Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology.
OBJECTIVE
During maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), the cytotoxic metabolites of methotrexate (MTX polyglutamates) and mercaptopurine (6MP) (thioguanine nucleotides [6TGN]) accumulate intracellularly, including in erythrocytes (E-MTX and E-6TGN) with large interindividual variations. In the present Nordic Society for Pediatric Hematology and Oncology (NOPHO) study, the relation of E-MTX and E-6TGN to relapse risk was explored.


METHODS
Two hundred ninety-seven patients with non-B-cell ALL, aged 1 to 14 years, on oral MTX and 6MP had E-MTX and E-6TGN levels measured three to 35 (median, eight) and three to 75 (median, nine) times, respectively. For each patient, a mean of all E-MTX (mE-MTX) and E-6TGN (mE-6TGN) measurements was calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX-6TGN), since MTX and 6MP may have synergistic action.


RESULTS
For patients in remission, the median mE-MTX and mE-6TGN values were 4.7 nmol/mmol hemoglobin (Hgb) (range, 0.4 to 10.3) and 173 nmol/mmol Hgb (range, 58 to 846). With a median follow-up duration of 66 months for patients in remission, 64 patients relapsed. Cox regression analysis identified mE-MTX-6TGN and sex to be the most significant parameters to predict relapse (global P = .001). Factors that predicted a better prognosis were high mE-MTX 6TGN and female sex. Patients who had a mE-MTX-6TGN less than the product of the median mE-MTX and median mE-6TGN (813 [nmol/mmol Hgb]2) had a significantly poorer event-free survival (EFS) than did patients with higher values (5-year probability of EFS [pEFS5y], 0.70 v 0.86; P = .001).


CONCLUSIONS
The pharmacokinetics of MTX and 6MP may have significant influence on the risk of relapse. The value of dose adjustments by E-MTX and E-6TGN remains to be determined.
Schmiegelow
K
K
Nordic Society for Pediatric Hematology and Oncology, Copenhagen.
Schrøder
H
H
Gustafsson
G
G
Kristinsson
J
J
Glomstein
A
A
Salmi
T
T
Wranne
L
L
D000284:Administration, Oral; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000378:metabolism*; D008727:Methotrexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000097:blood; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D011379:Prognosis; D012008:Recurrence; D012044:Regression Analysis; D012074:Remission Induction; D012306:Risk; D013873:Thionucleotides / Q000097:blood*; D013997:Time Factors
D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D015122:Mercaptopurine; D008727:Methotrexate