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Hematologic Malignancies-Lymphoma and Chronic Lymphocytic Leukemia
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Health Disparities and the Global Landscape of Lymphoma Care Today
Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.
Abstract
Lymphoma encompass a wide variety of distinct disease entities, including, but not limited to, subtypes of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). In the last 3 decades, therapeutic advancements have resulted in substantial improvements in lymphoma outcome. In most high-income regions, HL is a largely curable disease and for patients with two frequent subtypes of NHL, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), survival has dramatically improved with the incorporation of rituximab as a standard treatment approach. Despite these advances, outcomes vary between and across populations. This review will provide updated information about health disparities in lymphoma in the United States and across the globe.
KEY POINTS
Lymphoma is the seventh most frequent cancer diagnosis in the world, and there is substantial variation in epidemiologic trends for individual subtypes.
Recent therapeutic advancements have improved our ability to treat patients with many lymphoma subtypes, particularly DLBCL and HL, which are now curable in many instances.
In the United States, the characteristics, incidence rates, and survival rates for NHL and HL vary between racial groups.
Although lymphoma is less commonly diagnosed among black populations, these populations fare worse than white populations for a number of lymphoma subtypes.
Health disparities are complex associations between social, environmental, biologic, and patient-centered factors that may help explain differences in lymphoma outcomes in vulnerable patient populations.
The World Health Organization (WHO) classification of lymphoid neoplasms continues to evolve, recognizing distinct entities that can be broadly characterized as not only NHL and HL, but also plasma cell neoplasm and lymphoid leukemia.1 According to 2012 estimates, there were almost 566,000 new cases of lymphoma worldwide and about 305,000 deaths.2 When the main entities (HL, NHL, and multiple myeloma) are examined separately, the incidences of the respective cancer types do not rank highly, yet in combination, lymphoma was the seventh most frequent cancer diagnosis in the world.2
Focusing on NHL and HL, the last several decades have seen a dramatic improvement in survival outcomes. New treatment options and supportive care measures have resulted in unprecedented rates of long-term cure for HL with less toxic treatment approaches.3 For patients with two frequent subtypes of NHL, DLBCL and FL, survival has also substantially improved as a result of the incorporation of rituximab into standard treatment regimens.4-6 Survival of patients with other subtypes of NHL (e.g., peripheral T-cell lymphoma [PTCL]) has not kept the same pace; however, a number of new agents are now available.7,8 Despite these improvements, differences in lymphoma outcome within and between populations are observed.
The National Institute on Minority Health and Health Disparities defines health disparities as “differences in incidence, prevalence, morbidity, mortality, and burden of diseases and other adverse health conditions that exist among specific population groups.”9 Race and gender are the most frequently studied health disparities that may impact outcomes for some cancers; however, other factors such as socioeconomic status (SES), access to and type of health insurance, distance to the health care facility, cultural factors, and health literacy have been found to be relevant as well.10-13 Middle-income countries are also particularly prone to health disparities.14 This review will summarize the global landscape of lymphoma and identify health disparities that have been investigated in subtypes of NHL and HL, primarily in U.S. populations.
GLOBOCAN, a project of the International Agency for Research on Cancer, provides contemporary estimates of cancer incidence and mortality rates in each country of the world using different methods depending on accuracy and availability of data.15 The 2012 estimates and 2035 projections that summarize the burden of NHL and HL worldwide are shown in Table 1. GLOBOCAN estimates that there were over 385,000 NHL and nearly 66,000 HL incident cases and nearly 200,000 NHL and over 25,000 HL deaths globally in 2012.15 For NHL, new cases occurred equally in high- and middle- to lower-income regions; however, deaths occurred more frequently in middle- to lower-income countries (62%). In the same year for HL, the vast majority of new cases and deaths (56% and 75%, respectively) occurred in middle- to lower-income regions of the world. High-income regions include all regions in Europe, Northern America, Australia/New Zealand, and Japan. Middle- to lower-income regions include all regions of Africa, Asia (excluding Japan), Latin America and the Caribbean, Melanesia, Micronesia, and Polynesia. Projections suggest that both incidence and mortality rates for NHL and HL will increase by 2035, possibly because of improved diagnostic techniques, industrialization, aging populations, and rising HIV infection in certain regions.16,17
