Identifying Appropriate Patient Groups and Drug Targets in DLBCL

In their article in this issue of ONCOLOGY, Nastoupil, Rose, and Flowers give a very careful assessment of the options for treating diffuse large B-cell lymphoma (DLBCL), with a focus on the importance of dose density in improving outcomes in this disease. They highlight the relative lack of unambiguously significant advances obtained from “tweaking” the R-CHOP (rituximab [Rituxan]–cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) regimen by altering the total number of cycles or the interval between cycles. They also find that for nontransplant candidates, we are currently pinning our hopes for advancement on the Cancer and Leukemia Group B (CALGB) 50303 trial, which compares infusional vs bolus therapy and remains in the midst of accrual more than 6 years after its initiation. In addition, the authors are appropriately cautious in concluding that high-dose therapy with stem cell rescue might be justified in the small subset of young DLBCL patients with high risk as assessed by the International Prognostic Index (IPI). One is struck by the consideration of several recent high-profile trials in this disease without exploration of fundamentally new drugs. In their final paragraph, the authors include the obligatory list of novel agents that might reasonably be tested in DLBCL, but if it takes the better part of a decade to run a DLBCL phase III study in this country, because of the large sample size required to confirm small differences, then we need to substantially improve our precision in identifying patients who might benefit from novel therapy.

Personalizing DLBCL Care

Although personalized clinical medicine sparked the differential treatment of non-Hodgkin lymphomas as a larger entity over the past 20 years, through advances in morphologic and immunohistochemistry-driven classification schemes, we have made less progress in personalizing the treatment of DLBCL. To date we have not identified a druggable or even an actionable genetic aberration, although nongerminal center B-cell of origin is under investigation as a specific indication to consider bortezomib (Velcade).[1-3] Attempts at the ultimate personalization with idiotype-based vaccines in lymphoma have largely fallen short of goals thus far.[4-6] Personalized cell-transfer strategies remain early in development and ambitious in their logistics.[7,8] Even a very well validated clinical IPI remains largely predictive and not a driver to choose therapy in this disease.

Identifying High-Risk Patients

Our best opportunities to make advances in the care of DLBCL are to look at the highest-risk subsets, which require us to move beyond the IPI and its subtle iterations. Two of the groups at highest risk include the trendy-to-discuss patients who are primarily refractory to anthracycline-based combination chemo-immunotherapy, and the less trendy-to-discuss but probably larger population of older patients who never get treated with an anthracycline to begin with. Neither group is going to benefit substantially by altering the dose nor schedule of currently available drugs, and both should be early targets for agents with novel mechanisms of action.

The anthracycline-resistant population is partially but incompletely identifiable at time of initial management planning through identification of MYC oncogene rearrangement.[9,10] Ongoing research looking for informative serum proteins, germline or somatic genetic variants, microenvironment cellular profiles, or perhaps a bio-informatic–driven algorithm involving all of the above will likely soon make this group more readily identifiable.[11-14] Early utilization of functional imaging in DLBCL to establish early detection of R-CHOP resistance has yielded inconclusive results, as nicely described by Nastoupil and coauthors.

The cohort of minimally treated patients is more easily determined at the time of management planning-they are old and have poor performance status and comorbidities-but these patients are harder to study because they do not often show up at institutions generating most of the DLBCL research in the US.[15,16] Common approaches to “novel” strategies in this population are fundamentally similar to those reviewed by Nastoupil and colleagues; that is, simply looking at dose modifications (but in this case with reduced dose intensity) of the drugs in the R-CHOP regimen.[17,18]

Conclusions

Perhaps the most effective strategy to advance the treatment of DLBCL involves three parallel approaches that have nothing to do with tinkering with the delivery of currently available drugs. On one front, we should aggressively vet all candidate agents with novel mechanisms that demonstrate early signals of activity and modest toxicity, focusing on phase II trials in the two high-risk subsets discussed above. While it is certainly rational to direct some candidates to certain subsets based on biology, such as studying drugs that target the B-cell receptor signaling pathway in DLBCL of activated B-cell origin, most are nonspecific enough to evaluate in any identifiable high-risk population. Sponsors should appreciate that if their new drugs are useful in either of the above settings, then they are likely to be useful to DLBCL patients as a whole, whereas if they are only useful in patients for whom R-CHOP already has a high success rate, then they are not really needed. Second, biomarker research should continue to further refine our ability to quickly identify which patients are not likely to do well with R-CHOP–like regimens. Finally, fundamental genomic discovery should continue with the confidence that both actionable and even druggable genetic aberrations are certain to emerge, and this will allow for the most focused clinical investigation strategy.

Financial Disclosure:Dr. Link serves on the scientific advisory board of, and is a compensated consultant for, Genentech. He also is a compensated consultant with Millennium, Seattle Genetics, and DSMB for Rigel Inc.

References:

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