Risk of Second Malignant Neoplasm Is Related to TPMT Activity and Duration of MTX/6MP Maintenance Therapy of ALL.
Authors: Schmiegelow Kjeld , Al-Modhawi Ibrahim , Berendtz Mikael , Forestier Erik , Hasle Henrik , Heyman Mats , Kristinsson Jon , Nygaard Randi , Vettenranta Kim 
Published: October 2019

Abstract
Risk of SMN has been linked to irradiation, alkylating agents, and topo-II inhibitors with less attention to factors that may interfere with repair of treatment induced DNA damage. Due to mutations, 10% of children with ALL have low thiopurine methyl transferase (TPMT) activity with low 6-mercaptopurine (6MP) and -metabolite methylation and increased intracellular levels of cytotoxic 6-thioguanine nucleotides, which could affect DNA-repair. 1703 Nordic children 1.0–14.9y were diagnosed with ALL 1/92–10/01. 1617 were treated by the NOPHO 92 protocol, obtained CR1 after induction therapy, and were then treated by risk group based on WBC and age (standard risk (SR): 2.0–9.9y and WBC <10; intermediate risk (IR): 1.0–1.9y or ≥10.0y and/or WBC 10–49.9) and presence of high (HR) or very high risk (VHR) features: WBC ≥50.0, T-ALL, CNS or testicular disease, t(9;22), t(4;11), M3 d15 or M2/M3 d29. VHR included pts with certain HR features and age >5y (due to RTx). During CR1, 121 non-SCT pts received CNS RTx and 53 received a SCT. After multidrug induction/consolidation therapy (Gustafsson Leukemia 2000) oral 6MP (75mg/m2)/MTX (20mg/m2/w) maintenance therapy was given to SR, IR and HR pts from weeks 13, 32, and 63. VHR pts received LSA2L2 maintenance from week 48. TPMT status was available for 603 patients. 528 were classified as wild type (WT), 72 as heterozygous, 3 as deficient. The pEFS10y of the 1617 pts was 0.75. Thirty-four pts died in CR1. 330 relapsed. Eighteen patients developed SMN (3 after SCT in CR1) 10–98 months (median 40) from Dx, and 11 of these died. Eleven of the 15 SMNs in the 1564 non-SCT pts occurred in the SR-group. In multivariate analysis, the risk of SMN was significantly related to the duration of maintenance therapy (highest in SR-ALL, p=0.01) and to low TPMT-activity (p=0.003), but not to sex, age or WBC at Dx, immunophenotype (B- vs T-lineage), or CNS RTx. Four of 75 TPMT low activity pts developed SMN vs 3 of 528 TPMT wild type pts (5% vs 1% risk, p<0.001). In contrast, the 10y risk of relapse was significantly higher for the TPMT wild type pts (18% vs 8% at 10y, p<0.05). The excessive risk of SMN in pts who received the least chemo-/radio-intensive induction and consolidation therapy (SR) indicates that their longer duration of MTX/6MP maintenance therapy may have increased their risk for SMN through DNA-damage or interference with DNA-repair, not least for the pts that carry TPMT-mutations.
Treatment and occurrence of SMN SR IR HR VHR *each represent a patient with an SMN after SCT in CR1; NA=not applicable No of patients 554 586 292 167 Anthracycline (mg/m.sq.) 120 240 240 360 Cyclophosphamide (mg/m.sq.) 0 3000 3000 6000 Prophylactic CNS RTx No No No Yes Total duration of Tx 2.5y 2.0y 2.0y 2.0y Duration of MTX/6MP (weeks) 117 72 41 0 AML/MDS/other 6/5/0 1/1/1 2*/0/1* 0/0/1* TPMT (WT/low) 248/27 221/36 53/12 6/0 SMN TPMT (WT/low) 3/2 0/1 0/1 0/NA