We present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compared with the general population and all cancer survivors in the databases. We hypothesize that CLL cells interact with T-cells in the microenvironment, facilitating malignant transformatio

Choi, Goda

Kater, Armon P.

Stam, Olga CG

Tonino, Sanne H.

van den Broek, Esther C

van Noesel, C.J.M.

NARCIS 

Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia

University of Groningen

   University of GroningenIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi, Goda; van den Broek, Esther C; Stam, Olga CG; van Noesel, C.J.M.; Tonino, Sanne H.;Kater, Armon P.Published in:Annals of Hematology & OncologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Choi, G., van den Broek, E. C., Stam, O. CG., van Noesel, C. J. M., Tonino, S. H., & Kater, A. P. (2015).Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Annals ofHematology & Oncology, 2(2), [1023 ].CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reservedAnnals of Hematology & OncologyOpen AccessAbstractWe present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compared with the general population and all cancer survivors in the databases. We hypothesize that CLL cells interact with T-cells in the microenvironment, facilitating malignant transformation.Keywords: Chronic lymphocytic leukemia; T-cell lymphoma; Neoplastic cell transformation; Cohort studiesIntroductionChronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by progressive accumulation of mature B-cells in peripheral blood and secondary lymphoid organs. Primary causes of death include infections and secondary malignancies [1], suggesting an immunodeficiency in CLL patients [2]. Recent epidemiological data demonstrated that the increased risk of other primary malignancies in CLL patients is independent of treatment or surveillance bias [3]. Most likely, CLL is not a disease limited to B-cells only, but also affects other components of the immune system due to extensive crosstalk between CLL cells and their microenvironment [4]. In this report, we present a patient with therapy-refractory CLL in whom post-mortem examination revealed the presence of a T-cell lymphoma. We further studied the coincidence of T-cell malignancies and CLL within two population-based cancer registries, and found an excess risk of T-cell malignancies in patients with CLL. Case PresentationA 75-year-old male patient with therapy-refractory CLL was referred to our hospital. CLL had been diagnosed 7 years earlier (initially Rai 0) and during the last 3 years, he was intermittently treated with Chlorambucil. One month before admission, he had a painful cervical node, from which a biopsy revealed CD5 positive, cycline-D1 negative B-cells, compatible with CLL and without signs of transformation. Upon admission, patient presented with fever, dysphagia, and general malaise. His blood counts showed a pancytopenia with hemoglobin 7.9 g/dL (12.1 a month before), leukocytes 2,300/μl (50% lymphocytes), and platelets 10,000/μl (80,000 before). Without clinical signs of a specific infection, he was treated with broad-spectrum antibiotics. A bone marrow biopsy was performed, showing80% CLL cells (positive for CD5/CD19/CD23/CD20dim) and dysplasia in the myeloid and erythroid lineages. Within hours, he had progressive respiratory failure due to either sepsis or transfusion-related lung injury. Despite ventilatory support, Case ReportIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi G1*, van den Broek EC3*, Stam OCG2, van Noesel CJM2, Tonino SH1 and Kater AP11Department of Hematology, University of Amsterdam, Netherlands2Department of Pathology, University of Amsterdam, Netherlands3Integraal Kankercentrum Zuid, Eindhoven, Netherlands*Corresponding author: G Choi, University Medical Center Groningen, Department of Hematology (HPC DA21) Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Tel: 31 50 361 2354; Fax: 31 50 361 5960; Email: c.w.choi@umcg.nlReceived: December 04, 2014; Accepted: January 16, 2015; Published: January 19, 2015patient’s condition rapidly deteriorated and he died within a few hours.Post-mortem examination showed signs of multi-organ failure, including congested lungs without microbial infiltrates. There was hepatosplenomegaly and lymphadenopathy. Immunohistochemistry studies showed diffuse infiltrates of small, basophilic cells, positive for CD5, CD20 and CD23 (in liver, spleen, and bone marrow). Remarkably, the spleen contained, apart from CLL, areas with large cells with atypical nuclei positive for CD3, CD8, and Granzyme B, and negative for CD4, CD5, CD20, CD23, CD30, ALK1, CD79a, PAX-5, EBV, and keratin.Ki67 showed a high proliferation index in these areas. Altogether, this patient was found to have CLL and a high-grade peripheral T-cell lymphoma NOS (Figure 1). Molecular analyses of both spleen and liver lesions demonstrated clonal B-cell receptor and clonal T-cell receptor rearrangements, confirming both malignancies. Analysis was also performed on banked peripheral Figure 1: Spleen section with T-cell lymphoma (*) and CLL, stained with (A) H&E, (B) CD79a, (C) CD3, (D) CD5 monoclonal antibodies (50x magnification). Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 02Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.comblood from 3 years earlier, excluding the presence of the malignant T-cell clone at an earlier stage of disease.This case demonstrated that a large-cell T-cell lymphoma had developed in a patient with a chronic B-cell leukemia. In the classical Richter’s syndrome, CLL cells are believed to transform into a large cell B-cell lymphoma, after acquisition of additional molecular lesions [5]. Rarely, in large cellular lymphomas complicating CLL, there is any clonal relationship with CLL. There have been case reports of Hodgkin’s disease [6-8] and T-cell lymphoma [9-11] found in CLL patients.Cohort studyTo estimate the incidence of T-cell lymphomas among CLL patients, we performed a retrospective study within the Netherlands Cancer Registry (NCR) database. We retrieved all cancer cases diagnosed in the Netherlands between 1989 and 2008 and included patients diagnosed with a first primary invasive cancer (n =1,270,595). Patients were followed until the occurrence of T-cell lymphoma, death, or end of follow-up (December 31, 2008). The order of the cancer diagnosis was determined according to the International Rules for Multiple Primary Cancers (ICD-O, [12]). All T-cell malignancies diagnosed after CLL diagnosis were included, using ICD-O-2 codes 9700-9702, 9705, 9708, 9714, 9716-9719, 9827, 9831, 9834, 9948 and ICD-O-3 codes 9591, 9593, 9675, 9680, 9684, 9702-9704, 9713, 9823, 9825 combined with type=T-cell. As a measure of excess risk, Standardized Incidence Ratio (SIR) was calculated as the ratio of the observed number of cases in the cohort to the expected number of cases. The number of expected cases was calculated by multiplying the person-years at risk by the age-, gender-, and calendar year-specific incidence rates in the background population. 