Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia.
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).
U.O.C. Ematologia, Ospedale dell'Angelo e Ospedale SS. Giovanni e Paolo, Mestre-Venezia renato.bassan@ulss12.ve.it.
Renato
R
Bassan
Laboratorio di Epidemiologia Clinica delle Malattie Cardiovascolari, Fondazione Mario Negri Sud, S.Maria Imbaro, Chieti.
Arianna
A
Masciulli
U. O. C. Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo.
Tamara
T
Intermesoli
Ematologia 2, Presidio Ospedaliero Molinette, A.O.U. Città della Salute e della Scienza, Torino.
Ernesta
E
Audisio
Divisione di Ematologia, Spedali Civili, Brescia.
Giuseppe
G
Rossi
U.O. di Ematologia e TMO, Ospedale S.Gerardo, Monza Brianza.
Enrico Maria
EM
Pogliani
Divisione di Ematologia e TMO, Ospedale S. Maurizio, Bolzano.
Vincenzo
V
Cassibba
S.C. Ematologia, Azienda Ospedaliera S. Croce e Carle, Cuneo.
Daniele
D
Mattei
U.O. Ematologia e Centro TMO, Ospedale Armando Businco, Cagliari.
Claudio
C
Romani
U.O. Ematologia e TMO, Fondazione IRCSS Cà Granda, Ospedale Maggiore Policlinico, Milano.
Agostino
A
Cortelezzi
Ematologia e TMO, Ospedale S. Raffaele, Milano, Italy.
Consuelo
C
Corti
U.O.C. Ematologia, Ospedale dell'Angelo e Ospedale SS. Giovanni e Paolo, Mestre-Venezia.
Anna Maria
AM
Scattolin
U. O. C. Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo.
Orietta
O
Spinelli
U. O. C. Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo.
Manuela
M
Tosi
U. O. C. Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo.
Margherita
M
Parolini
Ematologia 2, Presidio Ospedaliero Molinette, A.O.U. Città della Salute e della Scienza, Torino.
Filippo
F
Marmont
Divisione di Ematologia, Spedali Civili, Brescia.
Erika
E
Borlenghi
U.O. di Ematologia e TMO, Ospedale S.Gerardo, Monza Brianza.
Monica
M
Fumagalli
Divisione di Ematologia e TMO, Ospedale S. Maurizio, Bolzano.
Sergio
S
Cortelazzo
S.C. Ematologia, Azienda Ospedaliera S. Croce e Carle, Cuneo.
Andrea
A
Gallamini
Laboratorio di Epidemiologia Clinica delle Malattie Cardiovascolari, Fondazione Mario Negri Sud, S.Maria Imbaro, Chieti.
Rosa Maria
RM
Marfisi
U. O. C. Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo.
Elena
E
Oldani
U. O. C. Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo.
Alessandro
A
Rambaldi
D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003561:Cytarabine / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D056990:Post-Exposure Prophylaxis / Q000379:methods*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000188:drug therapy*; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D003561:Cytarabine