UKALL 2003, A Randomised Trial Investigating Treatment Intensification for Children and Young Adults with Minimal Residual Disease Defined High Risk Acute Lymphoblastic Leukaema
Authors: Vora Ajay J , Goulden Nicholas , Mitchell Christopher D , Hough Rachael , Rowntree Clare , Richards Susan M 
Published: October 2019

Abstract 136

Treatment modification according to Minimal Residual Disease (MRD) status at the end of induction and week 11 was investigated in a randomised control trial, UKALL 2003. Consecutively diagnosed children and young adults (up to age 25 years) with ALL were recruited from the UK and Republic of Ireland between October 2003 and June 2011. In the trial overall, we have observed a significant improvement in event-free survival (EFS) compared with its predecessor, ALL 97/99 (5-year EFS 87 vs 80%, log rank p<0.0005) most probably related to use of dexamethasone and pegylated asparaginase in all patients. Here we report the results of the MRD high risk randomisation which closed to recruitment on 30 June 2011.

Patients in the trial were initially stratified by NCI risk, blast karyotype, and morphological marrow response at day 8/15 of induction for allocation to one of 3 treatment regimens, escalating in intensity (A, B, C). NCI standard risk (SR) patients received a 3 drug induction (Regimen A) whilst high risk (HR) patients received 4 drugs including daunorubicin (Regimen B). Patients with a slow early response at day 8 (NCI HR) or day 15 (NCI SR) of induction and patients with poor risk cytogenetics were transferred to Regimen C. Patients without poor risk cytogenetics and who had a rapid early response were eligible for the MRD randomisations. MRD was measured using Real Time Quantitative PCR with a sensitivity of 10−4.

Five hundred and thirty three patients who had an MRD >/= 10−4at day 29 of induction were entered into a randomisation comparing standard treatment (Regimens A or B = standard arm, n = 266) with the more intensive Regimen C (intensification arm, n = 267). Of these, 332 (62%) were NCI SR and 201 (38%) NCI HR. With follow-up to October 2011 (median 3 years 11 months), the 5 year EFS is significantly better for patients in the intensification arm (91%) compared with the standard arms (82%) due to a halving of relapse risk (OR 0.57, 95% CI 0.34 – 0.95, 2p = 0.03). The improved EFS translates into a trend for better overall survival (OR 0.57, 95% CI 0.31 – 1.05, p= 0.07). There was no heterogeneity in benefit of Regimen C for sub-groups defined by NCI risk, immunophenotype or cytogenetics. The risk of death in remission was not significantly different in the two arms (Intensification = 7, Standard = 9, OR 0.76, 2p = 0.6) but there was an excess of SAEs and AEs related to asparaginase (hypersensitivity, p=0.0003 and pancreatitis, p = 0.01) and intravenous methotrexate (mucositis, p=0.03 and vomiting, p = 0.03) in the intensification arm.

This randomised study provides evidence that treatment intensification is of benefit to patients defined as high risk by MRD measured at day 29 of induction. The excess toxicity related to asparaginase and intravenous methotrexate did not result in an increase in treatment related mortality. Taken together with the results of the low risk randomisation, reported at ASH in 2010, UKALL 2003 has demonstrated that within a NCI directed CCG backbone, MRD based stratification provides the optimal approach to risk directed therapy.

Disclosures:

No relevant conflicts of interest to declare.