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Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Calgary, Alberta, Canada Ryan Healey a,b , Jay L. Patel a,b , Lawrence de Koning a,b , Christopher Naugler a,b,c,∗ a b c
Department of Pathology & Laboratory Medicine University of Calgary, Calgary, AB, Canada Calgary Laboratory Services, Calgary, AB, Canada Department of Family Medicine University of Calgary, Calgary, Alberta, Canada
a r t i c l e
i n f o
Article history: Received 18 December 2014 Received in revised form 20 January 2015 Accepted 29 January 2015 Available online xxx Keywords: Chronic lymphocytic leukemia Monoclonal B-cell lymphocytosis Incidence Epidemiology Flow cytometry Canada
a b s t r a c t This study provides an update on the incidence of chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) in a major Canadian city using the 2008 World Health Organization (WHO) diagnostic criteria. Incidence calculations were performed using data from a centralized flow cytometry laboratory servicing southern Alberta, Canada. The age-standardized incidence of 4.01 cases of CLL per 100,000 person-years is nearly half the rate previously reported in Canada. Compared to previous criteria based on absolute lymphocyte count rather than absolute B-cell count, utilizing the 2008 WHO criteria resulted in a 47.6% decline in CLL incidence (8.42 cases per 100,000 using 1996 criteria). As a consequence, MBL rates are 64% higher. In contrast to 1996 criteria showing a peak CLL incidence between ages 70-74, age-specific incidence rates show a continuous increase with advancing age using the 2008 guidelines. We also report a higher male to female ratio of CLL than previous Canadian reports (1.80:1). CLL incidence in southern Alberta is lower than rates recently reported in the United States using the same criteria. This difference may be due in part to the low median age and the lower proportion of persons of Caucasian European ancestry present in our study population. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction Hematological malignancies comprise approximately 6–10% of all cancers depending on geographic region [1]. Similar to other developed nations, hematological malignancies are the fourth most frequently diagnosed cancer in Canadian men (behind prostate, colorectal, and lung) and women (behind breast, lung, and colorectal). The incidence of non-Hodgkin lymphoma/leukemia (NHL) in Canada has increased two-fold since 1970 to 13.2 per 100,000 (age standardized), which is more than triple that of developing regions [1–3]. In Alberta, cancer causes 36% of deaths in men and women above the age of 35 [4]. Of these cancers, 10.3% are of hematological origin in men and 7.9% in women. An estimated 1 in every
Abbreviations: CLL, chronic lymphocytic leukemia; MBL, monoclonal B-cell lymphocytosis; CMA, Calgary metropolitan area; WHO, World Health Organization; NCI-WG, National Cancer Institute-sponsored Working Group; NHL, non-Hodgkin lymphoma/leukemia; CLS, Calgary Laboratory Services. ∗ Corresponding author at: Diagnostic & Scientific Centre 9-3535 Research Road NW Calgary, AB, Canada T2L 2K8. Tel.: +1 403 770 3756; fax: +1 403 770 3292. E-mail addresses: [email protected] (R. Healey), [email protected] (J.L. Patel), [email protected] (L. de Koning), [email protected] (C. Naugler).
105 men and 1 in 136 women in Alberta are predicted to die from a form of blood cancer [5]. Of all hematological malignancies, chronic lymphocytic leukemia (CLL) is thought to compose the highest proportion of leukemias in the Western world [6]. The current definition of CLL based on the 2008 World Health Organization (WHO) guidelines presents the disorder as a blood cancer of monoclonal, immunophenotypically distinct mature B-lymphocytes in the blood having an absolute count above 5.0 × 109 L−1 [7,8]. In the absence of this numerical criterion, patients must show evidence of disease related symptoms/cytopenias or extramedullary disease for a diagnosis of CLL. Patients who do not meet these diagnostic criteria are considered to have monoclonal B-cell lymphocytosis (MBL), which may or may not portend progression to overt CLL [9,10]. Benign MBL and malignant CLL have an identical immunophenotype by flow cytometry, thus differentiating the two typically rests on clinical findings and absolute monoclonal B-cell count [11]. MBL has been shown to exist in a significant proportion of the normal population, particularly in older adults [12]. Although frequent in the elderly, MBL is not an inevitable consequence of immune system ageing [13]. Indeed, patients with MBL are often discovered incidentally and do not require treatment. A small subset of patients with MBL, however, may develop CLL or other lymphoproliferative disorders over time
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and clinical follow-up or monitoring is often recommended. Once a diagnosis of CLL is confirmed, patients may be treated upfront with multi-agent chemotherapy or on a watch and wait basis. Treatment depends on clinical stage and risk factors such as patient age, white blood cell count, and cytogenetics. CLL is more common in men, but the reason for this increased male incidence is not well understood [14]. Depending on cytogenetic abnormalities present in the patient, median survival can range from 7.9 to 24.4 years [15]. Past studies have well established that incidence rates for CLL and other NHL subtypes vary in different ethnic populations around the world [16,17]. Notably, CLL incidence is much higher in North American European Caucasians than in persons of Asian, African, and Hispanic ancestry living in Canada and the US [18–22]. Chinese CLL incidence in British Columbia (BC), Canada is thought to be as much as 10 times lower than in Caucasians of European descent (BC Chinese CLL incidence of 1.71 per 100,000 person-years) [22]. Chinese, Japanese, Filipino, and Korean Asians in Los Angeles have age-adjusted CLL incidence rates between 0.6 and 1.0 per 100,000 [18]. In the US, Caucasians have CLL incidence rates 1.4 times higher than African Americans and 2.96 times higher than Hispanics [20]. CLL prognosis, age at diagnosis, and survival rates, however, may be worse in ethnic groups with lower incidence rates [21]. CLL in Korean patients, for example, is more aggressive than Western CLL and often presents with an atypical phenotype [23]. The cause of CLL incidence differences between ethnic groups is not well understood. Asian and Caucasian ethnic groups show some differences in CLL genomic abnormalities, but are for the most part very similar at the DNA level [24,25]. Environmental