ReviewPrognostication of diffuse large B-cell lymphoma in the molecular era: moving beyond the IPI
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
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The NCCN-IPI remains the gold standard prognostic score for DLBCL
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The most important biological prognostic factor remains MYC and BCL2 assessed both by IHC and FISH, which has additive prognostic value to the IPI
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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
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Clinicians should use validated scoring systems rather than
Research agenda
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Novel prognostic markers should be specifically tested in predetermined subgroup analyses as part of clinical trials
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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.
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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 GeneticsCitation 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/HematologyCitation 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, BreastCitation 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.
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