Abstract:

Objective: To compare the efficacy and adverse effects of CHFU-LCH 2006 protocol (simply called 2006 protocol) to CHFU-LCH 2012 protocol［simply called 2012 protocol, which was updated to simplify groups, remove methotrexate (MTX) and unify treatment time to 12 months］ formulated by Children's Hospital of Fudan University (our hospital) to treat Langerhans cell histiocytosis (LCH). Methods: Newly diagnosed childhood LCH patients, who were treated in our hospital from January 1, 2006 to November 31, 2012, were enrolled in 2006 protocol and patients from December 1, 2012 to December 31, 2015 were enrolled for 2012 protocol. Diagnosis of patients in both groups was made by pathology. Children who did not complete the initial 6-week treatment were excluded. The subjects were further divided into single-system LCH (SS-LCH) and multisystem LCH (MS-LCH) subgroups. All patients were followed up until March 31, 2017. Effective treatment outcomes were categorized as non active disease (NAD) or active disease better (AD Better). The 5-year expected overall survival rate (OS) and event-free survival rate (EFS) were estimated by Kaplan-Meier analysis. Adverse reactions to chemotherapy were classified into grade 0~4 according to WHO criteria for acute and subacute toxicity. Response to chemotherapy between the two groups were compared at 6 and 12 weeks. In addition, we followed and compared disease progression, recurrence and mortality and the 5-year expected OS, EFS, as well as occurrence of adverse reaction between the two groups. Results: There were 96 patients (64 boys and 32 girls, median age 3.4 years, median follow-up duration 6.6 years) enrolled for 2006 protocol. In 2012 group, 86 patients (59 boys and 27 girls, median age 2.9 years, median follow-up duration 3.7 years) were included. There was no significant difference between the two groups in gender, age of diagnosis, clinical classification and risk organ involvement (RO+). ① There was no significant difference in the response to therapy at 6 and 12 weeks and disease recurrence in either MS-LCH or SS-LCH subgroups between 2006 group and 2012 group; ② Among patients in MS-LCH subgroup, there were 4 cases and 5 cases respectively in 2006 group and 2012 group quitting the protocol and were transferred to other rescue protocols. 5 cases and 4 cases died, respectively in the two groups. ③ There were totally 93 children categorized as MS-LCH in our study. The rate of EFS and OS in patients with MS-LCH younger than 2 years were significantly lower than those older than 2 years ［EFS: (41.9±8.1) % vs (62.6±7.5) %; OS: (80.8±6.2) % vs (98.0±2.0) %, respectively］, P<0.05. The rate of EFS and OS among RO+ MS-LCH patients were also significantly lower than RO- MS-LCH patients ［EFS: (37.4±8.0) % vs (66.0±7.3) %; OS: (80.4±6.3)% vs (98.0±2.0)%］, P<0.05. Among RO- MS-LCH patients, the rate of EFS and OS were not significantly different between children younger than 2 years and those older than 2 years. The EFS rate was significantly lower in children who did not respond to the initial 6-week therapy than those responded ［(33.1±7.9) % vs (70.8±7.2) %］, P<0.05. ④ The 5-year expected EFS of SS-LCH subgroup was (84.8±5.3) % and (86.7±5.6) % for 2006 and 2012 groups, the 5-year expected OS was 100% in both treatment groups. The 5-year expected EFS of MS-LCH subgroup was (50.0±7.1) % and (53.2±10.0) %, the 5-year expected OS was (90.0±4.1) % and (90.6±4.5) % for the 2006 and 2012 group and there was no statistical difference identified between the two treatment groups. ⑤ The Grade 3 and 4 chemotherapy related adverse reactions occurred in 50% (25/50) of patients with MS-LCH in the 2006 group, which was significantly higher than 23.3% (10/43) in 2012 group (P=0.0080). Conclusion: The CHFU-LCH 2012 protocol was not inferior to 2006 protocol with less adverse reaction to chemotherapy.