Page 150 - Haematologica - Vol. 105 n. 6 - June 2020

S. Ferrero et al.
mutations and TP53 disruptions into the MIPI-c prognos- tic index (complete data available for 172 patients), we assigned a score to each of the single variables, based on the multivariate Cox regression analysis. MIPI-c low, low- intermediate and intermediate-high risk classes scored 0 points, MIPI-c high-risk class scored 1 point, while KMT2D mutations as well as TP53 disruption scored 2 points (Table 3). Patients were then grouped into three risk classes, according to their total score, in the “MIPI-g” index, namely: i) 0 points, low risk group (LR 121 patients, 70.3%); ii) 1-2 points, intermediate risk group (IR 38 patients, 22.1%); iii) ≥3 points, high risk group (HR 13 patients, 7.6%). PFS and OS at 4-years for low-, interme- diate-, and high-risk groups were 72.0%, 42.2%, 11.5% (P<0.0001) and 94.5%, 65.8%, 44.9% (P<0.0001), respec- tively (Figure 5). The MIPI-g index improved the model discrimination ability, with a C-statistics of 0.675 for PFS (bootstrapping corrected 0.654) and 0.776 for OS (boot- strapping corrected 0.747), as compared to MIPI-c alone (C-statistics 0.592 and 0.7, respectively).
Validation set
Most KMT2D variants considered in the Nordic study have been removed by our mutational calling, since these were missense variants not reported in COSMIC. At the end of the re-analysis, from the original 28 mutations, 21
were excluded. Two previously unrecognized frameshift mutations have been identified by our bioinformatics pipeline, overall accounting for a total of nine KMT2D mutations (all disrupting, as expected for KMT2D) in the Nordic validation series. In the Nordic validation series, KMT2D mutated patients showed a similar increased risk for OS, with a median OS of 12.7 years (95% confidenec interval [CI] not evaluable) for WT versus 8.4 (95% CI: 0- 17.6) for mutated cases. The Nordic validation series also replicated the MIPI-g score. The re-analysis of TP53 muta- tions confirmed the original data of Eskelund et al., with median OS of 12.7 (95% CI not evaluable) for WT cases and 2.0 years (95% CI: 1.2-2-8) for mutated cases. Consistently, also the MIPI-g validation on the Nordic series showed similar results: 4-year OS for LR (n=103), IR (n=36) and HR (n=13) MIPI-g groups were 91.3%, 72.2%, 15.4%.
Discussion
To identify new molecular predictors in MCL, we per- formed targeted resequencing and DNA profiling of puri- fied tumor samples collected from young patients enrolled in the ASCT-based prospective FIL-MCL0208 phase 3 trial (NCT02354313). Our study documents that: i) KMT2D
AB
CD
Figure 2. Prognostic impact of KMT2D and TP53 mutations. Kaplan-Meier estimates of progression free survival and overall survival of KMT2D (A, B), and TP53 (C, D) mutated versus wild-type (WT) patients. Cases harboring mutations (mut) in these genes are represented by the yellow line. Cases WT for these genes are repre- sented by the blue line. The Log-rank statistics P-values are indicated adjacent curves.
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