95% Confidence Intervals (95% CI) for SIRs were calculated based on a Poisson distribution. SAS software (SAS system 9.3, SAS Institute, Cary, NC) was used to perform the statistical analyses.As shown in Table 1, Dutch CLL patients exhibited a threefold excess risk of developing a T-cell malignancy when compared with the entire Dutch population (SIR 3.0; 95% CI, 1.3-5.8). To correct for possible increased detection among cancer survivors, we also compared CLL patients with all Dutch cancer survivors. This yielded a SIR of 1.7, however statistically non-significant (95% CI, 0.71-3.3). As this might be due to the small size of the cohort, we performed the same analysis on the Surveillance, Epidemiology and End Results (SEER) database. We retrieved all registered cancer cases diagnosed in the United States (US) of America between 1973 and 2010 and included patients diagnosed with a first primary invasive cancer (n =6,316,679). End of follow-up date was December 31, 2010. We found that US CLL patients exhibited a more than two-fold risk for T-cell malignancies compared with all US cancer survivors (SIR 2.1; 95% CI, 1.7-2.7).DiscussionWe here presented a patient with therapy-refractory CLL who died from multi-organ failure, in whom a T-cell lymphoma was detected at post-mortem examination. Within the Dutch NCR and larger US SEER databases, the epidemiological data corroborate the hypothesis that CLL predisposes patients for the development of T-cell malignancies. Indeed, there is a biologic rationale for increased incidence of clonal T-cell disorders in CLL. In CLL, there is an expansion of T-cells with a globally impaired function characterized by a pseudo-exhausted phenotype [13]. Also, microarray and functional studies showed that T-cells from CLL patients undergo significant changes on a molecular and structural level [14]. Clearly, CLL cells and T-cells have reciprocal interactions, inducing both expansion and intrinsic changes, and possibly facilitating malignant transformation. Of note, other factors may play a role in the pathogenesis of T-cell malignancies in CLL patients. We cannot exclude that previous treatment and/or immunosuppression would contribute to the pathogenesis of T-cell malignancies. In previous case reports, treatment with Chlorambucil, Fludarabine, and various immunosuppressive agents were described [10,11]. Compared with untreated follicular lymphoma patients, untreated CLL patients have a two-fold increased risk of second malignancies, as shown in a large Canadian cohort study [3]. Prolonged Chlorambucil treatment was not associated with an increase in second malignancies in a cohort of CLL patients [15], whereas most recently Benjamini et al. demonstrated that frontline treatment with Fludarabine, Cyclophosphamide, and Rituximab was associated with an increased risk of therapy related acute myeloid leukemia and Richter’s syndrome [16]. In these cohort studies, no cases of T-cell malignancy were described.In conclusion, albeit the low incidence, CLL patients have an increased risk of developing T-cell malignancies. It remains to be established whether malignant transformation of T-cells is facilitated by interactions with CLL cells, direct mutations induced by chemotherapy, or deficiency in adequate immunosurveillance related to CLL and/or use of immunomodulating agents.References1. Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, Garcia-Manero G . Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009; 27: 1637-1643.2. Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leuk Lymphoma. 2005; 46: 49-54.3. Beiggi S, Johnston JB, Seftel MD, Pitz MW, Kumar R, Banerji V, et al. Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study. Br J Cancer. 2013; 109: 1287–1290. 4. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011; 2011: 96-103.5. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical perspectives. Hematol Oncol. 2009; 27: 1-10.6. Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol. 1990; 93: 333-339.Compared withCLL patients all cancers general populationn Time at risk (PY) n (TCM) SIR 95% CI SIR 95% CINCR 13,504 61,631 8 1.7 (0.71-3.3) 3.0 (1.3-5.8)SEER 90,721 443,802 72 2.1 (1.7-2.7) n/aTable 1: Increased rates of T-Cell Lymphoma (TCL) as a second primary malignancy in patients with Chronic Lymphocytic Leukemia (CLL) as compared with all cancer patients and the general population in the Netherlands (NCR) or United States of America (SEER). CI, confidence interval; n, number of patients; n/a, not available; PY, patient-years; SIR, standardized-incidence ratio.Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 03Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.com7. Fayad L, Robertson LE, O’Brien S, Manning JT, Wright S, Hagemeister F, et al. Hodgkin’s disease variant of Richter’s syndrome: experience at a single institution. Leuk Lymphoma. 1996; 23: 333-337.8. Weisenberg E, Anastasi J, Adeyanju M, Variakojis D, Vardiman JW. Hodgkin’s disease associated with chronic lymphocytic leukemia. Eight additional cases, including two of the nodular lymphocyte predominant type. Am J Clin Pathol. 1995; 103: 479-484.9. Lee A, Skelly ME, Kingma DW, Medeiros LJ. B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter’s syndrome. Am J Clin Pathol. 1995; 103: 348-352.10. Martinez A, Pittaluga S, Villamor N, Colomer D, Rozman M, Raffeld M, et al. Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. Am J Surg Pathol. 2004; 28: 849-858.11. Novogrudsky A, Amorosi EL, Gottesman SR. High-grade T-cell lymphoma complicating B-cell chronic lymphocytic leukemia: an unusual manifestation of “Richter’s syndrome”. Am J Hematol. 2001; 66: 203-206.12. Working Group Report. International rules for multiple primary cancers (ICD-0 third edition). Eur J Cancer Prev. 2005; 14: 307-308.13. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013; 121: 1612-1621.14. Görgün G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005; 115: 1797-1805.15. Callea V, Brugiatelli M, Stelitano C, Gentile M, Nobile F, Morabito F. Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy. Leuk Lymphoma. 2006; 47: 2314-2320.16. Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. Leuk Lymphoma. Informa Clin Med. 2014; 1–8. Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reserved

