Although survival in children with acute lymphoblastic leukaemia has improved dramatically in the past few decades, this has not been the case for those who relapse. In a trial that compared the chemotherapeutic agents mitoxantrone with idarubicin in a radically different approach to treatment, mitoxantrone conferred a significant benefit in progression-free and overall survival.
In fact, the difference in survival between the two study groups was so noticeable that the authors stopped recruiting children into the trial much earlier than planned. The findings are reported in an Article published Online First and in an upcoming Lancet, and are being presented at the American Society of Hematology Meeting in Orlando, Florida, USA.
The study led by Prof Vaskar Saha, Cancer Research UK Children’s Cancer Group, School of Cancer and Enabling Sciences, The University of Manchester, Manchester, UK, studied 216 children aged between 1 and 18 years with relapsed acute lymphoblastic leukaemia recruited to the ALL R3 trial, an open-label randomised trial undertaken in 22 centres in the UK and Ireland, and nine in Australia and New Zealand.
The children received either mitoxantrone or idarubicin. Estimated 3-year progression-free survival was 35•9% (95% CI 25•9 – 45•9) in the idarubicin group versus 64•6% (54•2 – 73•2) in the mitoxantrone group (p=0•0004), and 3-year overall survival was 45•2% (34•5-55•3) versus 69•0% (58•5 – 77•3; p=0•004).
Mitoxantrone had less severe toxic side effects than idarubicin, but the authors say that the improved survival with mitoxantrone was attributable to better disease control.
The authors say: “The results from this trial clearly show that, compared with idarubicin, mitoxantrone significantly improves the outcome of children with relapsed acute lymphoblastic leukaemia.”
They add: “Mitoxantrone has only been infrequently used in therapeutic trials in childhood acute lymphoblastic leukaemia. A perception that optimisation has been reached with available drugs has shifted focus towards newer drugs and targeted therapy.
These drugs will be prohibitively expensive for many patients. Mitoxantrone is a cheap and readily available drug and clearly needs further clinical assessment in childhood acute lymphoblastic leukaemia. Our results suggest that, while we wait for targeted therapies to become a reality, conventional cytotoxics still have a role in treatment of acute lymphoblastic leukaemia.”
In a linked Comment, Prof Martin Schrappe, University Medical Centre Schleswig-Holstein, Campus Kiel, Germany, says that the difference in the effective of the drugs “translated into a clear survival advantage of more than 20%, which is one of the largest improvements ever achieved by a single modification of treatment.”
Schrappe also says that the ALL R3 trial makes an in important point about suitable endpoints for drug assessment. “Quantitative detection of minimal residual disease through well-standardised techniques has major prognostic importance in adult and paediatric leukaemia.
In this trial, minimal residual disease was measured in intermediate-risk patients at the end of the randomised treatment, but no difference could be detected between the two randomised groups. On the basis of minimal residual disease as a surrogate endpoint, this highly efficacious combination of drugs would not have been considered for further assessment.”
Source: The Lancet