In the adolescent and young adult population one of the issues to know how to treat them; there are differences between the paediatric and adult oncology organisations. So in the adolescent population some studies showed in the 2000s that patients that were treated in paediatric trials did better than those treated in adult trials. So at that time in the French GRAALL group we took the decision to increase the dose intensity of our trial in the whole population of patients aged 15-60 years old and to inspire from a paediatric approach with BFM-like induction with intense consolidation and also a delayed intensification and maintenance for older patients during two years. So globally we improved the results in all the subpopulations but mostly in the AYA population. Why? Because in the older population, the population older than 45 and mostly 55 years old, what we observed is an increased toxicity, an increased death risk during induction but also an increased risk of global treatment related mortality during all the trial. So in the current 2014 trial we split the population in two with patients younger than 45 and older than 45 and we decreased the doses in patients older than 45 to decrease the toxicity but we also improved the exposition to methotrexate and asparaginase in younger patients. We also discussed indications for allogenic stem cell transplantation since a previous study from our group showed that the patients that mostly benefit from this approach are MRD positive patients. Those indications for allogenic stem cell transplant will be reduced to the patients with a high MRD at complete remission so it will globally reduce the rate of patients that will be eligible for a transplant.

When you look at the AYA population and at the survival of this specific population you see that there is a dramatic drop after ten or fifteen years of long-term outcome. This drop in long-term outcome in the AYA population specifically is due to the difference in treatment attitudes but also in disease characteristics. The most important finding in intensifying the ALL characteristics in this age range was identification of the subgroup of Ph-like ALL in the last 5-6 years. This population, this subpopulation of Ph-like, is relatively frequent in the AYA population, up to one third of the patients. In this subpopulation of patients you may find druggable targets including ABL-like; you may find translocation involving ABL-like targets or JAK2 that may be druggable by tyrosine kinase inhibitors or JAK-STAT pathway inhibitors. In the patient we report here during this workshop it was a 24 year old patient with a very high white blood cell count at diagnosis and very resistant to front line therapy. After the induction the patient was resistant in haematological complete remission with a high MRD level of 10-1. At that time we identified a gene fusion with ABL-1 involved so we decided to treat this patient as we would treat a Ph positive ALL. Finally this patient responded to tyrosine kinase inhibitors and as it was not enough we decided to add to this tyrosine kinase inhibitor blinatumomab which is also a non-targeted immunotherapy. He achieved a complete molecular remission and was finally transplanted with a mother. It was a haploidentical transplant and we reset the tyrosine kinase inhibitor after transplant. Now she’s well one year after transplant.  This case illustrated that we are still just at the beginning of the story and we don’t really know how to manage these patients. These patients are infrequent so it’s difficult to have specific trials but the first results of the first case reports, but also the in vivo research, ex vivo research, are very positive and led us to expect a good response for this patient to targeted therapy.