NOTCH1 Activation Neutralizes the Unfavorable Prognostic Effect of PTEN Mutations in BFM-Treated Children with T-ALL

Abstract 740

Despite recent advances in treatment results of pediatric T-ALL, approximately 20% of the patients relapse and then have a dismal prognosis. Therefore, we aimed to identify molecular biomarkers that help in stratifying patients according to risk early in the course of treatment. We have analysed the clinical interaction of PTEN and NOTCH1 mutations in a cohort of 301 children with T-ALL who were treated on ALL-BFM protocols. We found heterozygous exon 7 PTEN mutations in 50 patients (17%). PTEN mutations occurred in 19% of male and 9% of female patients (p=0.05) and were more common in leukemias without (21%) than in those with (12%) activating NOTCH1 mutations (p=0.04). Patients with PTEN mutations showed a poor prednisone response (PPR) significantly more frequently than those patients without PTEN mutations (58% vs. 37%; p= 0.007; odds ratio 2.4; 95%CI = 1.3–4.4, p=0.006). Furthermore, in a multivariate analysis including variables known to be associated with prednisone response (sex, age at diagnosis, presenting WBC count at diagnosis and T-cell immunophenotype), the negative effect of PTEN mutations retained its significant effect (odds ratio =2.6, 95% CI= 1.3–5.2, p=0.005). On day 33, only 4% of the patients with PTEN mutations showed a favorable MRD response as compared to 29% of PTEN non-mutated patients (p=0.001). On day 78, the MRD response remained unfavorable significantly more frequently than in patients without a PTEN mutation, although this difference was less pronounced (57% vs. 39%; p = 0.05). Logistic regression analysis showed that patients with PTEN mutations carried a 9.2 fold higher risk of not achieving a favorable MRD level on day 33 (95% CI 2.2–3.9, p=0.003) and a 2.1 fold higher risk for an unfavorable MRD on day 78 (95% CI 1.1–1.4, p=0.02). In a multivariate analysis with known variables to be associated with treatment response (sex, age at diagnosis, presenting WBC count at diagnosis and T-cell immunophenotype), the negative effect of PTEN mutation retained its significant effect on day 33 (Odds ratio= 11, 95% CI= 2.5–48.5, p= 0.001) and on day 78 (Odds ratio =2, 95% CI= 1–4.1, p=0.05). These differences between PTEN-mutated and PTEN-non-mutated patients in early treatment response were maintained as a trend towards an inferior pEFS of 0.82 vs. 0.70 (p=0.07).

We next tested how PTEN mutations clinically interact with NOTCH1 mutations. The comparison of early treatment response showed that leukemias with NOTCH1 and PTEN mutations had a similar rate of PPR and unfavorable MRD day 33 responses as those leukemias with PTEN mutations only (61% vs. 56%, p=0.8; 94% vs. 96 %, p=1), whereas patients with NOTCH1 mutations only exhibited the known low rate of PPR and unfavorable day 33 MRD response (27%, p=0.006 and 64%, p=0.008). Leukemias with neither mutation showed intermediate rates of PPR (48%) and unfavorable day 33 MRD response (79%). These data indicate that the unfavorable effect of PTEN mutations dominates over the favorable effect of NOTCH1 activation during early induction. By contrast, the analysis of MRD responses on day 78 and of long term survival showed that the favorable effect of NOTCH1 neutralizes the unfavorable effect of PTEN. The groups with both, PTEN and NOTCH1 mutations or NOTCH1 mutations only show a similar pEFS of 0.88 and 0.87, respectively, while the group with PTEN mutations only shows a significantly inferior pEFS of 0.61. These results indicate that PTEN mutations represent unfavorable biomarkers in BFM-treated pediatric T-ALL patients when not combined with NOTCH1 mutations and that NOTCH1 activation neutralizes this unfavorable effect at the end of induction and in long- term outcome. Activating NOTCH1 mutations thus remain the dominant favorable risk marker in BFM-treated children with T-ALL.