Lymphoma and Myeloma
DOI: 10.1200/JCO.19.01937 Journal of Clinical Oncology - published online before print February 21, 2020
Impaired Immune Health in Survivors of Diffuse Large B-Cell Lymphoma
2Center for Oncology Hematology Outcomes Research and Training (COHORT) and Division of Hematology and Oncology, University of California Davis School of Medicine, Sacramento, CA
3Cancer Prevention Institute of California, Fremont, CA
4Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA
5Center for Translational Population Sciences, Cedars-Sinai Medical Center, Los Angeles, CA
Therapeutic advances for diffuse large B-cell lymphoma (DLBCL) have led to an increasing number of survivors. Both DLBCL and its treatments perturb the immune system, yet little is known about immune health during extended survivorship.
In this retrospective cohort study, we compared 21,690 survivors of DLBCL from the California Cancer Registry (CCR) to survivors of breast, prostate, head and neck, and melanoma cancers. We linked their CCR records to a statewide database documenting hospital, emergency room, and ambulatory surgery visits and investigated the incidence of autoimmune conditions, immune deficiencies, and infections 1-10 years after cancer diagnosis.
We found elevated incidence rate ratios (IRRs) for many immune-related conditions in survivors of DLBCL compared with other cancer survivors, including significantly and consistently elevated IRRs for viral and fungal pneumonias (up to 10.8-fold), meningitis (up to 5.3-fold), as well as humoral deficiency (up to 17.6-fold) and autoimmune cytopenias (up to 12-fold). IRRs for most conditions remained high even in the late survivorship period (5-10 years after cancer diagnosis). The elevated risks could not be explained by exposure to chemotherapy, stem-cell transplantation, or rituximab, except for IRRs for humoral deficiency, which were consistently higher after the incorporation of rituximab into DLBCL treatments.
To our knowledge, this is the largest cohort study with extended follow-up to demonstrate impaired immune health in survivors of DLBCL. The observed persistent, elevated risks for autoimmune diseases, immune deficiencies, and infectious conditions may reflect persistent immune dysregulation caused by lymphoma or treatment and may lead to excess morbidity and mortality during survivorship. Improved understanding of these risks could meaningfully improve long-term care of patients with DLBCL.
Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma, is an aggressive lymphoma that is fatal without treatment but curable with current therapies. Survival for patients with DLBCL has improved significantly since rituximab, a monoclonal antibody against the B-cell protein CD20, was introduced in 1997, soon becoming the standard of care.1-5 Treatment with rituximab plus combination chemotherapy and corticosteroids results in 50%-75% 5-year survival3,6 and has resulted in an increasing number of long-term survivors. Although it has been demonstrated that survivors of DLBCL suffer from cardiac disease,7-9 neuropathy,7,10,11 secondary malignancies,12,13 decreased bone density,14 and other conditions,7,8,15-17 little is known about their immune health.
As a cancer of immune cells, DLBCL perturbs immune networks, resulting in qualitative and quantitative dysfunction via a reduction in normal B cells and loss of normal communication between B cells and other immune cells.18-20 In addition, treatments for DLBCL, including rituximab,21,22 corticosteroids,23 newer agents such as lenalidomide,24 and radiotherapy and chemotherapy,25 all have profound effects on the immune system. Whether these result in lasting changes to immune function, especially changes that might persist in the absence of active disease and treatment, is unknown.
Certain autoimmune diseases, immune deficiency syndromes, and infections are associated with the pathogenesis of DLBCL, but the majority of DLBCL cases arise in the absence of such conditions.26-32 To our knowledge, no studies have assessed whether survivors of DLBCL have altered risk of developing new-onset autoimmune and infectious diseases or immune deficiencies during mid- to long-term survivorship due to disease- or treatment-related immune impairments. Knowledge of such risks could lead to improved care of survivors of lymphoma and to new strategies for mitigating these risks.
Therefore, we created a large retrospective cohort using population-based California Cancer Registry (CCR) data, which we linked to individual-level data on hospitalizations and emergency department and ambulatory surgery visits from the California Office of Statewide Health Planning and Development (OSHPD). In this cohort of DLBCL survivors, we examined the incidence of autoimmune diseases, immune deficiencies, and infectious diseases and compared them to incidence in similarly constructed cohorts of breast cancer, prostate cancer, head and neck cancer, and melanoma survivors. To focus on conditions with onset during survivorship, we excluded diagnoses identified before or within 1 year after cancer diagnosis. We chose comparison cohorts to include cancers with high disease-free, treatment-free survival rates (breast, prostate, melanoma), use of high-intensity initial therapy (head and neck cancer), and nonepithelial origin (melanoma).
