[Tolerability of 6-mercaptopurine in children with acute lymphoblastic leukemia].
OBJECTIVE
6-Mercaptopurine (6-MP) has been the backbone of maintenance chemotherapy for acute lymphoblastic leukemia (ALL), the response to 6-MP is highly variable, adverse events leading to discontinuation or dose-reduction (children intolerant) of 6-MP occur in many children with ALL. The aim of this study was to investigate the tolerability of 6-MP and to optimize thiopurine use.


METHODS
The authors evaluated in a prospective manner the tolerance of 6-MP in ALL children from Oct. 1, 2004 to Sept. 30, 2007 who were newly diagnosed in Beijing Children's Hospital, using BCH-ALL-2003 protocols, during the maintenance therapy and followed up to Sept. 30, 2008. All children had a treatment period of at least 3 months for maintenance therapy.


RESULTS
Totally 133 children including 81 boys and 52 girls at median age of 67 months (18 - 188 months), 100% of the patients went into complete remission (CR) on day 33 of induction chemotherapy, and the median time to CR was 26 months (6 - 47 months). All the children had maintenance therapy from 3 to 25 months (mean 13.5 +/- 7.4) and 72(54%) received 6-MP standard doses continuously for total courses, the median daily dose of 6-MP was 46 mg/(m(2).d) 6-MP, their WBC was (3 - 4) x 10(9)/L, ANC (1.5 - 2) x 10(9)/L, they had no severe liver toxicity. In 4 children the dose of 6-MP was increased to 125% because WBC was higher than 6 x 10(9)/L, ANC higher than 3 x 10(9)/L. Sixty one children (46%) had poor tolerability to 6-MP, they experienced adverse events that led to discontinuation (n = 19) or dose reduction (n = 42) of 6-MP, the actual mean dose for the 42 cases was 25 - 30 mg/(m(2).d) and the time to occurrence of toxic effects was 2.5 weeks. Reasons for discontinuation or dose reduction were severe myelotoxicity occurred in 48 children, hepatotoxicity in 12, and skin rash in one.


CONCLUSIONS
In this cohort of ALL children, the difference of tolerance to oral 6-MP was obvious, 54% of the children well tolerated 6-MP during the whole course at oral standard dose, and severe granulocytopenia did not occur. However, 46% developed severe granulopenia or hepatotoxicity, the dosage had to be reduced in order to decrease the probability of severe toxicity. It is suggested that standard dose of 6-MP is not always the maximum tolerant dose in some children and inadequate dose may be the cause of therapy failure.
Ma
Xiao-li
XL
Hematology Center, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.
Wang
Bin
B
Guo
Hai-ying
HY
Zhang
Yong-hong
YH
Zhu
Guang-hua
GH
Duan
Yan-long
YL
Yang
Jing
J
Zhang
Da-wei
DW
Jin
Ling
L
Zhang
Rui
R
Zhang
Li
L
Xie
Jin
J
Wu
Min-yuan
MY
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011446:Prospective Studies
D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine