Elsevier

Blood Reviews

Volume 32, Issue 5, September 2018, Pages 400-415
Blood Reviews

Review
Prognostication of diffuse large B-cell lymphoma in the molecular era: moving beyond the IPI

https://doi.org/10.1016/j.blre.2018.03.005Get rights and content

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with variable outcomes. Despite the majority of patients being cured with combination chemoimmunotherapy, up to 30% eventually succumb to the disease. Until recently, baseline prognostic assessment has centred on the International Prognostic Index (IPI), although this index is yet to impact strongly on treatment choice. Molecular features such as cell of origin, MYC and BCL-2 genetic alterations and protein overexpression were identified over a decade ago, yet their prognostic value is still not fully elucidated. Adding complexity are the plethora of new clinical, biological and molecular prognostic markers described in the recent literature, most of which lack independent validation, likely act as surrogate markers for those already in common use and have yet to substantially impact on therapeutic decision making. This review comprehensively assesses the value of individual prognostic markers in the clinical setting and their potential to predict response to novel agents, and ways to optimise their use in future research.

Introduction

Diffuse large B-cell lymphoma (DLBCL) comprises approximately 30% of all lymphomas [1]. It is a biologically and clinically heterogenous disease. While the majority are cured with upfront chemoimmunotherapy, approximately 50% will relapse and one third of patients will die from their disease [2]. Treatment decisions in 2018 still remain largely informed by the same clinical factors outlined in the original International Prognostic Index (IPI) described in 1993 [3]. Attempts to refine the IPI in the rituximab era have been variably successful and adoption in both recent clinical trials and routine care has been low.

In the last decade there has been dramatic improvement in understanding lymphoma biology and identification of multiple new molecular markers of potential prognostic value and clinical relevance. Some of these have led to development of targeted and novel therapies with the largely unsubstantiated hope thus far of improving precision of patient management in first-line treatment. However, many of these are only accessible in a subset of diagnostic laboratories and cancer care facilities and subject to variation in testing methods. Their uptake has been piecemeal and often not validated in patient populations beyond the initial analysed cohort. Consensus is lacking as to what constitutes a feasible and widely applicable ‘standard of care’ in the evaluation of newly diagnosed DLBCL.

This review comprehensively evaluates reported prognostic variables in DLBCL and will focus on the biological characteristics of the lymphoma, including cell of origin (COO), protein expression, genetic changes and the tumour microenvironment. Rarer clinicopathological subtypes such as EBV positive DLBCL of the elderly, primary cutaneous DLBCL leg type and lymphoid granulomatosis will not be included in this review.

Section snippets

International prognostic indices

In early lymphoma prognostication tools, only patient-related factors and extent of disease (i.e. Ann-Arbor staging) were included [4]. The IPI and its subsequent revisions, the R-IPI and the National Comprehensive Cancer Network (NCCN) IPI apply similar clinical and biochemical features in different iterations in an attempt to improve their discriminating power [3,5,6] (Table 1). The NCCN-IPI varies from its predecessors in that it assesses specific extra-nodal sites of high risk, whereas the

Radiological and molecular imaging features

Disease bulk by computed tomography (CT) has been shown by multivariate analysis to predict poor prognosis in both CHOP and R-CHOP treated patients, with a maximum tumour diameter of 10cm being most significant in the MINT trial, which notably only included younger patients with otherwise more favourable risk disease [72]. FDG positron emission tomography combined with CT (FDG-PET-CT) scanning is superior to CT alone, upstaging of 10–20% of patients compared with CT scanning [73]. This is most

Tumour associated markers:

Most of the markers described above are either surrogate markers of high tumour burden or reflect patient characteristics relating to fitness for therapy. Hence, they do not address underlying tumour biology per se. Advances in the understanding of DLBCL biology revealed the heterogeneity of this disease. Understanding the molecular mechanisms involved in a patients' tumour has the potential to identify druggable targets for upfront personalised intensification as well as improved therapy

Discussion

The proliferation of factors associated with DLBCL prognosis is making this area increasingly complex. The challenge is to determine which are most significant, cost effective and potentially impactful on emerging treatment alternatives and clinical trial design. Few studies have assessed the interplay between multiple prognostic factors due to the challenge of limited tissue supply, availability of testing methods and cost. This is demonstrated in Table 5, which represents the prognostic

Conclusion:

Prognostication of de novo DLBCL at diagnosis is increasingly complex and potentially expensive. Outside a trial setting, tests should only be done if they are of proven significance and are cost effective. Clinicians should only prognosticate patients with newly diagnosed DLBCL using published, reproducible data which show independent significance and incorporates patient and disease related factors. Studies reporting results of new prognostic markers should ensure that these markers are

Practice points

  • The NCCN-IPI remains the gold standard prognostic score for DLBCL

  • The most important biological prognostic factor remains MYC and BCL2 assessed both by IHC and FISH, which has additive prognostic value to the IPI

  • Biological prognostic factors may add powerful prognostic information. However, lack of comparison in multivariate analyses which include other relevant prognostic markers makes interpretation of their true relevance difficult