Eligible persons in the CCR database were age ≥ 18 years, resided in California when diagnosed with one of 5 primary invasive cancers (DLBCL, breast cancer, prostate cancer, head and neck cancer, and melanoma) between January 1, 1991 and December 31, 2012, and survived ≥ 1 year from diagnosis; HIV/AIDS was exclusionary (Data Supplement). Patient records were linked to OSHPD discharge records from hospitalizations, emergency room visits, and ambulatory surgery encounters. Please see the Data Supplement for details of derivation of cohorts and subcohorts used for sensitivity analyses.
All study protocols were overseen by the institutional review board of the University of California, Davis and by the California Committee for the Protection of Human Subjects.
Informed by prior studies,28,33 we identified 595 International Classification of Diseases 9th revision (ICD-9) codes for conditions we considered immune related. To avoid comparing diagnoses with very few events in the dataset, our primary analyses used 41 diagnoses that were present at a rate of at least 5 events per 10,000 patients in the DLBCL cohort and two additional diagnoses of clinical interest, dermatomyositis/polymyositis and autoimmune hepatitis (Data Supplement). A secondary analysis included all 595 immune-related ICD-9 codes grouped into 18 diagnostic categories (Data Supplement).
We used descriptive statistics to characterize each cohort. We compared the incidence of autoimmune and infectious diseases and immune deficiencies among survivors of DLBCL with each of the other survivor cohorts during the 1-10–year period after cancer diagnosis. We estimated incident rate ratios (IRRs) using multivariable Poisson regression models adjusted for age at cancer diagnosis (18-39, 40-64, and ≥ 65 years), sex, race/ethnicity (white, Hispanic, and other), and year of cancer diagnosis (1991-1996, 1997-2002, 2003-2007, and 2008-2012). We used negative binomial models when overdispersion was evident. For the comparisons to survivors of female breast cancer and survivors of prostate cancer, we included only female and only male survivors of DLBCL, respectively. To focus on diseases with onset during survivorship, we excluded conditions occurring before or within 1 year after cancer diagnosis. To account for multiple comparisons, we applied a P-value threshold of ≤ .0002 for interpretation of statistical significance on the basis of a Bonferroni correction34 with 43 primary and 18 secondary diagnoses in 4 pairwise comparisons.
To evaluate risks over time, we estimated the cumulative incidence of a subset of immune-related conditions accounting for death as a competing risk. To quantify the risks in the later survivorship period, we calculated adjusted IRRs comparing survivors of DLBCL to the other survivor cohorts for the late survivorship period 5-10 years after cancer diagnosis, excluding diagnoses seen before the 5-year mark.
All analyses were conducted using SAS version 9.4 software (SAS Institute, Cary, NC).
The final study population included 21,690 survivors of DLBCL and comparator cohorts of 337,591 survivors of female breast cancer, 325,533 survivors of prostate cancer, 44,245 survivors of head and neck cancer, and 73,196 survivors of melanoma (Data Supplement). These cancer cohorts had relatively similar distributions for age, race/ethnicity, year of cancer diagnosis, neighborhood socioeconomic status (SES), and insurance coverage, except the melanoma cohort, in which patients were more likely to be of non-Hispanic white race/ethnicity, of higher neighborhood SES, and privately insured, and the head and neck cancer cohort, which included a higher proportion of males (Table 1). Survivors of DLBCL were more likely to have advanced-stage disease at diagnosis, but lymphoma is staged differently from the other cancers.35 A similar proportion of survivors across the cohorts had at least one captured OSHPD encounter in the 1-10–year period after cancer diagnosis (range, 73%-78%). The median number of encounters per patient in each cohort was 2.
In comparison with female survivors of breast cancer, female survivors of DLBCL had significantly increased incidence rates for 30 of the 43 conditions included in the primary analysis. These included humoral deficiency (IRR, 17.6; 95% CI, 12.4 to 24.9), autoimmune hemolytic anemia (IRR, 12.0; 95% CI, 8.4 to 17.1), fungal pneumonia (IRR, 7.4; 95% CI, 5.1 to 10.9), sicca syndrome (IRR, 4.3; 95% CI, 3.1 to 5.9), viral pneumonia (IRR, 3.9; 95% CI, 2.7 to 5.7), meningitis (IRR, 3.8; 95% CI, 2.2 to 6.5), and systemic lupus erythematosus (IRR, 2.2; 95% CI, 1.5 to 3.1; Fig 1A; Data Supplement). The only diagnosis more frequent in survivors of breast cancer was cervicitis/endocervicitis (IRR, 0.41; 95% CI, 0.27 to 0.61).
