Original Article
Incidence of Chronic Lymphocytic Leukemia and High-Count Monoclonal B-Cell Lymphocytosis Using the 2008 Guidelines Timothy G. Call, MD1; Aaron D. Norman, MPH2; Curtis A. Hanson, MD3; Sara J. Achenbach, MS2; Neil E. Kay, MD1; Clive S. Zent, MD4; Wei Ding, MD1; James R. Cerhan, MD, PhD2; Kari G. Rabe, MS2; Celine M. Vachon, PhD2; Emily J. Hallberg, MPH2; Tait D. Shanafelt, MD1; and Susan L. Slager, PhD2
BACKGROUND: The 1996 National Cancer Institute Working Group (NCI-WG 96) guidelines classified disease in individuals who had a B-cell clone with chronic lymphocytic leukemia (CLL) immunophenotype as CLL if their absolute lymphocyte count was 5 3 109=L. The 2008 International Workshop on CLL guidelines (IWCLL 2008) classified disease as CLL if the absolute B-cell count was 5 3 109=L or as monoclonal B-cell lymphocytosis (MBL) if the absolute B-cell count was 40 years have detectable clonal B-cell populations with an immunophenotype consistent with CLL, referred to as low-count monoclonal B-cell lymphocytosis (MBL).5,7 In addition to population screening studies, substantial numbers of patients have borderline or mildly elevated lymphocyte counts identified on routine, clinically obtained, automated complete blood counts (CBCs). This high-count MBL is detected when a clonal B-cell population is identified during the evaluation of such patients using flow cytometry yet does not meet the diagnostic criteria for CLL. The majority of these express a CLL immunophenotype, but a small percentage may type as other low-grade lymphoproliferative disorders.5,7 Population screening studies for low-count MBL have been reported, and the risk of progression to CLL is low.8,9 High-count MBL has been associated with a risk of progression to CLL requiring treatment of approximately 1% per
Corresponding author: Timothy G. Call, MD, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; Fax: (507) 266-4972; [email protected] 1 Division of Hematology, Mayo Clinic, Rochester, Minnesota; 2Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota; 3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 4James P. Wilmot Cancer Center, Rochester, New York; 5Department of Hematology=Oncology, Mayo Clinic, Scottsdale, Arizona
DOI: 10.1002/cncr.28690, Received: November 26, 2013; Revised: January 16, 2014; Accepted: February 21, 2014, Published online April 7, 2014 in Wiley Online Library (wileyonlinelibrary.com)
2000
Cancer
July 1, 2014
CLL=MBL Incidence-IWCLL 2008 Guidelines/Call et al
year.5,9 Molecular markers, such as CD38 (cluster of differentiation 38 [a type II membrane glycoprotein]) expression, may be associated with outcome in patients with high-count MBL.10 The classification criteria for CLL have changed several times in the last 25 years. Before 2008, the diagnosis of CLL was based on the 1996 National Cancer Institutesponsored Working Group guidelines (NCI-WG 96), which classified individuals who had a B-cell clone with characteristic immunophenotype as CLL if their absolute lymphocyte count (ALC) was 5 3 109=L.11 The updated 2008 International Workshop on CLL guidelines (IWCLL 2008) classify disease that has a characteristic immunophenotype as CLL if the patient’s absolute B-cell count is 5 3 109=L.12 Individuals with clonal B-cell populations who have an absolute B-cell count 11 3 109=L) was the best level to anchor the diagnosis to overall and treatment-free survival,15 a finding that was confirmed in population-based studies from Italy.20 It should be noted that the incidence rates reported here are higher than those from the most recent report by the Surveillance, Epidemiology, and End Results (SEER) Program but similar to the incidence rates reported from the province of Manitoba, Canada, where there is centralized flow cytometry.21,22 A similar difference in incidence rates (vs SEER) was noted in our prior study of Olmsted County, Minnesota.1,2 These differences are likely because of more complete ascertainment in Olmsted County than SEER because of both centralized flow cytometry (as in Manitoba14,15) and centralized record keeping, which studies indicate can result in better ascertainment and increased incidence.23 Defining the incidence of clinically evident highcount MBL will have implications for clinical practice. Evidence is emerging that that individuals with highcount MBL not only are at risk for progression to CLL but also appear to have increased susceptibility to significant infection and second cancers.24,25 Having a unique International Classification of Diseases code for clinically identified MBL will be important for tracking and future monitoring studies. Recommendations for monitoring of individuals with high-count MBL have now been published.7 In conclusion, the incidence of CLL was stable over the last 25 years based on pre-2008 criteria. However, changes made to CLL diagnostic guidelines in 2008 have resulted in the reclassification of a significant percentage of patients who were previously diagnosed with CLL to a diagnosis of high-count MBL. This change in definition has had a profound impact on the epidemiologic and 2004
