Age, sex, race, and ethnic background remain the key demographic data that are collected and reported in cancer statistics and cancer outcomes research. Although it has been well established that there are significant racial differences in lymphoid malignancies[1, 2] few studies have investigated the relationships between race, the patterns of presentation for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), treatment selection, and clinical outcomes with modern therapies. A Surveillance, Epidemiology, and End Results (SEER) registry study comparing 27,703 white patients and 2059 black patients with CLL/SLL diagnosed in the United States from 1992 to 2007 showed that black patients presented at younger age, with more advanced stage, and had worse survival than white patients. However, all registry-based studies have been limited by lack of uniform pathology review, disagreement in coding systems for lymphoid malignancies that have changed over time, and incomplete or missing data on stage, race, important clinical and laboratory prognostic factors, treatment, treatment response, and follow-up. Moreover, prior institutional studies and even some population-based studies have had insufficient numbers of African American (AA) patients to perform comparisons across racial groups.
To overcome some of these limitations, a retrospective cohort study was conducted of consecutive patients with a confirmed diagnosis of CLL receiving care at 2 major academic medical centers in the United States, as reported by Falchi et al in this issue of Cancer. The authors identified via retrospective review 84 untreated AA patients referred to The University of Texas MD Anderson Cancer Center, Houston, Texas, and Duke University Medical Center, Durham, North Carolina, and constructed a comprehensive data set with complete ascertainment of demographic and clinical data and treatment information in order to assess the impact of race on disease presentation, treatment selection, and outcomes. This group was compared with 1571 untreated nonblack (NB) patients referred to the same institutions. The article describes the clinical characteristics, response to therapy, and survival of AA patients and describes comparison with NB patients. The study indicates that there are racial differences in CLL patterns of presentation and outcomes. AA patients with CLL presented with lower median hemoglobin levels, higher beta2-microglobulin (β2-m) levels, and more commonly presented with unmutated IGHV gene (65% versus 47%), ZAP70 expression (58% versus 32%), and chromosome 17p or 11q deletion (28% versus 17%), all of which are associated with worse outcomes. AA patients in this sample more commonly required first-line therapy during the period of follow-up and had a markedly shorter median time to initiation of therapy (14 months versus 57 months in NB patients). When compared to a group of 487 NB patients matched to the AA cohort based on treatment regimens, the AA group, despite having similar overall response rates, had significantly shorter median event-free survival (36 months versus 61 months, P = .007) and overall survival (152 months versus not reached, P = .0001). In multivariate analyses, race was an independent predictor of shorter event-free and overall survival. Moreover, these racial differences in survival persisted across different levels of β2-m, IGHV gene mutational status (mutated or unmutated), and cytogenetic abnormalities. These results corroborate the findings of the prior study of CLL/SLL in 13 SEER registries, suggesting that AA patients in the United States present with more advanced-stage disease and have worse survival, but advance the field by providing additional clinical details to understand the nature of these racial disparities.
Despite its size, this study was limited by the relatively smaller number of black patients as is the case with nearly all US-based and European lymphoma population studies that predominantly have examined white patients. In this academic center–based retrospective study, AA patients composed 5.1% of the study population. Another limitation of this study is the lack of central pathology review across the 2 institutions. Changes in the World Health Organization classification of lymphoid malignancies over the time period studied also could potentially complicate the adjudication of diagnoses across eras.[2, 7] However, the change in diagnosis definitions over time is unlikely to influence the findings here, because these academic institutions involved expert hematopathologists in the determination of CLL/SLL, and there is no reason to suspect that there was differential misclassification of cases of CLL across racial categories over time. A greater challenge for this report and many other studies of racial disparities is the coding of race in clinical data sets through use of patient self-report or “observed” definitions from various health professionals. These methods of coding race can mask numerous factors, such as inherited traits, health education, income, health insurance status, and other psychosocial forces that may influence differences in cancer incidence across racial categories and disparities in cancer outcomes. Improved methods for coding race in clinical environments and capturing salient features of race that influence clinical outcomes are greatly needed if we wish to disentangle the factors that influence outcomes and to develop strategies that improve survival based on a revised understanding of racial disparities.
Other potential limitations of this retrospective study design could include missing or incomplete data on staging, race, and treatment, or exclusion of cases with missing data. This study did not exclude patients, had stage information for all patients, and reported on all patients with untreated disease at the 2 centers. The amount of missing data and the patient characteristics at baseline in this setting appear comparable to registry data with the exception that the age at diagnosis for both groups was similar and younger than the typical age of onset for CLL. Several other studies have demonstrated that AA patients tend to present with lymphoid malignancies at a younger age than do white patients,[3, 8-10] and show that the lymphoid malignancies including CLL in the NB population have a median age at diagnosis in the seventh decade.[3, 8] The authors attribute these differences in age at diagnosis to the nature of referrals to academic medical centers, which is plausible and has been observed in other studies of racial disparities in lymphoid malignancies. Despite these potential shortcomings, this data set had the critical advantage of collection of important laboratory and treatment data beyond what occurs in typical cancer registries, which will be essential to improving our understanding of racial difference in treatment response outcomes as patients in these cohorts continue to be followed.
Although the observations of racial differences in cancer outcomes, including CLL, unfortunately are not new, the demonstration that these differences in survival persist even when similar therapies are administered for CLL is a novel finding, and it suggests that AA patients may have different disease biology than NB patients. Other studies have suggested that there are racial and socioeconomic differences in the use of therapies for lymphoid malignancies in the United States.[9, 10, 12] Developing interventions to address the broader disparities in treatment selection and treatment outcomes identified in claims-based cohort studies requires improved understanding of the context in which cancer treatments are selected for patients across racial groups.[11, 13] Socioeconomic factors and health education are other mediators that may contribute to poorer outcomes for AA patients with cancer. These and other factors may prohibit or limit access to care, thus leading to disparities. As the authors point out, time from diagnosis to referral was shorter for AA than NB patients in this study, making referral delay an unlikely cause of worse prognosis for the AA patients included in this analysis, although this does not rule out the possibility that delays in diagnosis could have occurred before referral to the academic center. These results suggest that additional effort to identify specific therapies that are more likely to benefit AA patients (and others) with poor-risk CLL may be needed even after improved access to care is achieved.
At present, there is limited understanding of the racial differences in CLL biology and the factors that influence the poor outcome in the AA population. As a result, there is substantial need for prospective studies seeking to identify clinically predictive factors that can aid in treatment selection for AA patients with CLL and other lymphoid malignancies. Focused disparities research studies are necessary to determine whether differences in underlying genetic predisposition or exposures exist among black and white patients with CLL, which might explain the differences in relative incidence, predisposition to poor-risk disease, and reduced survival.
The report by Falchi et al provides meaningful information regarding the role of known prognostic factors and baseline characteristics across racial groups and provides data on the impact of these characteristics on the outcomes of therapy for AA patients with CLL. This represents the largest study performed of this type with detailed clinical data and is supported by a similar study in diffuse large B-cell lymphoma which also suggests racial differences in survival may persist even when black and white patients receive the same treatment. In the future, developing significant clinical research studies of disparities in leukemia will require collection of biological specimens as well as clinical data to examine the racial differences in the molecular and biological markers and their impact on racial differences in leukemia presentation and outcomes. Future studies in CLL can use this work as a cornerstone for investigating racial disparities in this disease.