Abstract
Background: Mutations in fms-like tyrosine kinase 3 are thought to be relevant to leukemogenesis. Two types of mutations are described; internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), which mostly affects asparate 835 (D835). ITD mutation is present in 20–30% of patients with acute myelogenous leukemia (AML) and is associated with poor outcome (Yanada, M. et al. Leukemia. 2005 ;19:1345–9). The role of stem cell transplant (SCT) is not established in patients with AML and FLT3 mutation.
Patients and Method: 125 patients (59% male) with AML and FLT3 mutation treated at M.D. Anderson Cancer Center between the years 2003 to 2007 were included in this analysis of predictors for survival. Age, PS, WBC, platelet count, hemoglobin level, bilirubin, creatinine, albumin, beta 2 microglobulin (B2M), response (CR/CRp vs others), transplant recipient status (yes/no) were included in uni and multi-variate analysis.
Results: Seventy-seven percent patients had ITD mutation and fourteen patients (11%) had both ITD and D835 mutation. Median age was 59 years (range, 17–84), WBC count 17.3 x 106/ml (range, 1–300.5), platelet count 50 x 109/ml (range, 7–313) and hemoglobin 8.1 gm/dL (range, 4.2–13.9). Most (98%) had a performance status of 0–2 (median=1) and cytogenetic was diploid in 72%. All patients underwent cytarabine based induction chemotherapy.
Fifty-seven percent patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and induction related death rate was 9%. Eighty-six (69%) patients died and median overall survival (OS) was 10.4 months (95% CI of 7.62 to 14.08 months). There was no difference in OS between ITD mutation and D835 mutation. Twenty-seven patients (22%) underwent stem cell transplantation; 13 in CR1, 7 with bone marrow blast ≥ 10%). On univariate analysis transplant recipient status, PS, response, age, creatinine, albumin and B2M were significantly associated with OS. Patients who underwent transplant had a better OS (median = 15.7 months versus 7.6 months, p=.007) (Fig.1). On multi-variate analysis transplant recipient status, PS, ITD mutation and creatinine impacted OS. Age was a marginally significant predictor for OS.
Conclusion: Stem cell transplantation in CR/CRp appears to improve OS in patients with AML and FLT3 mutation. Results of trials incorporating FLT3 inhibitors into induction/consolidation regimens are eagerly awaited.
Fig.1: Survival by transplant status in patient with AML and FLT3 mutation Fig.1:. Survival by transplant status in patient with AML and FLT3 mutation
Myelodysplastic Syndrome and Acute Myelogenous Leukemia as a Late Clonal Complication in Children With Acquired Aplastic Anemia