Abstract
Poster Board I-592
Several somatic genetic abnormalities have been identified in T-ALL but therapeutic stratification still relies on clinical markers. NOTCH1 and/or FBXW7 (N/F) mutations both lead to activation of the NOTCH1 pathway and are amongst the most frequent mutations in T-ALL. We identified N/F mutations as a good prognostic marker, found in 70% of patients within the French LALA-94 and GRAALL-2003 prospective adult T-ALL trials, whereas the German GMALL group reported that low ERG and BAALC (E/B) transcript expression also predicts a highly favorable outcome in 41% of adult T-ALL (Baldus et al. J Clin Oncol. 2007 25(24):3739-45). In order to compare the predictive prognosis value of N/F mutations versus low E/B expression, we analyzed 189 adult T-ALL for both, including 107 previously reported cases and 82 unreported cases included within the ongoing GRAALL-2005 trial up to the first planned interim analysis.
E/B were quantified by real time RT-PCR and the comparative cycle threshold (Ct) method was used to determine the relative expression levels for ERG and BAALC to ABL. T-ALL patients were classified as low E/B expressers (E/Blow) or high E/B expressers (E/Bhigh) as previously reported by Baldus et al. Despite the use of ABL rather than GPI as internal control, we observed the same incidence of E/Blow. 41% (n=77) of T-ALLs were classified as E/Blowand 59% (n=112) as E/Bhigh. 68% (n=128) of cases were mutated for NOTCH1 and/or FBXW7 (N/Fmut) and 32% (n=61) were germline for both (N/FGL). As expected E/Bhigh correlated with an immature phenotype (p<0.0001). There was no association between E/B expression level and F/Nmut (p=0.5) and no significant correlation for either N/F or E/B status with age and leucocytosis at diagnosis.
There was no difference in overall survival (OS) and event free survival (EFS) between E/Bhigh and E/Blow (4-years OS: 57% v 55 %; 4-years EFS: 46% v 47%). In contrast, N/Fmut compared with N/FGL had a better OS (67% v 36%; P= .002) and EFS (56% v 32%; P=.008). When the LALA and GRAALL protocols were analyzed separately, N/Fmut retained their significant favorable outcome, including in the GRAALL-2003 and GRAALL-2005 trials, which give overall good results for T-ALL. E/B expression did not impact on prognosis in either the GRAALL trials (E/Bhigh OS =68% EFS= 64% v E/Blow OS= 62% EFS=50%) or the LALA trials (E/Bhigh OS =46% EFS= 30% v E/Blow OS= 39% EFS=29%) individually.
Taken overall, our data demonstrate that N/Fmut, but not low E/B expression, identify a major subgroup (68%) of adult T-ALL with a highly favorable outcome that could justify individual therapeutic stratification for T-ALL. N/F mutation status is also better suited to individual patient stratification than the continuous spectrum of ERG and BAALC transcript expression.
No relevant conflicts of interest to declare.
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Author notes
Asterisk with author names denotes non-ASH members.