Long Term Overall Survival of Greater Than 98% in Childhood ALL Patients with Good Risk Features and Low Risk MRD:Â Results from a Large Multi-Center Randomized Controlled Trial, UKALL 2003
Authors: Bartram Jack , O'Connor David , Enshaei Amir , Moorman Anthony V , Harrison Christine , Wade Rachel , Clack Rachel , Hancock Jeremy , Samarasinghe Sujith , Moppett John , Vora Ajay J. , Goulden Nicholas 
Published: October 2019

Background:
Overall survival (OS) for childhood ALL treated on contemporary protocols is now > 90%. For low risk patients the risk of treatment related mortality (TRM) is now similar to the risk of death due to disease relapse. The only way to improve TRM and morbidity in this group is to identify even lower risk patients and reduce therapy. We analysed outcomes for patients with low risk MRD at end of induction (EOI) therapy treated on UKALL 2003, to identify a very low risk group who could potentially benefit from protocols that further reduce TRM.
Methods:
UKALL 2003 trial recruited 3126 patients aged 1-25 years with Philadelphia-negative ALL between Oct 1, 2003, and June 30, 2011. Treatment was initially stratified based on NCI risk and cytogenetic results. Subsequent treatment was directed by MRD from bone marrow (BM) measured using EuroMRD approved real-time quantitative PCR method for immunoglobulin and T-cell receptor gene rearrangements at EOI therapy. Analysis was performed on the 2666 patients with available MRD results and focused on patients with low risk MRD combined with other patient characteristics - cytogenetic risk group, white cell count (WCC) and age to identify those subgroups with extremely good event free survival (EFS). Low risk MRD at EOI was defined a level <0.005%. Patients with MRD ≥ 0.005% were considered high risk. Good risk cytogenetics included the presence of ETV6-RUNX1 or high hyperdiploidy.
Results:
Overall 52% (n=1391) of patients had MRD < 0.005% with the remaining 48% (n=1275) of patients with MRD ≥ 0.005%. 5yr OS 97.6 (95% CI 96.6-98.3) vs. 89.1% (87.2-90.7, p<0.0001) and 5yr EFS 94.4 (93.1-95.6) vs. 83.6% (81.4-85.5, p<0.0001). 53% (n=1407) of the patients with MRD results available had good risk cytogenetics, of which 60% (n=843) had MRD<0.005%. This group (with low risk MRD and good risk cytogenetics) makes up 31.6% of the whole trial cohort and has 5yr EFS 96.0% (94.5-97.3) and 5yr OS 98.9% (97.9-99.4). The outcome was similar irrespective of NCI high risk features (i.e. WCC>50 / age>10yrs). Long term survival remained excellent with 10 year EFS 93.9% (OS 98.2%). There were 32 relapses in the low risk MRD/ good risk cytogenetics group (relapse sites: 11 BM, 7 combined BM and central nervous system (CNS), 3 BM + other site, 6 isolated CNS and 5 other site, non BM/CNS), giving an overall relapse rate of 3.8% with a salvage rate of 81%. The relapse death rate was 0.7% (n=6) with TRM of 0.8% (n=7). The low risk group can be further sub divided into a group of 442 patients (16.6% of whole trial) with undetectable MRD at EOI and good risk cytogenetics who have a 5yr EFS of 97.4% (5yr OS 99.5%).
Conclusion:
This excellent long term outcome for a third of all patients with childhood ALL, low risk MRD and good risk cytogenetics in a large multi-center randomized controlled trial supports exploration of further reduction of therapy in this group to reduce TRM. This strategy is further supported by the observation that the rate of TRM is now similar the relapse death rate in this group, coupled with the very high salvage rates for those patients who do relapse. The superior OS for patients with undetectable MRD and good risk cytogenetics further highlights the additive strength of MRD to accurately predict outcome in the low risk cytogenetic group.

Disclosures
No relevant conflicts of interest to declare.