FLT3-ITD and Age Are the Major Prognostic Factors In Relapsed AML with Normal Karyotype

Abstract 1719

Acute myeloblastic leukemia with normal karyotype (CN-AML) is a heterogenous disease. During the past years, a wide variety of somatic gene mutations has been described in these patients. For several of these mutations, a prognostic impact in first-line therapy of patients with CN-AML has clearly been established in numerous large studies. In contrast, data on the influence of these aberrations on outcome after relapse are limited. We analyzed 98 adult patients up to 60 years of age (median age 47 years) with CN-AML in first relapse for clinical and molecular risk factors for survival. All patients were treated within two prospective multicenter trials. First-line treatment consisted of double induction and intensive consolidation therapy with high dose cytarabine, autologous or allogeneic stem cell transplantation. Leukemic blasts were analyzed for genetic aberrations in the genes FLT3, NPM1, CEBPA, WT1, IDH1 and IDH2. Median duration of first CR was 9.1 months. 33% of the patients had an FLT3-ITD, 50% a mutation in NPM1, 8% in CEBPA, 11% in WT1, 12% in IDH1 and 11% in IDH2. 28% had the genotype NPM1mutated/FLT3-ITDnegative. Seventy-seven of the patients received intensive re-induction chemotherapy after relapse, 17 patients directly received an allogeneic stem cell transplantation and only four patients received no further intensive treatment. A second CR was achieved in 52% of the 77 patients with re-induction. Presence of an FLT3-ITD (OR 0.24; 95% CI 0.07 – 0.80), duration of CR1 < 6 months (OR 0.24; 95% CI 0.06 – 0.92) and age above 47 years (OR 0.31; 95% CI 0.10 – 0.98) were associated with significantly inferior CR2 rates. Median survival after relapse was 9.7 months and six-year survival was 27%. In multivariate analysis, age above 47 years (HR 2.66, 95% CI 1.55 – 4.55) and FLT3-ITD (HR 2.06; 95% CI 1.22 – 3.94) were the only independent prognostic factors for survival. Other clinical or molecular parameters had no impact on survival. Patients with none of these risk factors (n = 27) had a six-year survival of 54%. In patients with one (n = 43) or both (n = 18) of these factors, survival was significantly inferior (15% and 6% six-year survival respectively). This was even true when only patients were considered who received an allogeneic stem cell transplantation after relapse (n = 51). In these patients, six-year survival was 64% when none of these risk factors was present, 24% for one risk factor and 20% for patients with both factors. In conclusion, FLT3-ITD and older age are the major prognostic factors in relapsed CN-AML. Patients with none of these factors have a relatively good outcome after re-induction and allogeneic stem cell transplantation. In contrast, patients with at least one of these risk factors have a dismal prognosis and might be considered for investigational treatment approaches after relapse.