We present a patient with chemotherapy-refractory Chronic LymphocyticLeukemia (CLL) in whom postmortem examination showed hepatosplenomegaly,with both multiple small-cellular CLL lesions and large-cellular, monoclonalT-cell infiltrates. Following this case, the co-incidence of T-cell malignancies andCLL was studied using Dutch and American cancer registry databases. Analysisshowed an excess risk for T-cell malignancies in CLL patients, with increasedstandardized incidence ratios compared with the general population and allcancer survivors in the databases. We hypothesize that CLL cells interact withT-cells in the microenvironment, facilitating malignant transformatio

Dissertations of the University of Groningen

   University of GroningenIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi, Goda; van den Broek, Esther C; Stam, Olga CG; van Noesel, C.J.M.; Tonino, Sanne H.;Kater, Armon P.Published in:Annals of Hematology & OncologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Choi, G., van den Broek, E. C., Stam, O. CG., van Noesel, C. J. M., Tonino, S. H., & Kater, A. P. (2015).Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Annals ofHematology & Oncology, 2(2), Article 1023 .CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 31-10-2023Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reservedAnnals of Hematology & OncologyOpen AccessAbstractWe present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compared with the general population and all cancer survivors in the databases. We hypothesize that CLL cells interact with T-cells in the microenvironment, facilitating malignant transformation.Keywords: Chronic lymphocytic leukemia; T-cell lymphoma; Neoplastic cell transformation; Cohort studiesIntroductionChronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by progressive accumulation of mature B-cells in peripheral blood and secondary lymphoid organs. Primary causes of death include infections and secondary malignancies [1], suggesting an immunodeficiency in CLL patients [2]. Recent epidemiological data demonstrated that the increased risk of other primary malignancies in CLL patients is independent of treatment or surveillance bias [3]. Most likely, CLL is not a disease limited to B-cells only, but also affects other components of the immune system due to extensive crosstalk between CLL cells and their microenvironment [4]. In this report, we present a patient with therapy-refractory CLL in whom post-mortem examination revealed the presence of a T-cell lymphoma. We further studied the coincidence of T-cell malignancies and CLL within two population-based cancer registries, and found an excess risk of T-cell malignancies in patients with CLL. Case PresentationA 75-year-old male patient with therapy-refractory CLL was referred to our hospital. CLL had been diagnosed 7 years earlier (initially Rai 0) and during the last 3 years, he was intermittently treated with Chlorambucil. One month before admission, he had a painful cervical node, from which a biopsy revealed CD5 positive, cycline-D1 negative B-cells, compatible with CLL and without signs of transformation. Upon admission, patient presented with fever, dysphagia, and general malaise. His blood counts showed a pancytopenia with hemoglobin 7.9 g/dL (12.1 a month before), leukocytes 2,300/μl (50% lymphocytes), and platelets 10,000/μl (80,000 before). Without clinical signs of a specific infection, he was treated with broad-spectrum antibiotics. A bone marrow biopsy was performed, showing80% CLL cells (positive for CD5/CD19/CD23/CD20dim) and dysplasia in the myeloid and erythroid lineages. Within hours, he had progressive respiratory failure due to either sepsis or transfusion-related lung injury. Despite ventilatory support, Case ReportIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi G1*, van den Broek EC3*, Stam OCG2, van Noesel CJM2, Tonino SH1 and Kater AP11Department of Hematology, University of Amsterdam, Netherlands2Department of Pathology, University of Amsterdam, Netherlands3Integraal Kankercentrum Zuid, Eindhoven, Netherlands*Corresponding author: G Choi, University Medical Center Groningen, Department of Hematology (HPC DA21) Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Tel: 31 50 361 2354; Fax: 31 50 361 5960; Email: c.w.choi@umcg.nlReceived: December 04, 2014; Accepted: January 16, 2015; Published: January 19, 2015patient’s condition rapidly deteriorated and he died within a few hours.Post-mortem examination showed signs of multi-organ failure, including congested lungs without microbial infiltrates. There was hepatosplenomegaly and lymphadenopathy. Immunohistochemistry studies showed diffuse infiltrates of small, basophilic cells, positive for CD5, CD20 and CD23 (in liver, spleen, and bone marrow). Remarkably, the spleen contained, apart from CLL, areas with large cells with atypical nuclei positive for CD3, CD8, and Granzyme B, and negative for CD4, CD5, CD20, CD23, CD30, ALK1, CD79a, PAX-5, EBV, and keratin.Ki67 showed a high proliferation index in these areas. Altogether, this patient was found to have CLL and a high-grade peripheral T-cell lymphoma NOS (Figure 1). Molecular analyses of both spleen and liver lesions demonstrated clonal B-cell receptor and clonal T-cell receptor rearrangements, confirming both malignancies. Analysis was also performed on banked peripheral Figure 1: Spleen section with T-cell lymphoma (*) and CLL, stained with (A) H&E, (B) CD79a, (C) CD3, (D) CD5 monoclonal antibodies (50x magnification). Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 02Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.comblood from 3 years earlier, excluding the presence of the malignant T-cell clone at an earlier stage of disease.This case demonstrated that a large-cell T-cell lymphoma had developed in a patient with a chronic B-cell leukemia. In the classical Richter’s syndrome, CLL cells are believed to transform into a large cell B-cell lymphoma, after acquisition of additional molecular lesions [5]. Rarely, in large cellular lymphomas complicating CLL, there is any clonal relationship with CLL. There have been case reports of Hodgkin’s disease [6-8] and T-cell lymphoma [9-11] found in CLL patients.Cohort studyTo estimate the incidence of T-cell lymphomas among CLL patients, we performed a retrospective study within the Netherlands Cancer Registry (NCR) database. We retrieved all cancer cases diagnosed in the Netherlands between 1989 and 2008 and included patients diagnosed with a first primary invasive cancer (n =1,270,595). Patients were followed until the occurrence of T-cell lymphoma, death, or end of follow-up (December 31, 2008). The order of the cancer diagnosis was determined according to the International Rules for Multiple Primary Cancers (ICD-O, [12]). All T-cell malignancies diagnosed after CLL diagnosis were included, using ICD-O-2 codes 9700-9702, 9705, 9708, 9714, 9716-9719, 9827, 9831, 9834, 9948 and ICD-O-3 codes 9591, 9593, 9675, 9680, 9684, 9702-9704, 9713, 9823, 9825 combined with type=T-cell. As a measure of excess risk, Standardized Incidence Ratio (SIR) was calculated as the ratio of the observed number of cases in the cohort to the expected number of cases. The number of expected cases was calculated by multiplying the person-years at risk by the age-, gender-, and calendar year-specific incidence rates in the background population. 