Risk-Adjusted Therapies Yield Equivalent Outcomes for Adolescents and Young Adults (AYAs) Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia (T-ALL) on Children's Oncology Group (COG) Studies AALL0434 and AALL1231

Introduction Previous clinical trials have reported that adolescent and young adult (AYA) patients treated for T-cell acute lymphoblastic leukemia (T-ALL) have lower disease-free survival (DFS) and overall survival (OS) and increased toxicity as compared to younger patients. Results for the AYA cohort treated on two COG international phase 3 trials for T-ALL are reported here. Patients and Methods AALL0434 enrolled 1562 T-ALL patients (2007-2014) and AALL1231 enrolled 615 T-ALL patients (2014-2019) treated on augmented BFM (ABFM) regimens. AYA patients were defined as age ≥16 years of age (AALL0434: n=226; AALL1231: n = 107). Both studies allowed enrollment up to age 31 years. On AALL0434, participants were randomized to receive escalating dose methotrexate (CMTX) without leucovorin rescue + pegaspargase or high dose MTX (HDMTX) + leucovorin rescue. Intermediate and high-risk patients were randomized to receive or not receive six 5-day courses of nelarabine (Nel). Risk group assignments in AYA vs non-AYA patients can be found in Table 1. On AALL1231, participants were randomized to receive or not receive bortezomib in Induction and Delayed Intensification. Key differences between AALL0434 and AALL1231 ABFM backbones included the use of prednisone in induction in AALL0434 versus dexamethasone in AALL1231, and cranial radiation therapy in the majority of AALL0434 participants versus only in patients with central nervous system involvement in AALL1231. Results On AALL0434, the 4-year DFS for AYA was 81% compared to 84% for those <16 years old (P=0.5965), and OS was 88% and 90% respectively (P=0.3478). AYA patients randomized to CMTX (n=70) had a superior DFS compared to those randomized to HDMTX (n=72) with 4-year DFS 96% versus 78% respectively (P=0.0038). No disadvantage was seen among AYA subjects who received nelarabine versus those who did not, as shown by a 4-year DFS 85% versus 89%, respectively (N=54) (P=0.8116), albeit the sample size was small. On AALL1231, the 4-year EFS for AYA (n=107) was 82.7±3.9% compared to 82.2 ±1.7% for non-AYA (n=508) (P=0.727), and OS was 86.5 ±3.5% and 88.4 ±1.5% respectively (P=0.553). No difference in outcome was seen for AYA patients randomized to receive/not receive bortezomib. Combined outcome data for AALL0434 and AAL1231 demonstrates 4-year EFS for AYA (n=333) of 82.2+2.4% vs 83.9+0.9% for non-AYA (n=1844) (P=0.52) (Figure 1) and OS of 87.5+2.1% vs 90+0.8% respectively (P=0.19). Significant differences in patient characteristics in AALL0434 were higher initial white blood counts (P=0.0004) and higher risk group category (P=0.0002) for AYA patients. There were no significant differences in the AALL0434 AYA cohort compared to younger patients in CNS disease status, race, ethnicity, remission status at end of induction, or day 29 end of induction minimal residual disease (MRD). Toxicity rates were not significantly different in non-AYA vs AYA patients with the exception of upper respiratory infection (9.4% vs 1.8%; P=0.0001) and osteonecrosis (4.8% vs 17.7%; P<0.0001) in AALL0434. Rates of sepsis, catheter-related infection, and other infections were not significantly different between AYA and younger patients in AALL0434. Analysis of patient characteristics and toxicity rates in AALL1231, as well as analysis of the combined toxicity data for AALL0434 and AAL1231, are currently underway and will be presented at the meeting. Conclusion COG AALL0434 and AALL1231 show outstanding overall outcomes for AYA patients with no significant difference in survival between AYA and non-AYA patients on either study, despite differences in the ABFM backbones and the higher risk features seen among the AYA group in AALL0434. There were similar occurrences of therapy-related toxicities for AYA and non-AYA study participants on AALL0434. Despite small numbers, CMTX holds a survival advantage for AYA T-ALL patients, with no survival disadvantage seen among AYA T-ALL patients who received Nel. Bortezomib does not offer significant benefit for AYA T-ALL patients.

