ASCO 2012：儿童方案治疗AYA白血病患者

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ASCO 2012：儿童方案治疗AYA白血病患者
       美国临床肿瘤学会(ASCO)年会报告的一项临床试验表明，青少年和年轻成人(AYA)白血病患者接受儿童方案治疗，可改善５年无事件生存率，但疗效仍不及儿童患者。

       在这项由儿童肿瘤协作组完成的随机III期试验中，研究者入组2,571例最大年龄为30岁的AYA患者，以比较高危B-前体细胞急性淋巴细胞性白血病(ALL)治疗方案效果。其中，501例患者年龄≥16岁。既往经验表明，该年龄组患者预后劣于儿童患者。

       主要作者、缅因州儿童癌症项目医学主任、儿童肿瘤协作组AALL0232方案研究主席Eric Larsen博士报告的结果表明， AYA患者5年无事件生存率为68%，高于既往试验的50%~60%，但低于儿童患者的80%(P<0.0001)；AYA患者总生存率(79.8% vs. 88.4%，P<0.0001)和缓解率(97.2% vs. 98.8%，P=0.0134)也相对较低，后者定义为诱导治疗后骨髓原始细胞<5%。研究者认为该差异很大程度上是由于AYA患者骨髓复发率较高(15.2% vs. 9.0%，P<0.0007)。虽然AYA患者CNS复发率略高(5.2% vs. 3.7%)，但差异并不显著(P=0.5776)。

       此外，AYA患者复发率高于儿童，5年累计复发率为21.3% vs. 13.4%(P=0.0018)。尽管诱导治疗死亡率AYA和儿童无显著差异(2.4% vs. 1.8%， P=0.36)，但诱导缓解后5年死亡率显著高于儿童(5.5% vs. 2.1%，P<0.0001)。5年后，两个年龄组生存曲线趋于平稳，但仍见缓解，这也凸显了参考指标的重要性。Larsen博士指出：“在临床实践和研究领域，我们从不声称某患者真正治愈，但生存超过5年后，患者复发的可能性非常小。”

       Larsen博士在去年年会上曾报告该试验结果，发现给予患者50倍标准剂量的甲氨蝶呤可降低复发率。他指出，该研究是首个入组30岁患者的儿童ALL试验。通常，儿童研究入组患者年龄最高为18岁，但研究者希望AYA患者接受更为积极的儿童治疗方案可以改善预后。

       会议主持人、纽约斯隆-凯特林癌症纪念中心妇科肿瘤医学中心主任Carol Aghajanian博士评论称：“这是一个有待研究的领域。我的确见过年轻成人患有儿科肿瘤，该把他们作为典型成人还是作为儿童加以治疗呢？我们需要确认该类患者并对其疾病进行生物学研究，以便明确合适的治疗方案。”

       Larsen博士总结指出，上述分析结果提示，要想改善AYA ALL患者预后，应更好地控制疾病进展和降低药物毒性。AYA患者更易耐药，且对副作用也更敏感。AYA患者预后不佳可能与多种因素有关，包括疾病生物学差异导致癌症更具侵袭性和对化疗副作用耐受性较差。此外，还可能包括社会经济因素，因为AYA患者通常为大学生或正在求职者。依从性不好也是预后不佳的一个因素。尽管父母负责儿童口服用药，但青少年有时希望自己服药，结果却并不理想。

原文摘要
Outcome in adolescent and young ** (AYA) patients compared with younger patients treated for high-risk B-precursor acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group study AALL0232.


Background: Historically, AYA patients (>16yrs of age) with HR-ALL have an inferior outcome compared to HR-ALL patients 1-15 yrs old, due to increased rates of both relapse and toxicity.

Methods: AALL0232 was a phase III randomized trial for patients 1-30 years of age with newly diagnosed B-precursor HR-ALL that utilized a 2 x 2 factorial design with an augmented intensity Berlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to receive dexamethasone versus prednisone during Induction and high dose methotrexate versus escalating Capizzi methotrexate during Interim Maintenance I. A total of 2,574 eligible, evaluable, non-Down Syndrome, non-very high risk patients were randomized between January 2004 and January 2011. AYA patients comprised 20% of this group (n=501; 16-21 yrs: 466 and 22-30 yrs: 35).

Results: The 5-yr event-free survival (EFS) and overall survival (OS) rates were 68.0% and 79.8% for AYA patients compared to 80.9% and 88.4% for younger patients (p<0.0001). The 5-yr cumulative incidence of relapse was 21.3% for AYA patients and 13.4% for younger patients (p=0.0018), largely due to higher rate of marrow relapse (15.2% vs. 9.0%; p<0.0007) and not CNS relapse (5.2% vs. 3.7%; p=0.5776). In addition, fewer AYA patients achieved remission, defined as <5% marrow blasts at end induction (97.2% vs. 98.8%; p=0.0134). There was no significant difference in induction mortality between AYA and younger patients, 2.4% vs. 1.8% (p=0.36). However post-induction remission deaths were significantly higher in AYA compared with younger patients, 5.5% vs. 2.1% at 5 years (p<0.0001).

Conclusions: This is the largest cohort of AYA ALL patients presented to date and confirms high cure rates for AYA patients treated on pediatric ALL trials. AYA HR-ALL patients had lower EFS and OS compared to younger patients, primarily attributable to both higher rates of marrow relapses and remission deaths. Effective strategies to improve the outcome of AYA patients with HR-ALL should be aimed at both furthering leukemia eradication and lowering toxicity of therapy for this patient population.