Comparing male survivors of DLBCL to survivors prostate cancer, survivors of DLBCL had significantly increased incidence of 28 conditions, including humoral deficiency (IRR, 17.4; 95% CI, 12.6 to 24.1), autoimmune hemolytic anemia (IRR, 11.6; 95% CI, 7.6 to 17.8), fungal pneumonia (IRR, 10.8; 95% CI, 7.7 to 15.2), viral pneumonia (IRR, 6.4; 95% CI, 4.6 to 9.0), sicca syndrome (IRR, 5.9; 95% CI, 3.1 to 11.1), and meningitis (IRR, 5.3; 95% CI, 3.3 to 8.5; Fig 1B; Data Supplement). No conditions were statistically more frequent among survivors of prostate cancer than male survivors of DLBCL.
When compared with survivors of head and neck cancer, 15 conditions displayed significantly increased incidence rates in survivors of DLBCL, including humoral deficiency (IRR, 11.5; 95% CI, 6.9 to 19.1), autoimmune hemolytic anemia (IRR, 7.7; 95% CI, 4.4 to 13.5), viral and fungal pneumonia (IRR, 4.1; 95% CI, 2.7 to 6.3; and IRR, 3.9; 95% CI, 2.7 to 5.7, respectively), and meningitis (IRR, 3.1; 95% CI, 1.8 to 5.2; Fig 2A; Data Supplement). Notably, survivors of head and neck cancer had an increased incidence of bacterial pneumonias and skin and fascial infections compared with survivors of DLBCL (IRR, 0.49; 95% CI, 0.45 to 0.54; and IRR, 0.77; 95% CI, 0.72 to 0.83, respectively).
Twenty-eight diagnoses were differentially incident when survivors of DLBCL were compared with survivors of melanoma, including humoral deficiency (IRR, 13.2; 95% CI, 9.0 to 19.2), autoimmune hemolytic anemia (IRR, 9.1; 95% CI, 5.8 to 14.3), fungal and viral pneumonias (IRR, 8.5; 95% CI, 5.7 to 12.6; and IRR, 6.6; 95% CI, 4.4 to 9.9, respectively), and sicca syndrome (IRR, 5.3; 95% CI, 3.4 to 8.1; Fig 2B; Data Supplement). No diagnoses were statistically more common in the melanoma cohort.
To control for exposure to systemic therapy, we performed a sensitivity analysis restricting the DLBCL and breast cancer cohorts to patients who received chemotherapy. We found similarly elevated incidence rates in this analysis, including for humoral deficiency (IRR, 20.2; 95% CI, 12.7 to 32.0), autoimmune hemolytic anemia (IRR, 11.3; 95% CI, 7.0 to 18.3), fungal pneumonia (IRR, 7.6; 95% CI, 4.8 to 12.1), viral pneumonia (IRR, 4.6; 95% CI, 3.0 to 7.1), and cervicitis/endocervicitis (IRR, 0.35; 95% CI, 0.22 to 0.54; Data Supplement).
Because stem-cell transplantation (SCT) is used in the treatment of DLBCL but not the other cancer types, we repeated our regression analyses excluding patients in all cohorts who underwent SCT. Consistently across all comparisons, we observed that IRRs were minimally changed relative to the original analysis (Data Supplement). To focus on survivors likely cured by primary therapy, we excluded both patients who underwent SCT and patients who died of their primary cancer. Again, IRRs were largely preserved (Data Supplement).
To evaluate the effects of evolving treatments over time while retaining power to detect low-incidence conditions, we focused on the potential impact of rituximab, the most prominent change in DLBCL treatment during the studied time period. IRRs between survivors of DLBCL and those of other cancers were not consistently different in the pre-rituximab period compared with the post-rituximab period, with the exception of the IRR for humoral deficiency (Data Supplement). This ranged from 5.5-10.9 in the pre-rituximab period, compared with 16.8-20.8 in the post-rituximab period (Data Supplement).
