Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-1942).
BACKGROUND
Although mercaptopurine (MP) is conventionally used to treat childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is a more potent thiopurine in vitro and, when administered orally to patients, achieves cytotoxic drug concentrations in the cerebrospinal fluid (CSF). We performed a pilot study incorporating oral and 24-hr continuous IV infusion (CIVI) TG in children with newly diagnosed standard-risk ALL.


METHODS
Children with newly diagnosed standard-risk ALL (age 1-10 years, WBC<50 k) were eligible. Multi-agent chemotherapy was patterned after the Children's Cancer Group (CCG) 105 trial, with the addition of CIVI-TG (480 mg/m2) during consolidation, interim maintenance and maintenance, and substitution of oral TG (60 mg/m2/day) for oral MP during maintenance.


RESULTS
Fifty-eight patients (31 female), median age 4.3 years, were enrolled. At 8 years, the relapse-free and overall survival probabilities were 83% and 88%. There were no CNS relapses. Six patients (five males) experienced reversible veno-occlusive disease (VOD) while receiving oral TG, and the study was amended to discontinue TG, changing all patients to oral MP. Red cell TG nucleotide concentrations during oral TG averaged 95 ng (570 pmol)/8x10(8) RBC, greater than concentrations reported with oral MP.


CONCLUSIONS
Although the absence of CNS relapses in this pilot study suggests that TG may contribute to the prevention of CNS recurrences, the development of VOD negatively impacts the risk:benefit ratio of substituting TG for MP.
Jacobs
Shana S
SS
Children's National Medical Center, Washington, District of Columbia, USA. jacobss@mail.nih.gov
Stork
Linda C
LC
Bostrom
Bruce C
BC
Hutchinson
Ray
R
Holcenberg
John
J
Reaman
Gregory H
GH
Erdmann
Gary
G
Franklin
Janet
J
Neglia
Joseph P
JP
Steinberg
Seth M
SM
Balis
Frank M
FM
Adamson
Peter C
PC
D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D010865:Pilot Projects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D016019:Survival Analysis; D013866:Thioguanine / Q000008:administration & dosage* / Q000009:adverse effects
D000964:Antimetabolites, Antineoplastic; D013866:Thioguanine