clinical characteristics of these 2 entities. This change will need to be further evaluated in ongoing incidence studies of CLL and MBL and will also need to be taken into account during future epidemiologic and clinical studies. FUNDING SUPPORT This study was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health (NIH) under Award R01AG034676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Support also was provided in part from NIH grants CA118444 and CA95241.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Call TG, Noel P, Habermann TM, Beard CM, O’Fallon WM, Kurland LT. Incidence of leukemia in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc. 1994;69:315-322. 2. Call TG, Phyliky RL, Noel P, et al. Incidence of chronic lymphocytic leukemia in Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in initial stage at diagnosis. Mayo Clin Proc. 1994;69:323-328. 3. Kyle RA, Nobrega FT, Kurland LT, Elveback LR. The 30-year trend of leukemia in Olmsted County, Minnesota, 1935 through 1964. Mayo Clin Proc. 1968;43:342-353. 4. Linos A, Kyle RA, Elveback LR, Kurland LT. Leukemia in Olmsted County, Minnesota, 1965-1974. Mayo Clin Proc. 1978;53:714-718. 5. Rawstron AC, Bennett FL, O’Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359:575-583. 6. Rawstron AC, Green MJ, Kuzmicki A, et al. Monoclonal B lymphocytes with the characteristics of “indolent” chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood. 2002;100:635-639. 7. Shanafelt TD, Ghia P, Lanasa MC, Landgren O, Rawstron AC. Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia. 2010;24:512-520. 8. Fazi C, Scarfo L, Pecciarini L, et al. General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood. 2011;118:6618-6625. 9. Scarfo L, Fazi C, Ghia P. MBL versus CLL: how important is the distinction? Hematol Oncol Clin North Am. 2013;27:251-265. 10. Shanafelt TD, Kay NE, Rabe KG, et al. Survival of patients with clinically identified monoclonal B-cell lymphocytosis (MBL) relative to the age- and sex-matched general population. Leukemia. 2012;26: 373-376. 11. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87:4990-4997. 12. 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;111:5446-5456. 13. Shanafelt TD, Kay NE, Rabe KG, et al. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol. 2009;27:3959-3963. 14. Shanafelt TD, Kay NE, Call TG, et al. MBL or CLL: which classification best categorizes the clinical course of patients with an absolute
Cancer
July 1, 2014
CLL=MBL Incidence-IWCLL 2008 Guidelines/Call et al
15.
16.
17.
18. 19.
lymphocyte count 53109 L21 but a B-cell lymphocyte count
Incidence of Chronic Lymphocytic Leukemia and High-Count Monoclonal B-Cell Lymphocytosis Using the 2008 Guidelines Timothy G. Call, MD1; Aaron D. Norman, MPH2; Curtis A. Hanson, MD3; Sara J. Achenbach, MS2; Neil E. Kay, MD1; Clive S. Zent, MD4; Wei Ding, MD1; James R. Cerhan, MD, PhD2; Kari G. Rabe, MS2; Celine M. Vachon, PhD2; Emily J. Hallberg, MPH2; Tait D. Shanafelt, MD1; and Susan L. Slager, PhD2
BACKGROUND: The 1996 National Cancer Institute Working Group (NCI-WG 96) guidelines classified disease in individuals who had a B-cell clone with chronic lymphocytic leukemia (CLL) immunophenotype as CLL if their absolute lymphocyte count was 5 3 109=L. The 2008 International Workshop on CLL guidelines (IWCLL 2008) classified disease as CLL if the absolute B-cell count was 5 3 109=L or as monoclonal B-cell lymphocytosis (MBL) if the absolute B-cell count was 40 years have detectable clonal B-cell populations with an immunophenotype consistent with CLL, referred to as low-count monoclonal B-cell lymphocytosis (MBL).5,7 In addition to population screening studies, substantial numbers of patients have borderline or mildly elevated lymphocyte counts identified on routine, clinically obtained, automated complete blood counts (CBCs). This high-count MBL is detected when a clonal B-cell population is identified during the evaluation of such patients using flow cytometry yet does not meet the diagnostic criteria for CLL. The majority of these express a CLL immunophenotype, but a small percentage may type as other low-grade lymphoproliferative disorders.5,7 Population screening studies for low-count MBL have been reported, and the risk of progression to CLL is low.8,9 High-count MBL has been associated with a risk of progression to CLL requiring treatment of approximately 1% per
Corresponding author: Timothy G. Call, MD, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; Fax: (507) 266-4972; [email protected] 1 Division of Hematology, Mayo Clinic, Rochester, Minnesota; 2Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota; 3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 4James P. Wilmot Cancer Center, Rochester, New York; 5Department of Hematology=Oncology, Mayo Clinic, Scottsdale, Arizona
DOI: 10.1002/cncr.28690, Received: November 26, 2013; Revised: January 16, 2014; Accepted: February 21, 2014, Published online April 7, 2014 in Wiley Online Library (wileyonlinelibrary.com)
2000
Cancer
July 1, 2014
CLL=MBL Incidence-IWCLL 2008 Guidelines/Call et al
