The role of biomarkers in the management of patients with lymphoma: promise versus reality.

In this issue of Clinical Lymphoma & Myeloma, two articles appear regarding prognostic biomarkers in lymphoma. Mitrovic and colleagues detail a single-institution retrospective study in which patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–like regimens with or without rituximab.1 CD43, a sialoglycoprotein with multiple functions that include cell migration, apoptosis, and cell survival, is expressed on T cells, myeloid cells, and certain B-cell subsets.2-5 It is aberrantly expressed in some B-cell lymphomas, and it is used as part of a panel of markers for the diagnosis of small B-cell lymphomas, T-cell lymphomas, and myeloid sarcoma.6-8 The authors confirmed CD43 expression in a subset of DLBCL and showed that CD43+ DLBCL had inferior complete response rates, 2-year event-free survival, and overall survival (OS) compared with CD43– cases. Strikingly, the effect appeared to be primarily seen in the subset of patients that received rituximab and in patients with low International Prognostic Index (IPI). Thus, CD43 might be a biologic prognostic marker for patients with otherwise favorable clinical factors treated with modern immunochemotherapy regimens. The second article reviews the proceedings of the European School of Haematology (ESH)–European Haematology Association (EHA) workshop on biomarkers and prognosis in malignant lymphoma. This article summarizes the current thinking of a collection of leaders in clinical and translational lymphoma research.9 To illustrate some of the advances while adhering to space and scope restraints, this discussion will focus on 3 entities that have been the subject of the intense activity (follicular lymphoma [FL], mantle cell lymphoma [MCL], and DLBCL), followed by commentary about potential application. In FL, a major theme is the balance between molecular genetic and microenvironmental models.9 The former model involves acquired genetic alterations that take place after the primary IGH-BCL2 translocation (present at low levels in normal individuals) and are involved in oncogenesis and progression of FL.10,11 Recent highresolution single-nucleotide polymorphism (SNP) array studies add to known areas of alteration that include deletion of chromosome 6q (del[6q]), del(1p32-26), +7, +12, and +X, among others.10 In particular, uniparental disomy (UPD; copy-neutral loss of heterozygosity [LOH]) detected by SNP array analysis has been shown to be common at chromosome 1p and chromosome 6p.11 Furthermore, A20 (involved in regulating the nuclear factor– B pathway) and PERP (involved in p53-mediated apoptosis) at chromosome 6q23.3-24.1 have been identified as candidate genes in this homozygously deleted region. These findings have been extended with clinical correlates suggesting that UPD at 1p36 is associated with poor OS and UPD at 16p is associated with transformation and shorter progression-free survival.12 The microenvironmental model, spurred by expression profiling studies and subsequent in situ studies of inflammatory cell infiltrates, posits that non-neoplastic immune response signatures reflect inflammatory cell constituents (such as macrophages and regulatory T-cells) in the tumor microenvironment that interact with the tumor cells and affect the clinical behavior and outcome of FL.13-16 Indeed, FL-associated macrophages have been shown to be a poor prognostic factor in at least 3 separate studies.15,17,18 Controversy and conflicting data, however, do exist for certain markers and might be due to technique and/or treatment regimens.19,20 In a different strategy that would be applicable across other lymphoma types, constitutional SNPs of candidate genes have been examined in FL. In particular, SNPs in IL8, IL2, IL12B, IL1RN, DNA repair genes, and 1 carbon metabolism gene have been associated with short survival.21,22 Such observations await confirmation and detailed biologic studies to explain the mechanisms involved. This will identify useful biomarkers in the host germline that influence lymphoma behavior and could further our understanding of lymphoma biology. For MCL, agreement exists that proliferation of tumor cells is a major determinant of prognosis.23 This is driven home by the observation that overexpression of cyclin D1 and cell-cycle dysregulation is present in almost all cases. In cyclin D1–negative MCL cases, there appears to be alteration in other cyclin D genes.24 As outlined in the ESH-EHA article in this issue,9 proliferation index as assessed by Ki-67 is a practical assay evaluated in patients in the setting of multicenter clinical trials. Indeed, a Mantle Cell Lymphoma IPI that includes a weighting for proliferation has been proposed.25 Diffuse large B-cell lymphoma has arguably seen the most activity in developing prognostic markers that improve upon the IPI. Studies have been greatly aided by information gleaned from genome-wide expression studies. These studies have identified germinal center B-cell–like (GCB) and activated B-cell–like (ABC) subtypes of DLBCL as well as mediastinal large B-cell lymphoma as distinct sets of cases. The GCB and ABC types of DLBCL have different prognoses, with the latter having shorter survival times compared with the former, independent of the IPI.26 Functional gene signatures related to germinal center, lymph node, proliferation, and class II major histocompatibility complex could also be indentified and used to determine a prognostic model that has predicted outcome in patients with DLBCL.27 Importantly, in the ESH-EHA workshop, Clinical Lymphoma & Myeloma Vol. 9, No. 2, 121-123, 2009 DOI: 10.3816/CLM.2009.n.031