Diffuse Large B-Cell Lymphoma in the Very Elderly: The Case for Refining Our Clinical Trials

As life expectancy and the number of geriatric patients continue to rise, the incidence of diffuse large B-cell lymphoma (DLBCL) in the elderly will undoubtedly continue to increase as well. A limited understanding of the disease pathogenesis and lack of screening further suggest that preventative strategies are unlikely to slow this rate in the near future and that more efficacious and less toxic treatment regimens will be needed.

Latta and colleagues comprehensively summarize the existing data, leaving the reader with a practical guide on how to tailor treatment for the very elderly patient with DLBCL in the current era. However, their recommendations are limited to dose adjustments of chemoimmunotherapy regimens established through investigations of younger, fitter patients, and standard supportive measures. This is by no means a deficiency in the accompanying article but rather reflects the lack of prospectively collected clinical trial data guiding treatment of our oldest patients. Several studies have demonstrated that the mean age of cancer patients in the general population is older than that of those enrolled into clinical trials.[1] DLBCL is no exception.

Current data generated in elderly cancer patients are difficult to apply to DLBCL. Despite a growing number of investigations, most have been performed in patients with solid tumors. Because DLBCL is a disease that can be effectively palliated and cured with systemic therapy, a more aggressive treatment strategy is at times justified, especially given that improvements in performance status (when reduced by lymphoma) can be observed with lymphoma-directed therapy, as detailed by Latta and colleagues. However, outcomes in the elderly are clearly worse, and toxicity more frequent, creating a somewhat unique risk/benefit balance that may make treatment decisions in this population challenging.

It is also difficult to extrapolate from data generated in younger DLBCL patients. Consequently, prospective randomized studies have been performed in older, fitter patients with DLBCL.[2,3] At times, results in this older population have diverged from the results of similar studies in younger patients, confirming the need for such trials.[4,5] While it is difficult to extrapolate clinical trial results defined in the young to older patients, it may be nearly impossible to do so in the very elderly, given differences in disease pathogenesis, comorbidities, functional impairment, cognitive decline, and socioeconomic difficulties.[6] With this in mind, Peyrade and collegues conducted a prospective evaluation of “R-miniCHOP” (rituximab plus reduced doses [compared to regular R-CHOP] of cyclophosphamide, doxorubicin, vincristine, and prednisone) in selected fit patients older than 80 years of age, demonstrating an overall survival of 59% at 2 years.[7] While these results are very useful, further investigations are needed, since population studies in this group, reflecting outcomes in the general population, appear even more inferior.[8] In sum, additional well-controlled prospective studies specific for very elderly DLBCL patients are needed.

Several factors support the feasibility of such studies in the near future. Increasing collaboration within cooperative groups is already facilitating clinical trials in disease subsets and specific age groups. Furthermore, as the United States cooperative group structure continues to evolve, intergroup/nationwide trial participation may become the norm rather than the exception, as it is at present. The availability of oncologists with specific geriatric training to provide input into trial protocol design may increase enrollment of older patients and ensure successful trial completion. Lastly, non-cytotoxic agents effective in DLBCL are now becoming increasingly available. The immunomodulatory agent lenalidomide (Revlimid) and the Bruton tyrosine kinase inhibitor ibrutinib have demonstrated notable single-agent efficacy in DLBCL.[9,10] Since the elderly are more likely to be diagnosed with the activated B-cell subtype of DLBCL, these agents may be particularly suited for study in this population, given their activity in this subgroup and their limited toxicity profile.

Several clinical trial design options are possible to meet this growing need. Studies testing single novel agents or non-myelosupressive combinations may be most appropriate for the very elderly. An ongoing clinical trial designed for less fit elderly Hodgkin lymphoma patients is testing single-agent brentuximab vedotin (Adcetris) as first-line therapy in those not fit to receive standard ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine). Since this histology is far less common in the elderly, a similar protocol design is feasible in DLBCL. Alternatively, for older fit patients, a track record of successful trials has been established. Appropriate inclusion criteria, along with the use of geriatric assessment tools and geriatric oncology input, will continue to ensure that as new agents are added to standard combination therapies, and as treatment paradigms become more complex, clinical trial results will continue to be generalizable to the predominately older DLBCL population.

In summary, further prospective clinical trials in very elderly patients with DLBCL are clearly needed. Complementing the growing need for such trials, an evolving clinical trial infrastructure, geriatric oncology support, and novel therapeutics are making such studies feasible in the current era.

Financial Disclosure: Dr. Barr is a Lymphoma Research Foundation Clinical Investigator and is supported in part by the Wilmot Research Foundation and the University of Rochester SPORE in Lymphoma grant (CA-130805-02). He has been a paid consultant for Seattle Genetics.

References:

REFERENCES

1. Dale W, Mohile SG, Eldadah BA, et al. Biological, clinical, and psychosocial correlates at the interface of cancer and aging research. J Natl Cancer Inst. 2012;104:581-9.

2. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-42.

3. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:3121-7.

4. Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004;104:634-41.

5. Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004;104:626-33.

6. Mohile S, Dale W, Hurria A. Geriatric oncology research to improve clinical care. Nat Rev Clin Oncol. 2012;9:571-8.

7. Peyrade F, Jardin F, Thieblemont C, et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12:460-8.

8. Nabhan C, Smith SM, Helenowski I, et al. Analysis of very elderly (≥80 years) non-Hodgkin lymphoma: impact of functional status and co-morbidities on outcome. Briti J Haematol. 2012;156:196-204.

9. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell–like than in germinal center B-cell–like phenotype. Cancer. 2011;117:5058-66.

10. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. ASH Annual Meeting Abstracts. 2012;120:686.