UKALL 2003, A Randomised Trial Investigating Treatment Reduction for Children and Young Adults with Minimal Residual Disease Defined Low Risk Acute Lymphoblastic Leukaemia

Abstract 496

UKALL 2003 is an ongoing randomised controlled trial investigating treatment modification according to Minimal Residual Disease (MRD) status at the end of induction and week 11 in children and young adults (up to age 25 years) with ALL. Whilst the randomisation testing the benefit of intensification for an MRD defined high risk group remains open, a treatment reduction randomisation for MRD low risk patients closed in August 2009 after recruiting the target number of patients. Over 2600 patients have so far been enrolled into the trial and we have observed a significant improvement in 5 year event-free (EFS) compared with its predecessor, ALL 97/99, (EFS 87 vs 80%, p<0.0005), most probably related to use of dexamethasone and pegylated asparaginase in all patients. Here we report the results of the MRD low risk randomisation.

Patients in the trial are 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 receive a 3 drug induction (Regimen A) whilst high risk (HR) patients receive 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 are transferred to Regimen C. Patients without poor risk cytogenetics and who have a rapid early response are eligible for the MRD randomisations. MRD was measured using Real Time Quantitative PCR with a sensitivity of 10⁻⁴.

Five hundred and twenty-one patients who were either MRD negative at day 29 of induction or positive < 10⁻⁴ at day 29 but negative by week 11 entered a randomisation comparing two courses of delayed intensification (standard arm, n = 261) with one (treatment reduction arm, n = 260). Of these patients, 342 (65%) were NCI SR and 179 (35%) NCI HR. With follow-up to October 2009 (median 2 years 9 months), there is no difference in 5 year EFS for patients in the standard (94%) or reduced treatment arms (96%). As shown in table 1, the number of patients with relapse is similar in both arms but there was a non-significant excess of deaths in remission, serious adverse events and grade 3/4 toxicity in recipients of 2 DIs. 7/10 relapses have involved the CNS. The 3 CR deaths in the 2 DI arm were due to gram negative sepsis (DI1), pulmonary haemorrhage (DI2) and RSV pneumonitis (Maintenance, Down). There have been no relapses or CR deaths among 23 MRD low risk patients in the 16 – 25 age group.

This randomised study provides evidence that treatment can be reduced for around 40% of children and young adults who show rapid clearance of MRD by the end of induction. These patients have an excellent outcome with < 5% risk of relapse on a treatment protocol that does not include cranial radiotherapy or high dose methotrexate and gives minimal exposure to anthracyclines and alkylating agents. Future trials should test the feasibility of further reductions in treatment for this group of patients.