Incidence and Prognosis of RTKs and RAS Mutations in CBF AML. A Retrospective Study of French Adult ALFA and Pediatric LAME Trials.

Introduction: In core binding factor (CBF) acute myeloid leukemia (AML), the disruption of CBFa (AML1) or CBFb genes through t(8;21) or inv(16) impairs normal hematopoietic differentiation, but is considered to be insufficient to induce leukemogenesis. The need of an additionnal oncogenic event that promotes cellular proliferation has been suggested. This proliferative signal may be delivered by mutated receptor tyrosine kinases (RTKs) or RAS proto-oncogenes. In a retrospective study, we evaluate the incidence and the prognosis of RTKs (FLT3/D835, KIT/D816 and KIT/Ex8 insertion/deletion) and N/K-RAS mutations in patients with CBF AML.

Patients: Genomic DNA were obtained from the bone marrow or blood of 81 patients under 60 years with CBF AML (t(8;21)/inv(16) : 48/33) : 21 treated in the pediatric LAME trial (27/6) and 60 in the adult ALFA trial (33/15) between 1990 and 2004. The median follow-up is 5 years.

Results: RTKs mutations are found in 15/74 (20%) patients. KIT mutations are present in 11/74 (15%) patients, at a lower rate than previously described. KIT/D816 mutations are observed in 2/49 (4%) t(8;21) patients and 1/32 (3%) inv(16) patients. KIT/Ex8 mutations are slightly more present in inv(16) than in t(8;21) patients (5/32 vs 3/42, 16% vs 7%). One of the 5/81 patients (6%) with FLT3/D835 mutations also presents a KIT/Ex8 mutation. RAS mutations rates are significantly higher in inv(16) than in t(8;21) patients (11/33 vs 4/38, 33% vs 11%), with mostly N-RAS mutations (75%). No correlation between RTKs or RAS mutations and age or WBC is observed. Four patients did not achieve complete remission (CR rate : 95%), 2 with FLT3/D835 and 3 with RAS mutations. In univariate analysis, RTKs mutations are significantly associated with a shorter OS and EFS (p=.001 and p=.02, resp.) KIT mutations are associated with a shorter EFS and RFS (p=.002 and p=.003) in t(8;21) patients but do not affect the outcome of inv(16) patients in our study. Patients with FLT3/D835 mutations have significantly shorter OS, EFS and RFS (p<.0001, p<.0001 and p=.0007, resp.). The outcome of each subgroup of CBF AML is affected by FLT3/D835 status. RAS mutations have no impact on outcome. Multivariate analysis show a persistent significant prognostic impact of RTKs mutations on OS, RFS and EFS.

Conclusion: Inv(16) and t(8;21) cytogenetics are classically associated with a low risk of relapse. Patients with CBF AML are no more considered by many teams for allogeneic stem cell transplantation, even with a related donor. However, screening for RTKs mutations may identify patients with a more adverse outcome and thus susceptible to benefit from intensified protocols or tyrosine kinase inhibitors.