Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01.
OBJECTIVE
We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL).


METHODS
Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m(2) fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m(2), adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations.


RESULTS
Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS.


CONCLUSIONS
There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.
Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, 02215, USA. lynda_vrooman@dfci.harvard.edu
Lynda M
LM
Vrooman
Kristen E
KE
Stevenson
Jeffrey G
JG
Supko
Jane
J
O'Brien
Suzanne E
SE
Dahlberg
Barbara L
BL
Asselin
Uma H
UH
Athale
Luis A
LA
Clavell
Kara M
KM
Kelly
Jeffery L
JL
Kutok
Caroline
C
Laverdière
Steven E
SE
Lipshultz
Bruno
B
Michon
Marshall
M
Schorin
Mary V
MV
Relling
Harvey J
HJ
Cohen
Donna S
DS
Neuberg
Stephen E
SE
Sallan
Lewis B
LB
Silverman
D000293:Adolescent; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000633:toxicity; D001215:Asparaginase / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage* / Q000633:toxicity; D018572:Disease-Free Survival; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D005500:Follow-Up Studies; D050723:Fractures, Bone / Q000139:chemically induced; D006801:Humans; D007223:Infant; D007239:Infections / Q000209:etiology; D008297:Male; D008991:Monitoring, Physiologic; D015999:Multivariate Analysis; D010020:Osteonecrosis / Q000139:chemically induced; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone; D001215:Asparaginase