factors may play a role, as CLL incidence is lower in foreign-born versus US-born Asians [26]. Perhaps most compelling is the association of certain HLA gene polymorphisms with CLL disease incidence, as abnormalities in immune surveillance genes may allow for the development of CLL more readily in whites than in African-American and Hispanic populations [27]. Determining the true incident rate of CLL is critical for understanding of the etiology and pathogenesis of this disease and for informing health care administrators tasked with resource allocation. CLL epidemiology is challenging for a number of reasons [28,29]. Unlike other cancers, registry data has been shown to underestimate CLL disease incidence [30,31]. CLL is usually a slow-progressing disease thus patients may not be entered into a cancer registry until treatment starts, often months to years after initial diagnosis. The change from the National Cancer Institutesponsored Working Group in 1996 (1996 NCI-WG) to the current 2008 WHO diagnostic criteria has also affected CLL epidemiology. NCI-WG guidelines in 1996 included B-cells, T-cells, NK-cells, and other lymphocyte subsets in an absolute blood lymphocyte count above 5.0 × 109 L−1 [32]. This is problematic, as reactive T-cell populations are often present, and can falsely elevate the number of CLL diagnoses in a population. The 2008 WHO criteria have effectively decreased the incidence of CLL by excluding lymphocytes other than monoclonal B-cells from the absolute numerical cut-off, subsequently reclassifying patients with low monoclonal B-cell counts and no clinical symptoms as MBL. These reclassified low-count CLL populations are sometimes referred to as high-count MBL [33]. An accurate best estimate of the true incidence of CLL and high-count MBL thus requires application of the current diagnostic criteria to patient diagnostic data gathered from a centralized flow cytometry laboratory servicing a large patient population. The goal of this study was to provide an update on the current incidence of CLL and MBL in south-central Alberta and standardized to Canadian, US, and world populations based on the most current diagnostic criteria. In addition, this study provides new insights into the epidemiological impact of the 2008 WHO guidelines on CLL incidence in a large Canadian patient cohort. The effect of ethnic makeup on incidence rates in a major Canadian city is also
discussed. For this study we used 2012–2014 patient data from a single publically funded flow cytometry laboratory in Calgary, Alberta servicing all of southern Alberta, but we limited our analysis to the Calgary metropolitan area (CMA) population of just over 1.2 million residents. 2. Methods 2.1. Ethics statement Ethics approval for this study was obtained from the Conjoint Health Research Ethics Board at the University of Calgary (Ethics ID no. CHREB13-1126). 2.2. Source of data A retrospective cohort design was used in this study. Patient data was obtained from the Calgary Laboratory Services (CLS) centralized flow cytometry laboratory located at the Foothills Medical Centre in Calgary, Alberta. This single laboratory is unique in that it provides immunophenotyping testing for a catchment area that includes approximately 1.8 million residents from Calgary and southern Alberta. We examined raw digital records of all flow cytometry tests performed over a two-year period from March 21, 2012 until March 21, 2014. Complete blood counts (CBC) performed within 31 days of flow cytometry testing were obtained by linking flow cytometry reports to CLS Laboratory Information System (LIS) data using provincial health card numbers. Notably, 80% of flow cytometry cases had CBC results performed on the same day. Sex and age at time of flow cytometry testing were also retrieved from the LIS. 2.3. Case identification Based on specimen type, blood and bone marrow cases were identified from the CLS flow cytometry laboratory database. Duplicate cases on a single patient were removed, with the most recent record kept. Bone marrows also having diagnostic blood data for a single patient were removed as duplicates. Incident and prevalent cases were differentiated by searching for any previous diagnostic flow cytometry and pathology records (available from 1989 onward). Prevalent cases were excluded. Because we have immunophenotyping data for the previous 25 years, and because any patients with established CLL would be highly likely to have had a flow cytometry investigation during this period, we are confident that our dataset includes only incident cases. Digital reports were searched to confirm the accuracy of immunophenotype according to the 2008 WHO guidelines [7], disease codes according to the International Classification of Diseases for Oncology (ICD-O), and percent disease. Any unclear or discrepant cases were independently reviewed by a hematopathologist (JLP). CLL and MBL cases (ICD-O code 9823) were identified by 10-color flow cytometry as having a clonal B-cell population with monotypic surface light chain expression and positivity for CD19, CD20, CD23, and CD5, but not FMC-7 or CD10. A small number of MBL cases showed variable expression for CD23 and FMC-7, as is often seen diagnostically in the context of CLL and MBL. Clonal B-cell concentration was determined by multiplying the percent of nucleated cells reported by flow cytometry by the absolute white blood cell count from the CBC. According to the 2008 WHO guidelines, any incident cases having a concentration of malignant B-cells of 5.0 × 109 L−1 or greater were classified as CLL. All CLL immunophenotypes not meeting this B-cell concentration cut-off at diagnosis were classified as MBL. Incident cases were also classified according to the 1996 NCI-WG guidelines [32] to compare CLL/MBL incidence rates to those reported in previous Canadian studies [22,31]. According to these guidelines,
Please cite this article in press as: Healey R, et al. Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Calgary, Alberta, Canada. Leuk Res (2015), http://dx.doi.org/10.1016/j.leukres.2015.01.015
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Table 1 Features of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in the Calgary metropolitan area. CLL
Total cases Male/female Median age at diagnosis (range) ABC × 109 L−1 ALC × 109 L−1
MBL
1996 NCI-WG
2008 WHO
1996 NCI-WG
2008 WHO
149 1.57 68.0 (36–93) 4.3 (0.1–86.1) 8.3 (5.0–100.7)
70 1.80 71.5 (36–93) 10.3 (5.1–86.1) 15.6 (5.2–100.7)
45 1.65 66.0 (31–87) 1.6 (0.1–5.9) 4.1 (0.9–4.9)
124 1.48 67.5 (31–90) 2.5 (0.1–4.9) 5.5 (0.9–15.0)
ABC: absolute B-cell count, ALC: absolute lymphocyte count.