  • Clinicians should use validated scoring systems rather than

Research agenda

  • Novel prognostic markers should be specifically tested in predetermined subgroup analyses as part of clinical trials

  • Markers with the potential to predict response to novel agents should be the subject of predetermined stratifications in clinical trial design

Authors disclosures

JW: Honoraria: Bristol-Myers Squibb. GC: Research funding: Bristol-Myers Squibb, Merck Serono, Novartis, Pharmacyclics, Hutchison Medipharma, Incyte, Bayer. AG: Advisory board: Bristol-Myers Squibb, Merck Sharpe Dohme, Takeda, Roche, Gilead, Amgen. EH: Research Funding: Bristol-Myers Squibb, Merck Serono, Merck Sharpe Dohme, Celgene. Honoraria: Roche, Janssen, Bristol-Myers Squibb. Travel expenses: Roche, Takeda, Janssen. Advisory Board: Janssen, Celgene.

References (194)

  • J. Judd et al.

    Low level of blood CD4(+) T cells is an independent predictor of inferior progression-free survival in diffuse large B-cell lymphoma

    Clin Lymphoma Myeloma Leuk

    (2017)
  • X. Wei et al.

    Low lymphocyte-to-monocyte ratio predicts unfavorable prognosis in non-germinal center type diffuse large B-cell lymphoma

    Leuk Res

    (2014)
  • M. Roschewski et al.

    Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study

    Lancet Oncol

    (2015)
  • D. Ennishi et al.

    Soluble interleukin-2 receptor retains prognostic value in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP (RCHOP) therapy

    Ann Oncol

    (2009)
  • K.A. Yoh et al.

    The prognostic significance of elevated levels of serum ferritin before chemotherapy in patients with non-Hodgkin lymphoma

    Clin Lymphoma Myeloma Leuk

    (2014)
  • M. Pfreundschuh et al.

    Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study

    Lancet Oncol

    (2008)
  • M. Tout et al.

    Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study Association report

    Blood

    (2017)
  • S.H. Swerdlow et al.

    The 2016 revision of the World Health Organization classification of lymphoid neoplasms

    Blood

    (2016)
  • G. Ott et al.

    Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL

    Blood

    (2010)
  • M. Gleeson et al.

    The Activated B-Cell Subtype of Diffuse Large B-Cell Lymphoma As Determined By Whole Genome Expression Profiling on Paraffin Embedded Tissue Is Independently Associated With Reduced Overall and Progression Free Survival in the Rituximab Era: Results From the UK NCRI R-CHOP 14 v 21 Phase III Trial. 58th American Society of Haematology Annual Meeting and Exposition

    (2016)
  • A.A. Alizadeh et al.

    Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment

    Blood

    (2011)
  • C.P. Hans et al.

    Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray

    Blood

    (2004)
  • G. Gutierrez-Garcia et al.

    Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

    Blood

    (2011)
  • A. Smith et al.

    Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network

    Br J Cancer

    (2011)
  • M.A. Shipp et al.

    A predictive model for aggressive non-Hodgkin's lymphoma. The international non-Hodgkin's Lymphoma prognostic factors project

    N Engl J Med

    (1993)
  • S.A. Rosenberg

    Validity of the Ann Arbor staging classification for the non-Hodgkin's lymphomas

    Cancer Treat Rep

    (1977)
  • K.T. Prochazka et al.

    NCCN-IPI score-independent prognostic potential of pretreatment uric acid levels for clinical outcome of diffuse large B-cell lymphoma patients

    Br J Cancer

    (2016)
  • C. Montalban et al.

    Validation of the NCCN-IPI for diffuse large B-cell lymphoma (DLBCL): the addition of beta2 -microglobulin yields a more accurate GELTAMO-IPI

    Br J Haematol

    (2017)
  • M. Nijland et al.

    Treatment of initial parenchymal central nervous system involvement in systemic aggressive B-cell lymphoma

    Leuk Lymphoma

    (2017)
  • D. Chihara et al.

    Dose-adjusted EPOCH-R and mid-cycle high dose methotrexate for patients with systemic lymphoma and secondary CNS involvement

    Br J Haematol

    (2017)
  • A.J. Ferreri et al.

    High doses of antimetabolites followed by high-dose sequential chemoimmunotherapy and autologous stem-cell transplantation in patients with systemic B-cell lymphoma and secondary CNS involvement: final results of a multicenter phase II trial

    J Clin Oncol

    (2015)
  • Q.Q. Cai et al.

    New risk factors and new tendency for central nervous system relapse in patients with diffuse large B-cell lymphoma: a retrospective study

    Chin J Cancer

    (2016)
  • T.C. El-Galaly et al.

    Uterine, but not ovarian, female reproductive organ involvement at presentation by diffuse large B-cell lymphoma is associated with poor outcomes and a high frequency of secondary CNS involvement

    Br J Haematol

    (2016)
  • C.D. Fletcher et al.

