Utility of a Second Interim Maintenance Phase to Improve Outcomes for Pediatric Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group

Intensification of chemotherapy for pediatric B-cell acute lymphoblastic leukemia (B-ALL) has improved survival. In recently completed Children's Oncology Group (COG) frontline trials for B-ALL, a second interim maintenance (IM2) phase including escalating dose methotrexate, vincristine, ±pegaspargase was utilized to intensify therapy. On AALL1131 for high risk B-ALL (HR-ALL), very high risk (VHR) patients received IM2. On AALL0932 for standard risk B-ALL (SR-ALL), patients were randomized to steroid/vincristine pulses every 4 (q4weeks) or 12 weeks (q12weeks); all patients received IM2 to maintain treatment intensity in the context of dose-reduced Maintenance therapy. However, the efficacy of IM2 has never been established in either HR-ALL or SR-ALL. Thus, we performed secondary analyses comparing outcomes for matched cohorts treated ±IM2 in sequential COG trials in HR-ALL treated on AALL0232 (no IM2) and AALL1131 (+IM2) and in SR-ALL treated on AALL0331 (no IM2) and AALL0932 (+IM2). The primary objective was to compare disease-free (DFS) and overall survival (OS) in patients receiving identical systemic COG ALL therapy ±IM2. Secondary objectives were to examine the efficacy of IM2 in SR-ALL with the current standard q12week steroid/vincristine pulses and within cytogenetic subsets. Eligibility criteria for these analyses were designed to match treatment arms between trials. For HR-ALL, inclusion criteria were age ≥13 years old and end of induction (EOI) minimal residual disease (MRD) <0.01%, based on eligibility for the AALL1131 VHR arm. For SR-ALL, patients with neutral or favorable cytogenetics (ETV6::RUNX1 or double trisomies 4 and 10) and EOI MRD <0.01% were included. Patients with BCR::ABL1, KMT2A rearrangement, hypodiploidy, or EOI MRD ≥0.01% were excluded due to treatment variation among trials. Statistical analyses compared DFS and OS via log-rank test and were reported at five years with standard errors. Cox multivariable models analyzed hazard ratios (HR) adjusted for presenting features (demographics, white blood cell count, cytogenetics, central nervous system status). In HR-ALL, 249 patients from AALL0232 and 65 patients from AALL1131 VHR were eligible. For AALL1131 VHR versus AALL0232, the addition of IM2 was not associated with a difference in DFS (85%±4.7 vs 85%±2.5, p=0.91) or OS (90%±4.0 vs 90%±2.1, p=0.63). In SR-ALL patients receiving q4week pulses in Maintenance, 1,317 patients were eligible from AALL0331 and 1,186 patients from AALL0932. As compared to AALL0331, addition of IM2 in AALL0932 was associated with significantly higher DFS (94%±0.7 vs 91%±0.8, p= 0.0024) and OS (99%±0.4 vs 97%±0.5, p<0.0001). In the Cox multivariable model comparing SR-ALL patients receiving q4week pulses, IM2 significantly decreased risk for an event (HR 0.67, p=0.0048). In SR-ALL patients enrolled in AALL0932 who were randomized to receive q12week pulses (n=1,178), addition of IM2 was associated with higher DFS and OS versus AALL0331 (95%±0.7 vs 91%±0.8, p<0.0001 and 99%±0.3 vs 97%±0.5, p<0.0001, respectively). However, adjusted Cox models demonstrated the decreased event risk was largely in those with neutral cytogenetics (HR=0.62, p=0.0179), with OS (HR=0.58, p=0.0783). No difference in DFS/OS was noted in SR-ALL with favorable cytogenetics. Within the limitations of unplanned subset analyses, we determined that IM2 may be able to be safely omitted in MRD-negative patients with HR-ALL or with SR-ALL with favorable cytogenetics and that IM2 may provide a survival advantage for patients with SR-ALL, neutral cytogenetics, and MRD <0.01%. Whether IM2 is necessary in patients with higher risk B-ALL due to adverse cytogenetics or persistent MRD was not addressed in these analyses.

