Preliminary Outcomes of Children and Young Adults with Acute Lymphoblastic Leukaemia and Down Syndrome (DS-ALL) on UKALL 2011. Reduction in Treatment-Related Mortality with De-Escalated Therapy
Authors: Ghorashian Sara , Samarasinghe Sujith , Kirkwood Amy A , Hough Rachael , Rowntree Clare , Lawson Sarah , Goulden Nicholas John , Pond Emma , Kearns Pamela R. , Moorman Anthony V. , Moppett John , Vora Ajay 
Published: October 2019

Introduction

Reported outcomes for children with Downs syndrome (DS) and acute lymphoblastic leukaemia (ALL) treated on our previous national study, UKALL 2003, were inferior compared to non-DS children. 5 year event free survival (EFS) for DS children was 65.6% vs. 87.7% for non-DS children and 5 year overall survival (OS) was 70.0% vs. 92.2% (British Journal of Haematology 2014; 165: 552-555). Excess treatment related mortality (TRM, 21.6% vs. 3.3% at 5 years) in children with DS-ALL was primarily due to infection. Similar results have been reported by other study groups.

In our successor study, UKALL 2011, we employed several steps of de-escalation for DS-ALL patients compared to standard therapy. Here, we report that de-escalated therapy has resulted in a dramatic reduction in TRM for children with DS-ALL treated in the UK. Methods

DS-ALL patients treated on UKALL 2011 had their treatment modified in the following respects: 1)NCI high risk patients did not receive anthracycline in induction unless they had a slow early response at day 15; 2) two years maintenance was given for both boys and girls; 3) no pulses were given in maintenance for MRD low risk patients.

In addition, we recommended use of prophylactic antibiotics during induction and intensive phases of treatment. Fisher's exact test was used to compare induction mortality in the DS and non-DS pts. OS was defined as time from registration to death. EFS was defined as time from registration to first event (induction failure, relapse, second malignancy or death from any cause). The Kaplan-Meier method was used for survival estimation. Results

The UKALL 2011 trial opened to recruitment on 26th April 2012 and has recruited 2362 patients, of whom 50 have Down syndrome, in the period up to 22nd February 2018. The study is open in 41 centres in UK and Ireland and included patients with both ALL and lymphoblastic lymphoma (LBL). The baseline characteristics of the patients recruited up to this date are shown in the table below. For DS-ALL, Day 29 MRD was available for 48 patients and was low risk in 25 cases (50%), risk in 19 (38 %) and no result was obtained in 4 (8 %). The therapy was generally well-tolerated, there have been no cases of therapy curtailment due to toxicity and only one patient due to receive intensified therapy per MRD risk assessment was unable to escalate due to toxicity.

At a median follow-up of 32.7 months, there have been 4 events. These include two relapses (relapse rate: 4.1% (1.1-15.5) at 3 years) and two TRMs (one TRM in induction and the other in consolidation; both due to infection). Three year EFS is: 92.9% (95% CI: 79.1 - 97.7) with a three year OS of 95.9% (84.5 - 99.0). The remarkably low induction TRM for DS children on UKALL 2011 (1 death out of 50 patients, 2%), is comparable to that of non-DS children treated on the same protocol with a 3 drug induction (12 out of 1174 children, 1% induction TRM; induction TRM in DS-ALL vs non-DS-ALL p=0.42). It is also comparable to the induction TRM in DS-ALL noted in the latter half of the UKALL 2003 study (1/40, 2.5%) when the aforementioned treatment modifications were first implemented in the UK.

Importantly, this TRM is a quarter of that when an historic cohort of DS-ALL children were treated with a 4-drug induction on our previous study (UKALL 2003, DS-ALL TRM 4/46 patients i.e. 8 %, p=0.19). Conclusion

These preliminary results suggest that de-escalation of treatment is successful in reducing treatment related mortality for children with DS-ALL without increasing the risk of early relapse, however longer term follow-up is needed.

Disclosures

Ghorashian: Celgene: Other: travel support; Novartis: Honoraria. Hough:University College London Hospital's NHS Foundation Trust: Employment. Kearns:Pfizer: Consultancy, Research Funding; Galen: Research Funding. Vora:Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board; Amgen: Other: Advisory board; Novartis: Other: Advisory board.