KMT2D AND TP53 MUTATIONS PREDICT POOR PFS AND OS IN MANTLE CELL LYMPHOMA RECEIVING HIGH‐DOSE THERAPY AND ASCT: THE FONDAZIONE ITALIANA LINFOMI (FIL) MCL0208 PHASE III TRIAL

Abstract

Introduction: Within the landscape of mutated genes in mantle cell lymphoma (MCL), only TP53 disruption has been so far associated with outcome. Here we present the clinical update of the deep sequencing MCL gene panel analysis in the prospective FIL‐MCL0208 phase III trial (NCT02354313, high‐dose immunochemotherapy followed by autologous transplantation for untreated, advanced stage <65 years MCL) based on the data from the second interim analysis. Methods: A targeted resequencing gene panel, including coding exons and splice sites of the ATM, BIRC3, CCND1, KMT2D, TP53, TRAF2, WHSC1, and NOTCH1 genes was analyzed in tumor DNA from baseline bone marrow CD19+ purified MCL cells and, to filter out polymorphisms, in the paired normal genomic DNA (55% of cases) using a TruSeq Custom Amplicon target enrichment system followed by deep next generation sequencing (Illumina, median depth of coverage 2356x). Variants represented in >10% of the alleles were called with VarScan2 with the somatic function when the paired germline DNA was available. For patients lacking germline DNA, a bioinformatics pipeline including a number of stringent filters was applied to protect against the misclassification of polymorphisms as somatic variants. Clinical data were updated at the time of the second interim analysis (January, 2017). Results: Out of the 300 enrolled patients, 176 were evaluable for mutations. Median follow‐up of the cohort was 36 months, and 3‐years PFS and OS were 66% and 86%, respectively. Patients not included in the study, due to unavailable tumor DNA (n = 124) showed superimposable clinical features and outcome. Mutations of TP53 (9% of cases) and KMT2D (11% of cases) associated with an increase in the hazard of progression both in univariate analysis as well as after adjusting for MIPI, Ki67 and blastoid variant: HR 3.87 (95% CI 1.64 to 9.13), p < 0.002 and HR 3.66 (95% CI 1.77 to 7.56), p < 0.001, respectively. These results translated into an increase of the hazard of death in both TP53 and KMT2D mutated patients both in univariate analysis as well as adjusting for MIPI, Ki67 and blastoid variant HR 4.26 (95% CI 1.34 to 13.57), p = 0.014 and HR 3.09 (95% CI 1.07 to 8.86), p = 0.036, respectively. On these bases, a survival model was proposed based on the TP53 and KMT2D mutation status: 3‐years PFS and OS were 25% and 64% for patients carrying either TP53 or KMT2D mutations or both vs 75% and 92% for patients without any of these mutations (Figure 1). Conclusion: The updated clinical results of the FIL‐MCL0208 trial show that: i) bothTP53 and KMT2D mutations independently associate with shorter PFS and OS in younger MCL patients receiving high‐dose therapy; ii) KMT2D mutations seem to be as detrimental as TP53 mutations, at least in terms of PFS; iii) given the negative prognostic impact of these mutations, they might be used to select high‐risk patients for novel therapeutic approaches.