Prognostic modeling in diffuse large B‐cell lymphoma in the era of immunochemotherapy: Where do we go from here?

Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring lymphoid malignancy in the United States; it is diagnosed in more than 27,000 individuals annually and accounts for approximately 25% of adult cases of nonHodgkin lymphoma. DLBCL represents a significant clinical problem for cancer outcomes research in that it is a curable disease for some, but not all, patients. Although untreated DLBCL patients have an expected survival of less than 1 year, with modern immunochemotherapy, more than 50% of patients are alive at 5 years and are considered cured. More recently, event-free survival at 2 years has been shown to represent a meaningful endpoint because patients who achieve that benchmark exhibit overall survival (OS) similar to that of ageand sex-matched controls in the general population. Unfortunately, DLBCL patients who experience early relapse or primary treatment failure after standard therapy with rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) experience poor outcomes. In the accompanying article, Howlader et al present a risk-stratified model to estimate DLBCL cure rates in the rituximab era on the basis of data available in the Surveillance, Epidemiology, and End Results (SEER) registry. SEER provides population-based information on cancer incidence and survival in the United States and covers approximately 30% of the US population. The model and approach described by Howlader et al can form a foundation for future risk-prediction models that incorporate data on known differences in demographic, socioeconomic, clinical, and biological factors. Such models would be useful in supporting individual patients’ and clinicians’ understanding of the baseline expectations for DLBCL survival as well as patient-specific factors that could alter this course. Since the 1990s, the combination chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard for DLBCL because of a randomized controlled trial showing that CHOP was less toxic than intensive regimens and produced equivalent survival. In 2002, a randomized trial comparing CHOP and CHOP plus rituximab, the first monoclonal antibody anticancer therapy, demonstrated that R-CHOP improved the 2-year OS rate from 57% to 70%. Follow-up data from this and other randomized trials confirmed the benefits of R-CHOP. For eligible patients with relapsed DLBCL, salvage chemotherapy followed by consolidation with autologous stem cell transplantation has been established as a preferred standard-of-care treatment strategy that can cure at least 30% of relapsed patients, whereas salvage chemotherapy alone cures less than 10%. Despite these advances, patients with DLBCL have disparate outcomes based on clinical factors, biological subtypes, race, and even insurance status. Howlader et al have attempted to refine cure estimates by assessing risk-stratified outcomes in a large data set. This model included the following: Ann Arbor stage; age at diagnosis; sex; race; Hispanic ethnicity; marital status; a population-level measure of poverty; and a crude measure of the initial course of therapy assessing chemotherapy, radiation, or both. In agreement with prior analyses, worse DLBCL-specific mortality was associated with an older age and advanced stage at diagnosis, male sex, black race, Hispanic ethnicity, and not being married. However, several clinical data elements known to affect the prognosis are not routinely captured in SEER data. For example, the International Prognostic Index (IPI) score for DLBCL identifies stage 3/4 disease, an elevated lactate dehydrogenase level, an age> 60 years, an Eastern Cooperative Oncology Group performance status 2, and the involvement of >1 extranodal site as poor prognostic factors. The laboratory and performance status measures in the IPI were not captured for the majority of the patients diagnosed during 2002-2011 in the SEER-13 registries that were included in this study. However, IPI data are available for a subset of DLBCL patients in SEER and have been examined in other prognostic models using SEER data.