Table 2 Incidence rates per 100,000 person-years for CLL and MBL in the Calgary metropolitan area population and standardized to Canadian, US, and world reference populations. CLL
Calgary metropolitan area Canada (2011) United States (2000) World (2000 WHO) World (1960 Segi)
MBL
1996 NCI-WG
2008 WHO
1996 NCI-WG
2008 WHO
6.13 8.42 6.87 4.89 4.36
2.88 4.01 3.27 2.20 1.93
1.85 2.47 2.02 1.48 1.31
5.10 6.88 5.63 4.17 3.74
incident cases having an absolute lymphocyte count of 5.0 × 109 L−1 or greater were classified as CLL. Cases below this cut-off were called MBL. ArcGIS (v10.1) geomapping software was used to restrict CLL and MBL patient postal code locations to those patients residing in the 2011 CMA of Calgary. This area encompasses approximately 1.215 million residents of south-central Alberta and includes the cities of Calgary and Airdrie; the communities of Cochrane, Chestermere, Crossfield, Irricana, and Beiseker; the Rocky View County; and the Tsuu T’ina First Nation [34]. 2.4. Incidence rate calculations CLL/MBL incident and age-standardized rates were calculated using published methods [35,36]. We considered two years of incident CLL and MBL, thus the total number of cases in our dataset was divided in half to calculate an annual rate. Age-specific incidence rates in southern Alberta were calculated for five-year age groups from 0 to 85+ in the 2011 CMA population [34]. Incidence rates were then standardized to 2011 Canada [37], 2000 United States [38], 2000 WHO world [39], and 1969 Segi world [40] populations. 3. Results There were 316 incident cases of CLL and MBL identified in this study. Of the observed cases, 194 fell within the Calgary Metropolitan Area of south-central Alberta at time of diagnosis. Demographic features, absolute B-cell count (ABC), and absolute lymphocyte count (ALC) of this population are summarized in Table 1. Using the 2008 WHO criteria, 70 and 124 CMA patients were classified as CLL and MBL, respectively. When the 1996 NCI-WG criteria were applied, these numbers changed, respectively, to 149 and 45. Incidence rates of CLL and MBL per 105 person-years standardized to Canada, United States, and world standard populations are summarized in Table 2. Application of the 2008 WHO criteria caused a decrease in the incidence of CLL by an average of 54% in the observed populations. The incidence of MBL was, on average, 64% higher. CLL and MBL incidence rates for 5-year age groups in the Calgary Metropolitan Area are summarized in Fig. 1. In contrast to the 1996 NCI-WG guidelines that show a peak incidence at ages 70–74, CLL incidence is highest in the 85+ age group using the 2008 WHO criteria. For MBL, the 2008 WHO criteria cause incidence rates to peak and then plateau between the ages of 70 to 79. MBL incidence
then declines, or perhaps transforms to CLL, as age increases. This pattern differs substantially from the MBL trend observed when the 1996 NCI-WG criteria are used. Using these guidelines, MBL incidence is lower and shows a consistent, moderate increase with age. 4. Discussion This study provides an update on the current status of CLL and MBL in a major Canadian city using the 2008 WHO diagnostic criteria. In addition, this study is the first to determine CLL- and MBL-specific incidence rates in the province of Alberta [41]. Previous Canadian epidemiological studies have reported CLL incidence rates for specific ethnic groups [19,22] or based on diagnostic criteria that are no longer in use in most clinical laboratories [31]. A high CLL incidence in Canada (7.99 per 100,000) has been previously reported using the 1996 NCI-WG criteria. Using the same criteria, we calculated a current incidence of 8.42 per 100,000 person-years, suggesting an increase in Canadian CLL disease burden. However, if diagnosis, staging, and treatment of CLL are based on current 2008 WHO criteria, the true incidence of CLL is substantially lower than previous Canadian reports. Based on an absolute count of immunophenotyped malignant B-cells at 5.0 × 109 L−1 or greater, we report a standardized CLL incidence of 4.01 per 100,000 persons in Canada per year. This rate is 50% less than that previously reported in Manitoba—primarily due to the difference in diagnostic criteria used. The 2008 criteria reclassify a proportion of Rai Stage 0 patients from CLL to MBL [42]. These changes have little impact on the clinical management of CLL, as a watchful waiting approach to treatment is typically used for both MBL and Rai Stage 0 patients. We also report a higher ratio of males to females with CLL (M:F = 1.80) compared to previous Canadian studies. We reasoned that this may be due to a larger male to female ratio in the CMA population. This was not the case, however, as the ratio of males to females in all age groups above 25 was almost exactly 1:1 [34]. Our data show that the increased M:F ratio is almost entirely due to the 2008 criteria. Previous CLL ratios reported in Manitoba and BC range between 1.32 and 1.50, respectively [22,31]. Interestingly, when the 1996 NCI-WG criteria used in previous studies were applied to our population, the M:F ratio dropped to 1.57. This same change in M:F ratio using the 2008 WHO criteria was recently observed in a US study [33]. An additional impact of the 2008 WHO criteria thus appears to be a higher relative reported incident rate of CLL in North American men.
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Fig. 1. CLL and MBL five-year incidence rates in the Calgary metropolitan area using 1996 NCI-WG and 2008 WHO diagnostic criteria.
The standardized US CLL incidence rate of 3.27 per 100,000 reported in the current study (Table 2) is substantially lower than the US CLL rate recently reported in Olmsted County, Minnesota using the same 2008 criteria (6.8 per 100,000) [33]. Several factors may explain this difference. The ethnic make-up of the CMA population differs substantially from that of Olmstead County, Minnesota. According to the 2011 Canadian National Household Survey [43], the Calgary metropolitan is roughly composed of the following groups: 3.2% North American Aboriginal, 71.5% North American European, 0.8% Caribbean, 1.7% Hispanic, 2.4% African, 19.9% Asian, and 0.4% Oceanic. In contrast, only 14.3% of the population of Olmsted County identified as non-white in 2006 [44]. Lower rates of CLL in Asian, Hispanic, and African ethnic groups may contribute to the lower CLL incidence rate observed in the current study. In addition, standardizing CLL incidence in the CMA to the 2010 US white population (as was done in the Minnesota study) decreases the denominator population by approximately one quarter [45], leading to a significant increase in predicted CLL incidence. Note that the median age in the CMA and Olmsted County populations were nearly identical (35.7 and 36 years old, respectively in 2006) [34,44]. When CLL/MBL incidence rates in the CMA are age-standardized to Canada, US, and world populations, several rate differences emerge (Table 2). This is related, in part, to differences in median age observed in the CMA, Canadian, and standard United States, Segi, and WHO populations. In 2011, the proportion of the population aged 65 and over was 14.8% in Canada, 13.0% in the United States, and 9.8% in the CMA [34,37]. Interestingly, the proportion of persons aged 65 and over in the CMA more closely resembles the Segi and WHO populations (7.0% and 8.23%, respectively) [39,40].
