Measuring DNA-TGN May Help Determine Whether Patients With ALL Receive Sufficient Maintenance Therapy Intensity

Author’s Perspective

Study co-author Kjeld Schmiegelow, MD: “Maintenance-treatment intensity may be difficult to monitor by blood counts due to their large intra-individual variations. DNA-TGN seems to be a novel alternative parameter that furthermore benefits from blood samples being transportable due to the stability of DNA-TGN. This population-based study demonstrates a strong association between DNA-TGN and relapse rate. Patients with low DNA-TGN on conventional 6-mercaptopurine and methotrexate maintenance therapy can increase their DNA-TGN by a different treatment approach (this research is ongoing) in order to reduce relapse rates.”

To prevent disease relapse in pediatric patients with acute lymphocytic leukemia (ALL), most patients receive maintenance therapy with 6-mercaptopurine and methotrexate, with dosing typically adjusted based on patients’ white blood cell counts. However, because these measurements can be confounded by age, ethnicity, and other variables, therapeutic drug monitoring by measurement of relevant cytotoxic metabolites could be a more useful approach for tailoring maintenance therapy in this patient population.

In a substudy of the phase III NOPHO (Nordic Society of Pediatric Hematology and Oncology) ALL2008 trial, Stine Nygaard Nielsen, MD, from the Department of Pediatrics and Adolescent Medicine at the University Hospital, Rigshospitalet in Copenhagen, Denmark, and co-authors assessed whether DNA-incorporated thioguanine nucleotide (DNA-TGN) concentrations in blood leukocytes during maintenance therapy were associated with relapse-free survival (RFS) (primary endpoint). Their results, published in the Lancet Oncology, suggest that adjusting dosing to maintain higher DNA-TGN levels could reduce relapse frequency.

The NOPHO ALL2008 study enrolled pediatric patients from 23 hospitals across Nordic and Baltic countries between November 26, 2008, and June 14, 2016, who had been diagnosed with non–high-risk precursor B- or T-cell leukemia. This substudy included 918 patients (median age = 4.2 years, range = 2.9-7.3 years) who reached maintenance therapy in first remission and had at least one DNA-TGN measurement available.

Maintenance therapy consisted of mercaptopurine 75 mg/m2 once-daily and methotrexate 20 mg/m2 once-weekly (doses were adjusted by a target white blood cell count of 1.5-3.0×109 cells/L).

Five patients died during first remission, nine patients developed a secondary cancer, and 40 patients relapsed after a median of 956 days (range = 2,271-1,722 days) after diagnosis.

After a median follow-up of 4.6 years (range = 3.1-6.1 years), the five-year RFS was 92.4 percent (95% CI 90.4-94.5). The researchers found that RFS was significantly associated with DNA-TGN concentration (hazard ratio [HR] = 0.81 per 100 fmol/μg DNA increase; 95% CI 0.67-0.98; p=0.029). By contrast, RFS was not significantly associated with erythrocyte TGN, erythrocyte methotrexate, or erythrocyte methylated mercaptopurine metabolite levels.

RFS also was associated with age at diagnosis (HR=1.11; 95% CI 1.04-1.19; p=0.0023) and female sex, though this did not reach statistical significance (HR=0.94; 95% CI 0.50-1.75; p=0.84) but not white blood cell count at diagnosis (HR=1.02; 95% CI 1.00-1.05; p=0.093).

The investigators performed a subgroup analysis of the 526 patients who were minimal residual disease (MRD) positive on day 29. Thirty-one of those patients had disease relapse, but the authors observed a significant association between DNA-TGN and relapse-free survival in the MRD-positive population (adjusted HR=0.72 per 100 fmol/μg increase in DNA-TGN; 95% CI 0·57−0·91; p=0.007).

“Our study supports DNA-TGN as a new therapeutic drug monitoring marker both as an endpoint for the interactions between upstream 6-mercaptopurine and methotrexate metabolites and, more importantly, for the risk of relapse,” the authors concluded.

The study is limited by its design as a cohort sub-study. A prospective, randomized trial is needed to confirm these results.

The authors reported no conflicts of interest.

Source: Nielsen SN, Grell K, Nersting J, et al. DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial. Lancet Oncol. 2017;18:515-24.