Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

Abstract

Myelotoxicity during thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme thiopurine methyltransferase (TPMT) and thus more thiopurine converted into 6-thioguanine nucleotides. Of 601 children with acute lymphoblastic leukemia (ALL) who were treated by the NOPHO ALL-92 protocol, 117 had TPMT genotype determined, whereas for 484 patients only erythrocyte TPMT activity was available. The latter were classified as heterozygous, if TPMT activity was <14 IU/ml, or deficient (<1.0 IU/ml). 526 patients had TPMT wild type, 73 were presumed heterozygous, and two were TPMT deficient. Risk of relapse was higher for the 526 TPMT wild type patients than for the remaining 75 patients (18 vs 7%, P=0.03). In Cox multivariate regression analysis, sex (male worse; P=0.06), age (higher age worse, P=0.02), and TPMT activity (wild type worse; P=0.02) were related to risk of relapse. Despite a lower probability of relapse, patients in the low TPMT activity group did not have superior survival (P=0.82), possibly because of an excess of secondary cancers among these 75 patients (P=0.07). These data suggest that children with ALL and TPMT wild type might have their cure rate improved, if the pharmacokinetics/-dynamics of TPMT low-activity patients could be mimicked without a concurrent excessive risk of second cancers.

Figures

Figure 1

Treatment elements of standard (SR), intermediate (IR), and high risk (HR) ALL according to the NOPHO ALL-92 protocol (see also the text). =oral prednisolone (60 mg/m2/day). v & V=vincristine (2.0 mg/m2). A=doxorubicin (40 mg/m2 i.v.), =Erwinia asparaginase (30 000 IU/m2 per day for 10 days). o=intrathecal MTX by age. M=high-dose MTX (5 g/m2/24 h or 8 g/m2 (HR only)). V/P=vincristine (2.0 mg/m2 × 1)/prednisolone (60 mg/m2/day for 7 days) reinductions. MTX 20 mg/m2/week. 6MP 75 mg/m2/day. c=cyclophosphamide (1 g/m2 i.v.). Low-dose AraC (75 mg/m2). 6MP or 6TG 60 mg/m2/day. U=daunorubicin (30 mg/m2), =Erwinia asparaginase (30.000 IU/m2 two times weekly for 2 weeks). HC=high dose AraC (2 g/m2 two times daily for 3 days). v/p=vincristine (2.0 mg/m2 × 1)/prednisolone (40 mg/m2/day for 7 days) reinductions without or with (/m) methotrexate i.t. in age-adjusted doses.

Figure 2

Risk of relapse with respect to the TPMT activity. Lower curve: TPMT low-activity patients (TPMT heterozygous (N=73) or TPMT deficient (N=2), relapse risk: 7±3%). Upper curve: TPMT wild-type patients (N=526, relapse risk: 18±2%); P=0.03.

Figure 3

Risk of relapse with respect to the TPMT activity and the average absolute neutrophil counts (ANC) during maintenance therapy. The median for all patients is 1.96 × 109/l. (a) TPMT wild type and ANC ≥1.96 × 109/l, relapse risk: 23±3%; (b) TPMT wild type and ANC <1.96 × 109/l, relapse risk: 13±2%; (c) TPMT low activity and ANC ≥1.96 × 109/l, relapse risk: 9±6%; (d) TPMT low activity and ANC <1.96 × 109/l, relapse risk: 6±4%; P=0.001 (trend analysis, log-rank Mantel–Cox linear trend analysis).