year.5,9 Molecular markers, such as CD38 (cluster of differentiation 38 [a type II membrane glycoprotein]) expression, may be associated with outcome in patients with high-count MBL.10 The classification criteria for CLL have changed several times in the last 25 years. Before 2008, the diagnosis of CLL was based on the 1996 National Cancer Institutesponsored Working Group guidelines (NCI-WG 96), which classified individuals who had a B-cell clone with characteristic immunophenotype as CLL if their absolute lymphocyte count (ALC) was 5 3 109=L.11 The updated 2008 International Workshop on CLL guidelines (IWCLL 2008) classify disease that has a characteristic immunophenotype as CLL if the patient’s absolute B-cell count is 5 3 109=L.12 Individuals with clonal B-cell populations who have an absolute B-cell count 11 3 109=L) was the best level to anchor the diagnosis to overall and treatment-free survival,15 a finding that was confirmed in population-based studies from Italy.20 It should be noted that the incidence rates reported here are higher than those from the most recent report by the Surveillance, Epidemiology, and End Results (SEER) Program but similar to the incidence rates reported from the province of Manitoba, Canada, where there is centralized flow cytometry.21,22 A similar difference in incidence rates (vs SEER) was noted in our prior study of Olmsted County, Minnesota.1,2 These differences are likely because of more complete ascertainment in Olmsted County than SEER because of both centralized flow cytometry (as in Manitoba14,15) and centralized record keeping, which studies indicate can result in better ascertainment and increased incidence.23 Defining the incidence of clinically evident highcount MBL will have implications for clinical practice. Evidence is emerging that that individuals with highcount MBL not only are at risk for progression to CLL but also appear to have increased susceptibility to significant infection and second cancers.24,25 Having a unique International Classification of Diseases code for clinically identified MBL will be important for tracking and future monitoring studies. Recommendations for monitoring of individuals with high-count MBL have now been published.7 In conclusion, the incidence of CLL was stable over the last 25 years based on pre-2008 criteria. However, changes made to CLL diagnostic guidelines in 2008 have resulted in the reclassification of a significant percentage of patients who were previously diagnosed with CLL to a diagnosis of high-count MBL. This change in definition has had a profound impact on the epidemiologic and 2004
clinical characteristics of these 2 entities. This change will need to be further evaluated in ongoing incidence studies of CLL and MBL and will also need to be taken into account during future epidemiologic and clinical studies. FUNDING SUPPORT This study was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health (NIH) under Award R01AG034676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Support also was provided in part from NIH grants CA118444 and CA95241.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Call TG, Noel P, Habermann TM, Beard CM, O’Fallon WM, Kurland LT. Incidence of leukemia in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc. 1994;69:315-322. 2. Call TG, Phyliky RL, Noel P, et al. Incidence of chronic lymphocytic leukemia in Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in initial stage at diagnosis. Mayo Clin Proc. 1994;69:323-328. 3. Kyle RA, Nobrega FT, Kurland LT, Elveback LR. The 30-year trend of leukemia in Olmsted County, Minnesota, 1935 through 1964. Mayo Clin Proc. 1968;43:342-353. 4. Linos A, Kyle RA, Elveback LR, Kurland LT. Leukemia in Olmsted County, Minnesota, 1965-1974. Mayo Clin Proc. 1978;53:714-718. 5. Rawstron AC, Bennett FL, O’Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359:575-583. 6. Rawstron AC, Green MJ, Kuzmicki A, et al. Monoclonal B lymphocytes with the characteristics of “indolent” chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood. 2002;100:635-639. 7. Shanafelt TD, Ghia P, Lanasa MC, Landgren O, Rawstron AC. Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. Leukemia. 2010;24:512-520. 8. Fazi C, Scarfo L, Pecciarini L, et al. General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood. 2011;118:6618-6625. 9. Scarfo L, Fazi C, Ghia P. MBL versus CLL: how important is the distinction? Hematol Oncol Clin North Am. 2013;27:251-265. 10. Shanafelt TD, Kay NE, Rabe KG, et al. Survival of patients with clinically identified monoclonal B-cell lymphocytosis (MBL) relative to the age- and sex-matched general population. Leukemia. 2012;26: 373-376. 11. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87:4990-4997. 12. 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;111:5446-5456. 13. Shanafelt TD, Kay NE, Rabe KG, et al. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol. 2009;27:3959-3963. 14. Shanafelt TD, Kay NE, Call TG, et al. MBL or CLL: which classification best categorizes the clinical course of patients with an absolute
Cancer
July 1, 2014
CLL=MBL Incidence-IWCLL 2008 Guidelines/Call et al
15.
16.
17.
18. 19.
lymphocyte count 53109 L21 but a B-cell lymphocyte count