The young median age and high relative proportion (28.5%) of nonwhite persons in the CMA population likely explain some of the decreased CLL and MBL incidence rates observed. Differences in healthcare models between Canada and the US may also explain some variation in incidence rates [46,47]. Increased access to care for the elderly and for persons of lower economic status may affect the number of cancer cases reported in flow cytometry databases. This difference may increase the number of MBL cases reported due to earlier detection and lower the median age observed at CLL diagnosis. Equal access to care, however, might suggest a higher number of observed CLL cases in the Canadian population when compared to that seen in the US. This was not the case. The large decrease in CLL incidence reported does not reflect a significant improvement in CLL treatment or prevention, but rather a somewhat arbitrary change in the diagnostic criteria for this disease. No major biological event occurs when the MBL/CLL cut-off of 5.0 × 109 L−1 B-cells is breached–though there is data to suggest that very low clonal B-cell counts are of doubtful clinical significance and large ones are more likely to be significant, non-indolent clones. More often we are presented with situations in-between, highlighting the need for discovery of more prognostic biomarkers such as TP53 and ZAP-70. This study has limitations in that it would have been strengthened by an analysis of patient long-term follow-up and survival data. As this data was not available for our study cohort, future epidemiological studies are warranted. In conclusion, the 2008 WHO CLL criteria have substantially altered several epidemiologic characteristics of CLL and MBL in south-central Alberta, Canada. The incident rate of CLL is nearly half the Canadian rate previously reported and a higher proportion
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of these cases occur in men. In addition, our adjusted CLL and MBL rates are lower in Canada than in the United States. This may be due to differences in healthcare delivery systems, median age, and in the proportion of persons of Asian, Hispanic, African, and white European ancestry in the study populations. Finally, we report a different CLL age pattern using the 2008 WHO criteria, with CLL incidence increasing with age across all age groups. Conflict of interest statement The authors have no conflicts of interest to declare. Acknowledgments Ryan Healey co-conceived the study, retrieved and analyzed the flow cytometry data, performed the epidemiological calculations, and wrote the first draft of the manuscript. Christopher Naugler co-conceived the study design, coordinated data retrieval, critically reviewed the manuscript, and is the corresponding author. Jay Patel co-conceived the study, provided hematopathology expertise, and critically reviewed the manuscript. Lawrence de Koning provided epidemiological expertise and critically reviewed the manuscript. The authors would like to thank Peter Peller for his assistance with ArcGIS software analysis, patient location tracking, and Census Canada data retrieval. The authors also acknowledge Jeannine Viczko for her assistance in LIS data retrieval. References [1] Globocan. Estimated cancer incidence, mortality and prevalence worldwide in 2012. World Health Organization International Agency for Research on Cancer; 2012. http://globocan.iarc.fr/Pages/fact sheets population.aspx (accessed December 31, 2013). [2] Liu S, Semenciw R, Mao Y. Increasing incidence of non-Hodgkin’s lymphoma in Canada, 1970–1996: age-period-cohort analysis. Hematol Oncol 2003;21:57–66. [3] Skrabek P, Turner D, Seftel M. Epidemiology of non-hodgkin lymphoma. Transfus Apher Sci 2013;49:133–8. [4] Alberta Health Services. Cancer in Alberta: 2008 report on statistics in Alberta. Alberta Health Services; 2008. cancer http://www.albertahealthservices.ca/poph/hi-poph-surv-cancer-cancerin-alberta-2008.pdf (accessed December 31, 2013). [5] Alberta Health Services. Cancer in Alberta: 2010 report on cancer statistics in Alberta—leukemia. Alberta Health Services; 2010. http://www.albertahealthservices.ca/poph/hi-poph-surv-cancer-leukemia2010.pdf (accessed March 17, 2014). [6] Montserrat E, Moreno C. Chronic lymphocytic leukaemia: a short overview. Ann Oncol 2008;19(Suppl. 7):vii320–5. [7] Swerdllow S, Campo E, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues. France: IARC Press; 2008, 2008. [8] Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446–56. [9] Dagklis A, Fazi C, Scarfo L, Apollonio B, Ghia P, Monoclonal B. lymphocytosis in the general population. Leuk Lymphoma 2009;50:490–2. [10] Nieto WG, Teodosio C, Lopez A, et al. Non-CLL-like monoclonal B-cell lymphocytosis in the general population: prevalence and phenotypic/genetic characteristics. Cytometry B Clin Cytom 2010;78(Suppl. 1):S24–34. [11] Shanafelt TD, Kay NE, Jenkins G, et al. B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood 2009;113:4188–96. [12] Rawstron AC, Bennett FL, O’Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med 2008;359:575–83. [13] Soosapilla A, Pepperell D, Best G, et al. Monoclonal B-Lymphocytosis in over 90 year olds is common but not inevitable, and has a prevalence comparable to individuals 65-90 years old. Leuk Lymphoma 2014, ePub: 2014/12/17, ISSN: 1029-2403 (Electronic), 1026-8022 (Linking), DOI: 10.3109/10428194.2014.976822. [14] Molica S. Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leuk Lymphoma 2006;47:1477–80. [15] Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999;94:1848–54. [16] Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL. The clinical and epidemiological burden of chronic lymphocytic leukaemia. Eur J Cancer Care (Engl) 2004;13:279–87.