To evaluate the relative burden of these excess risks over time, we computed cumulative incidence curves for diagnoses of interest from 1 to 10 years after cancer diagnosis. Cumulative incidence for humoral deficiency, sicca syndrome, autoimmune hemolytic anemia, and immune thrombocytopenia, was considerably higher for survivors of DLBCL than the other cohorts (Fig 3A-3D). Cumulative incidence for many infections, including viral and fungal pneumonias, was also much greater in the DLBCL cohort (Fig 3E-3I). Patients with head and neck cancer accumulated the highest incidence of bacterial pneumonias, followed by survivors of DLBCL (Fig 3J).
To formally quantify risks during late survivorship, when the risk for DLBCL relapse and receipt of salvage therapies is low,36-38 we estimated IRRs for the period 5-10 years after cancer diagnosis. Here, we still observed significantly elevated IRRs for most conditions, including humoral deficiency (IRRs, 5.7-11.9), autoimmune hemolytic anemia (IRRs, 4.9-9.1), and fungal (IRRs, 4.2-5.7) and viral (IRRs 3.8-4.9) pneumonias (Fig 4). Bacterial pneumonias were seen more commonly in survivors of DLBCL compared with the breast, prostate, and melanoma cohorts (IRRs, 1.6-1.9; P < .00001 for all) but less commonly compared with survivors of head and neck cancer (IRR, 0.46; 95% CI, 0.40 to 0.54). The IRRs from this analysis (years 5-10) were only 22% lower on average than those from the primary analysis (years 1-10; Data Supplement). Event counts for the full and the late survivorship periods are presented in Data Supplement.
We hypothesized that survivors of other lymphomas may experience immune dysregulation similar to survivors of DLBCL. Comparing survivors of DLBCL to survivors of Hodgkin lymphoma (HL), another hematologic malignancy with significant disease-free, treatment-free survival, we found 10 diagnoses differentially incident. All but one was more common among survivors of DLBCL, and 3 met the adjusted significance threshold of P ≤ .0002 (Data Supplement), suggesting less difference in immune health between survivors of DLBCL and HL than in the other comparisons.
For a broader assessment of immune dysregulation in survivors of DLBCL we performed a secondary analysis that captured all 595 immune-related diagnosis codes, categorized into 18 clinical groupings (Data Supplement). Survivors of DLBCL had higher incidence of specific immune deficiencies (IRRs, 7.0-13.3); hematologic autoimmune conditions (IRRs, 1.9-3.1); gastrointestinal, renal, and hepatic conditions (IRRs, 1.4-2.3); and diffuse autoimmune diseases (IRRs, 1.2-1.6) across all 4 comparisons and other categories across 2-3 comparisons (Fig 5; Data Supplement). Survivors of head and neck cancer experienced more skin and bone infections (IRR, 0.76; 95% CI, 0.70 to 0.82), respiratory infections (IRR, 0.86; 95% CI, 0.81 to 0.91), and oral infections (IRR, 0.10; 95% CI, 0.06 to 0.17).
In survivors of DLBCL compared with survivors of four different cancers, we demonstrate significantly increased incidence of infectious conditions, immune deficiencies, and autoimmune diseases, notably viral and fungal pneumonias, meningitis, humoral deficiency, hematologic autoimmune conditions, and sicca syndrome. Through multiple sensitivity analyses, we show that the majority of these excess risks are not driven by exposure to systemic chemotherapy, SCTs, or rituximab. We also show that excess risks are not driven by relapsing disease, as they persist during disease-free, treatment-free, long-term survival, determined by studying 5-year survivors and by exclusion of patients with relapsed/refractory disease.
It is intriguing that diagnoses commonly concurrent with lymphoma, such as autoimmune hemolytic anemia, immune thrombocytopenia, and sicca syndrome, were also likely to arise during DLBCL survivorship. It is unlikely that these conditions simply failed to be excluded as preexisting conditions, because similar results were seen in the analysis of late survivorship, where conditions recorded up to 5 years after cancer diagnosis were excluded. These autoimmune conditions may develop because of long-lasting changes to immune networks by lymphoma and/or past treatments. Alternatively, they may exist subclinically, be resistant to lymphoma treatments, and manifest later in life. Evidence from preclinical models suggests clonal relationships between self-reactive and malignant B-cell clones can exist,39 which may also explain why known lymphoma-related conditions emerged with the strongest signals.