引言 先前的临床试验报告称，与较年轻的患者相比，接受治疗的青少年和年轻成人（AYA）患者在T细胞急性淋巴细胞白血病（T - ALL）方面无病生存期（DFS）和总生存期（OS）更低，且毒性增加。在此报告了在两项儿童肿瘤学组（COG）国际3期T - ALL试验中AYA队列的治疗结果。 患者与方法 AALL0434纳入了1562名T - ALL患者（2007 - 2014年），AALL1231纳入了615名T - ALL患者（2014 - 2019年），这些患者均接受强化的柏林 - 法兰克福 - 蒙斯特（ABFM）方案治疗。AYA患者定义为年龄≥16岁（AALL0434：n = 226；AALL1231：n = 107）。两项研究均允许招募年龄至31岁的患者。 在AALL0434试验中，参与者被随机分配接受无亚叶酸钙解救的递增剂量甲氨蝶呤（CMTX）+培门冬酶或高剂量甲氨蝶呤（HDMTX）+亚叶酸钙解救。中危和高危患者被随机分配接受或不接受6个疗程、每个疗程5天的奈拉滨（Nel）治疗。AYA与非AYA患者的风险组分配情况见表1。在AALL1231试验中，参与者被随机分配在诱导期和延迟强化期接受或不接受硼替佐米治疗。 AALL0434和AALL1231的ABFM方案主要差异包括：AALL0434在诱导期使用泼尼松，而AALL1231使用地塞米松；AALL0434的大多数参与者接受颅脑放射治疗，而AALL1231仅在中枢神经系统受累的患者中使用。 结果 在AALL0434试验中，AYA患者的4年无病生存率为81%，而＜16岁患者为84%（P = 0.5965），总生存率分别为88%和90%（P = 0.3478）。被随机分配到CMTX组（n = 70）的AYA患者无病生存率优于被随机分配到HDMTX组（n = 72）的患者，4年无病生存率分别为96%和78%（P = 0.0038）。接受奈拉滨治疗的AYA患者与未接受者相比，未显示出劣势，4年无病生存率分别为85%和89%（N = 54）（P = 0.8116），尽管样本量较小。在AALL1231试验中，AYA患者（n = 107）的4年无事件生存率为82.7±3.9%，而非AYA患者（n = 508）为82.2±1.7%（P = 0.727），总生存率分别为86.5±3.5%和88.4±1.5%（P = 0.553）。被随机分配接受/不接受硼替佐米治疗的AYA患者在治疗结果上没有差异。 AALL0434和AALL1231的综合结果数据显示，AYA患者（n = 333）的4年无事件生存率为82.2 + 2.4%，而非AYA患者（n = 1844）为83.9 + 0.9%（P = 0.52）（图1），总生存率分别为87.5 + 2.1%和90 + 0.8%（P = 0.19）。 AALL0434中患者特征的显著差异在于AYA患者初始白细胞计数更高（P = 0.0004）且风险组类别更高（P = 0.0002）。在AALL0434中，AYA队列与较年轻患者在中枢神经系统疾病状态、种族、民族、诱导期末缓解状态或诱导期第29天结束时的微小残留病（MRD）方面没有显著差异。 除了AALL0434中的上呼吸道感染（9.4%对1.8%；P = 0.0001）和骨坏死（4.8%对17.7%；P＜0.0001）外，非AYA患者与AYA患者的毒性发生率没有显著差异。在AALL0434中，AYA患者和较年轻患者在败血症、导管相关感染和其他感染的发生率方面没有显著差异。 AALL1231中患者特征和毒性发生率的分析以及AALL0434和AALL1231综合毒性数据的分析目前正在进行中，并将在会议上展示。 结论 儿童肿瘤学组的AALL0434和AALL1231试验显示AYA患者总体治疗结果良好，在两项研究中AYA患者和非AYA患者的生存期没有显著差异，尽管ABFM方案存在差异且AALL0434中AYA组存在更高风险特征。在AALL0434中，AYA和非AYA研究参与者的治疗相关毒性发生情况相似。尽管数量较少，但CMTX对AYA T - ALL患者具有生存优势，接受Nel的AYA T - ALL患者未显示出生存劣势。硼替佐米对AYA T - ALL患者没有显著益处。