The Need for Continued Vigilance in Patients with Diffuse Large B-Cell Lymphoma

This JCO Podcast provides observations and commentary on the JCO article 'Late Relapses in Patients With Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy' by Yang et My name is Ann LaCasce, and I am an Associate Professor of Medicine at the Dana-Farber Cancer Institute in Boston, USA.  My oncologic specialty is lymphoma. This podcast discusses the recent paper evaluating the risk of late relapse in patients with diffuse large B-cell lymphoma who are event free 24 months after diagnosis. The goal of upfront chemoimmunotherapy in patients with diffuse large B-cell lymphoma (DLBCL) is the permanent eradication of disease. In the era of rituximab, few studies with sufficient follow-up have examined the risk of late recurrence.  An analysis of patients with DLBCL from the University of Iowa/Mayo and validated in a separate cohort from the French Study Group of Adult Lymphoma demonstrated that patients who were alive and disease free at 24 months from diagnosis had overall survival rates equivalent to the age and sex matched general population.  Despite this finding suggesting cure, late relapses are not uncommon.   In this manuscript, patients enrolled in the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence with newly diagnosed diffuse large B-cell lymphoma or DLBCL with concurrent indolent lymphoma were identified.  847 of the 1324 patients treated with chemoimmunotherapy with or without radiotherapy between 2002 and 2015 were event free at 24 months.  These patients were subsequently analyzed for late relapse.  The majority of patients (87%) had DLBCL without evidence of co-existing indolent lymphoma. With a median follow-up of 62.9 months, 78 patients developed recurrent disease, and the cumulative incidence of late relapse was approximately 7% at 3 years, 9% at 5 years and 10 % at 8 years after achieving EFS24.  Of the patients who developed recurrent lymphoma, 55 had DLBCL alone at baseline and 23 had DLBCL with concurrent indolent lymphoma. Among the patients with DLBCL alone.  36 developed recurrent DLBCL and 13 ad indolent lymphoma (12 with follicular lymphoma and 1 with marginal zone lymphoma).  6 patients did not have pathologic confirmation of disease subtype at the time of recurrence. For the 59% of patients with cell of origin data determined using the Hans algorithm, rates of relapse in patients with DLBCL alone did not differ between those with germinal center derived (GCB) versus non-GCB subtypes.  Individuals with GCB DLBCL were more likely to relapse with indolent lymphoma. Of the 23 patients with concurrent indolent lymphoma at baseline, 9 relapsed with DLBCL and the remaining 11 relapsed with indolent lymphoma 10 of whom had the same subtype at initial presentation (7 with follicular lymphoma, 1 marginal zone lymphoma, 1 chronic lymphocytic leukemia, one unspecified).  One patient who had current DLBCL and FL relapsed with MCL and the subtype was unknown in 3.  Patients with concurrent indolent lymphoma at initial diagnosis were more likely to experience late relapse which was driven by indolent recurrence.  In multivariable analysis, concurrent indolent lymphoma and GCB subtype were independent predictors of relapse.  In patients with DLBCL alone, GCB subtype was associated with indolent relapse but not DLBCL relapse.  Advanced stage and higher IPI score were associated with higher risk of recurrent DLBCL but not indolent relapse.  In terms of outcome, median survival after recurrence was approximately 39 months after EFS24, 30 months for those with DLBCL and the median was not reached in patients with indolent lymphoma.   This study emphasizes the importance of long- term follow-up of our patients with DLBCL.  Hematologists/oncologists typically see patients frequently after the completion of initial therapy but over time, visits become less frequent or not at all for some patients who remain in remission beyond the 5 year mark. Multiple studies have examined surveillance strategies in this setting. The likelihood of identifying recurrent disease in an asymptomatic patient with a normal physical exam is extremely low. In addition, there is no clear evidence that surveillance imaging or early detection of an asymptomatic recurrence impacts on overall survival. This is particularly true for patients who relapse with indolent disease, some of whom may be followed expectantly.   Others may be candidates for low-dose palliative radiation or reduced intensity therapies.  The National Comprehensive Cancer Network Guidelines , which are widely used by physicians as well as payors to determine insurance coverage, recommends symptom guided imaging in patients with a history of early stage DLBCL and CT scans no more often than 6 months for up to 2 years after the completion of therapy in patients with advanced stage disease. Imaging is associated with false positives, radiation exposure and is expensive for our health care system. In addition, anxiety associated with scans is common and may have negative impact on patients.   None-the-less, given that recurrences do occur, educating survivors and their physicians, including primary care providers, to be vigilant for the development of persistent symptoms without clear explanation, as well as B symptoms and lymphadenopathy is important. Setting expectations with patients is also essential, as is caution in using the term cure.  Although the vast majority of patients who remain in remission beyond 2 years after the completion of initial therapy are likely to remain disease free, a small minority will go on to develop recurrent aggressive or indolent lymphoma.  In patients with GCB subtype of DLBCL, discussion of the risk of the subsequent development of an indolent lymphoma may be warranted. Future studies examining changes in cell free DNA during and after therapy, as well as the development of other novel biomarkers may eventually allow us to be more accurate in our prognostication for patients.  In addition, understanding the biology of late recurrence to ascertain whether the recurrence represents the original clone or is distinct may ultimately be important for therapeutic approaches and outcome.   This concludes this JCO Podcast. Thank you for listening.