Humoral deficiency (ie, hypogammaglobulinemia) was much more common in survivors of DLBCL. Approximately 15% of patients with DLBCL have hypogammaglobulinemia at diagnosis, and another 40% develop it after treatment with rituximab.40 Delayed or persistent hypogammaglobulinemia has been observed in rituximab-treated patients.41-43 We observed substantially higher IRRs for humoral deficiency after the introduction of rituximab than in the years prior. Interestingly, no other diagnosis was consistently different across cohorts after the introduction of rituximab, suggesting that most of the excess risks we observed cannot be attributed to rituximab exposure.
Survivors of DLBCL experienced increased incidence of many infections, particularly viral and fungal infections, the immune response to which relies on innate immune cells and T cells, signaling the breadth of immune dysfunction seen in survivors of a B-cell lymphoma. These risks were similar when we controlled for the effects of systemic chemotherapy, SCTs, or rituximab, suggesting they may be driven by lymphoma biology or by unevaluated factors. Although we did not directly assess the impact of infections on mortality, increased mortality from infections has been demonstrated for survivors of DLBCL, including those who survived ≥ 5 years.44
The few immune-related diagnoses more frequent in the comparator cohorts were known or plausible associations. Survivors of head and neck cancer are at high risk for skin, oral, and lung infections as a result of impairments wrought by cancer, surgery, radiation, and chemotherapy,45,46 and these higher risks were evident in our study. Increased incidence of cervicitis among survivors of breast cancer has not previously been demonstrated, but low estrogen states confer greater susceptibility to cervicitis,47 and many patients with breast cancer are induced into low-estrogen states as part of their treatment.
This study was strengthened by the use of a large, complete, population-based cohort of patients with cancer and its linkage to a comprehensive, statewide database of hospitalizations, emergency room visits, and ambulatory surgery visits. By comparing survivors of DLBCL to survivors of several other cancer types, we were able to uncover differences likely to be specific to lymphoma. The consistency of our results across cancer cohorts strengthens the findings, and by excluding conditions occurring up to 1 year after cancer diagnosis (or up to 5 years in a secondary analysis), we were able to focus on conditions with presumed onset during survivorship.
There are limitations to our study. We captured noncancer diagnoses only for cancer survivors who visited a hospital or emergency department or had ambulatory surgery. Without data from outpatient clinic visits, our results likely underestimate the absolute incidence of these conditions. This limitation applies to each survivor cohort; therefore, IRRs should be accurate measures of relative incidence. The data sources may introduce ascertainment bias toward diagnoses more likely to result in hospital, emergency room, or ambulatory surgery encounters, although this may also impart greater clinical significance, because of the associated morbidity and health care utilization.
The study findings are also limited by differences in disease biology and treatment across cohorts; however, comparison of DLBCL to several disparate cancers mitigates this concern, and the consistency across comparisons and sensitivity analyses controlling for major treatment differences strengthens our findings. DLBCL was our chosen model for hematologic malignancy because of sufficient prevalence and extended disease-free survival. We attempted to determine whether immune dysregulation may plague survivors of other hematologic malignancies via a limited comparison with HL. Many fewer conditions were differentially incident in this analysis relative to the comparisons against solid tumors, suggesting that factors intrinsic to the etiology of lymphoid malignancy may contribute to impaired immune health during survivorship.
Our findings support the hypothesis that immune derangements in survivors of DLBCL can be both wide ranging and long lasting. A better understanding of the increased health risks and resultant morbidity and mortality faced by survivors of lymphomas is now needed to identify opportunities to intervene. These data should also motivate longer-term follow-up of patients with DLBCL in interventional trials to capture differences in these late effects and to detect risks that may be associated with newer therapies.
Except for after SCT, there are no specific guidelines for vaccination of survivors of DLBCL, yet we observed higher rates for vaccine-preventable diseases such as influenza and bacterial pneumonias, suggesting a potential role for standardized vaccination of all patients with DLBCL. For current clinical practice, efforts to follow existing general vaccination recommendations should be redoubled, as vaccination rates among patients with DLBCL48 are poor.
To our knowledge, this is the first study to show significant and widespread increases in the risks for infectious conditions, immune deficiencies, and autoimmune diseases among survivors of DLBCL. Understanding the underlying biology of these excess immune risks will help improve the care of survivors of DLBCL and may ultimately direct improvements in the clinical management of lymphoma.
Presented in part at the 59th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 9, 2018, and at the 15th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 20, 2019.
