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Prognostic and therapeutic stratification in CLL: focus on 17p deletion and p53 mutation

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Abstract

Chronic lymphocytic leukemia (CLL), a disorder for which B cell heterogeneity and increased cellular proliferation play central pathogenic roles, displays several genetic abnormalities that are associated with poor prognosis and have therapeutic implications. In this review, we discuss the prognostic role and therapeutic implications of chromosome 17p deletions and TP53 mutations in CLL. Unlike other recurrent genetic abnormalities, the frequency of TP53 alterations is relatively low in newly diagnosed patients, but increases sharply with disease progression, which suggests that these alterations represent an evolutionary mechanism of resistance. In comparison with patients without such abnormalities, those with 17p deletions and TP53 mutations have lower response rates and more aggressive disease. One important consequence of the diverse molecular mechanisms that affect the TP53 pathway is the need to assess both the presence of 17p deletion and TP53 mutations before treatment initiation. Several authors have attempted to incorporate TP53 abnormalities in different prognostic models for CLL, and the recent International Prognostic Index for Chronic Lymphocytic Leukemia formally considers patients with TP53 abnormalities (deletion 17p or TP53 mutation or both) as high-risk. Several novel agents may improve results in patients with CLL, including in those with TP53 mutations. Ibrutinib, idelalisib, and venetoclax have been approved in various settings and countries for treatment of CLL. Further progress in targeted therapy and judicious use of chemotherapy, monoclonal antibodies, and reduced-intensity allogeneic transplantation will provide patients with CLL in general, and those with TP53 abnormalities in particular, with a better prognosis.

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Acknowledgments

AbbVie participated in the interpretation of data, review, and approval of the content. All authors participated in writing, review, and approval of this manuscript. Medical writing services and editorial support was provided by Everardo D. Saad and Ana Elisa B. Bueno da Silva of Dendrix and was funded by AbbVie.

Funding

Dendrix provided medical writing services in the development of this manuscript, funded by AbbVie.

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Authors and Affiliations

  1. Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo/ICESP, Av. Dr. Eneas de Carvalho Aguiar, 155, 1 andar, Cerqueira Cesar, São Paulo, 05403-000, Brazil

    Valeria Buccheri

  2. Hospital Santa Marcelina, São Paulo, Brazil

    Wolney Gois Barreto

  3. Hospital das Clínicas de Porto Alegre, Santa Casa de Porto Alegre, Fundação Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil

    Laura Maria Fogliatto

  4. Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil

    Marcelo Capra

  5. AbbVie, São Paulo, Brazil

    Mariana Marchiani

  6. Faculdade de Medicina, Universidade de São Paulo/Hospital Sírio Libanês, São Paulo, Brazil

    Vanderson Rocha

  7. Churchill Hospital, NHS-BT, Oxford, UK

    Vanderson Rocha

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  1. Valeria Buccheri
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  2. Wolney Gois Barreto
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  3. Laura Maria Fogliatto
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  4. Marcelo Capra
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  5. Mariana Marchiani
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Correspondence to Valeria Buccheri.

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Conflict of interest

Valeria Buccheri has declared no conflicts of interest for this publication. Clinical research activities as PI: Janssen, Takeda, AbbVie, Roche, Merck; speaker: Janssen, Takeda.

Wolney Barreto has declared no conflicts of interest for this publication. Speaker: Roche, Janssen.

Laura Fogliatto has declared no conflicts of interest for this publication. Clinical research activities as PI: Janssen, Takeda, AbbVie, Roche, Merck, Celgene; speaker: Novartis, Roche.

Marcelo Capra has declared no conflicts of interest for this publication. Clinical research activities as: Janssen, Takeda, AbbVie, Roche; advisory board: Janssen, Takeda, Cellgene; speaker: Janssen.

Mariana Marchiani has declared no conflicts of interest for this publication. AbbVie employee and may own AbbVie stock or stock options.

Vanderson Rocha has declared no conflicts of interest for this publication. National advisory board: Amgen, Celgene, Takeda, Zodiac; international advisory board: Pfizer, Jazz Therapeutics; speaker: Amgen, Celgene, Takeda, Zodiac, Pfizer, Jazz Therapeutics, Janssen.

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Buccheri, V., Barreto, W.G., Fogliatto, L.M. et al. Prognostic and therapeutic stratification in CLL: focus on 17p deletion and p53 mutation. Ann Hematol 97, 2269–2278 (2018). https://doi.org/10.1007/s00277-018-3503-6

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