Towards a Pediatric Approach in Adults with Acute Lymphoblastic Leukemia (ALL): The GRAALL-2003 Study.

Introduction: In a recent French FRALLE versus LALA comparison, we have demonstrated a large benefit in outcome when adolescents and young adults were treated in a pediatric rather than an adult ALL protocol (Boissel JCO 2003). Similar provocative results have been observed in three other pediatric versus adult ALL studies (Stock ASH 2000, de Bont Leukemia 2004, Testi ASH 2004). One explanation may be the larger amounts of steroids, vincristine (VCR), and L-asparaginase (L-aspa) administered in pediatric patients. The GRAALL-2003 study was thus designed to offer a pediatric approach in adults with Ph-negative ALL until 60 years of age.

Methods: Treatment included a 5-drug induction, high dose-intensity consolidation blocks, delayed intensification, and 2-year maintenance. The comparison with the former LALA-94 protocol showed a 8.6-fold, 3.7-fold, and 16-fold increase in cumulative doses of prednisone, VCR, and L-aspa, respectively. One difference with childhood ALL therapy remained indication of allogeneic SCT in first CR which was offered to all patients with high-risk factor and a donor. In addition, induction was reinforced with a hyper-cyclophosphamide sequence (HyperC) in case of poor early response (cortico- and/or chemoresistant ALL). In the present report, 212 GRAALL-2003 patients with Philadelphia-negative ALL aged 15–55 years with a median follow-up of 18 months were compared to 712 patients previously treated in the LALA-94 trial.

Results: Cohorts were comparable in terms of prognostic factors. CR rate was significantly higher in GRAALL patients (93 vs 88%, P=0.02) due to a reduction in resistant disease (0.5 vs 8%, P<0.001) with comparable induction death (6 vs 5%, P=0.37) rate. When compared to the LALA-94 study, 2-year EFS and overall survival were markedly improved (56 vs 41% and 66 vs 54%; P=0.0002 and 0.02, respectively). Similar differences were observed after censoring SCT patients at transplant time, underlining the role played by chemotherapy modification. Because of a worse tolerance to induction and post-remission therapy, the benefit associated with the GRAALL approach decreased with advanced age, becoming not statistically significant over 40 years of age. Finally, outcome improvement was higher in T- than in B-lineage ALL (2-year overall survival, 75 vs 51% and 61 vs 56%; P=0.016 and 0.25, respectively). Among patients with T-ALL, poor early responders (allocated to HyperC induction) tended to have a better EFS than good early responders, suggesting a major role of HyperC in this ALL subset.

Conclusion: In conclusion, a pediatric approach benefits to younger adults with ALL.