Supported by a grant from the Stanford Cancer Institute and by NIH Grant R35CA19735301A1 (R.L.). The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention’s National Program of Cancer Registries, under cooperative agreement 5NU58DP003862-04/DP003862; the National Cancer Institute’s SEER Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute. This publication was also made possible in part by postdoctoral fellowships to T.S. from the National Institutes of Health Grant No. 5T32HL120824-04 and the American Cancer Society Grant No. PF-17-239-01-LIB, as well as the Parker Institute of Cancer Immunotherapy.
The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions or official views of the State of California, Department of Public Health, the National Cancer Institute, the Centers for Disease Control and Prevention or their Contractors and Subcontractors, the National Institutes of Health, the American Cancer Society, or the Parker Institute of Cancer Immunotherapy.
See accompanying Editorial on page 1648
Conception and design: Tanaya Shree, Sally L. Glaser, Holden T. Maecker, Robert W. Haile, Ronald Levy, Theresa H. M. Keegan
Financial support: Ronald Levy, Theresa H. M. Keegan
Administrative support: Ronald Levy, Theresa H. M. Keegan
Collection and assembly of data: Qian Li
Data analysis and interpretation: Tanaya Shree, Qian Li, Sally L. Glaser, Ann Brunson, Ronald Levy, Theresa H. M. Keegan
Manuscript writing: Tanaya Shree, Qian Li, Ronald Levy, Theresa H. M. Keegan
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Employment: AbbVie (I)
Stock and Other Ownership Interests: AbbVie (I)
Consulting or Advisory Role: Caris Life Sciences
Research Funding: Amgen, Ionis Pharmaceuticals
Stock and Other Ownership Interests: Merck, Five Prime Therapeutics
Consulting or Advisory Role: Five Prime Therapeutics, BeiGene, Inate Pharma, Immune Design, Corvus Pharmaceuticals, Checkmate Pharmaceuticals, GigaGen, Quadriga, TeneoBio, Dragonfly Therapeutics, Abpro, Apexigen, Nurix, Viracta Therapeutics, Forty Seven
Research Funding: Bristol-Myers Squibb (Inst), Janssen (Inst)
Research Funding: Shire (Inst)
No other potential conflicts of interest were reported.
|1.||Noone A, Howlader N, Krapcho M, et al: SEER Cancer Statistics Review, 1975-2015. 2018. https://seer.cancer.gov/csr/1975_2015/ Google Scholar|
|2.||Molina A: A decade of rituximab: Improving survival outcomes in non-Hodgkin’s lymphoma. Annu Rev Med 59:237-250, 2008 Crossref, Medline, Google Scholar|
|3.||Sehn LH, Donaldson J, Chhanabhai M, et al: Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23:5027-5033, 2005 Link, Google Scholar|
|4.||Shenoy PJ, Malik N, Nooka A, et al: Racial differences in the presentation and outcomes of diffuse large B-cell lymphoma in the United States. Cancer 117:2530-2540, 2011 Crossref, Medline, Google Scholar|
|5.||Komrokji RS, Al Ali NH, Beg MS, et al: Outcome of diffuse large B-cell lymphoma in the United States has improved over time but racial disparities remain: Review of SEER data. Clin Lymphoma Myeloma Leuk 11:257-260, 2011 Crossref, Medline, Google Scholar|
|6.||Ziepert M, Hasenclever D, Kuhnt E, et al: Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol 28:2373-2380, 2010 Link, Google Scholar|
|7.||Moser EC, Noordijk EM, Carde P, et al: Late non-neoplastic events in patients with aggressive non-Hodgkin’s lymphoma in four randomized European Organisation for Research and Treatment of Cancer trials. Clin Lymphoma Myeloma 6:122-130, 2005 Crossref, Medline, Google Scholar|
|8.||Haddy TB, Adde MA, McCalla J, et al: Late effects in long-term survivors of high-grade non-Hodgkin’s lymphomas. J Clin Oncol 16:2070-2079, 1998 Link, Google Scholar|
|9.||Hershman DL, McBride RB, Eisenberger A, et al: Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin’s lymphoma. J Clin Oncol 26:3159-3165, 2008 Link, Google Scholar|
|10.||Boyette-Davis JA, Cata JP, Driver LC, et al: Persistent chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine. Cancer Chemother Pharmacol 71:619-626, 2013 Crossref, Medline, Google Scholar|
