Lack of Benefit of Extended Vincristine and Dexamethasone Pulses during Maintenance Treatment of Childhood Acute Lymphoblastic Leukemia: A Multicenter Randomized Controlled Study of Chinese Children Cancer Group (CCCG)-ALL-2015
Authors: Zhu Xiaofan , Shen Shuhong , Cai Jiaoyang , Hu Shaoyan , Gao Ju , Zhang Hui , Fang Yongjun , Ju Xiuli , Zhai Xiaowen , Wu Xuedong , Liang Changda , Tian Xin , Hu Qun , Wang Ningling , Jin Runming , Jiang Hui , SUN Lirong , Yang Minghua , Pan Kaili , Li Chi Kong , Yang Jun J. , Cheng Cheng , Tang JingYan , Pui Ching-Hon 
Published: November 2019

Introduction: The efficacy of extended duration of vincristine (VCR) and dexamethasone (DEX) pulses in the treatment of childhood acute lymphoblastic leukemia (ALL) is uncertain in the context of contemporary chemotherapy. By contrast, the long-term sequelae of vincristine-induced peripheral neuropathy and dexamethasone-related metabolic syndrome, osteonecrosis, and neurocognitive impairment are well recognized. We therefore conducted a randomized study in the CCCG-ALL-2015 protocol participated by 20 hospitals in China to compare the event-free survival (EFS) and overall survival (OS) between children with newly diagnosed ALL who did or did not receive extended duration of VCR+DEX pulses during maintenance treatment.
Methods: After remission induction and consolidation treatment with high-dose methotrexate and mercaptopurine, all patients received antimetabolite-based maintenance treatment. During the initial 20-week of maintenance treatment, low-risk (LR) patients received two reinduction cycles and three pulses of VCR+DEX pulses, while intermediate-/high-risk (I/HR) patients received daily mercaptopurine interrupted every three weeks with PEG-asparaginase, mercaptopurine, daunorubicin, and VCR+DEX pulses for 5 courses followed by a reinduction treatment. During the subsequent maintenance treatment, all patients received VCR+DEX pulses every 4 weeks for 5 cycles. All Philadelphia chromosome (Ph)-negative patients were then stratified and randomized during the fifth cycle of maintenance course (between weeks 51 and 53) to or not to receive the VCR+DEX pulse every 8 weeks for 7 cycles between weeks 54 and 109; the remaining maintenance treatment between weeks 110 and 125 consisted of only mercaptopurine and methotrexate.
Results: Between January 2015 and December 2018, 3985 eligible Ph-negative patients, including 2318 (58.2%) LR patients and 1667 (41.8%) I/HR patients, were enrolled in the study. With a median follow-up of 2.53 years (IQR 1.82-3.26), the 4-year event-free survival (EFS) and overall survival (OS) rates were 91.6% (95% CI 89.4-93.9) and 98.8% (95% CI 98.2-99.4) in the LR patients, and 85.9% (95% CI 83.2-88.7) and 95.4% (95% CI 93.8-96.9) in the I/HR patients, respectively.
The 4-year OS were 99.0% (95%CI, 98.3%-99.8%) in the 1145 LR patients randomized to receive VCR+DEX pulse (LR-A) and 98.6% (95% CI, 97.7%-99.5%) in the 1173 LR patients not to receive the pulse (LR-B, hazard ratio 1.5, 95% CI 0.6-4.0; p=0.374, Fig 1A). The 4-year EFS were 91.1% (95% CI, 87.4%-95.1%) in LR-A group and 92.0% (95% CI, 89.6%-94.5%) in LR-B group (hazard ratio 1.3, 95% CI 0.8-1.9; P=0.27; Figure 1B). There were no significant differences between LR-A and LR-B group among patients with or without the t (12;21) (ETV6-RUNX1) in univariate analysis (Table1).
Likewise, there was no significant difference in the 4-year OS between the 834 I/HR patients who did (I/HR-A) and the 833 I/HR patients who did not (I/HR-B) receive the pulse: 94.3% (95% CI, 91.7%-97.0%) versus 96.3% (95%CI 94.6%-98.0%, hazard ratio 0.8, 95% CI 0.4-1.4; P=0.421) (Fig 1C). The 4-year EFS were 83.6% (95%CI 79.2%-88.3%) for I/HR-A group and 88.1% (95%CI 85.1%-91.2%, P=0.372) for I/HR-B group (hazard ratio 0.9, 95% CI 0.6-1.2; P=0.37) (Figure 1D). There were no significant differences between I/HR-A and I/HR-B group among patients with B-ALL, T-ALL or t (1;19) (TCF3-PBX1) in the univariate analysis (Table1).
Conclusion: The additional pulses of VCR+DEX pulse beyond one year of maintenance treatment had no impact on 4-year EFS or OS among LR or I/HR patients. If this finding remains unchanged with additional follow-up, the VCR+DEX pulses can be omitted after one year of maintenance therapy in childhood ALL.

Disclosures
No relevant conflicts of interest to declare.