Françoise Huguet, Eric Delabesse, Institut Universitaire du Cancer, Toulouse; Sylvie Chevret, Nicolas Boissel, Hervé Dombret, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP); Université Paris Diderot; Agnès Buzyn, Vahid Asnafi, Elizabeth Macintyre, Hôpital Necker, AP-HP; Université Paris Descartes, Paris; Thibaut Leguay, Centre Hospitalier Universitaire, Pessac; Xavier Thomas, Véronique Lhéritier, Hôpital Lyon-Sud, Pierre Bénite; Martine Escoffre-Barbe, Centre Hospitalier Universitaire, Rennes; Patrice Chevallier, Marie C. Béné, Centre Hospitalier Universitaire, Nantes; Mathilde Hunault, Norbert Ifrah, Centre Hospitalier Universitaire, Angers; Norbert Vey, Institut Paoli-Calmettes, Marseille; Caroline Bonmati, Centre Hospitalier Universitaire, Nancy; Stéphane Lepretre, Centre Henri Becquerel, Rouen; Jean-Pierre Marolleau, Centre Hospitalier Universitaire, Amiens; Philippe Rousselot, Centre Hospitalier, Versailles; Jean-Yves Cahn, Centre Hospitalier Universitaire Grenoble-Alpes, La Tronche, France; Thomas Pabst, Inselspital; Swiss Group for Clinical Cancer Research, Bern; and Yves Chalandon, Swiss Group for Clinical Cancer Research, Bern; Hôpital Universitaire, Geneva, Switzerland.
J Clin Oncol. 2018 Aug 20;36(24):2514-2523. doi: 10.1200/JCO.2017.76.8192. Epub 2018 Jun 4.
Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.
评估在接受儿童启发式方案治疗的新诊断费城染色体阴性急性淋巴细胞白血病成人患者中，随机增加高剂量环磷酰胺（hyper-C）剂量强化的作用，并确定在这种情况下治疗耐受性的最高年龄限制。
共纳入 787 例可评估患者（B/T 谱系分别为 525 例和 262 例，中位年龄为 36.1 岁），他们在首次诱导和晚期强化期间随机接受标准剂量环磷酰胺或 hyper-C。通过潜在接受全计划剂量治疗的患者在每个治疗阶段实际接受的中位数剂量来评估化疗的依从性。
总体完全缓解（CR）率为 91.9%。中位随访 5.2 年后，5 年无事件生存（EFS）和总生存（OS）率分别为 52.2%（95%CI，48.5%至 55.7%）和 58.5%（95%CI，54.8%至 61.9%）。随机接受 hyper-C 治疗并未增加 CR 率或延长 EFS 或 OS。由于治疗耐受性较差，年龄的增加持续影响 CR 率、EFS 和 OS，55 岁是最佳年龄截止点。在 5 年时，年龄小于 55 岁的患者 EFS 为 55.7%（95%CI，51.8%至 59.4%），而年龄较大的患者为 25.8%（95%CI，19.9%至 35.6%）（危险比，2.16；P<0.001）。观察到对整个计划化疗的依从性较低的年龄≥55 岁的患者从 hyper-C 中获益显著，而年轻患者则没有。
在一线儿童样成人急性淋巴细胞白血病治疗中引入 hyper-C 方案并未带来显著获益。总体而言，年龄≥55 岁的患者对强化儿童衍生治疗的耐受性较差。
