Excellent Outcome Of MRD Low Risk Patients Is Sustained With Greater Than 10 Years Follow Up – Results Of UK ALL Trials 1997 -2003
Authors: Bartram Jack , Clack Rachel , Wade Rachel , Vora Ajay J , Hancock Jeremy , Mitchell Chris , Kinsey Sally , Steward Colin , Moppett John P , Goulden Nicholas 
Published: October 2019

Abstract

Background
Sensitive measurement of minimal residual disease (MRD) at the end of induction, to a minimum limit of detection of 0.01% is known to highlight a large group of patients (>40%) with an excellent (>90%) short term EFS. The UKALL 2003 study showed treatment reduction is feasible in children and young adults with no MRD >0.01% at day 28 of therapy (Vora et al, Lancet Oncology 2013). Nevertheless, follow up in that study and other recent trials is relatively short, raising concerns about using this result to infer the safety of further therapy reduction in the future. In order to provide insight into the applicability of this result, we have studied the longer term outcome of patients with MRD <0.01% at day 28 in our non-interventional pilot studies; UK ALL 97, 97/99 and 2003.

Methods
We examined 225 patients treated on one of the 3 trials between 1997 and 2003 for whom MRD results were available. The UK Medical Research Council (MRC) protocol ALL97 (1997–1999) had a 5 year EFS of 74% and OS 83.5%, and its amended version ALL 97/99 (1999–2002) had a 5 year of EFS 80% and OS 88%. These studies both compared in a randomised fashion, the efficacy and toxicity of dexamethasone with prednisolone, and 6-thioguanine with 6-Mercaptopurine. The successor trial ALL 2003, had a 5 year EFS of 87.7% and an OS of 91.3%, using more intensive induction including dexamethasone for all patients and PEGylated asparaginase. These trials provided an opportunity to determine the impact of MRD clearance on EFS and OS, with extended follow-up. MRD status at the end of induction chemotherapy was defined as low risk if no MRD was detected by at least one marker sensitive to 0.01%. In the ALL 97 study, MRD was measured by radiolabelled allele specific oligoprobing (sensitive to 0.01%); in ALL 99 and 2003 it was measured using the Euro-MRD RQ PCR of antigen receptor genes (quantitative range 0.01%).

Results
100 patients (44%) were low risk by MRD at end of induction. The median range of follow-up across the trials was 7 years 4 months to 12 years 11 months (longest individual follow up 14 years 1 month). There was no significant difference in NCI risk group between MRD positive and negative patients.

Discussion
Our pilot data defines a cohort of 44% of children with ALL who have a very good EFS and an excellent long term OS. Of 100 day 28 MRD low risk patients, 6 died: 1 because of toxicity at 1 month post diagnosis; and 1 from influenza 147 months post diagnosis whilst in CR; only 4 patients had relapses, at 17, 45, 74 and 125 months post diagnosis.

Conclusion
The excellent outcome for childhood ALL with low risk MRD after induction chemotherapy is sustained in the intermediate to long term. This result supports the potential for further reduction in therapy in subsequent trials for these children, without risk of worsening outcome.

Disclosures:
No relevant conflicts of interest to declare.