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Estimated worldwide age-standardized incidence and mortality rates for both NHL and HL are presented in Fig. 1.15 NHL is more common in high-income regions, with the highest incidence rates found in Australia, Western and Northern Europe, and Northern America. Lower rates are found in Asia, Eastern Europe, and Africa, with the exception of certain areas where Burkitt lymphoma is endemic (Fig. 1A). East Asian countries such as South Korea and Singapore, which have experienced dramatic economic progress over the last three decades, have shown the largest increase in NHL in Asia.18 Epidemiologic studies analyzing the distribution of NHL subtypes across the world are challenged by the evolving classification systems, coding, and ability to confirm diagnoses; however, substantial differences in the relative frequencies of NHL subtypes exist. Asian populations typically have higher proportions of mature natural killer (NK)/T-cell lymphomas and mucosa-associated lymphoid tissue lymphoma, and lower proportions of FL and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) than Western populations.19,20 The higher proportions of mucosa-associated lymphoid tissue lymphoma in Asia and mature NK/T-cell neoplasms in the southeastern parts of Japan are attributed to the high prevalence of Helicobacter pylori and human T-lymphotropic virus 1 (HTLV-1), respectively. Although the disparity between East and West suggests the influence of ethnicity, the disparity between identical or similar ethnic populations residing in different regions indicates a possible environmental influence.21 In a study of lymphoma in Asian populations living in the United States from the Surveillance, Epidemiology, and End Results (SEER) program conducted from 1988 to 2004, Clark et al reported that incidence rates of FL, CLL/SLL, and nodular sclerosis HL were significantly higher in U.S.-born Asian populations (second generation immigrants or beyond) compared with foreign-born Asian populations (first generation immigrants), supporting the role of environmental factors in lymphomagenesis.22
FIGURE 1. Estimated Age-Standardized Rates of Incidence Cases and Deaths of Non-Hodgkin Lymphoma (A and B) and Hodgkin Lymphoma (C and D), Both Sexes
HL accounts for no more than 0.5% of the total cancer burden worldwide in 2012; however, its unusual biology, epidemiology, and positive response to treatment draws ample attention.15 The overall incidence of HL varies greatly throughout the world (Fig. 1C) and the pathogenesis of this geographic discrepancy is not known; however, environmental and lifestyle factors have been theorized as potential factors. Unlike NHL, which shows an exponential increase in age-specific incidence, age-specific incidence rates of HL are bimodal, with the first peak occurring during ages 15 to 34 and the second after age 60 in European, American, Hispanic, and Australian populations.23 In middle-income countries, the incidence of HL is characteristically high in early childhood and among the oldest age groups. Affluent standards of living during childhood have been associated with an increased risk of young-adult HL, suggesting a delayed exposure to a common infectious agent, whereas the opposite is true for children living in less favorable living conditions.24 Therapeutic advancements, improved diagnostic ability, and health care access and management have made HL a largely curable disease in many areas of the world. Declines in mortality by more than 75% in North America, Western Europe, and Japan are reported.6,25 Appreciable declines in HL mortality were also observed in most of Latin America, with the exception of Cuba, Costa Rica, Mexico, and Venezuela.24,26
In 2016, there were an expected 81,080 new cases of lymphoma diagnosed in the United States (8,500 cases of HL, 72,580 cases of NHL).27 The 5-year relative survival rate for HL more than doubled from 40% in white patients from 1960 to 1963 (only data available) to 88.3% for all races between 2005 and 2011.27 The 5-year relative survival rate is 94.1% for patients with HL who are younger than 45 at diagnosis.27 The 5-year relative survival rate for NHL rose from 31% in white patients from 1960 to 1963 (only data available) to 71.9% for all races between 2005 and 2011.27
Incidence rates of NHL in the United States nearly doubled between 1970 and 1990, but have stabilized since the late 1990s.28 NHL has been associated with broadly categorized immune-related conditions including immunodeficiency, autoimmune disease, infection, and allergy.29-32 Although the incidence of NHL is somewhat lower among the black population compared with the white population, the black population has higher rates of extranodal NHL subtypes, PTCL and mycosis fungoides.33 These disparities coupled with findings that associations between immune system–related gene polymorphisms and NHL vary by race have suggested that genetic predisposition may play a role in immune-related NHL.34 In a study of over 4 million U.S. veterans, infection, autoimmune, and allergic conditions were all associated with increased risk of NHL.35 The black population had a slightly higher risk of NHL associated with infections than the white population (likelihood ratio test p = .002), with a notable exception of risk associated with HIV, which was twofold higher in the white population.35 Allergies also tended to be more strongly associated with risk of NHL in the black population than the white population (likelihood ratio test, p = .05), whereas risks associated with autoimmune conditions were similar by race (likelihood ratio test, p = .5).35 The authors hypothesized that these patterns could reflect underlying genetic differences in immune response between racial groups.