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Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Calgary, Alberta, Canada Ryan Healey a,b , Jay L. Patel a,b , Lawrence de Koning a,b , Christopher Naugler a,b,c,∗ a b c
Department of Pathology & Laboratory Medicine University of Calgary, Calgary, AB, Canada Calgary Laboratory Services, Calgary, AB, Canada Department of Family Medicine University of Calgary, Calgary, Alberta, Canada
a r t i c l e
i n f o
Article history: Received 18 December 2014 Received in revised form 20 January 2015 Accepted 29 January 2015 Available online xxx Keywords: Chronic lymphocytic leukemia Monoclonal B-cell lymphocytosis Incidence Epidemiology Flow cytometry Canada
a b s t r a c t This study provides an update on the incidence of chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) in a major Canadian city using the 2008 World Health Organization (WHO) diagnostic criteria. Incidence calculations were performed using data from a centralized flow cytometry laboratory servicing southern Alberta, Canada. The age-standardized incidence of 4.01 cases of CLL per 100,000 person-years is nearly half the rate previously reported in Canada. Compared to previous criteria based on absolute lymphocyte count rather than absolute B-cell count, utilizing the 2008 WHO criteria resulted in a 47.6% decline in CLL incidence (8.42 cases per 100,000 using 1996 criteria). As a consequence, MBL rates are 64% higher. In contrast to 1996 criteria showing a peak CLL incidence between ages 70-74, age-specific incidence rates show a continuous increase with advancing age using the 2008 guidelines. We also report a higher male to female ratio of CLL than previous Canadian reports (1.80:1). CLL incidence in southern Alberta is lower than rates recently reported in the United States using the same criteria. This difference may be due in part to the low median age and the lower proportion of persons of Caucasian European ancestry present in our study population. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction Hematological malignancies comprise approximately 6–10% of all cancers depending on geographic region [1]. Similar to other developed nations, hematological malignancies are the fourth most frequently diagnosed cancer in Canadian men (behind prostate, colorectal, and lung) and women (behind breast, lung, and colorectal). The incidence of non-Hodgkin lymphoma/leukemia (NHL) in Canada has increased two-fold since 1970 to 13.2 per 100,000 (age standardized), which is more than triple that of developing regions [1–3]. In Alberta, cancer causes 36% of deaths in men and women above the age of 35 [4]. Of these cancers, 10.3% are of hematological origin in men and 7.9% in women. An estimated 1 in every
Abbreviations: CLL, chronic lymphocytic leukemia; MBL, monoclonal B-cell lymphocytosis; CMA, Calgary metropolitan area; WHO, World Health Organization; NCI-WG, National Cancer Institute-sponsored Working Group; NHL, non-Hodgkin lymphoma/leukemia; CLS, Calgary Laboratory Services. ∗ Corresponding author at: Diagnostic & Scientific Centre 9-3535 Research Road NW Calgary, AB, Canada T2L 2K8. Tel.: +1 403 770 3756; fax: +1 403 770 3292. E-mail addresses: [email protected] (R. Healey), [email protected] (J.L. Patel), [email protected] (L. de Koning), [email protected] (C. Naugler).
105 men and 1 in 136 women in Alberta are predicted to die from a form of blood cancer [5]. Of all hematological malignancies, chronic lymphocytic leukemia (CLL) is thought to compose the highest proportion of leukemias in the Western world [6]. The current definition of CLL based on the 2008 World Health Organization (WHO) guidelines presents the disorder as a blood cancer of monoclonal, immunophenotypically distinct mature B-lymphocytes in the blood having an absolute count above 5.0 × 109 L−1 [7,8]. In the absence of this numerical criterion, patients must show evidence of disease related symptoms/cytopenias or extramedullary disease for a diagnosis of CLL. Patients who do not meet these diagnostic criteria are considered to have monoclonal B-cell lymphocytosis (MBL), which may or may not portend progression to overt CLL [9,10]. Benign MBL and malignant CLL have an identical immunophenotype by flow cytometry, thus differentiating the two typically rests on clinical findings and absolute monoclonal B-cell count [11]. MBL has been shown to exist in a significant proportion of the normal population, particularly in older adults [12]. Although frequent in the elderly, MBL is not an inevitable consequence of immune system ageing [13]. Indeed, patients with MBL are often discovered incidentally and do not require treatment. A small subset of patients with MBL, however, may develop CLL or other lymphoproliferative disorders over time
http://dx.doi.org/10.1016/j.leukres.2015.01.015 0145-2126/© 2015 Elsevier Ltd. All rights reserved.
