Ten Year Outcomes of UKALL 2003: A Randomised Clinical Trial of Adjusting Treatment Intensity Based on Minimal Residual Disease

The UKALL 2003 trial aimed to safely reduce treatment intensity in low-risk patients and intensify therapy in high-risk patients based on minimal residual disease (MRD) stratification. The MRD risk patients were randomly assigned to standard (Regimen A/B) or augmented (Regimen C) post remission therapy, whilst the MRD low risk patients were randomly allocated to receive one or a standard two delayed intensifications (DI). In the original analysis, the five-year event free survival in the MRD risk patients was superior in the augmented group whilst in the MRD low risk group there was no significant difference between one or two delayed intensifications. As late relapses may influence these results, particularly in the low-risk patients, we analysed ten-year outcomes for patients in the trial overall and by the randomisations.

There were a total of a total of 3113 eligible patients for analysis. The median follow up time was 9.4 years. In the overall trial population, 10-year relapse risk was 10.7 % (95%CI 9.6-11.92 %), with a 10-year event free survival (EFS) of 84.8 % (95 % CI 83.5-86.1 %) and overall survival (OS) of 89.6% (95%CI 88.4-90.6%). There was a higher risk of relapse on univariate and multivariate cox analysis with male gender, increasing age, increasing white cell count, MRD (high vs low), NCI Risk Group (High vs standard) and immunophenotype (T vs B cell). All except gender were also significant on univariate and multivariate analysis for event free and overall survival. Cytogenetic high risk patients treated on regimen C had a lower 10 year relapse risk (22.1 % (95% CI 15.1-31.6) compared to those who remained on regimen A/B (52.4 % (95% CI 28.9-80.1, p=0.016), although the OS rates were not significantly different (75.3 % (95% CI 65.8-82.5) vs 66.7 % (95%CI 37.5-84.6), p=0.3). The ten year cumulative incidence of second tumours was 1.16 %( 95 % CI 0.74-1.82).

521 MRD low risk patients were randomised (260 assigned to one delayed intensification and 261 to two delayed intensifications). The 10-year EFS was 91.7 % (95% CI 85.7-94.0) with one course of delayed intensification vs 93.7 % (95% CI 90.0-96.1) with two delayed intensifications (adjusted hazard ratio 0.73, (95% CI 0.38-1.40) p=0.3). The 10-year overall survival was 97.1 % (95 % CI 94.0-98.6) with one delayed intensification and 97.6 % (95 % CI 94.7-98.9) with two delayed intensifications (adjusted hazard ratio 0.69 % (95 % CI 0.24-1.99) P=0.5.

533 MRD high risk patients were randomised (266 assigned standard therapy and 267 assigned to augmented therapy). The 10-year EFS (was 82.1% (95 % CI 76.9-86.2) with standard therapy vs 87.1 % (95 % CI 82.4-90.6) with augmented therapy (adjusted hazard ratio 0.68 (95 % CI 0.44-1.06) p=0.09). The 10-year OS was 87.9 % (95% CI 83.2-91.4) with standard therapy vs 90.7 % (95 % CI 86.4-93.7) (adjusted hazard ratio 0.74(95%CI 0.44-1.27) p=0.3. The loss of significance in EFS between 5 and 10 years was due to additional relapses since the original publication, in the augmented arm. Nevertheless, there remained a benefit for augmented therapy in reducing marrow relapses: cumulative incidence of marrow relapse was 10.4% (95% CI 7.2-14.9) in standard arm vs 5.9% (95% CI 3.6-9.6) (adjusted hazard ratio 0.55 (0.28-1.03) p=0.06.

Long term outcome of UKALL 2003 confirms that low risk patients can safely de-escalate therapy and intensified therapy benefits high risk patients, especially those with high-risk cytogenetics.