Using biologic predictive factors to direct therapy of diffuse large B-cell lymphoma

Abstract

While diffuse large B-cell lymphoma (DLBCL) was once considered to be a single disease entity, recent biological insights have demonstrated that it can be divided up into at least three molecular subtypes. Gene expression profiling has revealed that DLBCL consists of a germinal center B-cell like subtype (GCB), an activated B-cell like subtype (ABC) and a primary mediastinal B-cell lymphoma subtype (PMBL). These three entities arise from different stages of B-cell differentiation and are characterized by distinct mechanisms of oncogenic activation. In GCB DLBCL, the BCL6 transcription factor may play an important role in tumor survival and treatment resistance and strategies that target this are under investigation. ABC DLBCL is characterized by high expression of target genes of the nuclear factor kappa B (NF-κB)/Rel family of transcription factors and strategies that target NF-κB are in clinical trials. PMBL is a distinct clinicopathologic entity that shares many molecular features with nodular sclerosis Hodgkin lymphoma (HL) and may benefit from dose intensity approaches and inhibition of the Janus kinases. Other biologic predictive factors such as MYC and BCL2 may be overexpressed in both the GCB and ABC subtypes and strategies that target these complexes are also being tested.

Keywords: B-cell receptor signaling; diffuse large B-cell lymphoma; gene expression profiling; germinal center; molecular subtypes; mutational analysis; nuclear factor kappa B.

Figure 1.

Oncogenic pathways for three subtypes of diffuse large B-cell lymphoma. On the basis of gene-expression profiling, diffuse large B-cell lymphoma can be divided into three molecular subtypes: the germinal-center B-cell-like (GCB) subtype, the activated B-cell-like (ABC) subtype, and primary mediastinal B-cell lymphoma (PMBL). These subtypes originate from various stages of B-cell differentiation and acquire distinct oncogenic abnormalities. The abnormalities that are listed are preferentially or exclusively observed in the indicated subtypes. Blue lines indicate activation and red lines indicate inhibition. AID, activation-induced cytidine deaminase; ITAM, immunoreceptor tyrosine-based activation motifs; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB. (Courtesy of Dr Louis Staudt, NCI.)

Figure 2.

Diagnosis and outcome of diffuse large B-cell lymphoma (DLBCL) subtypes by gene expression profiling subtypes. (A) Heat map showing expression of genes that discriminate between the germinal center B-cell like subtype (GCB) and activated B-cell like subtype (ABC) subtypes of DLBCL. Genes associated with the microenvironment, which have prognostic significance, are clustered into stromal 1 and 2 signatures. The stromal 1 signature genes are associated with extracellular matrix deposition and histiocytic infiltration and the stromal 2 signature genes are associated with increased tumor blood vessel density. (B) Kaplan–Meier estimates of progression free and overall survival are shown according to GCB or ABC DLBCL subtype in patients treated with R-CHOP based therapy. Median follow up is approximately 2 years [Lenz et al. 2008]. (Image courtesy of Dr Louis Staudt, NCI.)

Figure 3.

B-cell receptor (BCR) signaling pathway and potential targets. (A) Signaling through BCR leads to downstream activation of the nuclear factor kappa B (NF-κB) transcription factor, which is a driver pathway in activated B-cell like subtype (ABC) diffuse large B-cell lymphoma (DLBCL). Signaling also activates the Akt/mTOR and MAP kinase pathways. (B) Targeted therapies in ABC DLBCL to inhibit NF-κB are dependent on the presence or absence of activating mutations in CARD11. Tumors with activating mutations are likely to require inhibition of downstream targets (e.g. NF-κB activation) whereas those with wild type are likely to be sensitive to both downstream and upstream (e.g. inhibition of BTK or SYK) targets. (Image courtesy of Dr Louis Staudt, NCI.)

Figure 4.

Clinical treatment paradigm. (A) Patients initially received bortezomib alone at 1.3 mg/m² on days 1, 4, 8 and 11 every 21 days (Part A) unless they had disease which the investigators judged to required immediate chemotherapy such as impending or ongoing organ compromise; these patients only received Part B. Patients with progressive disease on Part A received bortezomib with DA-EPOCH (Part B). Of 31 diffuse large B-cell lymphoma (DLBCL) cases analyzed by gene expression profiling, 16 were excluded due to ineligible subtype by classification or did not receive Part A, leaving 5 activated B-cell like subtype (ABC) and 10 germinal center B-cell like subtype (GCB) cases eligible for analysis of outcome. Of 24 paraffin-embedded tumor biopsies analyzed by immunohistochemistry, 12 each were categorized as GCB and ABC (non-GCB) type [Hans et al. 2003]. By combining both methods, cases were identified as GCB in 15 and ABC in 12 and included in the analysis of outcome with Part B. (B) Response and overall survival of 27 patients with de novo GCB or ABC DLBCL who received DA-EPOCH-B. Overall survival of patients with ABC or GCB DLBCL showed a median survival of 10.8 and 3.4 months, respectively (p = 0.0026). Patients with ABC DLBCL also had a significantly higher complete and overall response rate compared with patients with GCB DLBCL [Dunleavy et al. 2009].

Figure 5.

Gene expression profiling of primary mediastinal B-cell lymphoma (PMBL) and comparisons with germinal center B-cell like subtype (GCB) and activated B-cell like subtype (ABC) diffuse large B-cell lymphoma (DLBCL) and Hodgkin’s lymphoma. (A) Heat map of genes that discriminate PMBL from other mediastinal large B-cell lymphomas and GCB and ABC DLBCL. (B) Heat map showing overlap in gene expression between PMBL and Hodgkin’s lymphomas, including CD30 and PDL2 [Rosenwald et al. 2003]. (Image courtesy of Dr Louis Staudt, NCI.)