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and clinical follow-up or monitoring is often recommended. Once a diagnosis of CLL is confirmed, patients may be treated upfront with multi-agent chemotherapy or on a watch and wait basis. Treatment depends on clinical stage and risk factors such as patient age, white blood cell count, and cytogenetics. CLL is more common in men, but the reason for this increased male incidence is not well understood [14]. Depending on cytogenetic abnormalities present in the patient, median survival can range from 7.9 to 24.4 years [15]. Past studies have well established that incidence rates for CLL and other NHL subtypes vary in different ethnic populations around the world [16,17]. Notably, CLL incidence is much higher in North American European Caucasians than in persons of Asian, African, and Hispanic ancestry living in Canada and the US [18–22]. Chinese CLL incidence in British Columbia (BC), Canada is thought to be as much as 10 times lower than in Caucasians of European descent (BC Chinese CLL incidence of 1.71 per 100,000 person-years) [22]. Chinese, Japanese, Filipino, and Korean Asians in Los Angeles have age-adjusted CLL incidence rates between 0.6 and 1.0 per 100,000 [18]. In the US, Caucasians have CLL incidence rates 1.4 times higher than African Americans and 2.96 times higher than Hispanics [20]. CLL prognosis, age at diagnosis, and survival rates, however, may be worse in ethnic groups with lower incidence rates [21]. CLL in Korean patients, for example, is more aggressive than Western CLL and often presents with an atypical phenotype [23]. The cause of CLL incidence differences between ethnic groups is not well understood. Asian and Caucasian ethnic groups show some differences in CLL genomic abnormalities, but are for the most part very similar at the DNA level [24,25]. Environmental factors may play a role, as CLL incidence is lower in foreign-born versus US-born Asians [26]. Perhaps most compelling is the association of certain HLA gene polymorphisms with CLL disease incidence, as abnormalities in immune surveillance genes may allow for the development of CLL more readily in whites than in African-American and Hispanic populations [27]. Determining the true incident rate of CLL is critical for understanding of the etiology and pathogenesis of this disease and for informing health care administrators tasked with resource allocation. CLL epidemiology is challenging for a number of reasons [28,29]. Unlike other cancers, registry data has been shown to underestimate CLL disease incidence [30,31]. CLL is usually a slow-progressing disease thus patients may not be entered into a cancer registry until treatment starts, often months to years after initial diagnosis. The change from the National Cancer Institutesponsored Working Group in 1996 (1996 NCI-WG) to the current 2008 WHO diagnostic criteria has also affected CLL epidemiology. NCI-WG guidelines in 1996 included B-cells, T-cells, NK-cells, and other lymphocyte subsets in an absolute blood lymphocyte count above 5.0 × 109 L−1 [32]. This is problematic, as reactive T-cell populations are often present, and can falsely elevate the number of CLL diagnoses in a population. The 2008 WHO criteria have effectively decreased the incidence of CLL by excluding lymphocytes other than monoclonal B-cells from the absolute numerical cut-off, subsequently reclassifying patients with low monoclonal B-cell counts and no clinical symptoms as MBL. These reclassified low-count CLL populations are sometimes referred to as high-count MBL [33]. An accurate best estimate of the true incidence of CLL and high-count MBL thus requires application of the current diagnostic criteria to patient diagnostic data gathered from a centralized flow cytometry laboratory servicing a large patient population. The goal of this study was to provide an update on the current incidence of CLL and MBL in south-central Alberta and standardized to Canadian, US, and world populations based on the most current diagnostic criteria. In addition, this study provides new insights into the epidemiological impact of the 2008 WHO guidelines on CLL incidence in a large Canadian patient cohort. The effect of ethnic makeup on incidence rates in a major Canadian city is also
discussed. For this study we used 2012–2014 patient data from a single publically funded flow cytometry laboratory in Calgary, Alberta servicing all of southern Alberta, but we limited our analysis to the Calgary metropolitan area (CMA) population of just over 1.2 million residents. 2. Methods 2.1. Ethics statement Ethics approval for this study was obtained from the Conjoint Health Research Ethics Board at the University of Calgary (Ethics ID no. CHREB13-1126). 2.2. Source of data A retrospective cohort design was used in this study. Patient data was obtained from the Calgary Laboratory Services (CLS) centralized flow cytometry laboratory located at the Foothills Medical Centre in Calgary, Alberta. This single laboratory is unique in that it provides immunophenotyping testing for a catchment area that includes approximately 1.8 million residents from Calgary and southern Alberta. We examined raw digital records of all flow cytometry tests performed over a two-year period from March 21, 2012 until March 21, 2014. Complete blood counts (CBC) performed within 31 days of flow cytometry testing were obtained by linking flow cytometry reports to CLS Laboratory Information System (LIS) data using provincial health card numbers. Notably, 80% of flow cytometry cases had CBC results performed on the same day. Sex and age at time of flow cytometry testing were also retrieved from the LIS. 2.3. Case identification Based on specimen type, blood and bone marrow cases were identified from the CLS flow cytometry laboratory database. Duplicate cases on a single patient were removed, with the most recent record kept. Bone marrows also having diagnostic blood data for a single patient were removed as duplicates. Incident and prevalent cases were differentiated by searching for any previous diagnostic flow cytometry and pathology records (available from 1989 onward). Prevalent cases were excluded. Because we have immunophenotyping data for the previous 25 years, and because any patients with established CLL would be highly likely to have had a flow cytometry investigation during this period, we are confident that our dataset includes only incident cases. Digital reports were searched to confirm the accuracy of immunophenotype according to the 2008 WHO guidelines [7], disease codes according to the International Classification of Diseases for Oncology (ICD-O), and percent disease. Any unclear or discrepant cases were independently reviewed by a hematopathologist (JLP). CLL and MBL cases (ICD-O code 9823) were identified by 10-color flow cytometry as having a clonal B-cell population with monotypic surface light chain expression and positivity for CD19, CD20, CD23, and CD5, but not FMC-7 or CD10. A small number of MBL cases showed variable expression for CD23 and FMC-7, as is often seen diagnostically in the context of CLL and MBL. Clonal B-cell concentration was determined by multiplying the percent of nucleated cells reported by flow cytometry by the absolute white blood cell count from the CBC. According to the 2008 WHO guidelines, any incident cases having a concentration of malignant B-cells of 5.0 × 109 L−1 or greater were classified as CLL. All CLL immunophenotypes not meeting this B-cell concentration cut-off at diagnosis were classified as MBL. Incident cases were also classified according to the 1996 NCI-WG guidelines [32] to compare CLL/MBL incidence rates to those reported in previous Canadian studies [22,31]. According to these guidelines,
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Table 1 Features of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in the Calgary metropolitan area. CLL
Total cases Male/female Median age at diagnosis (range) ABC × 109 L−1 ALC × 109 L−1
MBL
1996 NCI-WG
2008 WHO
1996 NCI-WG
2008 WHO
149 1.57 68.0 (36–93) 4.3 (0.1–86.1) 8.3 (5.0–100.7)
70 1.80 71.5 (36–93) 10.3 (5.1–86.1) 15.6 (5.2–100.7)
45 1.65 66.0 (31–87) 1.6 (0.1–5.9) 4.1 (0.9–4.9)
124 1.48 67.5 (31–90) 2.5 (0.1–4.9) 5.5 (0.9–15.0)
ABC: absolute B-cell count, ALC: absolute lymphocyte count.
