Children and Adolescent Health, Aarhus University Hospital, Aarhus, Denmark.
Institute of Clinical Medicine, Faculty of Medicine, University of Aarhus, Aarhus, Denmark.
Blood. 2021 Apr 29;137(17):2373-2382. doi: 10.1182/blood.2020006583.
Truncation of asparaginase treatment due to asparaginase-related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1 to 17 years, diagnosed with ALL between July 2008 and February 2016, treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (including extended asparaginase exposure [1000 IU/m2 intramuscularly weeks 5-33]). Patients were included with delayed entry at their last administered asparaginase treatment, or detection of SI, and followed until relapse, death, secondary malignancy, or end of follow-up (median, 5.71 years; interquartile range, 4.02-7.64). In a multiple Cox model comparing patients with (n = 358) and without (n = 1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (HR; aHR) was 1.33 (95% confidence interval [CI], 0.86-2.06; P = .20). In a substudy including only patients with information on enzyme activity (n = 1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1% (95% CI, 6.9-15.4) vs 6.7% (95% CI, 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI, 1.05-2.74, P=.03). The unadjusted bone marrow relapse-specific HR was 1.83 (95% CI, 1.07-3.14, P=.03) and 1.86 (95% CI, 0.90- 3.87, P=.095) for any central nervous system relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible. This trial was registered at www.clinicaltrials.gov as #NCT03987542.
由于天冬酰胺酶相关毒性或沉默失活（SI）而中断天冬酰胺酶治疗在急性淋巴细胞白血病（ALL）中很常见，并且可能会增加复发风险。我们研究了 1401 名 1 至 17 岁的儿童在 2008 年 7 月至 2016 年 2 月期间根据北欧儿科血液学和肿瘤学学会（NOPHO）ALL2008 方案（包括延长天冬酰胺酶暴露[每周 5-33 周，1000IU/m2 肌内]）治疗 ALL 后的亚最佳天冬酰胺酶暴露后复发的风险。患者在最后一次接受天冬酰胺酶治疗时延迟进入，或检测到 SI，并随访至复发、死亡、继发恶性肿瘤或随访结束（中位随访时间 5.71 年；四分位距 4.02-7.64）。在比较因临床毒性而接受（n=358）和未接受（n=1043）截短天冬酰胺酶治疗的患者的多 Cox 模型中，调整后的复发特异性危险比（HR；aHR）为 1.33（95%置信区间[CI]，0.86-2.06；P=0.20）。在仅包括具有酶活性信息的患者的亚研究中（n=1115），301 例接受天冬酰胺酶治疗截短或 SI 的患者（157 例过敏反应，53 例胰腺炎，14 例血栓形成，31 例其他，46 例 SI）的 7 年累积复发率为 11.1%（95%CI，6.9-15.4），而其余 814 例患者的复发率为 6.7%（95%CI，4.7-8.6）。复发特异性 aHR 为 1.69（95%CI，1.05-2.74，P=0.03）。未经调整的骨髓复发特异性 HR 为 1.83（95%CI，1.07-3.14，P=0.03）和 1.86（95%CI，0.90-3.87，P=0.095）对于任何中枢神经系统复发。这些结果强调了治疗药物监测和在可行时适当调整天冬酰胺酶治疗的重要性。该试验在 www.clinicaltrials.gov 上注册为 #NCT03987542。