    Central nervous system involvement in diffuse large B-cell lymphoma: an analysis of risks and prevention strategies in the post-rituximab era

    Leuk Lymphoma

    (2014)
  • H.R. Guirguis et al.

    Impact of central nervous system (CNS) prophylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature

    Br J Haematol

    (2012)
  • Y. Kanemasa et al.

    Central nervous system relapse in patients with diffuse large B cell lymphoma: analysis of the risk factors and proposal of a new prognostic model

    Ann Hematol

    (2016)
  • R. Kansara et al.

    Site of central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) by the CNS-IPI risk model

    Br J Haematol

    (2017)
  • R. Kridel et al.

    Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era

    Br J Haematol

    (2017)
  • N. Schmitz et al.

    CNS International prognostic index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP

    J Clin Oncol

    (2016)
  • N. Tomita et al.

    The standard international prognostic index for predicting the risk of CNS involvement in DLBCL without specific prophylaxis

    Leuk Lymphoma

    (2018)
  • J. Campbell et al.

    The prognostic impact of bone marrow involvement in patients with diffuse large cell lymphoma varies according to the degree of infiltration and presence of discordant marrow involvement

    Eur J Haematol

    (2006)
  • Y. Cao et al.

    Mutations or copy number losses of CD58 and TP53 genes in diffuse large B cell lymphoma are independent unfavorable prognostic factors

    Oncotarget

    (2016)
  • L.H. Sehn et al.

    Impact of concordant and discordant bone marrow involvement on outcome in diffuse large B-cell lymphoma treated with R-CHOP

    J Clin Oncol

    (2011)
  • H.J. Adams et al.

    FDG PET/CT for the detection of bone marrow involvement in diffuse large B-cell lymphoma: systematic review and meta-analysis

    Eur J Nucl Med Mol Imaging

    (2014)
  • K.R. Carson et al.

    Increased body mass index is associated with improved survival in United States veterans with diffuse large B-cell lymphoma

    J Clin Oncol

    (2012)
  • M. Pfreundschuh et al.

    Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients

    Br J Haematol

    (2017)
  • S.I. Go et al.

    Prognostic impact of sarcopenia in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone

    J Cachexia Sarcopenia Muscle

    (2016)
  • D.H. Kim et al.

    Absolute lymphocyte counts predicts response to chemotherapy and survival in diffuse large B-cell lymphoma

    Leukemia

    (2007)
  • M.C. Cox et al.

    Low absolute lymphocyte count is a poor prognostic factor in diffuse-large-B-cell-lymphoma

    Leuk Lymphoma

    (2008)
  • J. Wang et al.

    Lymphocyte-to-monocyte ratio is associated with prognosis of diffuse large B-cell lymphoma: correlation with CD163 positive M2 type tumor-associated macrophages, not PD-1 positive tumor-infiltrating lymphocytes

    Oncotarget

    (2017)
  • Cited by (49)

    • Evidence-based review of genomic aberrations in diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS): Report from the cancer genomics consortium lymphoma working group

      2022, Cancer Genetics
      Citation Excerpt :

      Close to 50% of all MYC-rearranged cases may have a BCL2 and/or BCL6 rearrangement and are classified as high-grade B cell lymphoma or double- and triple-hit lymphoma [5,59]. Double-expressor DLBCL overexpress MYC and BCL2, are seen in 30% of DLBCL, NOS cases, and are more common in the ABC subtype (33–46% ABC vs. 17% GCB) [60]. In the ABC subtype, activation of BCR and NF-kB signaling may cause overexpression of MYC; while in the GCB subtype, overexpression is due to translocation between MYC and BCL2 [61].

    • Prognostic and therapeutic value of somatic mutations in diffuse large B-cell lymphoma: A systematic review

      2021, Critical Reviews in Oncology/Hematology
      Citation Excerpt :

      However, these clinical parameters do not address the underlying biological heterogeneity of DLBCL. Consequently, some limitations remain, such as poor characterization and huge heterogeneity, resulting in difficulties to predict survival; in fact, the utility of IPI in the era of immunochemotherapy has not been established, and the subsequent revisions that have appeared (the R-IPI and the NCCN-IPI) also fail to adequately identify extremely high-risk groups response precisely enough to design risk adapted therapies (Wight et al., 2018). In recent years the application of gene expression profiling (GEP) to the study of DLBCL was a major advance which further clarified DLBCL heterogeneity and provided a rationale for subdividing cases into groups.

    • Epidemiological features of primary breast lymphoma patients and development of a nomogram to predict survival

      2021, Breast
      Citation Excerpt :

      First, as this was a retrospective study, biases were unavoidable. Second, many variables that could have an impact on survival are not recorded in the SEER database, such as several biomarkers, B symptoms, and the IPI [36]. Therefore, many potential prognostic factors could not be included in the prediction model.

    View all citing articles on Scopus
    1

    Address: Olivia Newton John Cancer and Wellness Centre, Level 4, 145 Studley Road, Heidelberg, Vic, 3084, Australia.

    View full text