DLBCL, FL, and CLL/SLL account for the majority of all NHL in the United States. In a SEER study of these three subtypes diagnosed between 1992 and 2010, racial differences in patient characteristics, incidence, and survival were detected.36 The non-Hispanic white population had the highest incidence rates for all three subtypes, followed by the Hispanic white and black populations.36 Overall, CLL/SLL had the highest age at diagnosis. For all three subtypes, however, age distribution was substantially different across races. For DLBCL, the non-Hispanic white population tended to be older than the other races.36 For FL and CLL/SL, the non-Hispanic whites and Asian/Pacific Islander populations were older than the Hispanic white and black populations.36 For DLBCL, the black population had the highest rate of extranodal involvement (70.52%), whereas for CLL/SLL, the Asian and Pacific Islander populations had the highest rate (92.22%).36 For all three subtypes, the non-Hispanic white population had the highest 5-year relative survival rates, followed by the Hispanic white population. When stratified by stage, the racial difference was substantial.36
DLBCL is the most common subtype of NHL in the world, accounting for approximately 30% to 40% of all newly diagnosed cases.15 In the United States, there is a male predominance and incidence rates vary by ethnicity with the white population demonstrating higher rates than the black, Asians, American Indian, and Alaskan native populations, in decreasing order.37 Without treatment, over 50% of patients with DLBCL survive less than 1 year; however, with the introduction of rituximab in approximately 2002, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)–based therapies increased the 5-year overall survival from approximately 45% with CHOP alone to 60% to 70%.38 Clinical prognostic models have identified age, stage, extranodal sites, performance status, and serum lactate dehydrogenase as independentpredictors of clinical outcome with intensive chemotherapy and comprise the International Prognostic Index.39,40
Black patients with DLBCL have a risk of death that is 10% to 20% higher than the non-Hispanic white population in numerous studies, with survival differences persisting after the introduction of rituximab.12,41-44 Wang et al studied 13,321 patients diagnosed with NHL between 1992 and 1999 in a linked SEER-Medicare dataset.12 Although the black cohort was less likely to receive lymphoma therapy (odds ratio 0.68; 95% CI, 0.56–0.83) and had inferior all-cause mortality when compared with the white cohort, these differences were no longer significant after controlling for other factors and were best explained by differences in SES.12 In that study, 72% of the black cohort was in the poorest quartile of SES compared with 22% of the white cohort.12 The authors concluded that delayed therapy or SES (specifically poverty, education, and family income) partially explained their finding. In a retrospective analysis of a population-based dataset within the California cancer registry, Tao and colleagues considered the relationship between neighborhood SES and race/ethnicity.45 In 33,032 patients diagnosed with DLBCL in California from 1988 to 2009, patients living in lower SES neighborhoods had increased risks of all-cause and lymphoma-specific death compared with patients in higher SES neighborhoods.45 Neighborhood SES was determined using an index derived from principal components of seven indicator variables of SES (education level, proportion unemployed and with a blue collar job, proportion < 200% poverty line, and median household income, rent, and home value). Interestingly, the magnitude of disparity in survival associated with neighborhood SES was more pronounced in the modern era (post-rituximab adoption), in patients younger than age 65, and in patients who were married. In addition, uninsured and government-assisted insured patients experienced a 1.5-fold increased risk of death. Though notable disparities by race/ethnic groups existed, these differences were attenuated by neighborhood SES disparities.45 Place of residence was also studied by the Nebraska Lymphoma Study Group, which found that rural patients with lymphoma treated by community-based providers had inferior overall survival compared with urban residents treated by university-based providers, urban residents treated by community-based providers, and rural residents treated by university-based providers.46
Other studies have described insurance-related disparities among younger patients with NHL; however, these studies lacked important confounders of survival such as performance/comorbidity score, HIV status, international prognostic index, and chemotherapy use.47 Using the National Cancer Database to explore these insurance-related disparities, adjustment for these confounders resulted in an adjusted hazard ratio of 1.26 for patients who were uninsured and 1.52 for patients with Medicaid, indicating that insurance-related disparities are partly mediated by prevalence of known prognostic factors in DLBCL and/or by patients’ pre-existing medical conditions that determine eligibility for specific health insurance.48
Biologic differences have also been investigated in DLBCL health disparities. Gene expression profiling has identified at least two biologically distinct and prognostically meaningful molecular subgroups of DLBCL. Germinal center B-cell type (GCB) resembles a normal germinal center B cell and has a superior 5-year survival rate with standard R-CHOP therapy, whereas activated B-cell type (ABC) resembles an activated B cell and has inferior 5-year survival rates following standard R-CHOP compared with GCB tumors.49,50 Ethnic and racial differences in the frequency of ABC and GCB subtypes were identified in studies of patients with DLBCL from Malaysia, Japan, Turkey, China, Germany, and North America.51-54 A preliminary report of differences in GCB and ABC subtypes in the white and black populations, however, suggests there may not be the same effect on prognosis.55
