During the past decades the outcome of Mantle Cell Lymphoma (MCL) has improved substantially in younger patients. In a long-term update of the Nordic MCL2 trial we show very long response durations, but we also observe a continuous pattern of relapses even after 10 years of remission.(1)In the current study we examine the prognostic impact of aberrations in the most frequently mutated genes in MCL in a homogenously and optimally treated patient cohort, with a long-term follow-up.
MATERIAL AND METHODS:
Freshly frozen DNA from diagnostic bone marrow samples from patients included in two prospective Nordic trials, MCL2 and MCL3 were analysed. In both trials patients received intensified first line induction therapy with alternating courses of R-CHOP and R-HD-Cytarabine and consolidation with high-dose therapy and ASCT. All patients signed an informed consent.(2,3) NGS was performed using the Ion Torrent Technology. A targeted panel of 8 genes frequently mutated in MCL was constructed on the basis of previous NGS studies.(4,5). Cut-off for calling a mutation was set to a variant allele frequency >3%. Median coverage was 2700X.
One-hundred-and-fifty-one patients were included in the study. All were previously untreated and <66 years (median 58, range 29-65). After a median follow-up of 9.2 years, median overall (OS) and progression-free survival (PFS) of all 151 patients were 12.5 and 8.2 years, respectively. Fifty-two patients carried 1 mutation and 32 patients had >1 mutation (2-4). Mutations were distributed as follows: ATM 42 (28%), KMT2D 27 (18%), WHSC1 8 (5%), TP53 15 (10%), CCND1 15 (10%), NOTCH2 4 (3%), NOTCH1 9 (6%), BIRC3 5 (3%). TP53 mutations were highly predictive of an inferior outcome (median OS and PFS were 19 and 12 months, respectively; p<0.0001 for both outcomes) and were confirmed in multivariate analyses (OS: p<0.0001, HR=12.2; PFS: p<.0001, HR=15.4).
Here we evaluate the prognostic impact of mutations in eight genes that are commonly involved in MCL in a cohort of 151 younger patients uniformly treated by a current standard-of-care regimen. We demonstrate an exceedingly dismal outcome of patients carrying TP53 mutations and propose that these patients should be considered for an alternative frontline approach.