95% Confidence Intervals (95% CI) for SIRs were calculated based on a Poisson distribution. SAS software (SAS system 9.3, SAS Institute, Cary, NC) was used to perform the statistical analyses.As shown in Table 1, Dutch CLL patients exhibited a threefold excess risk of developing a T-cell malignancy when compared with the entire Dutch population (SIR 3.0; 95% CI, 1.3-5.8). To correct for possible increased detection among cancer survivors, we also compared CLL patients with all Dutch cancer survivors. This yielded a SIR of 1.7, however statistically non-significant (95% CI, 0.71-3.3). As this might be due to the small size of the cohort, we performed the same analysis on the Surveillance, Epidemiology and End Results (SEER) database. We retrieved all registered cancer cases diagnosed in the United States (US) of America between 1973 and 2010 and included patients diagnosed with a first primary invasive cancer (n =6,316,679). End of follow-up date was December 31, 2010. We found that US CLL patients exhibited a more than two-fold risk for T-cell malignancies compared with all US cancer survivors (SIR 2.1; 95% CI, 1.7-2.7).DiscussionWe here presented a patient with therapy-refractory CLL who died from multi-organ failure, in whom a T-cell lymphoma was detected at post-mortem examination. Within the Dutch NCR and larger US SEER databases, the epidemiological data corroborate the hypothesis that CLL predisposes patients for the development of T-cell malignancies. Indeed, there is a biologic rationale for increased incidence of clonal T-cell disorders in CLL. In CLL, there is an expansion of T-cells with a globally impaired function characterized by a pseudo-exhausted phenotype [13]. Also, microarray and functional studies showed that T-cells from CLL patients undergo significant changes on a molecular and structural level [14]. Clearly, CLL cells and T-cells have reciprocal interactions, inducing both expansion and intrinsic changes, and possibly facilitating malignant transformation. Of note, other factors may play a role in the pathogenesis of T-cell malignancies in CLL patients. We cannot exclude that previous treatment and/or immunosuppression would contribute to the pathogenesis of T-cell malignancies. In previous case reports, treatment with Chlorambucil, Fludarabine, and various immunosuppressive agents were described [10,11]. Compared with untreated follicular lymphoma patients, untreated CLL patients have a two-fold increased risk of second malignancies, as shown in a large Canadian cohort study [3]. Prolonged Chlorambucil treatment was not associated with an increase in second malignancies in a cohort of CLL patients [15], whereas most recently Benjamini et al. demonstrated that frontline treatment with Fludarabine, Cyclophosphamide, and Rituximab was associated with an increased risk of therapy related acute myeloid leukemia and Richter’s syndrome [16]. In these cohort studies, no cases of T-cell malignancy were described.In conclusion, albeit the low incidence, CLL patients have an increased risk of developing T-cell malignancies. It remains to be established whether malignant transformation of T-cells is facilitated by interactions with CLL cells, direct mutations induced by chemotherapy, or deficiency in adequate immunosurveillance related to CLL and/or use of immunomodulating agents.References1. Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, Garcia-Manero G . Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009; 27: 1637-1643.2. Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leuk Lymphoma. 2005; 46: 49-54.3. Beiggi S, Johnston JB, Seftel MD, Pitz MW, Kumar R, Banerji V, et al. Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study. Br J Cancer. 2013; 109: 1287–1290. 4. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011; 2011: 96-103.5. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical perspectives. Hematol Oncol. 2009; 27: 1-10.6. Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol. 1990; 93: 333-339.Compared withCLL patients all cancers general populationn Time at risk (PY) n (TCM) SIR 95% CI SIR 95% CINCR 13,504 61,631 8 1.7 (0.71-3.3) 3.0 (1.3-5.8)SEER 90,721 443,802 72 2.1 (1.7-2.7) n/aTable 1: Increased rates of T-Cell Lymphoma (TCL) as a second primary malignancy in patients with Chronic Lymphocytic Leukemia (CLL) as compared with all cancer patients and the general population in the Netherlands (NCR) or United States of America (SEER). CI, confidence interval; n, number of patients; n/a, not available; PY, patient-years; SIR, standardized-incidence ratio.Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 03Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.com7. Fayad L, Robertson LE, O’Brien S, Manning JT, Wright S, Hagemeister F, et al. Hodgkin’s disease variant of Richter’s syndrome: experience at a single institution. Leuk Lymphoma. 1996; 23: 333-337.8. Weisenberg E, Anastasi J, Adeyanju M, Variakojis D, Vardiman JW. Hodgkin’s disease associated with chronic lymphocytic leukemia. Eight additional cases, including two of the nodular lymphocyte predominant type. Am J Clin Pathol. 1995; 103: 479-484.9. Lee A, Skelly ME, Kingma DW, Medeiros LJ. B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter’s syndrome. Am J Clin Pathol. 1995; 103: 348-352.10. Martinez A, Pittaluga S, Villamor N, Colomer D, Rozman M, Raffeld M, et al. Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. Am J Surg Pathol. 2004; 28: 849-858.11. Novogrudsky A, Amorosi EL, Gottesman SR. High-grade T-cell lymphoma complicating B-cell chronic lymphocytic leukemia: an unusual manifestation of “Richter’s syndrome”. Am J Hematol. 2001; 66: 203-206.12. Working Group Report. International rules for multiple primary cancers (ICD-0 third edition). Eur J Cancer Prev. 2005; 14: 307-308.13. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013; 121: 1612-1621.14. Görgün G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005; 115: 1797-1805.15. Callea V, Brugiatelli M, Stelitano C, Gentile M, Nobile F, Morabito F. Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy. Leuk Lymphoma. 2006; 47: 2314-2320.16. Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. Leuk Lymphoma. Informa Clin Med. 2014; 1–8. Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reserved