Hematopoietic cell transplantation is a complex, highly specialized and resource-intensive procedure indicated for relapsed DLBCL and other types of lymphoma. In a retrospective study of 687 autologous stem cell transplant recipients with lymphoma, there was no significant impact of race on transplant outcomes; however, there was an association between SES and outcomes. Patients from areas of low median income had lower overall survival after autologous stem cell transplant compared with those of high median income, including patients who had survived without evidence of disease progression for 1 year after transplantation. The authors concluded that patients with low SES with lymphoma are a high-risk population that may need additional support through autologous stem cell transplant.56
Although FL is the second most common NHL in western countries, incidence elsewhere, particularly in Asia, is lower.15 The t(14;18) translocation leading to BCL2 rearrangement is present in 90% of FLs in Western populations, but occurs in only about 60% of FLs in Asian populations.57 Tumors without BCL2 rearrangements tend to have BCL6 rearrangements and grade IIIB morphology and can be associated with DLBCL.58 Hence, FLs in Asian populations are morphologically and phenotypically similar to those in Western populations, although a subset might have different pathogenic pathways.57
FL survival has improved since the mid-1970s, possibly because of the introduction of new therapies such as rituximab. In a population-based study of nearly 16,000 patients in California with FL, overall and FL-specific survival improved 22% and 37%, respectively, from 1988 to 1997 and 1998 to 2005, and were observed in all racial and ethnic groups.59 The Asian/Pacific Islander populations had better survival than the non-Hispanic white, Hispanic, and black populations who had similar outcomes. Lower neighborhood SES was associated with worse survival in patients across all stages of disease (p for trend < .01). Patients with the lowest SES quintile had a 49% increased risk of death from all causes and 31% increased risk of death from FL compared with patients with the highest SES.59
In 2,744 enrolled patients in the National LymphoCare Study, the largest prospective cohort to date of FL in the United States, only 3% and 5% of patients were black or Hispanic, respectively, and 90% of patients were white.60 Compared with the white cohort, more patients in the black and Hispanic cohorts were diagnosed younger than age 45 and patients from the black cohort tended to have higher FLIPI scores at the time of presentation compared with the white or Hispanic cohorts, although the difference was not significant.60 Patients from the Hispanic cohort were more commonly diagnosed with grade 3 FL compared with patients from the black and white cohorts (29%, 13%, and 18%, respectively) and more commonly received rituximab plus chemotherapy as initial therapy compared with the white cohort (66% vs. 50%), whereas the black cohort less commonly received anthracyclines (49% vs. 64%).60 At a median follow-up of 52 months, progression-free survival was similar between the black and white cohorts, but was longer in the Hispanic cohort, and there was no difference in overall survival.60 In a study of over 18,000 patients with FL from the SEER database between 1992 and 2009, 5-year overall survival improved across most races/ethnicities after the introduction of chemoimmunotherapy.61 Interestingly, the Asian/Pacific Islanders populations did not demonstrate much improvement, perhaps because of relative superior outcomes prior to the introduction of rituximab.61
CLL is the most common form of adult leukemia in the United States and is grouped with SLL in the WHO classification.1 Incidence rates are higher among males than females and highest among the white population, intermediate among the black population, and lowest among the Asian/Pacific Islander populations.62 The black population with CLL/SLL present at a younger age (67 vs. 70) and had worse survival than the white population in a large SEER study.63 The etiology of the survival disparity has not been adequately studied; however, in a study from the Mayo Clinic CLL database, outcomes between the white and black populations were comparable, suggesting differences may be due to disparities in access to care and management rather than differences in disease biology.64
PTCLs are uncommon malignancies, accounting for 10% to 15% of all NHLs. Ethnic and geographic variations account for differences in prevalence; however, with rates ranging from 24% in Asia to 4% in North America.20 The reason behind this variation is not entirely clear, but may relate to exposure or genetic susceptibility to pathogenic agents in Asian countries, notably HTLV-1 infection in adult T-cell leukemia/lymphoma and Epstein-Barr virus infection in NK/T-cell lymphoma.20
In a study of over 13,000 patients with PTCL identified from 2000 to 2012 in the SEER registry, compared with the non-Hispanic white cohort, the black cohort had a higher incidence of PTCL not otherwise specified, anaplastic large-cell lymphoma, and adult T-cell leukemia/lymphoma and a lower incidence of angioimmunoblastic T-cell lymphoma.65 The Asians/Pacific Islander cohort had a higher incidence of angioimmunoblastic T-cell lymphoma, extranodal nasal-type NK/T-cell lymphoma and NK-cell leukemia, and adult T-cell leukemia/lymphoma and a lower incidence of anaplastic large-cell lymphoma. The Hispanic cohort had a higher incidence of angioimmunoblastic T-cell lymphoma and extranodal nasal-type NK/T-cell lymphoma and NK-cell leukemia, whereas the Native American cohort had a lower incidence of PTCL not otherwise specified.65 Survival varied significantly by race/ethnicity with the black cohort in particular experiencing shorter survival for most subtypes, highlighting the need for stronger recruitment of patients from the black population to clinical trials of PTCL.65 Future studies of SES factors and biologic differences in PTCL may help better understand these disparities.
