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Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Current treatments result in continued complete remission in over 80% of patients, however up to 20% relapse due to small numbers of surviving cells. Measurement of this minimal residual disease (MRD) at day 33 and day 79 is used in a current clinical trial, Australian and New Zealand Children’s Haematology/Oncology Group (ANZCHOG) Study 8 to decide patient treatment risk group. The level of MRD in a remission sample is defined as the amount of amplifiable gene rearrangement relative to the patient’s diagnosis sample. The hypothesis tested in this study was that MRD level at day 15 is also prognostic of patient outcome. MRD was measured by real-time quantitative PCR detection of immunoglobulin and T-cell receptor gene rearrangements in bone marrow DNA at day 15 from 211 paediatric patients at two hospitals and analysed according to EuroMRD guidelines.
Day 15 MRD was highly prognostic of outcome (event-free-survival; EFS) at several thresholds especially at 1x10-2. About 61% of patients (28/46) who relapse have day 15 MRD greater than 1x10-2 and around 44% of patients with MRD above this threshold relapsed or had other events. Even after the exclusion of high risk patients, day 15 MRD was still prognostic of outcome (P=0.0001). It was also able to separate patients into three groups with different prognoses: patients with high MRD (≥1x10-2), lower MRD (<1x10-2) and no detectable MRD with 5-year EFS rate of 57%, 82% and 93% respectively. When day 15 MRD was assessed together with Study 8 risk group and NCI risk group in a multivariate risk analysis, day 15 MRD and NCI risk group retained significance, demonstrating the independent predictive value of day 15 MRD. Both high MRD at day 15 and high NCI risk groups were associated with two-fold increase of relative risk of events.
In a Cox multivariate analysis of day 15, 33 and 79 MRD, MRD at day 15 retained significance in predicting subsequent relapse and other events (P=0.0122). Patients with high MRD at both day 15 and day 33 appeared to be at highest risk, and
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the combination (day 15 MRD ≥1x10-2 and day 33 MRD ≥1x10-3) could be used for patient stratification. Patients with undetectable MRD at day 15 could be considered for reduced chemotherapy.
The use of a second marker in 37 relapsed patients provided additional useful information for 5 patients. Although limited by small numbers, these findings are consistent with earlier studies which concluded that a second marker is important in ensuring reliable and accurate MRD assessment for patient stratification.
It is clear that MRD at day 15 of therapy is predictive of outcome in ALL patients treated on a current Australian MRD intervention protocol. It could be used to identify additional patients at high risk of relapse; and therefore it is suggested that MRD at day 15 should be evaluated for all patients in future clinical trials. Earlier tailoring of treatments to best suit different risk groups could lead to further improvements in morbidity and mortality for ALL patients.