English

   University of GroningenIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi, Goda; van den Broek, Esther C; Stam, Olga CG; van Noesel, C.J.M.; Tonino, Sanne H.;Kater, Armon P.Published in:Annals of Hematology & OncologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Choi, G., van den Broek, E. C., Stam, O. CG., van Noesel, C. J. M., Tonino, S. H., & Kater, A. P. (2015).Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Annals ofHematology & Oncology, 2(2), [1023 ].CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 14-02-2023Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reservedAnnals of Hematology & OncologyOpen AccessAbstractWe present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compared with the general population and all cancer survivors in the databases. We hypothesize that CLL cells interact with T-cells in the microenvironment, facilitating malignant transformation.Keywords: Chronic lymphocytic leukemia; T-cell lymphoma; Neoplastic cell transformation; Cohort studiesIntroductionChronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by progressive accumulation of mature B-cells in peripheral blood and secondary lymphoid organs. Primary causes of death include infections and secondary malignancies [1], suggesting an immunodeficiency in CLL patients [2]. Recent epidemiological data demonstrated that the increased risk of other primary malignancies in CLL patients is independent of treatment or surveillance bias [3]. Most likely, CLL is not a disease limited to B-cells only, but also affects other components of the immune system due to extensive crosstalk between CLL cells and their microenvironment [4]. In this report, we present a patient with therapy-refractory CLL in whom post-mortem examination revealed the presence of a T-cell lymphoma. We further studied the coincidence of T-cell malignancies and CLL within two population-based cancer registries, and found an excess risk of T-cell malignancies in patients with CLL. Case PresentationA 75-year-old male patient with therapy-refractory CLL was referred to our hospital. CLL had been diagnosed 7 years earlier (initially Rai 0) and during the last 3 years, he was intermittently treated with Chlorambucil. One month before admission, he had a painful cervical node, from which a biopsy revealed CD5 positive, cycline-D1 negative B-cells, compatible with CLL and without signs of transformation. Upon admission, patient presented with fever, dysphagia, and general malaise. His blood counts showed a pancytopenia with hemoglobin 7.9 g/dL (12.1 a month before), leukocytes 2,300/μl (50% lymphocytes), and platelets 10,000/μl (80,000 before). Without clinical signs of a specific infection, he was treated with broad-spectrum antibiotics. A bone marrow biopsy was performed, showing80% CLL cells (positive for CD5/CD19/CD23/CD20dim) and dysplasia in the myeloid and erythroid lineages. Within hours, he had progressive respiratory failure due to either sepsis or transfusion-related lung injury. Despite ventilatory support, Case ReportIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi G1*, van den Broek EC3*, Stam OCG2, van Noesel CJM2, Tonino SH1 and Kater AP11Department of Hematology, University of Amsterdam, Netherlands2Department of Pathology, University of Amsterdam, Netherlands3Integraal Kankercentrum Zuid, Eindhoven, Netherlands*Corresponding author: G Choi, University Medical Center Groningen, Department of Hematology (HPC DA21) Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Tel: 31 50 361 2354; Fax: 31 50 361 5960; Email: c.w.choi@umcg.nlReceived: December 04, 2014; Accepted: January 16, 2015; Published: January 19, 2015patient’s condition rapidly deteriorated and he died within a few hours.Post-mortem examination showed signs of multi-organ failure, including congested lungs without microbial infiltrates. There was hepatosplenomegaly and lymphadenopathy. Immunohistochemistry studies showed diffuse infiltrates of small, basophilic cells, positive for CD5, CD20 and CD23 (in liver, spleen, and bone marrow). Remarkably, the spleen contained, apart from CLL, areas with large cells with atypical nuclei positive for CD3, CD8, and Granzyme B, and negative for CD4, CD5, CD20, CD23, CD30, ALK1, CD79a, PAX-5, EBV, and keratin.Ki67 showed a high proliferation index in these areas. Altogether, this patient was found to have CLL and a high-grade peripheral T-cell lymphoma NOS (Figure 1). Molecular analyses of both spleen and liver lesions demonstrated clonal B-cell receptor and clonal T-cell receptor rearrangements, confirming both malignancies. Analysis was also performed on banked peripheral Figure 1: Spleen section with T-cell lymphoma (*) and CLL, stained with (A) H&E, (B) CD79a, (C) CD3, (D) CD5 monoclonal antibodies (50x magnification). Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 02Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.comblood from 3 years earlier, excluding the presence of the malignant T-cell clone at an earlier stage of disease.This case demonstrated that a large-cell T-cell lymphoma had developed in a patient with a chronic B-cell leukemia. In the classical Richter’s syndrome, CLL cells are believed to transform into a large cell B-cell lymphoma, after acquisition of additional molecular lesions [5]. Rarely, in large cellular lymphomas complicating CLL, there is any clonal relationship with CLL. There have been case reports of Hodgkin’s disease [6-8] and T-cell lymphoma [9-11] found in CLL patients.Cohort studyTo estimate the incidence of T-cell lymphomas among CLL patients, we performed a retrospective study within the Netherlands Cancer Registry (NCR) database. We retrieved all cancer cases diagnosed in the Netherlands between 1989 and 2008 and included patients diagnosed with a first primary invasive cancer (n =1,270,595). Patients were followed until the occurrence of T-cell lymphoma, death, or end of follow-up (December 31, 2008). The order of the cancer diagnosis was determined according to the International Rules for Multiple Primary Cancers (ICD-O, [12]). All T-cell malignancies diagnosed after CLL diagnosis were included, using ICD-O-2 codes 9700-9702, 9705, 9708, 9714, 9716-9719, 9827, 9831, 9834, 9948 and ICD-O-3 codes 9591, 9593, 9675, 9680, 9684, 9702-9704, 9713, 9823, 9825 combined with type=T-cell. As a measure of excess risk, Standardized Incidence Ratio (SIR) was calculated as the ratio of the observed number of cases in the cohort to the expected number of cases. The number of expected cases was calculated by multiplying the person-years at risk by the age-, gender-, and calendar year-specific incidence rates in the background population. 95% Confidence Intervals (95% CI) for SIRs were calculated based on a Poisson distribution. SAS software (SAS system 9.3, SAS Institute, Cary, NC) was used to perform the statistical analyses.As shown in Table 1, Dutch CLL patients exhibited a threefold excess risk of developing a T-cell malignancy when compared with the entire Dutch population (SIR 3.0; 95% CI, 1.3-5.8). To correct for possible increased detection among cancer survivors, we also compared CLL patients with all Dutch cancer survivors. This yielded a SIR of 1.7, however statistically non-significant (95% CI, 0.71-3.3). As this might be due to the small size of the cohort, we performed the same analysis on the Surveillance, Epidemiology and End Results (SEER) database. We retrieved all registered cancer cases diagnosed in the United States (US) of America between 1973 and 2010 and included patients diagnosed with a first primary invasive cancer (n =6,316,679). End of follow-up date was December 31, 2010. We found that US CLL patients exhibited a more than two-fold risk for T-cell malignancies compared with all US cancer survivors (SIR 2.1; 95% CI, 1.7-2.7).DiscussionWe here presented a patient with therapy-refractory CLL who died from multi-organ failure, in whom a T-cell lymphoma was detected at post-mortem examination. Within the Dutch NCR and larger US SEER databases, the epidemiological data corroborate the hypothesis that CLL predisposes patients for the development of T-cell malignancies. Indeed, there is a biologic rationale for increased incidence of clonal T-cell disorders in CLL. In CLL, there is an expansion of T-cells with a globally impaired function characterized by a pseudo-exhausted phenotype [13]. Also, microarray and functional studies showed that T-cells from CLL patients undergo significant changes on a molecular and structural level [14]. Clearly, CLL cells and T-cells have reciprocal interactions, inducing both expansion and intrinsic changes, and possibly facilitating malignant transformation. Of note, other factors may play a role in the pathogenesis of T-cell malignancies in CLL patients. We cannot exclude that previous treatment and/or immunosuppression would contribute to the pathogenesis of T-cell malignancies. In previous case reports, treatment with Chlorambucil, Fludarabine, and various immunosuppressive agents were described [10,11]. Compared with untreated follicular lymphoma patients, untreated CLL patients have a two-fold increased risk of second malignancies, as shown in a large Canadian cohort study [3]. Prolonged Chlorambucil treatment was not associated with an increase in second malignancies in a cohort of CLL patients [15], whereas most recently Benjamini et al. demonstrated that frontline treatment with Fludarabine, Cyclophosphamide, and Rituximab was associated with an increased risk of therapy related acute myeloid leukemia and Richter’s syndrome [16]. In these cohort studies, no cases of T-cell malignancy were described.In conclusion, albeit the low incidence, CLL patients have an increased risk of developing T-cell malignancies. It remains to be established whether malignant transformation of T-cells is facilitated by interactions with CLL cells, direct mutations induced by chemotherapy, or deficiency in adequate immunosurveillance related to CLL and/or use of immunomodulating agents.References1. Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, Garcia-Manero G . Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009; 27: 1637-1643.2. Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leuk Lymphoma. 2005; 46: 49-54.3. Beiggi S, Johnston JB, Seftel MD, Pitz MW, Kumar R, Banerji V, et al. Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study. Br J Cancer. 2013; 109: 1287–1290. 4. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011; 2011: 96-103.5. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical perspectives. Hematol Oncol. 2009; 27: 1-10.6. Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol. 1990; 93: 333-339.Compared withCLL patients all cancers general populationn Time at risk (PY) n (TCM) SIR 95% CI SIR 95% CINCR 13,504 61,631 8 1.7 (0.71-3.3) 3.0 (1.3-5.8)SEER 90,721 443,802 72 2.1 (1.7-2.7) n/aTable 1: Increased rates of T-Cell Lymphoma (TCL) as a second primary malignancy in patients with Chronic Lymphocytic Leukemia (CLL) as compared with all cancer patients and the general population in the Netherlands (NCR) or United States of America (SEER). CI, confidence interval; n, number of patients; n/a, not available; PY, patient-years; SIR, standardized-incidence ratio.Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 03Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.com7. Fayad L, Robertson LE, O’Brien S, Manning JT, Wright S, Hagemeister F, et al. Hodgkin’s disease variant of Richter’s syndrome: experience at a single institution. Leuk Lymphoma. 1996; 23: 333-337.8. Weisenberg E, Anastasi J, Adeyanju M, Variakojis D, Vardiman JW. Hodgkin’s disease associated with chronic lymphocytic leukemia. Eight additional cases, including two of the nodular lymphocyte predominant type. Am J Clin Pathol. 1995; 103: 479-484.9. Lee A, Skelly ME, Kingma DW, Medeiros LJ. B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter’s syndrome. Am J Clin Pathol. 1995; 103: 348-352.10. Martinez A, Pittaluga S, Villamor N, Colomer D, Rozman M, Raffeld M, et al. Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. Am J Surg Pathol. 2004; 28: 849-858.11. Novogrudsky A, Amorosi EL, Gottesman SR. High-grade T-cell lymphoma complicating B-cell chronic lymphocytic leukemia: an unusual manifestation of “Richter’s syndrome”. Am J Hematol. 2001; 66: 203-206.12. Working Group Report. International rules for multiple primary cancers (ICD-0 third edition). Eur J Cancer Prev. 2005; 14: 307-308.13. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013; 121: 1612-1621.14. Görgün G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005; 115: 1797-1805.15. Callea V, Brugiatelli M, Stelitano C, Gentile M, Nobile F, Morabito F. Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy. Leuk Lymphoma. 2006; 47: 2314-2320.16. Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. Leuk Lymphoma. Informa Clin Med. 2014; 1–8. Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reserved