|11.||Kim BJ, Park HR, Roh HJ, et al: Chemotherapy-related polyneuropathy may deteriorate quality of life in patients with B-cell lymphoma. Qual Life Res 19:1097-1103, 2010 Crossref, Medline, Google Scholar|
|12.||Morton LM, Curtis RE, Linet MS, et al: Second malignancy risks after non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: Differences by lymphoma subtype. J Clin Oncol 28:4935-4944, 2010 Link, Google Scholar|
|13.||Tao L, Clarke CA, Rosenberg AS, et al: Subsequent primary malignancies after diffuse large B-cell lymphoma in the modern treatment era. Br J Haematol 178:72-80, 2017 Crossref, Medline, Google Scholar|
|14.||Svendsen P, Shekhrajka N, Nielsen KL, et al: R-CHOP(-like) treatment of diffuse large B-cell lymphoma significantly reduces CT-assessed vertebral bone density: A single center study of 111 patients. Leuk Lymphoma 58:1105-1113, 2017 Crossref, Medline, Google Scholar|
|15.||Frick MA, Vachani CC, Hampshire MK, et al: Patient-reported survivorship care practices and late effects after treatment of Hodgkin and non-Hodgkin lymphoma. JCO Clin Cancer Inform 10.1200/CCI.18.00015 Google Scholar|
|16.||Arden-Close E, Pacey A, Eiser C: Health-related quality of life in survivors of lymphoma: A systematic review and methodological critique. Leuk Lymphoma 51:628-640, 2010 Crossref, Medline, Google Scholar|
|17.||Oberoi D, White VM, Seymour JF, et al: The influence of unmet supportive care needs on anxiety and depression during cancer treatment and beyond: A longitudinal study of survivors of haematological cancers. Support Care Cancer 25:3447-3456, 2017 Crossref, Medline, Google Scholar|
|18.||Nassef Kadry Naguib Roufaiel M, Wells JW, Steptoe RJ: Impaired T-cell function in B-cell lymphoma: A direct consequence of events at the immunological synapse? Front Immunol 6:258, 2015 Crossref, Medline, Google Scholar|
|19.||Yamate T, Shono T, Shimada H, et al: Blistering disease associated with diffuse large B-cell lymphoma but without autoantibodies. J Dermatol 43:341-343, 2016 Crossref, Medline, Google Scholar|
|20.||Yang JH, Choi SJ, Won CH, et al: Paraneoplastic erythroderma: An unusual manifestation of diffuse large B-cell lymphoma. Int J Dermatol 52:1149-1151, 2013 Crossref, Medline, Google Scholar|
|21.||Aguiar-Bujanda D, Blanco-Sánchez MJ, Hernández-Sosa M, et al: Late-onset neutropenia after rituximab-containing therapy for non-Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk 15:761-765, 2015 Crossref, Medline, Google Scholar|
|22.||Cooper N, Arnold DM: The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases. Br J Haematol 149:3-13, 2010 Crossref, Medline, Google Scholar|
|23.||Coutinho AE, Chapman KE: The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 335:2-13, 2011 Crossref, Medline, Google Scholar|
|24.||Gribben JG, Fowler N, Morschhauser F: Mechanisms of action of lenalidomide in B-cell non-Hodgkin lymphoma. J Clin Oncol 33:2803-2811, 2015 Link, Google Scholar|
|25.||Wargo JA, Reuben A, Cooper ZA, et al: Immune effects of chemotherapy, radiation, and targeted therapy and opportunities for combination with immunotherapy. Semin Oncol 42:601-616, 2015 Crossref, Medline, Google Scholar|
|26.||Fallah M, Liu X, Ji J, et al: Autoimmune diseases associated with non-Hodgkin lymphoma: A nationwide cohort study. Ann Oncol 25:2025-2030, 2014 Crossref, Medline, Google Scholar|
|27.||Marcucci F, Mele A: Hepatitis viruses and non-Hodgkin lymphoma: Epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood 117:1792-1798, 2011 Crossref, Medline, Google Scholar|
|28.||Váróczy L, Gergely L, Zeher M, et al: Malignant lymphoma-associated autoimmune diseases--a descriptive epidemiological study. Rheumatol Int 22:233-237, 2002 Crossref, Medline, Google Scholar|
|29.||Cerhan JR, Kricker A, Paltiel O, et al: Medical history, lifestyle, family history, and occupational risk factors for diffuse large B-cell lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:15-25, 2014 Crossref, Medline, Google Scholar|