HL is classified into two major types: classic HL and nodular lymphocyte predominant HL, accounting for 95% and 5% of all HL cases, respectively.1 The incidence of HL overall has decreased by approximately 16% in the 1970s through 1997 in the United States.66 The reasons are unclear with only a small proportion of the decrease attributed to the shift in classification and misdiagnosis.66 Interestingly, an increase in HL incidence was observed in many female populations, including from the white and black populations.67 The upward trend in women has been associated with decreasing parity, implicating childbearing as a possible protective factor against HL.68
Racial and ethnic disparities in HL rates have been reported in the United States.69 In a retrospective study of over 16,000 cases in SEER from 1992 and 2007, a bimodal age distribution for the white and Asian/Pacific Islander populations exist, but not for the black or Hispanic populations.69 Further, HL was more common in the Hispanic population compared with the white population above age 65.69 Clinicopathologic racial differences included less common frequency of nodular sclerosis histology, more frequent presence of B symptoms, and more common advanced-stage disease for the Hispanic and black populations compared with the white population.69 The etiology of these differences is not known, although several factors have been hypothesized. SES has been shown to affect incidence, because individuals living with a higher SES have a higher risk of HL. Underscoring the etiologic complexity of HL, SES differences varied by age, race, histology, and gender in a California cohort, as did Epstein-Barr virus–positive cases in a smaller sample with uniformly reviewed pathology.70,71
Racial disparities in survival that persist after adjustment for SES have also been detected in HL.72,73 A possible explanation for these disparities is variation in initial treatment and management. Keegan et al have found that the black and Hispanic populations were more likely to receive chemotherapy alone (as compared with combined modality therapy) than the non-Hispanic white or Asian/Pacific Islander populations.73 A population-based study also showed that patients from the black and Hispanics populations, and patients residing in lower SES neighborhoods, had lower utilization of radiotherapy.74 In addition, inadequate health insurance is associated with later stage at diagnosis and undertreatment of HL.75-77
The incidence of nodular lymphocyte predominant HL is higher among the black population than other races.78 In a retrospective study of patients with nodular lymphocyte predominant HL using the National Cancer Database, patients from the black population were on average younger than patients from the white population (median age 42 vs. 45), more often female (49% vs. 29%), and more likely to have axillary lymph nodes as the primary site of disease (25% vs. 17%).78 They also had unfavorable SES characteristics, a higher rate of no treatment in patients with early-stage disease, and a longer time to therapy initiation (median, 53.5 vs. 47 days).78 Despite this, there was no significant difference between races with regard to stage distribution or survival. Overall survival at 7 years was 90.1% in patients with early-stage and 79.4% in patients with advanced-stage disease.76
The epidemiology of NHL and HL vary within and between geographic regions. In the United States, a number of studies indicate that the characteristics, incidence rates, and survival rates of various subtypes of lymphoma for certain racial groups are different from others. Although our ability to treat patients with NHL and HL has improved dramatically during the last 3 decades, health disparities exist, including for DLBCL and HL, the most curable lymphoma subtypes. Eliminating health disparities is a formidable and multifaceted task, which must address complex associations between social, environmental, biologic, and patient-centered factors. A framework developed by the National Institutes of Health Centers for Population Health and Health Disparities designed and proposed for DLBCL can be applied to other lymphoma subtypes (Fig. 2).79,80 A better understanding of these factors will be important to identifying modifiable barriers in treatment and facilitate steps to improve outcomes for all patients.
FIGURE 2. A Framework for Understanding the Relationships Between Social, Environmental, Biologic, and Patient-Related Factors and Disparities in DLBCL Survival
Numbers indicate example publications from the references that address specific factors.
Professional illustration by Debra T. Dartez.1
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. 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.
Speakers' Bureau: Celgene, Takeda
Research Funding: Kyowa Hakko Kirin
No relationship to disclose
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