Proceedings - University of Groningen

   University of GroningenIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi, Goda; van den Broek, Esther C; Stam, Olga CG; van Noesel, C.J.M.; Tonino, Sanne H.;Kater, Armon P.Published in:Annals of Hematology & OncologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Choi, G., van den Broek, E. C., Stam, O. CG., van Noesel, C. J. M., Tonino, S. H., & Kater, A. P. (2015).Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Annals ofHematology & Oncology, 2(2), [1023 ].CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-10-2022Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reservedAnnals of Hematology & OncologyOpen AccessAbstractWe present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compared with the general population and all cancer survivors in the databases. We hypothesize that CLL cells interact with T-cells in the microenvironment, facilitating malignant transformation.Keywords: Chronic lymphocytic leukemia; T-cell lymphoma; Neoplastic cell transformation; Cohort studiesIntroductionChronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by progressive accumulation of mature B-cells in peripheral blood and secondary lymphoid organs. Primary causes of death include infections and secondary malignancies [1], suggesting an immunodeficiency in CLL patients [2]. Recent epidemiological data demonstrated that the increased risk of other primary malignancies in CLL patients is independent of treatment or surveillance bias [3]. Most likely, CLL is not a disease limited to B-cells only, but also affects other components of the immune system due to extensive crosstalk between CLL cells and their microenvironment [4]. In this report, we present a patient with therapy-refractory CLL in whom post-mortem examination revealed the presence of a T-cell lymphoma. We further studied the coincidence of T-cell malignancies and CLL within two population-based cancer registries, and found an excess risk of T-cell malignancies in patients with CLL. Case PresentationA 75-year-old male patient with therapy-refractory CLL was referred to our hospital. CLL had been diagnosed 7 years earlier (initially Rai 0) and during the last 3 years, he was intermittently treated with Chlorambucil. One month before admission, he had a painful cervical node, from which a biopsy revealed CD5 positive, cycline-D1 negative B-cells, compatible with CLL and without signs of transformation. Upon admission, patient presented with fever, dysphagia, and general malaise. His blood counts showed a pancytopenia with hemoglobin 7.9 g/dL (12.1 a month before), leukocytes 2,300/μl (50% lymphocytes), and platelets 10,000/μl (80,000 before). Without clinical signs of a specific infection, he was treated with broad-spectrum antibiotics. A bone marrow biopsy was performed, showing80% CLL cells (positive for CD5/CD19/CD23/CD20dim) and dysplasia in the myeloid and erythroid lineages. Within hours, he had progressive respiratory failure due to either sepsis or transfusion-related lung injury. Despite ventilatory support, Case ReportIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi G1*, van den Broek EC3*, Stam OCG2, van Noesel CJM2, Tonino SH1 and Kater AP11Department of Hematology, University of Amsterdam, Netherlands2Department of Pathology, University of Amsterdam, Netherlands3Integraal Kankercentrum Zuid, Eindhoven, Netherlands*Corresponding author: G Choi, University Medical Center Groningen, Department of Hematology (HPC DA21) Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Tel: 31 50 361 2354; Fax: 31 50 361 5960; Email: c.w.choi@umcg.nlReceived: December 04, 2014; Accepted: January 16, 2015; Published: January 19, 2015patient’s condition rapidly deteriorated and he died within a few hours.Post-mortem examination showed signs of multi-organ failure, including congested lungs without microbial infiltrates. There was hepatosplenomegaly and lymphadenopathy. Immunohistochemistry studies showed diffuse infiltrates of small, basophilic cells, positive for CD5, CD20 and CD23 (in liver, spleen, and bone marrow). Remarkably, the spleen contained, apart from CLL, areas with large cells with atypical nuclei positive for CD3, CD8, and Granzyme B, and negative for CD4, CD5, CD20, CD23, CD30, ALK1, CD79a, PAX-5, EBV, and keratin.Ki67 showed a high proliferation index in these areas. Altogether, this patient was found to have CLL and a high-grade peripheral T-cell lymphoma NOS (Figure 1). Molecular analyses of both spleen and liver lesions demonstrated clonal B-cell receptor and clonal T-cell receptor rearrangements, confirming both malignancies. Analysis was also performed on banked peripheral Figure 1: Spleen section with T-cell lymphoma (*) and CLL, stained with (A) H&E, (B) CD79a, (C) CD3, (D) CD5 monoclonal antibodies (50x magnification). Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 02Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.comblood from 3 years earlier, excluding the presence of the malignant T-cell clone at an earlier stage of disease.This case demonstrated that a large-cell T-cell lymphoma had developed in a patient with a chronic B-cell leukemia. In the classical Richter’s syndrome, CLL cells are believed to transform into a large cell B-cell lymphoma, after acquisition of additional molecular lesions [5]. Rarely, in large cellular lymphomas complicating CLL, there is any clonal relationship with CLL. There have been case reports of Hodgkin’s disease [6-8] and T-cell lymphoma [9-11] found in CLL patients.Cohort studyTo estimate the incidence of T-cell lymphomas among CLL patients, we performed a retrospective study within the Netherlands Cancer Registry (NCR) database. We retrieved all cancer cases diagnosed in the Netherlands between 1989 and 2008 and included patients diagnosed with a first primary invasive cancer (n =1,270,595). Patients were followed until the occurrence of T-cell lymphoma, death, or end of follow-up (December 31, 2008). The order of the cancer diagnosis was determined according to the International Rules for Multiple Primary Cancers (ICD-O, [12]). All T-cell malignancies diagnosed after CLL diagnosis were included, using ICD-O-2 codes 9700-9702, 9705, 9708, 9714, 9716-9719, 9827, 9831, 9834, 9948 and ICD-O-3 codes 9591, 9593, 9675, 9680, 9684, 9702-9704, 9713, 9823, 9825 combined with type=T-cell. As a measure of excess risk, Standardized Incidence Ratio (SIR) was calculated as the ratio of the observed number of cases in the cohort to the expected number of cases. The number of expected cases was calculated by multiplying the person-years at risk by the age-, gender-, and calendar year-specific incidence rates in the background population. 95% Confidence Intervals (95% CI) for SIRs were calculated based on a Poisson distribution. SAS software (SAS system 9.3, SAS Institute, Cary, NC) was used to perform the statistical analyses.As shown in Table 1, Dutch CLL patients exhibited a threefold excess risk of developing a T-cell malignancy when compared with the entire Dutch population (SIR 3.0; 95% CI, 1.3-5.8). To correct for possible increased detection among cancer survivors, we also compared CLL patients with all Dutch cancer survivors. This yielded a SIR of 1.7, however statistically non-significant (95% CI, 0.71-3.3). As this might be due to the small size of the cohort, we performed the same analysis on the Surveillance, Epidemiology and End Results (SEER) database. We retrieved all registered cancer cases diagnosed in the United States (US) of America between 1973 and 2010 and included patients diagnosed with a first primary invasive cancer (n =6,316,679). End of follow-up date was December 31, 2010. We found that US CLL patients exhibited a more than two-fold risk for T-cell malignancies compared with all US cancer survivors (SIR 2.1; 95% CI, 1.7-2.7).DiscussionWe here presented a patient with therapy-refractory CLL who died from multi-organ failure, in whom a T-cell lymphoma was detected at post-mortem examination. Within the Dutch NCR and larger US SEER databases, the epidemiological data corroborate the hypothesis that CLL predisposes patients for the development of T-cell malignancies. Indeed, there is a biologic rationale for increased incidence of clonal T-cell disorders in CLL. In CLL, there is an expansion of T-cells with a globally impaired function characterized by a pseudo-exhausted phenotype [13]. Also, microarray and functional studies showed that T-cells from CLL patients undergo significant changes on a molecular and structural level [14]. Clearly, CLL cells and T-cells have reciprocal interactions, inducing both expansion and intrinsic changes, and possibly facilitating malignant transformation. Of note, other factors may play a role in the pathogenesis of T-cell malignancies in CLL patients. We cannot exclude that previous treatment and/or immunosuppression would contribute to the pathogenesis of T-cell malignancies. In previous case reports, treatment with Chlorambucil, Fludarabine, and various immunosuppressive agents were described [10,11]. Compared with untreated follicular lymphoma patients, untreated CLL patients have a two-fold increased risk of second malignancies, as shown in a large Canadian cohort study [3]. Prolonged Chlorambucil treatment was not associated with an increase in second malignancies in a cohort of CLL patients [15], whereas most recently Benjamini et al. demonstrated that frontline treatment with Fludarabine, Cyclophosphamide, and Rituximab was associated with an increased risk of therapy related acute myeloid leukemia and Richter’s syndrome [16]. In these cohort studies, no cases of T-cell malignancy were described.In conclusion, albeit the low incidence, CLL patients have an increased risk of developing T-cell malignancies. It remains to be established whether malignant transformation of T-cells is facilitated by interactions with CLL cells, direct mutations induced by chemotherapy, or deficiency in adequate immunosurveillance related to CLL and/or use of immunomodulating agents.References1. Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, Garcia-Manero G . Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009; 27: 1637-1643.2. Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leuk Lymphoma. 2005; 46: 49-54.3. Beiggi S, Johnston JB, Seftel MD, Pitz MW, Kumar R, Banerji V, et al. Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study. Br J Cancer. 2013; 109: 1287–1290. 4. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011; 2011: 96-103.5. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical perspectives. Hematol Oncol. 2009; 27: 1-10.6. Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol. 1990; 93: 333-339.Compared withCLL patients all cancers general populationn Time at risk (PY) n (TCM) SIR 95% CI SIR 95% CINCR 13,504 61,631 8 1.7 (0.71-3.3) 3.0 (1.3-5.8)SEER 90,721 443,802 72 2.1 (1.7-2.7) n/aTable 1: Increased rates of T-Cell Lymphoma (TCL) as a second primary malignancy in patients with Chronic Lymphocytic Leukemia (CLL) as compared with all cancer patients and the general population in the Netherlands (NCR) or United States of America (SEER). CI, confidence interval; n, number of patients; n/a, not available; PY, patient-years; SIR, standardized-incidence ratio.Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 03Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.com7. Fayad L, Robertson LE, O’Brien S, Manning JT, Wright S, Hagemeister F, et al. Hodgkin’s disease variant of Richter’s syndrome: experience at a single institution. Leuk Lymphoma. 1996; 23: 333-337.8. Weisenberg E, Anastasi J, Adeyanju M, Variakojis D, Vardiman JW. Hodgkin’s disease associated with chronic lymphocytic leukemia. Eight additional cases, including two of the nodular lymphocyte predominant type. Am J Clin Pathol. 1995; 103: 479-484.9. Lee A, Skelly ME, Kingma DW, Medeiros LJ. B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter’s syndrome. Am J Clin Pathol. 1995; 103: 348-352.10. Martinez A, Pittaluga S, Villamor N, Colomer D, Rozman M, Raffeld M, et al. Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. Am J Surg Pathol. 2004; 28: 849-858.11. Novogrudsky A, Amorosi EL, Gottesman SR. High-grade T-cell lymphoma complicating B-cell chronic lymphocytic leukemia: an unusual manifestation of “Richter’s syndrome”. Am J Hematol. 2001; 66: 203-206.12. Working Group Report. International rules for multiple primary cancers (ICD-0 third edition). Eur J Cancer Prev. 2005; 14: 307-308.13. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013; 121: 1612-1621.14. Görgün G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005; 115: 1797-1805.15. Callea V, Brugiatelli M, Stelitano C, Gentile M, Nobile F, Morabito F. Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy. Leuk Lymphoma. 2006; 47: 2314-2320.16. Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. Leuk Lymphoma. Informa Clin Med. 2014; 1–8. Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reserved