|30.||Ekström Smedby K, Vajdic CM, Falster M, et al: Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: A pooled analysis within the InterLymph Consortium. Blood 111:4029-4038, 2008 Crossref, Medline, Google Scholar|
|31.||Engels EA, Parsons R, Besson C, et al: Comprehensive evaluation of medical conditions associated with risk of non-Hodgkin lymphoma using Medicare claims (“MedWAS”). Cancer Epidemiol Biomarkers Prev 25:1105-1113, 2016 Crossref, Medline, Google Scholar|
|32.||Smedby KE, Hjalgrim H, Askling J, et al: Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J Natl Cancer Inst 98:51-60, 2006 Crossref, Medline, Google Scholar|
|33.||Rugbjerg K, Olsen JH: Long-term risk of hospitalization for somatic diseases in survivors of adolescent or young adult cancer. JAMA Oncol 2:193-200, 2016 Crossref, Medline, Google Scholar|
|34.||McDonald JH: Multiple comparisons, in McDonald JH (ed): Handbook of Biological Statistics (ed 3). Baltimore, MD, Sparky House Publishing, 2014, pp 254-260 Google Scholar|
|35.||Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 32:3059-3068, 2014 Link, Google Scholar|
|36.||Larouche JF, Berger F, Chassagne-Clément C, et al: Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: Clinical characteristics and outcome. J Clin Oncol 28:2094-2100, 2010 Link, Google Scholar|
|37.||Maurer MJ, Ghesquières H, Jais JP, et al: Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy. J Clin Oncol 32:1066-1073, 2014 Link, Google Scholar|
|38.||Sanz L, López-Guillermo A, Martínez C, et al: Risk of relapse and clinico-pathological features in 103 patients with diffuse large-cell lymphoma in complete response after first-line treatment. Eur J Haematol 61:59-64, 1998 Crossref, Medline, Google Scholar|
|39.||Jeelall YS, Wang JQ, Law HD, et al: Human lymphoma mutations reveal CARD11 as the switch between self-antigen-induced B cell death or proliferation and autoantibody production. J Exp Med 209:1907-1917, 2012 Crossref, Medline, Google Scholar|
|40.||Casulo C, Maragulia J, Zelenetz AD: Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymphoma Myeloma Leuk 13:106-111, 2013 Crossref, Medline, Google Scholar|
|41.||Irie E, Shirota Y, Suzuki C, et al: Severe hypogammaglobulinemia persisting for 6 years after treatment with rituximab combined chemotherapy due to arrest of B lymphocyte differentiation together with alteration of T lymphocyte homeostasis. Int J Hematol 91:501-508, 2010 Crossref, Medline, Google Scholar|
|42.||Levy R, Mahévas M, Galicier L, et al: Profound symptomatic hypogammaglobulinemia: A rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature. Autoimmun Rev 13:1055-1063, 2014 Crossref, Medline, Google Scholar|
|43.||Walker AR, Kleiner A, Rich L, et al: Profound hypogammaglobulinemia 7 years after treatment for indolent lymphoma. Cancer Invest 26:431-433, 2008 Crossref, Medline, Google Scholar|
|44.||Howlader N, Mariotto AB, Besson C, et al: Cancer-specific mortality, cure fraction, and noncancer causes of death among diffuse large B-cell lymphoma patients in the immunochemotherapy era. Cancer 123:3326-3334, 2017 Crossref, Medline, Google Scholar|
|45.||Hunter KU, Lee OE, Lyden TH, et al: Aspiration pneumonia after chemo-intensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors. Head Neck 36:120-125, 2014 Crossref, Medline, Google Scholar|
|46.||Xu B, Boero IJ, Hwang L, et al: Aspiration pneumonia after concurrent chemoradiotherapy for head and neck cancer. Cancer 121:1303-1311, 2015 Crossref, Medline, Google Scholar|
|47.||Marazzo JM: Cervicitis, in Klausner JD, Hook EW (eds): Current Diagnosis & Treatment of Sexually Transmitted Diseases. New York, NY, The McGraw-Hill Companies, 2007, pp 60-65 Google Scholar|
|48.||Chang A, Payne JB, Allen PB, et al: Influenza vaccination documentation rates during the first year after diagnosis of diffuse large B cell lymphoma. Clin Lymphoma Myeloma Leuk 19:239-243, 2019 Crossref, Medline, Google Scholar|