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J Clin Oncol. 2018 Aug 20;36(24):2514-2523. doi: 10.1200/JCO.2017.76.8192. Epub 2018 Jun 4.

Intensified Therapy of Acute Lymphoblastic Leukemia in Adults: Report of the Randomized GRAALL-2005 Clinical Trial.

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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.


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.

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