Table 2 Incidence rates per 100,000 person-years for CLL and MBL in the Calgary metropolitan area population and standardized to Canadian, US, and world reference populations. CLL
Calgary metropolitan area Canada (2011) United States (2000) World (2000 WHO) World (1960 Segi)
MBL
1996 NCI-WG
2008 WHO
1996 NCI-WG
2008 WHO
6.13 8.42 6.87 4.89 4.36
2.88 4.01 3.27 2.20 1.93
1.85 2.47 2.02 1.48 1.31
5.10 6.88 5.63 4.17 3.74
incident cases having an absolute lymphocyte count of 5.0 × 109 L−1 or greater were classified as CLL. Cases below this cut-off were called MBL. ArcGIS (v10.1) geomapping software was used to restrict CLL and MBL patient postal code locations to those patients residing in the 2011 CMA of Calgary. This area encompasses approximately 1.215 million residents of south-central Alberta and includes the cities of Calgary and Airdrie; the communities of Cochrane, Chestermere, Crossfield, Irricana, and Beiseker; the Rocky View County; and the Tsuu T’ina First Nation [34]. 2.4. Incidence rate calculations CLL/MBL incident and age-standardized rates were calculated using published methods [35,36]. We considered two years of incident CLL and MBL, thus the total number of cases in our dataset was divided in half to calculate an annual rate. Age-specific incidence rates in southern Alberta were calculated for five-year age groups from 0 to 85+ in the 2011 CMA population [34]. Incidence rates were then standardized to 2011 Canada [37], 2000 United States [38], 2000 WHO world [39], and 1969 Segi world [40] populations. 3. Results There were 316 incident cases of CLL and MBL identified in this study. Of the observed cases, 194 fell within the Calgary Metropolitan Area of south-central Alberta at time of diagnosis. Demographic features, absolute B-cell count (ABC), and absolute lymphocyte count (ALC) of this population are summarized in Table 1. Using the 2008 WHO criteria, 70 and 124 CMA patients were classified as CLL and MBL, respectively. When the 1996 NCI-WG criteria were applied, these numbers changed, respectively, to 149 and 45. Incidence rates of CLL and MBL per 105 person-years standardized to Canada, United States, and world standard populations are summarized in Table 2. Application of the 2008 WHO criteria caused a decrease in the incidence of CLL by an average of 54% in the observed populations. The incidence of MBL was, on average, 64% higher. CLL and MBL incidence rates for 5-year age groups in the Calgary Metropolitan Area are summarized in Fig. 1. In contrast to the 1996 NCI-WG guidelines that show a peak incidence at ages 70–74, CLL incidence is highest in the 85+ age group using the 2008 WHO criteria. For MBL, the 2008 WHO criteria cause incidence rates to peak and then plateau between the ages of 70 to 79. MBL incidence
then declines, or perhaps transforms to CLL, as age increases. This pattern differs substantially from the MBL trend observed when the 1996 NCI-WG criteria are used. Using these guidelines, MBL incidence is lower and shows a consistent, moderate increase with age. 4. Discussion This study provides an update on the current status of CLL and MBL in a major Canadian city using the 2008 WHO diagnostic criteria. In addition, this study is the first to determine CLL- and MBL-specific incidence rates in the province of Alberta [41]. Previous Canadian epidemiological studies have reported CLL incidence rates for specific ethnic groups [19,22] or based on diagnostic criteria that are no longer in use in most clinical laboratories [31]. A high CLL incidence in Canada (7.99 per 100,000) has been previously reported using the 1996 NCI-WG criteria. Using the same criteria, we calculated a current incidence of 8.42 per 100,000 person-years, suggesting an increase in Canadian CLL disease burden. However, if diagnosis, staging, and treatment of CLL are based on current 2008 WHO criteria, the true incidence of CLL is substantially lower than previous Canadian reports. Based on an absolute count of immunophenotyped malignant B-cells at 5.0 × 109 L−1 or greater, we report a standardized CLL incidence of 4.01 per 100,000 persons in Canada per year. This rate is 50% less than that previously reported in Manitoba—primarily due to the difference in diagnostic criteria used. The 2008 criteria reclassify a proportion of Rai Stage 0 patients from CLL to MBL [42]. These changes have little impact on the clinical management of CLL, as a watchful waiting approach to treatment is typically used for both MBL and Rai Stage 0 patients. We also report a higher ratio of males to females with CLL (M:F = 1.80) compared to previous Canadian studies. We reasoned that this may be due to a larger male to female ratio in the CMA population. This was not the case, however, as the ratio of males to females in all age groups above 25 was almost exactly 1:1 [34]. Our data show that the increased M:F ratio is almost entirely due to the 2008 criteria. Previous CLL ratios reported in Manitoba and BC range between 1.32 and 1.50, respectively [22,31]. Interestingly, when the 1996 NCI-WG criteria used in previous studies were applied to our population, the M:F ratio dropped to 1.57. This same change in M:F ratio using the 2008 WHO criteria was recently observed in a US study [33]. An additional impact of the 2008 WHO criteria thus appears to be a higher relative reported incident rate of CLL in North American men.
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Fig. 1. CLL and MBL five-year incidence rates in the Calgary metropolitan area using 1996 NCI-WG and 2008 WHO diagnostic criteria.
The standardized US CLL incidence rate of 3.27 per 100,000 reported in the current study (Table 2) is substantially lower than the US CLL rate recently reported in Olmsted County, Minnesota using the same 2008 criteria (6.8 per 100,000) [33]. Several factors may explain this difference. The ethnic make-up of the CMA population differs substantially from that of Olmstead County, Minnesota. According to the 2011 Canadian National Household Survey [43], the Calgary metropolitan is roughly composed of the following groups: 3.2% North American Aboriginal, 71.5% North American European, 0.8% Caribbean, 1.7% Hispanic, 2.4% African, 19.9% Asian, and 0.4% Oceanic. In contrast, only 14.3% of the population of Olmsted County identified as non-white in 2006 [44]. Lower rates of CLL in Asian, Hispanic, and African ethnic groups may contribute to the lower CLL incidence rate observed in the current study. In addition, standardizing CLL incidence in the CMA to the 2010 US white population (as was done in the Minnesota study) decreases the denominator population by approximately one quarter [45], leading to a significant increase in predicted CLL incidence. Note that the median age in the CMA and Olmsted County populations were nearly identical (35.7 and 36 years old, respectively in 2006) [34,44]. When CLL/MBL incidence rates in the CMA are age-standardized to Canada, US, and world populations, several rate differences emerge (Table 2). This is related, in part, to differences in median age observed in the CMA, Canadian, and standard United States, Segi, and WHO populations. In 2011, the proportion of the population aged 65 and over was 14.8% in Canada, 13.0% in the United States, and 9.8% in the CMA [34,37]. Interestingly, the proportion of persons aged 65 and over in the CMA more closely resembles the Segi and WHO populations (7.0% and 8.23%, respectively) [39,40].