儿童B细胞急性淋巴细胞白血病（B - ALL）化疗的强化提高了生存率。在近期完成的儿童肿瘤学组（COG）针对B - ALL的一线试验中，采用了包括递增剂量甲氨蝶呤、长春新碱、±培门冬酶的第二次中期维持（IM2）阶段来强化治疗。在针对高危B - ALL（HR - ALL）的AALL1131试验中，极高危（VHR）患者接受了IM2治疗。在针对标危B - ALL（SR - ALL）的AALL0932试验中，患者被随机分为每4周（q4周）或12周（q12周）接受类固醇/长春新碱脉冲治疗；所有患者都接受了IM2治疗，以便在维持治疗剂量减少的情况下保持治疗强度。然而，IM2在HR - ALL或SR - ALL中的疗效从未得到确定。因此，我们进行了二次分析，比较了在COG连续试验中接受±IM2治疗的匹配队列的结果，这些试验包括针对HR - ALL的AALL0232（无IM2）和AALL1131（有IM2）试验，以及针对SR - ALL的AALL0331（无IM2）和AALL0932（有IM2）试验。 主要目的是比较接受相同的COG ALL系统治疗±IM2的患者的无病生存期（DFS）和总生存期（OS）。次要目的是检验IM2在采用现行标准的q12周类固醇/长春新碱脉冲治疗的SR - ALL以及细胞遗传学亚组中的疗效。这些分析的入选标准旨在使试验之间的治疗组匹配。对于HR - ALL，入选标准为年龄≥13岁且诱导治疗结束（EOI）时微小残留病（MRD）<0.01%，这是基于AALL1131极高危组的入选标准。对于SR - ALL，纳入具有中性或有利细胞遗传学（ETV6::RUNX1或4号和10号染色体双三体）且EOI时MRD <0.01%的患者。由于试验间治疗差异，排除了BCR::ABL1、KMT2A重排、亚二倍体或EOI时MRD≥0.01%的患者。通过对数秩检验比较DFS和OS进行统计分析，并在五年时报告结果及标准误差。Cox多变量模型分析了针对呈现特征（人口统计学特征、白细胞计数、细胞遗传学、中枢神经系统状态）调整后的风险比（HR）。 在HR - ALL中，AALL0232的249名患者和AALL1131极高危组的65名患者符合条件。对于AALL1131极高危组与AALL0232相比，添加IM2与DFS（85%±4.7对85%±2.5，p = 0.91）或OS（90%±4.0对90%±2.1，p = 0.63）的差异无关。在维持治疗中接受q4周脉冲治疗的SR - ALL患者中，AALL0331的1317名患者和AALL0932的1186名患者符合条件。与AALL0331相比，AALL0932中添加IM2与显著更高的DFS（94%±0.7对91%±0.8，p = 0.0024）和OS（99%±0.4对97%±0.5，p < 0.0001）相关。在比较接受q4周脉冲治疗的SR - ALL患者的Cox多变量模型中，IM2显著降低了事件风险（HR 0.67，p = 0.0048）。在AALL0932中被随机分配接受q12周脉冲治疗的SR - ALL患者（n = 1178）中，与AALL0331相比，添加IM2与更高的DFS和OS相关（95%±0.7对91%±0.8，p < 0.0001和99%±0.3对97%±0.5，p < 0.0001）。然而，调整后的Cox模型表明，事件风险降低主要发生在具有中性细胞遗传学的患者中（HR = 0.62，p = 0.0179），对于OS（HR = 0.58，p = 0.0783）。在具有有利细胞遗传学的SR - ALL中，未观察到DFS/OS的差异。 在非计划亚组分析的局限性范围内，我们确定在HR - ALL的MRD阴性患者或具有有利细胞遗传学的SR - ALL患者中可能可以安全地省略IM2，并且IM2可能为具有SR - ALL、中性细胞遗传学且MRD <0.01%的患者提供生存优势。这些分析未涉及由于不良细胞遗传学或持续性MRD而处于更高风险的B - ALL患者是否需要IM2。