Novel Insights Into the Long-Term Immune Health of Diffuse Large B-Cell Lymphoma Survivors

Introduction of the anti-CD20 monoclonal antibody rituximab in 1997 substantially improved prognosis after a diagnosis of diffuse large B-cell lymphoma (DLBCL),¹ which affects > 27,000 individuals in the United States annually.² With the 5-year relative survival increasing from 43% in the early 1990s to > 65% since 2010 (Fig 1),³ attention has increasingly turned toward improving understanding of patients’ long-term health after DLBCL.

FIG 1.

Relative survival after diffuse large B-cell lymphoma (DLBCL) during 1992-2016, by year of diagnosis. Expected survival was estimated using the Ederer II method, and relative survival was calculated by dividing the observed by the expected survival rate using the actuarial method. Data were derived from 13 US population-based cancer registries from the National Cancer Institute SEER program, and analyses were conducted using SEER*Stat, version 8.3.6.^3,26

In the article that accompanies this editorial, Shree et al⁴ provide novel insights into long-term immune health among DLBCL survivors using large-scale registry and hospital data. Assembling a cohort of 21,690 patients with DLBCL identified from the California Cancer Registry and linked to discharge records from nonfederal hospitals across the state, the authors investigated the occurrence of autoimmune conditions, immune deficiencies, and infections during 1-10 years after diagnosis with DLBCL. Compared with survivors of breast cancer, prostate cancer, and melanoma, DLBCL survivors experienced > 3 times the incidence of viral or fungal pneumonia, meningitis, humoral deficiency (hypogammaglobulinemia), and autoimmune cytopenias.

With this analysis, Shree et al⁴ expand the scope of survivorship research in lymphoma and generate results that provide clues to DLBCL pathophysiology as well as a roadmap for long-term clinical care for survivors. To date, most survivorship research in DLBCL has relied on data from clinical trials, which have focused on typical treatment-related outcome measures (eg, overall survival, disease-free survival, CNS relapse) and have included relatively small patient populations (< 1,000). In the past 2 decades, the launch of several larger databases of patients with lymphoma began to expand DLBCL survivorship research, with broader data collection and longer-term follow-up for > 1,000 patients with DLBCL each in the National Comprehensive Cancer Network (NCCN) Non-Hodgkin Lymphoma Outcomes Database,⁵ the Lymphoma Specialized Program of Research Excellence (SPORE) Molecular Epidemiology Resource (MER) Cohort Study,⁶ and the Lymphoma Epidemiology of Outcomes (LEO) study.⁷ Although the authors⁴ lack key treatment and clinical details (eg, specific chemotherapeutic regimens, relapse) because of their use of cancer registry and hospital discharge data, the large size of the study population and long-term patient follow-up with systematically collected information on medical conditions represent a valuable complement to other survivorship research in DLBCL. Nevertheless, survivorship research in non-Hodgkin lymphoma lags substantially behind other patient populations, such as survivors of Hodgkin lymphoma⁸ and childhood cancer,⁹ emphasizing the importance of expanding efforts to support such research.

In contrast to the relatively few survivorship studies among patients with DLBCL, etiologic studies of DLBCL have been a major focus of epidemiologic research, and a number of infectious (eg, HIV, hepatitis C virus [HCV]) and other immune-related conditions (eg, certain autoimmune diseases, iatrogenic immunosuppression) have been identified as DLBCL risk factors.^10-12 Intriguingly, data from the current study suggest that DLBCL survivors also have increased risk of developing some of these same conditions after DLBCL diagnosis. To aid in the interpretation of their results, the authors conducted a series of sensitivity analyses, for example, restricting to conditions that first occurred > 5 years after DLBCL to effectively eliminate the possibility of prevalent conditions explaining their observations. In addition, although the findings were consistent across their primary comparison groups of breast cancer, prostate cancer, and melanoma survivors, a sensitivity analysis showed fewer differences in the occurrence of immune-related conditions in DLBCL survivors compared with Hodgkin lymphoma survivors. Finally, additional sensitivity analyses suggested that the results were not primarily driven by chemotherapy, hematopoietic stem-cell transplantation, or further treatment of relapsed/refractory disease. Overall, the results of Shree et al⁴ support the intriguing hypothesis that certain lymphomas and immune-related medical conditions may have shared etiology, perhaps on the basis of intrinsic immune characteristics. Although epidemiologic analyses of family history data support such patterns,¹³ initial results of genomics studies investigating an inherited basis for the associations have been conflicting,^14-16 suggesting that additional research with more detailed information on immune function is warranted.

Other conditions identified by Shree et al⁴ with increased incidence among DLBCL survivors have not previously been identified as risk factors for DLBCL, including hypogammaglobulinemia, pneumonia, and influenza. The current report⁴ implicates rituximab in the increased occurrence of hypogammaglobulinemia, consistent with previous studies, but not in pneumonia and influenza throughout the decade after DLBCL diagnosis. These results provide new insights into the pathophysiology of DLBCL and emphasize the likelihood that DLBCL is associated with long-term immune impairments, with potential impacts on morbidity and mortality. Long-term immune alterations in survivors of other lymphoid malignancies such as chronic lymphocytic leukemia/small lymphocytic lymphoma are well-known, likely because of the relapsing/remitting disease course and repeated treatments for more indolent lymphomas.^17,18 However, late relapse is rarer in DLBCL than many other lymphoma types,¹⁹ and increased infection-related risks have been reported only in a few mortality studies.²⁰ The current report⁴ highlights the need to better understand the contributions of intrinsic, therapy-related, and disease-related factors on immune health as well as impacts on long-term outcomes for all lymphoid malignancy survivors.

Even though the specific immune defects that characterize DLBCL pathophysiology are yet to be understood, the findings from Shree et al⁴ provide a roadmap for improving follow-up care for DLBCL survivors. The most important opportunity for improving care in the short term is to focus on infections. The current report⁴ highlights the need to address the excess incidence of vaccine-preventable diseases that occur in DLBCL survivors, such as influenza, by emphasizing the importance of adherence to current NCCN vaccination recommendations for cancer survivors.^21,22 In addition, other infections associated with DLBCL, such as HCV and Helicobacter pylori, have recently been shown to affect patients’ long-term health by increasing incidence of malignancies associated with these infections.²³ In light of evidence that undiagnosed infections are more common than expected among patients with cancer,²⁴ screening for treatable infections is another potential recommended approach for patients with appropriate history.

In the longer term, follow-up care for patients with DLBCL would be well served by improving understanding of the absolute rate of occurrence of immune-related medical conditions among survivors to design effective monitoring and intervention strategies. The quantification by Shree et al⁴ of the relative increase in risk of certain immune-related medical conditions provides valuable information regarding which conditions should be the focus of future efforts. However, their reliance on hospital discharge records means that they have likely underestimated the absolute incidence of these conditions, because less-severe cases are unlikely to require hospitalization. In addition, the study population was restricted to patients in nonfederal hospitals, but the incidence of lymphoma is known to be elevated in veterans who were exposed to Agent Orange and are more likely to be diagnosed and treated in federal facilities.²⁵ Thus, although these results still provide a substantially more comprehensive picture of immune-related sequelae than studies that are restricted to mortality as an outcome, patients with DLBCL are likely to experience even greater immune-related morbidity than described in the current report.⁴ As DLBCL treatments continue to evolve and prognosis continues to improve with advances in immunotherapy, the importance of additional research into DLBCL survivors’ long-term health will only continue to grow.

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Novel Insights Into the Long-Term Immune Health of Diffuse Large B-Cell Lymphoma Survivors

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