, all P＜0.05). The duration of both prothrombin time (PT) and activated partial thrombin time (APTT) showed a trend of initially increasing and then decreasing. After 21 days of treatment, the PT and APTT durations in the perasparagase group were longer than those in the L-asparaginase group (t＝2.985, P＜0.05). The levels of plasma fibrinogen (FIB) in both groups showed a trend of initially decreasing and then increasing. After 21 days of treatment, the FIB level in the perasparagase group was lower than that in the L-asparaginase group (t＝5.711, P＜0.05). The levels of serum D-dimer (D-D), fibrinogen degradation products (FDP), alanine aminotransferase (ALT), and total bile acid (TBil) showed a trend of initially increasing and then decreasing in both groups. After 21 and 46 days of treatment, the levels in the perasparagase group were higher than those in the L-asparaginase group (t＝3.566-40.745, all P＜0.05). During the treatment period, the incidence of total adverse reactions in the perasparagase group was higher than that in the L-asparaginase group (χ²＝7.341, P＜0.05). Conclusion Compared with L-asparaginase, using pegaspargase to treat children with ALL has a greater impact on the islet function, liver function and coagulation function, and the safety is relatively poor. However, it has better efficacy in reducing patient inflammatory response. Suitable drugs could be selected for clinical treatment according to the specific conditions of children.

关键词

急性淋巴细胞白血病 / 儿童 / 左旋门冬酰胺酶 / 培门冬酶 / 安全性

Key words

acute lymphoblastic leukemia / children / L-asparaginase / pegaspargase / security

参考文献

[1] Defilipp Z, Advani AS, Bachanova V, et al. Hematopoietic cell transplantation in the treatment of adult acute lymphoblastic leukemia: updated 2019 evidence-based review from the american society for transplantation and cellular therapy[J]. Biol Blood Marrow Transplant, 2019, 25(11): 2113-2123.

[2] Verma A, Chen K, Bender C, et al. PEGylated E. coli asparaginase desensitization: an effective and feasible option for pediatric patients with acute lymphoblastic leukemia who have developed hypersensitivity to pegasparagase in the absence of asparaginase erwinia chrysanthemi availability[J]. Pediatr Hematol Oncol, 2019, 36(5): 277-286.

[3] 张羽, 何彦瑶, 吴攀. 培门冬酶及左旋门冬酰胺酶治疗儿童急性淋巴细胞白血病的疗效及不良反应[J]. 临床药物治疗杂志, 2018, 16(10): 45-49.

[4] Schore RJ, Devidas M, Bleyer A, et al. Plasma asparaginase activity and asparagine depletion in acute lymphoblastic leukemia patients treated with pegaspargase on children's oncology group AALL07P4[J]. Leuk Lymphoma, 2019, 60(7): 1740-1748.

[5] 赵学勤, 王政委, 庄艳, 等. 左旋门冬酰胺酶及培门冬酶治疗小儿急性淋巴细胞白血病的疗效及实验室指标比较[J]. 儿科药学杂志, 2020, 26(10): 17-20.

[6] 王福玲. 世界医学会«赫尔辛基宣言»——涉及人类受试者的医学研究的伦理原则[J]. 中国医学伦理学, 2016, 29(3): 544-546.

[7] 中华医学会儿科学分会血液学组, «中华儿科杂志»编辑委员会. 儿童急性淋巴细胞白血病诊疗建议(第四次修订)[J]. 中华儿科杂志, 2014, 52(9): 641-644.

[8] Aldoss I, Pullarkat V. Indications for allogeneic hematopoietic cell transplantation for adults with philadelphia-chromosome negative acute lymphoblastic leukemia in first complete remission: all about MRD? [J]. Bone Marrow Transplant, 2019, 54(1): 3-5.

[9] Short NJ, Kantarjian H, Jabbour E. Soho state of the art updates & next questions: intensive and non-intensive approaches for adults with philadelphia chromosome-positive acute lymphoblastic leukemia[J]. Clin Lymphoma Myeloma Leuk, 2022, 22(2): 61-66.

[10] 孟艳, 翟小颖, 东蕾, 等. 益生菌对接受大剂量甲氨蝶呤的ALL患儿影响及经济学分析[J]. 中国妇幼健康研究, 2022, 33(2): 16-20.

[11] 陈晓娟, 邹尧, 刘晓明, 等. CCLG-ALL2008方案治疗不同分子生物学特征儿童急性淋巴细胞白血病的长期疗效分析[J]. 中国当代儿科杂志, 2019, 21(9): 890-893.

[12] Bassan R, Chiaretti S, Della SI, et al. Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial[J]. Blood Adv, 2023, 7(16): 4448-4461.

[13] Lynggaard LS, Rank CU, Hansen SN, et al. Asparaginase enzyme activity levels and toxicity in childhood acute lymphoblastic leukemia: a NOPHO ALL2008 study[J]. Blood Adv, 2022, 6(1): 138-147.

[14] Dunn KA, Connors J, Bielawski JP, et al. Investigating the gut microbial community and genes in children with differing levels of change in serum asparaginase activity during pegaspargase treatment for acute lymphoblastic leukemia[J]. Leuk Lymphoma, 2021, 62(4): 927-936.

[15] 鲍颖, 梁颜, 何丽, 等. 两种不同类型门冬酰胺酶在成人急性淋巴细胞白血病治疗中的疗效观察[J]. 安徽医药, 2018, 22(12): 2435-2438.

[16] 陈娜, 宋春兰, 景钰, 等. 两种门冬酰胺酶治疗儿童急性淋巴细胞白血病的近期效果及对患儿血清LDH、SF和ESR的影响[J]. 实用癌症杂志, 2021, 36(2): 337-340.

[17] Dunn KA, Forbrigger Z, Connors J, et al. Gut bacterial gene changes following pegaspargase treatment in pediatric patients with acute lymphoblastic leukemia[J]. Leuk Lymphoma, 2021, 62(13): 3244-3255.

[18] 谢晓恬, 周晓迅. 左旋门冬酰胺酶治疗儿童急性淋巴细胞白血病耐药机制研究[J]. 中华实用儿科临床杂志, 2019, 34(3): 166-169.

[19] Lau KM, Saunders IM, Goodman A. Pegaspargase-induced hypertriglyceridemia in a patient with acute lymphoblastic leukemia[J]. J Oncol Pharm Pract, 2020, 26(1): 193-199.

[20] Vrooman LM, Blonquist TM, Stevenson KE, et al. Efficacy and toxicity of pegaspargase and calaspargase pegol in childhood acute lymphoblastic leukemia: results of DFCI 11-001[J]. J Clin Oncol, 2021, 39(31): 3496-3505.

基金资助

无锡市“科教强卫工程”项目(FZXK001)