TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy
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TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. / Eskelund, Christian W.; Dahl, Christina; Hansen, Jakob W.; Westman, Maj; Kolstad, Arne; Pedersen, Lone B.; Montano-Almendras, Carmen P.; Husby, Simon; Freiburghaus, Catja; Ek, Sara; Pedersen, Anja; Niemann, Carsten; Raty, Riikka; Brown, Peter; Geisler, Christian H.; Andersen, Mette K.; Guldberg, Per; Jerkeman, Mats; Grønbæk, Kirsten.
I: Blood, Bind 130, Nr. 17, 2017, s. 1903-1910.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy
AU - Eskelund, Christian W.
AU - Dahl, Christina
AU - Hansen, Jakob W.
AU - Westman, Maj
AU - Kolstad, Arne
AU - Pedersen, Lone B.
AU - Montano-Almendras, Carmen P.
AU - Husby, Simon
AU - Freiburghaus, Catja
AU - Ek, Sara
AU - Pedersen, Anja
AU - Niemann, Carsten
AU - Raty, Riikka
AU - Brown, Peter
AU - Geisler, Christian H.
AU - Andersen, Mette K.
AU - Guldberg, Per
AU - Jerkeman, Mats
AU - Grønbæk, Kirsten
PY - 2017
Y1 - 2017
N2 - Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) andCDKN2A(20%),weresignificantly associatedwithinferioroutcomes(togetherwithMIPI, MIPI-c, blastoidmorphology, and Ki67 > 30%); however, inmultivariate analyses, only TP53 mutations (HR, 6.2; P <.0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P <.0001) andMIPI-c high-risk (HR, 2.6; P5.003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P <.0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.
AB - Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) andCDKN2A(20%),weresignificantly associatedwithinferioroutcomes(togetherwithMIPI, MIPI-c, blastoidmorphology, and Ki67 > 30%); however, inmultivariate analyses, only TP53 mutations (HR, 6.2; P <.0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P <.0001) andMIPI-c high-risk (HR, 2.6; P5.003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P <.0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.
U2 - 10.1182/blood-2017-04-779736
DO - 10.1182/blood-2017-04-779736
M3 - Journal article
C2 - 28819011
AN - SCOPUS:85032470705
VL - 130
SP - 1903
EP - 1910
JO - Blood
JF - Blood
SN - 0006-4971
IS - 17
ER -
ID: 185719731