TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

Christian W. Eskelund; Christina Dahl; Jakob W. Hansen; Maj Westman; Arne Kolstad; Lone B. Pedersen; Carmen P. Montano-Almendras; Simon Husby; Catja Freiburghaus; Sara Ek; Anja Pedersen; Carsten Niemann; Riikka Raty; Peter Brown; Christian H. Geisler; Mette K. Andersen; Per Guldberg; Mats Jerkeman; Kirsten Grønbæk

doi:10.1182/blood-2017-04-779736

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

Christian W. Eskelund, Christina Dahl, Jakob W. Hansen, Maj Westman, Arne Kolstad, Lone B. Pedersen, Carmen P. Montano-Almendras, Simon Husby, Catja Freiburghaus, Sara Ek, Anja Pedersen, Carsten Niemann, Riikka Raty, Peter Brown, Christian H. Geisler, Mette K. Andersen, Per Guldberg, Mats Jerkeman, Kirsten Grønbæk^*

^*Corresponding author for this work

Department of Clinical Medicine

140 Citations (Scopus)

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 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.

Original language	English
Journal	Blood
Volume	130
Issue number	17
Pages (from-to)	1903-1910
Number of pages	8
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2017-04-779736
Publication status	Published - 2017

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Eskelund, C. W., Dahl, C., Hansen, J. W., Westman, M., Kolstad, A., Pedersen, L. B., Montano-Almendras, C. P., Husby, S., Freiburghaus, C., Ek, S., Pedersen, A., Niemann, C., Raty, R., Brown, P., Geisler, C. H., Andersen, M. K., Guldberg, P., Jerkeman, M., & Grønbæk, K. (2017). TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood, 130(17), 1903-1910. https://doi.org/10.1182/blood-2017-04-779736

Eskelund, CW, Dahl, C, Hansen, JW, Westman, M, Kolstad, A, Pedersen, LB, Montano-Almendras, CP, Husby, S, Freiburghaus, C, Ek, S, Pedersen, A , Niemann, C, Raty, R, Brown, P, Geisler, CH, Andersen, MK, Guldberg, P, Jerkeman, M & Grønbæk, K 2017, 'TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy', Blood, vol. 130, no. 17, pp. 1903-1910. https://doi.org/10.1182/blood-2017-04-779736

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title = "TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy",

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 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.",

author = "Eskelund, {Christian W.} and Christina Dahl and Hansen, {Jakob W.} and Maj Westman and Arne Kolstad and Pedersen, {Lone B.} and Montano-Almendras, {Carmen P.} and Simon Husby and Catja Freiburghaus and Sara Ek and Anja Pedersen and Carsten Niemann and Riikka Raty and Peter Brown and Geisler, {Christian H.} and Andersen, {Mette K.} and Per Guldberg and Mats Jerkeman and Kirsten Gr{\o}nb{\ae}k",

year = "2017",

doi = "10.1182/blood-2017-04-779736",

language = "English",

volume = "130",

pages = "1903--1910",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "17",

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TY - JOUR

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

SN - 0006-4971

VL - 130

SP - 1903

EP - 1910

JO - Blood

JF - Blood

IS - 17

ER -

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

Abstract

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