Poster Presentation 29th Lorne Cancer Conference 2017

Targeted DNA Sequencing of Diagnostic Samples from the Nordic Mantle Cell Lymphoma trials, MCL2 and MCL3 (#153)

Christian Winther Eskelund 1 , Jakob W Hansen 1 , Christina Dahl 2 , Maj Westman 1 , Lone B Pedersen 1 , Riikka Räty 3 , Arne Kolstad 4 , Christian Geisler 1 , Mats Jerkeman 5 , Per Guldberg 2 , Kirsten Grønbæk 1
  1. Rigshospitalet, København N, DANMARK, Denmark
  2. Kræftens Bekæmpelse, Copenhagen, Denmark
  3. Helsinki University Central Hospital, Helsinki, Finland
  4. Oslo University Hospital, Oslo, Norway
  5. Lund University Hospital, Lund, Sweden

INTRODUCTION:

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.

RESULTS:

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).

CONCLUSION:

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.

  1. 1) Eskelund, C.W., Kolstad, A., Jerkeman, M., R€, R., Laurell, A., Eloranta, S., Smedby, K.E., Husby, S., Pedersen, L.B., Andersen, N.S., Eriksson, M., Kimby, E., Bentzen, H., Kuittinen, O., Lauritzsen, G.F., NilssonEhle, H., Ralfkiaer, E., Garde, C., Elonen, E., Brown, P., et al (2016) 15year followup of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. , 1–9.
  2. 2) Geisler, C.H., Kolstad, A., Laurell, A., Andersen, N.S., Pedersen, L.B., Jerkeman, M., Eriksson, M., Nordström, M., Kimby, E., Boesen, A.M., Kuittinen, O., Lauritzsen, G.F., Nilsson-Ehle, H., Ralfkiær, E., Åkerman, M., Ehinger, M., Sundström, C., Langholm, R., Delabie, J., Karjalainen-Lindsberg, M.L., et al (2008) Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: A nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood, 112, 2687–2693.
  3. 3) Kolstad, A., Laurell, A., Jerkeman, M., Grønbæk, K., Elonen, E., Räty, R., Pedersen, L.B., Loft, A., Bogsrud, T.V., Kimby, E., Hansen, P.B., Fagerli, U.M., Nilsson-Ehle, H., Lauritzsen, G.F., Lehmann, A.K., Sundstrom, C., Karjalainen-Lindsberg, M.L., Ralfkiaer, E., Ehinger, M., Delabie, J., et al (2014) Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma. Blood, 123, 2953–2959.
  4. 4) Bea, S., Valdes-Mas, R., Navarro, a., Salaverria, I., Martin-Garcia, D., Jares, P., Gine, E., Pinyol, M., Royo, C., Nadeu, F., Conde, L., Juan, M., Clot, G., Vizan, P., Di Croce, L., Puente, D. a., Lopez-Guerra, M., Moros, a., Roue, G., Aymerich, M., et al (2013) Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proceedings of the National Academy of Sciences, 110, 18250–18255
  5. 5) Zhang, J., Jima, D., Moffitt, A.B., Liu, Q., Czader, M., Hsi, E.D., Fedoriw, Y., Dunphy, C.H., Richards, K.L., Gill, J.I., Sun, Z., Love, C., Scotland, P., Lock, E., Levy, S., Hsu, D.S., Dunson, D. & Dave, S.S. (2014) The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood, 123, 2988–2996.