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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 LU and Ek, Sara LU , et al. (2017) In Blood 130(17). p.1903-1910
Abstract

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... (More)

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.

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publication status
published
subject
keywords
TP53, lymphoma, chemoimmunotherapy
in
Blood
volume
130
issue
17
pages
8 pages
publisher
American Society of Hematology
external identifiers
  • scopus:85032470705
  • pmid: 28819011
  • wos:000413766200008
ISSN
0006-4971
DOI
10.1182/blood-2017-04-779736
language
English
LU publication?
yes
id
29c0cdc2-0c4f-4dc1-854e-07b0f29020e2
date added to LUP
2017-11-13 09:37:51
date last changed
2018-07-08 04:28:18
@article{29c0cdc2-0c4f-4dc1-854e-07b0f29020e2,
  abstract     = {<p>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 &gt; 30%); however, inmultivariate analyses, only TP53 mutations (HR, 6.2; P &lt;.0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P &lt;.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 &lt;.0001). TP53 mutations were significantly associated with Ki67 &gt; 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.</p>},
  author       = {Eskelund, Christian W. and Dahl, Christina and Hansen, Jakob W. and Westman, Maj and Kolstad, Arne and Pedersen, Lone B. and Montano-Almendras, Carmen P. and Husby, Simon and Freiburghaus, Catja and Ek, Sara and Pedersen, Anja and Niemann, Carsten and Raty, Riikka and Brown, Peter and Geisler, Christian H. and Andersen, Mette K and Guldberg, Per and Jerkeman, Mats and Grønbæk, Kirsten},
  issn         = {0006-4971},
  keyword      = {TP53,lymphoma,chemoimmunotherapy},
  language     = {eng},
  month        = {10},
  number       = {17},
  pages        = {1903--1910},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy},
  url          = {http://dx.doi.org/10.1182/blood-2017-04-779736},
  volume       = {130},
  year         = {2017},
}