Abstract
Abstract 2611
Poster Board II-587
The prognostic heterogeneity of patients with intermediate-risk cytogenetics AML (AML-IR) is mostly clarified by determination of mutations of NPM1 gene (NPMmut) and internal-tandem duplication of FLT3 gene (FLT3-ITD). Nonetheless, other genetic lesions described in this population might contribute to a better prognostic categorization. In this context, we analyzed the presence of CEBPA mutations and associated features in patients with AML-IR lacking both NPMmut and FLT3-ITD. Overall, 136 patients (51% female; median age: 53, range: 17=74) diagnosed with de novo AML-IR (MRC definition) in our institution between 1994 and 2008 who received standard AML chemotherapy were included in the analysis. CEBPA mutations (CEBPAmut) were investigated by whole gene sequencing using 4 primer pairs according to previously reported methods (Fröhling et al, 2004). Sixty-five patients (48%) harbored NPM1 mutations, 30 of them having concomitant FLT3-ITD. Among NPM1 wild-type patients (NPMwt), FLT3-ITD, CEBPA and MLL mutations were detected in 18, 11, and 5 patients, respectively. Regarding cases with CEBPAmut, biallelic mutations were found in 8 patients, including 6 cases with combined mutations of N-terminal and bZIP domains and two homozygous mutations, whereas a single mutation in bZIP domain was found in the three remaining patients. As compared to patients with wild-type CEBPA (CEBPAwt), those with CEBPAmut were younger (29 vs. 53, p=0.027), and showed a trend to male predominance (73 vs. 46%, p=0.09) and lower WBC count at presentation (16 vs. 33.5 × 109/L, p=.095). Of note, CD7 antigen was aberrantly expressed in virtually all CEBPAmut cases (10/11), compared to only 21% of CEBPAwt patients (p<0.001). Moreover, an abnormal karyotype was observed in 4 patients with CEBPAmut. In the overall series, complete response rate (CR), survival (OS), and relapse incidence (RI) were 83%, 39±4% (5-yr), and 50±5% (5-yr), respectively. Independent favorable factors for survival were younger age (<median; RR: 1.9, 95% CI: 1.2-3, p=0.004), low WBC count at diagnosis (< median; RR: 1.7, 95% CI: 1.1–2.6, p=0.025) and NPMmut/FLT3-ITDneg status (RR: 2.4, 95% CI: 1.3–4.2, p=0.003). Remarkably, patients with CEBPAmut showed a favorable outcome, with a trend for a more prolonged survival, compared to patients with a high-risk NPM/FLT3 status (5-year OS in pts <60 years: 74±16% vs. 33±6%, p=0.087). Based on these results, patients were grouped in a favorable (i.e., either NPMmut /FLT3-ITDneg or CEBPAmut, FAV) or unfavorable molecular category (i.e., those with FLT3-ITD, double NPMwt and CEBPAwt configuration, or MLL abnormalities, UNFAV); these two groups had independent prognostic impact on OS (RR: 2.3, 95% CI: 1.3–4, p=0.001; see figure), RI (RR: 2.2, 95% CI: 1.2–4.3, p=0.016), and leukemia-free survival (RR: 2.2, 95% CI: 1.3–3.7, p=0.002). Importantly, the outcome of patients in the FAV group did not differ according to post-remission treatment (autologous vs. allogeneic stem-cell transplantation, SCT), whereas relapse risk was significantly higher in patients with unfavorable markers who received autologous SCT (60±13% vs. 18±12%, p=0.03). In summary, the assessment of CEBPA mutations, especially in patients lacking NPMmut and FLT3-ITD and expressing CD7 antigen, may refine the molecular prediction of prognosis and guide therapeutic strategy in patients with intermediate-risk AML.
Legend for figure. Survival of patients with intermediate-risk cytogenetics AML according to molecular risk
Legend for figure. Survival of patients with intermediate-risk cytogenetics AML according to molecular risk
No relevant conflicts of interest to declare.
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