ARTS repository - University of Groningen

   University of GroningenIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi, Goda; van den Broek, Esther C; Stam, Olga CG; van Noesel, C.J.M.; Tonino, Sanne H.;Kater, Armon P.Published in:Annals of Hematology & OncologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Choi, G., van den Broek, E. C., Stam, O. CG., van Noesel, C. J. M., Tonino, S. H., & Kater, A. P. (2015).Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Annals ofHematology & Oncology, 2(2), Article 1023 .CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 09-09-2023Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reservedAnnals of Hematology & OncologyOpen AccessAbstractWe present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compared with the general population and all cancer survivors in the databases. We hypothesize that CLL cells interact with T-cells in the microenvironment, facilitating malignant transformation.Keywords: Chronic lymphocytic leukemia; T-cell lymphoma; Neoplastic cell transformation; Cohort studiesIntroductionChronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by progressive accumulation of mature B-cells in peripheral blood and secondary lymphoid organs. Primary causes of death include infections and secondary malignancies [1], suggesting an immunodeficiency in CLL patients [2]. Recent epidemiological data demonstrated that the increased risk of other primary malignancies in CLL patients is independent of treatment or surveillance bias [3]. Most likely, CLL is not a disease limited to B-cells only, but also affects other components of the immune system due to extensive crosstalk between CLL cells and their microenvironment [4]. In this report, we present a patient with therapy-refractory CLL in whom post-mortem examination revealed the presence of a T-cell lymphoma. We further studied the coincidence of T-cell malignancies and CLL within two population-based cancer registries, and found an excess risk of T-cell malignancies in patients with CLL. Case PresentationA 75-year-old male patient with therapy-refractory CLL was referred to our hospital. CLL had been diagnosed 7 years earlier (initially Rai 0) and during the last 3 years, he was intermittently treated with Chlorambucil. One month before admission, he had a painful cervical node, from which a biopsy revealed CD5 positive, cycline-D1 negative B-cells, compatible with CLL and without signs of transformation. Upon admission, patient presented with fever, dysphagia, and general malaise. His blood counts showed a pancytopenia with hemoglobin 7.9 g/dL (12.1 a month before), leukocytes 2,300/μl (50% lymphocytes), and platelets 10,000/μl (80,000 before). Without clinical signs of a specific infection, he was treated with broad-spectrum antibiotics. A bone marrow biopsy was performed, showing80% CLL cells (positive for CD5/CD19/CD23/CD20dim) and dysplasia in the myeloid and erythroid lineages. Within hours, he had progressive respiratory failure due to either sepsis or transfusion-related lung injury. Despite ventilatory support, Case ReportIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi G1*, van den Broek EC3*, Stam OCG2, van Noesel CJM2, Tonino SH1 and Kater AP11Department of Hematology, University of Amsterdam, Netherlands2Department of Pathology, University of Amsterdam, Netherlands3Integraal Kankercentrum Zuid, Eindhoven, Netherlands*Corresponding author: G Choi, University Medical Center Groningen, Department of Hematology (HPC DA21) Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Tel: 31 50 361 2354; Fax: 31 50 361 5960; Email: c.w.choi@umcg.nlReceived: December 04, 2014; Accepted: January 16, 2015; Published: January 19, 2015patient’s condition rapidly deteriorated and he died within a few hours.Post-mortem examination showed signs of multi-organ failure, including congested lungs without microbial infiltrates. There was hepatosplenomegaly and lymphadenopathy. Immunohistochemistry studies showed diffuse infiltrates of small, basophilic cells, positive for CD5, CD20 and CD23 (in liver, spleen, and bone marrow). Remarkably, the spleen contained, apart from CLL, areas with large cells with atypical nuclei positive for CD3, CD8, and Granzyme B, and negative for CD4, CD5, CD20, CD23, CD30, ALK1, CD79a, PAX-5, EBV, and keratin.Ki67 showed a high proliferation index in these areas. Altogether, this patient was found to have CLL and a high-grade peripheral T-cell lymphoma NOS (Figure 1). Molecular analyses of both spleen and liver lesions demonstrated clonal B-cell receptor and clonal T-cell receptor rearrangements, confirming both malignancies. Analysis was also performed on banked peripheral Figure 1: Spleen section with T-cell lymphoma (*) and CLL, stained with (A) H&E, (B) CD79a, (C) CD3, (D) CD5 monoclonal antibodies (50x magnification). Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 02Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.comblood from 3 years earlier, excluding the presence of the malignant T-cell clone at an earlier stage of disease.This case demonstrated that a large-cell T-cell lymphoma had developed in a patient with a chronic B-cell leukemia. In the classical Richter’s syndrome, CLL cells are believed to transform into a large cell B-cell lymphoma, after acquisition of additional molecular lesions [5]. Rarely, in large cellular lymphomas complicating CLL, there is any clonal relationship with CLL. There have been case reports of Hodgkin’s disease [6-8] and T-cell lymphoma [9-11] found in CLL patients.Cohort studyTo estimate the incidence of T-cell lymphomas among CLL patients, we performed a retrospective study within the Netherlands Cancer Registry (NCR) database. We retrieved all cancer cases diagnosed in the Netherlands between 1989 and 2008 and included patients diagnosed with a first primary invasive cancer (n =1,270,595). Patients were followed until the occurrence of T-cell lymphoma, death, or end of follow-up (December 31, 2008). The order of the cancer diagnosis was determined according to the International Rules for Multiple Primary Cancers (ICD-O, [12]). All T-cell malignancies diagnosed after CLL diagnosis were included, using ICD-O-2 codes 9700-9702, 9705, 9708, 9714, 9716-9719, 9827, 9831, 9834, 9948 and ICD-O-3 codes 9591, 9593, 9675, 9680, 9684, 9702-9704, 9713, 9823, 9825 combined with type=T-cell. As a measure of excess risk, Standardized Incidence Ratio (SIR) was calculated as the ratio of the observed number of cases in the cohort to the expected number of cases. The number of expected cases was calculated by multiplying the person-years at risk by the age-, gender-, and calendar year-specific incidence rates in the background population. 95% Confidence Intervals (95% CI) for SIRs were calculated based on a Poisson distribution. SAS software (SAS system 9.3, SAS Institute, Cary, NC) was used to perform the statistical analyses.As shown in Table 1, Dutch CLL patients exhibited a threefold excess risk of developing a T-cell malignancy when compared with the entire Dutch population (SIR 3.0; 95% CI, 1.3-5.8). To correct for possible increased detection among cancer survivors, we also compared CLL patients with all Dutch cancer survivors. This yielded a SIR of 1.7, however statistically non-significant (95% CI, 0.71-3.3). As this might be due to the small size of the cohort, we performed the same analysis on the Surveillance, Epidemiology and End Results (SEER) database. We retrieved all registered cancer cases diagnosed in the United States (US) of America between 1973 and 2010 and included patients diagnosed with a first primary invasive cancer (n =6,316,679). End of follow-up date was December 31, 2010. We found that US CLL patients exhibited a more than two-fold risk for T-cell malignancies compared with all US cancer survivors (SIR 2.1; 95% CI, 1.7-2.7).DiscussionWe here presented a patient with therapy-refractory CLL who died from multi-organ failure, in whom a T-cell lymphoma was detected at post-mortem examination. Within the Dutch NCR and larger US SEER databases, the epidemiological data corroborate the hypothesis that CLL predisposes patients for the development of T-cell malignancies. Indeed, there is a biologic rationale for increased incidence of clonal T-cell disorders in CLL. In CLL, there is an expansion of T-cells with a globally impaired function characterized by a pseudo-exhausted phenotype [13]. Also, microarray and functional studies showed that T-cells from CLL patients undergo significant changes on a molecular and structural level [14]. Clearly, CLL cells and T-cells have reciprocal interactions, inducing both expansion and intrinsic changes, and possibly facilitating malignant transformation. Of note, other factors may play a role in the pathogenesis of T-cell malignancies in CLL patients. We cannot exclude that previous treatment and/or immunosuppression would contribute to the pathogenesis of T-cell malignancies. In previous case reports, treatment with Chlorambucil, Fludarabine, and various immunosuppressive agents were described [10,11]. Compared with untreated follicular lymphoma patients, untreated CLL patients have a two-fold increased risk of second malignancies, as shown in a large Canadian cohort study [3]. Prolonged Chlorambucil treatment was not associated with an increase in second malignancies in a cohort of CLL patients [15], whereas most recently Benjamini et al. demonstrated that frontline treatment with Fludarabine, Cyclophosphamide, and Rituximab was associated with an increased risk of therapy related acute myeloid leukemia and Richter’s syndrome [16]. In these cohort studies, no cases of T-cell malignancy were described.In conclusion, albeit the low incidence, CLL patients have an increased risk of developing T-cell malignancies. It remains to be established whether malignant transformation of T-cells is facilitated by interactions with CLL cells, direct mutations induced by chemotherapy, or deficiency in adequate immunosurveillance related to CLL and/or use of immunomodulating agents.References1. Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, Garcia-Manero G . Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009; 27: 1637-1643.2. Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leuk Lymphoma. 2005; 46: 49-54.3. Beiggi S, Johnston JB, Seftel MD, Pitz MW, Kumar R, Banerji V, et al. Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study. Br J Cancer. 2013; 109: 1287–1290. 4. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011; 2011: 96-103.5. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical perspectives. Hematol Oncol. 2009; 27: 1-10.6. Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol. 1990; 93: 333-339.Compared withCLL patients all cancers general populationn Time at risk (PY) n (TCM) SIR 95% CI SIR 95% CINCR 13,504 61,631 8 1.7 (0.71-3.3) 3.0 (1.3-5.8)SEER 90,721 443,802 72 2.1 (1.7-2.7) n/aTable 1: Increased rates of T-Cell Lymphoma (TCL) as a second primary malignancy in patients with Chronic Lymphocytic Leukemia (CLL) as compared with all cancer patients and the general population in the Netherlands (NCR) or United States of America (SEER). CI, confidence interval; n, number of patients; n/a, not available; PY, patient-years; SIR, standardized-incidence ratio.Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 03Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.com7. Fayad L, Robertson LE, O’Brien S, Manning JT, Wright S, Hagemeister F, et al. Hodgkin’s disease variant of Richter’s syndrome: experience at a single institution. Leuk Lymphoma. 1996; 23: 333-337.8. Weisenberg E, Anastasi J, Adeyanju M, Variakojis D, Vardiman JW. Hodgkin’s disease associated with chronic lymphocytic leukemia. Eight additional cases, including two of the nodular lymphocyte predominant type. Am J Clin Pathol. 1995; 103: 479-484.9. Lee A, Skelly ME, Kingma DW, Medeiros LJ. B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter’s syndrome. Am J Clin Pathol. 1995; 103: 348-352.10. Martinez A, Pittaluga S, Villamor N, Colomer D, Rozman M, Raffeld M, et al. Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. Am J Surg Pathol. 2004; 28: 849-858.11. Novogrudsky A, Amorosi EL, Gottesman SR. High-grade T-cell lymphoma complicating B-cell chronic lymphocytic leukemia: an unusual manifestation of “Richter’s syndrome”. Am J Hematol. 2001; 66: 203-206.12. Working Group Report. International rules for multiple primary cancers (ICD-0 third edition). Eur J Cancer Prev. 2005; 14: 307-308.13. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013; 121: 1612-1621.14. Görgün G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005; 115: 1797-1805.15. Callea V, Brugiatelli M, Stelitano C, Gentile M, Nobile F, Morabito F. Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy. Leuk Lymphoma. 2006; 47: 2314-2320.16. Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. Leuk Lymphoma. Informa Clin Med. 2014; 1–8. Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reserved