The young median age and high relative proportion (28.5%) of nonwhite persons in the CMA population likely explain some of the decreased CLL and MBL incidence rates observed. Differences in healthcare models between Canada and the US may also explain some variation in incidence rates [46,47]. Increased access to care for the elderly and for persons of lower economic status may affect the number of cancer cases reported in flow cytometry databases. This difference may increase the number of MBL cases reported due to earlier detection and lower the median age observed at CLL diagnosis. Equal access to care, however, might suggest a higher number of observed CLL cases in the Canadian population when compared to that seen in the US. This was not the case. The large decrease in CLL incidence reported does not reflect a significant improvement in CLL treatment or prevention, but rather a somewhat arbitrary change in the diagnostic criteria for this disease. No major biological event occurs when the MBL/CLL cut-off of 5.0 × 109 L−1 B-cells is breached–though there is data to suggest that very low clonal B-cell counts are of doubtful clinical significance and large ones are more likely to be significant, non-indolent clones. More often we are presented with situations in-between, highlighting the need for discovery of more prognostic biomarkers such as TP53 and ZAP-70. This study has limitations in that it would have been strengthened by an analysis of patient long-term follow-up and survival data. As this data was not available for our study cohort, future epidemiological studies are warranted. In conclusion, the 2008 WHO CLL criteria have substantially altered several epidemiologic characteristics of CLL and MBL in south-central Alberta, Canada. The incident rate of CLL is nearly half the Canadian rate previously reported and a higher proportion
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of these cases occur in men. In addition, our adjusted CLL and MBL rates are lower in Canada than in the United States. This may be due to differences in healthcare delivery systems, median age, and in the proportion of persons of Asian, Hispanic, African, and white European ancestry in the study populations. Finally, we report a different CLL age pattern using the 2008 WHO criteria, with CLL incidence increasing with age across all age groups. Conflict of interest statement The authors have no conflicts of interest to declare. Acknowledgments Ryan Healey co-conceived the study, retrieved and analyzed the flow cytometry data, performed the epidemiological calculations, and wrote the first draft of the manuscript. Christopher Naugler co-conceived the study design, coordinated data retrieval, critically reviewed the manuscript, and is the corresponding author. Jay Patel co-conceived the study, provided hematopathology expertise, and critically reviewed the manuscript. Lawrence de Koning provided epidemiological expertise and critically reviewed the manuscript. The authors would like to thank Peter Peller for his assistance with ArcGIS software analysis, patient location tracking, and Census Canada data retrieval. The authors also acknowledge Jeannine Viczko for her assistance in LIS data retrieval. References [1] Globocan. Estimated cancer incidence, mortality and prevalence worldwide in 2012. World Health Organization International Agency for Research on Cancer; 2012. http://globocan.iarc.fr/Pages/fact sheets population.aspx (accessed December 31, 2013). [2] Liu S, Semenciw R, Mao Y. Increasing incidence of non-Hodgkin’s lymphoma in Canada, 1970–1996: age-period-cohort analysis. Hematol Oncol 2003;21:57–66. [3] Skrabek P, Turner D, Seftel M. Epidemiology of non-hodgkin lymphoma. Transfus Apher Sci 2013;49:133–8. [4] Alberta Health Services. Cancer in Alberta: 2008 report on statistics in Alberta. Alberta Health Services; 2008. cancer http://www.albertahealthservices.ca/poph/hi-poph-surv-cancer-cancerin-alberta-2008.pdf (accessed December 31, 2013). [5] Alberta Health Services. Cancer in Alberta: 2010 report on cancer statistics in Alberta—leukemia. Alberta Health Services; 2010. http://www.albertahealthservices.ca/poph/hi-poph-surv-cancer-leukemia2010.pdf (accessed March 17, 2014). [6] Montserrat E, Moreno C. Chronic lymphocytic leukaemia: a short overview. Ann Oncol 2008;19(Suppl. 7):vii320–5. [7] Swerdllow S, Campo E, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues. France: IARC Press; 2008, 2008. [8] Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446–56. [9] Dagklis A, Fazi C, Scarfo L, Apollonio B, Ghia P, Monoclonal B. lymphocytosis in the general population. Leuk Lymphoma 2009;50:490–2. [10] Nieto WG, Teodosio C, Lopez A, et al. Non-CLL-like monoclonal B-cell lymphocytosis in the general population: prevalence and phenotypic/genetic characteristics. Cytometry B Clin Cytom 2010;78(Suppl. 1):S24–34. [11] Shanafelt TD, Kay NE, Jenkins G, et al. B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood 2009;113:4188–96. [12] Rawstron AC, Bennett FL, O’Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med 2008;359:575–83. [13] Soosapilla A, Pepperell D, Best G, et al. Monoclonal B-Lymphocytosis in over 90 year olds is common but not inevitable, and has a prevalence comparable to individuals 65-90 years old. Leuk Lymphoma 2014, ePub: 2014/12/17, ISSN: 1029-2403 (Electronic), 1026-8022 (Linking), DOI: 10.3109/10428194.2014.976822. [14] Molica S. Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leuk Lymphoma 2006;47:1477–80. [15] Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999;94:1848–54. [16] Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL. The clinical and epidemiological burden of chronic lymphocytic leukaemia. Eur J Cancer Care (Engl) 2004;13:279–87.
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