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Risk-Adapted Therapy for DLBCL
Beyond R-CHOP-21: Risk-Adapted Therapy for DLBCL

Released: March 10, 2015

Expiration: March 08, 2016

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In the landmark LNH-98.5 study, GELA demonstrated that adding rituximab to conventional CHOP chemotherapy resulted in clinically meaningful improvement in PFS and OS vs CHOP alone in elderly patients with DLBCL. This result has been confirmed in a number of trials and since that important development, several studies have been undertaken in an attempt to further improve the success of R-CHOP in DLBCL.

Dose Density
One strategy is to adjust the dose density of R-CHOP. Based on the findings that dose-dense CHOP (CHOP-14) was superior to standard CHOP (CHOP-21), 2 studies compared R-CHOP-14 with R-CHOP-21. One observation from the RICOVER-60 trial was that women older than 60 years of age had a superior PFS compared with men in the same age group. A similar effect was seen in a retrospective analysis of GELA studies of aggressive lymphoma with rituximab-based therapy. Pharmacokinetic analysis of the RICOVER-60 and MINT studies demonstrated that women older than 60 years of age have a slower clearance of rituximab compared with younger men and women and men older than 60 years of age. In an attempt to overcome the pharmacokinetic difference between men and women older than 60 years of age, the SEXIE-R-CHOP-14 trial evaluated the impact of increasing the dose of rituximab to 500 mg/m2 in male patients. In results presented at the 2014 ASCO annual meeting, male patients receiving 500 mg/m2 and women older than 60 years of age treated with the standard dose of 375 mg/m2 no longer exhibited differences in pharmacokinetics or PFS.

Improving the “R” in R-CHOP
Another avenue to enhance R-CHOP would be to substitute rituximab for a more effective anti-CD20 antibody. Obinutuzumab is a novel type II anti-CD20 antibody that has demonstrated greater direct apoptotic effects and enhanced antibody-dependent cell-mediated cytotoxicity than rituximab. Preliminary results of obinutuzumab plus CHOP in DLBCL presented at ASCO 2014 demonstrated that the combination is safe and effective. However, results of the head-to-head efficacy comparison of R-CHOP vs obinutuzumab plus CHOP in the phase III GOYA study are pending.

Treatment Based on Disease Category
Other efforts to improve outcomes with R-CHOP depend on proper characterization of each patient’s disease. Work from a number of groups has demonstrated that DLBCL is not a single pathologic entity. Gene expression profiling studies have demonstrated that the DLBCL-not otherwise specified category comprises 2 major subtypes based on the cell of origin (COO): germinal center (GC) and active B cell (ABC). COO is a clinically significant predictor of outcome with R-CHOP therapy. For example, PFS and OS are inferior for patients with an ABC DLBCL vs GC DLBCL subtype. To make clinical use of this information, the pathologist must determine the COO. The most definitive method requires gene expression profiling on fresh tissue. In addition, numerous immunohistochemistry (IHC) antibody panels have been reported that can roughly segregate GC and non-GC DLBCL.

Gene expression profiling and whole genome sequencing studies have revealed that GC and ABC DLBCL have distinctly different oncogenic programs. For example, ABC tumors are characterized by chronic active signaling through the B-cell receptor (BCR) and activation of the NF-κB pathway. By contrast, GC tumors exhibit increased genomic instability, activation of the MTOR/AKT pathway, and translocation of BCL2. Some of the recurrent mutations seen in DLBCL are distinctive based on COO. The clinical relevance of these mutations is a rapidly emerging area of investigation. Some have clear prognostic significance and others likely influence response or non-response to specific therapies.

New Therapeutic Approaches
As a consequence of the greater insight into tumor biology afforded by gene expression profiling and mutational analysis, novel therapeutic approaches are being developed that involve the addition of targeted therapies to standard R-CHOP. Lenalidomide is a potent immunomodulatory drug with multiple mechanisms of action that are centrally related to binding the E3-ubiquitin ligase and promoting accelerated degradation of the transcription factors IKZF1 and IKZF3 in both B and T cells. Early work demonstrated that lenalidomide has single-agent activity in relapsed/refractory DLBCL. A subsequent analysis suggested that the activity was largely restricted to non-GC DLBCL. Two studies have combined lenalidomide with R-CHOP (RL-CHOP); both demonstrated high ORR and CR rates that appear to be durable. Analyses of COO suggest that most of the benefit of RL-CHOP is in patients with non-GC or ABC DLBCL, whose outcomes were equivalent or superior to patients with GC DLBCL. There are 2 ongoing randomized clinical trials comparing RL-CHOP with R-CHOP in patients with DLBCL, which are currently enrolling. The randomized phase II ECOG 1412 trial is enrolling patients with all forms of DLBCL and includes a planned interim analysis to determine the impact of COO on outcomes with RL-CHOP. The ROBUST trial is a randomized phase III trial with enrollment restricted to patients with ABC DLBCL.

A trial of ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK), in relapsed/refractory DLBCL demonstrated activity in non-GC (ABC) DLBCL. This activity was affected by a number of recurrent mutations in ABC DLBCL. CD79 mutations tended to enhance activity whereas CARD11 mutations blocked activity. This outcome is logical since CD79 is upstream of BTK and CARD11 is downstream. Ibrutinib has been combined with R-CHOP and has been shown to be safe and effective in a small dose-finding study. There is now an ongoing phase III trial of R-CHOP vs ibrutinib plus R-CHOP in patients with non-GC DLBCL.

Bortezomib was also combined with R-CHOP, based on the observation that bortezomib accelerates the degradation of NF-κB. A pilot dose-finding study demonstrated that bortezomib could be safely combined with R-CHOP and found similar outcomes among patients with non-GC and GC DLBCL. Three large prospective randomized trials are under way comparing R-CHOP with bortezomib plus R-CHOP in DLBCL. Accrual for these trials is complete and we are awaiting results.

My Approach
In summary, R-CHOP-21 remains the standard of care for the treatment of DLBCL. However, based on data from the SEXIE-R-CHOP-14 trial, the dose of rituximab may need to be increased to 500 mg/m2 in selected patients. Nonetheless, there are several novel agents that have been combined with R-CHOP, including lenalidomide, ibrutinib, and bortezomib, that all appear to improve the outcome of patients with ABC DLBCL. Should risk adaptation based on COO be standard? Not yet. We need to have widespread use of robust tools that distinguish GC and ABC DLBCL. Furthermore, rather than making treatment decisions based on phase II data alone, I prefer to wait for results from the ongoing phase III studies. These data will be essential to definitively determine if adding novel agents to R-CHOP has clinical benefit. Nonetheless, my approach is to incorporate COO considerations into treatment selection for patients who are not participating in clinical trials, using IHC. For patients with advanced-stage GC DLBCL, I generally recommend therapy with DA-EPOCH-R; for patients with non-GC DLBCL, I recommend sequential R-CHOP/RICE. However, my first preference is for patients with advanced DLBCL to participate in clinical trials.

Your Thoughts?
Which of these strategies to improve upon R-CHOP would you consider incorporating into the treatment of patients with DLBCL? Join the conversation by posting your thoughts in the comments section below.

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Which treatment strategy would you be most likely to recommend for patients with advanced ABC DLBCL?
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