Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia.

Abstract

Developing optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized, phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m(2) in Philadelphia-negative B- and T-cell disease, respectively. The primary study objective was the comparative assessment of the risk/benefit ratio, combining the analysis of feasibility, toxicity and efficacy. In the liposomal cytarabine arm 17/71 patients (24%) developed grade 3-4 neurotoxicity compared to 2/74 (3%) in the triple therapy arm (P=0.0002), the median number of episodes of neurotoxicity of any grade was one per patient compared to zero, respectively (P=0.0001), and even though no permanent disabilities or deaths were registered, four patients (6%) discontinued intrathecal prophylaxis on account of these toxic side effects (P=0.06). Neurotoxicity worsened with liposomal cytarabine every 14 days (T-cell disease), and was improved by the adjunct of intrathecal dexamethasone. Two patients in the liposomal cytarabine arm suffered from a meningeal relapse (none with T-cell disease, only one after high-dose chemotherapy) compared to four in the triple therapy arm (1 with T-cell disease). While intrathecal liposomal cytarabine could contribute to improved, radiation-free central nervous system prophylaxis, the toxicity reported in this trial does not support its use at 50 mg and prompts the investigation of a lower dosage. (clinicaltrials.gov identifier: NCT-00795756).

• Authors: Renato Bassan, Arianna Masciulli, Tamara Intermesoli, Ernesta Audisio, Giuseppe Rossi, Enrico Maria Pogliani, Vincenzo Cassibba, Daniele Mattei, Claudio Romani, Agostino Cortelezzi, Consuelo Corti, Anna Maria Scattolin, Orietta Spinelli, Manuela Tosi, Margherita Parolini, Filippo Marmont, Erika Borlenghi, Monica Fumagalli, Sergio Cortelazzo, Andrea Gallamini, Rosa Maria Marfisi, Elena Oldani, Alessandro Rambaldi
• Journal: Haematologica (Haematologica) Vol. 100 Issue 6 Pg. 786-93 (Jun 2015) ISSN: 1592-8721 [Electronic] Italy
• PMID: 25749825 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Ferrata Storti Foundation.

Chemical References

• Antimetabolites, Antineoplastic
• Liposomes
• Cytarabine

Topics

• Adolescent
• Adult
• Aged
• Antimetabolites, Antineoplastic (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Cytarabine (administration & dosage)
• Female
• Humans
• Injections, Spinal
• Liposomes
• Male
• Middle Aged
• Pilot Projects
• Post-Exposure Prophylaxis (methods)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (diagnosis, drug therapy)
• Young Adult