   University of GroningenIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi, Goda; van den Broek, Esther C; Stam, Olga CG; van Noesel, C.J.M.; Tonino, Sanne H.;Kater, Armon P.Published in:Annals of Hematology & OncologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Choi, G., van den Broek, E. C., Stam, O. CG., van Noesel, C. J. M., Tonino, S. H., & Kater, A. P. (2015).Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Annals ofHematology & Oncology, 2(2), Article 1023 .CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 05-12-2023Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reservedAnnals of Hematology & OncologyOpen AccessAbstractWe present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compared with the general population and all cancer survivors in the databases. We hypothesize that CLL cells interact with T-cells in the microenvironment, facilitating malignant transformation.Keywords: Chronic lymphocytic leukemia; T-cell lymphoma; Neoplastic cell transformation; Cohort studiesIntroductionChronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by progressive accumulation of mature B-cells in peripheral blood and secondary lymphoid organs. Primary causes of death include infections and secondary malignancies [1], suggesting an immunodeficiency in CLL patients [2]. Recent epidemiological data demonstrated that the increased risk of other primary malignancies in CLL patients is independent of treatment or surveillance bias [3]. Most likely, CLL is not a disease limited to B-cells only, but also affects other components of the immune system due to extensive crosstalk between CLL cells and their microenvironment [4]. In this report, we present a patient with therapy-refractory CLL in whom post-mortem examination revealed the presence of a T-cell lymphoma. We further studied the coincidence of T-cell malignancies and CLL within two population-based cancer registries, and found an excess risk of T-cell malignancies in patients with CLL. Case PresentationA 75-year-old male patient with therapy-refractory CLL was referred to our hospital. CLL had been diagnosed 7 years earlier (initially Rai 0) and during the last 3 years, he was intermittently treated with Chlorambucil. One month before admission, he had a painful cervical node, from which a biopsy revealed CD5 positive, cycline-D1 negative B-cells, compatible with CLL and without signs of transformation. Upon admission, patient presented with fever, dysphagia, and general malaise. His blood counts showed a pancytopenia with hemoglobin 7.9 g/dL (12.1 a month before), leukocytes 2,300/μl (50% lymphocytes), and platelets 10,000/μl (80,000 before). Without clinical signs of a specific infection, he was treated with broad-spectrum antibiotics. A bone marrow biopsy was performed, showing80% CLL cells (positive for CD5/CD19/CD23/CD20dim) and dysplasia in the myeloid and erythroid lineages. Within hours, he had progressive respiratory failure due to either sepsis or transfusion-related lung injury. Despite ventilatory support, Case ReportIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi G1*, van den Broek EC3*, Stam OCG2, van Noesel CJM2, Tonino SH1 and Kater AP11Department of Hematology, University of Amsterdam, Netherlands2Department of Pathology, University of Amsterdam, Netherlands3Integraal Kankercentrum Zuid, Eindhoven, Netherlands*Corresponding author: G Choi, University Medical Center Groningen, Department of Hematology (HPC DA21) Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Tel: 31 50 361 2354; Fax: 31 50 361 5960; Email: c.w.choi@umcg.nlReceived: December 04, 2014; Accepted: January 16, 2015; Published: January 19, 2015patient’s condition rapidly deteriorated and he died within a few hours.Post-mortem examination showed signs of multi-organ failure, including congested lungs without microbial infiltrates. There was hepatosplenomegaly and lymphadenopathy. Immunohistochemistry studies showed diffuse infiltrates of small, basophilic cells, positive for CD5, CD20 and CD23 (in liver, spleen, and bone marrow). Remarkably, the spleen contained, apart from CLL, areas with large cells with atypical nuclei positive for CD3, CD8, and Granzyme B, and negative for CD4, CD5, CD20, CD23, CD30, ALK1, CD79a, PAX-5, EBV, and keratin.Ki67 showed a high proliferation index in these areas. Altogether, this patient was found to have CLL and a high-grade peripheral T-cell lymphoma NOS (Figure 1). Molecular analyses of both spleen and liver lesions demonstrated clonal B-cell receptor and clonal T-cell receptor rearrangements, confirming both malignancies. Analysis was also performed on banked peripheral Figure 1: Spleen section with T-cell lymphoma (*) and CLL, stained with (A) H&E, (B) CD79a, (C) CD3, (D) CD5 monoclonal antibodies (50x magnification). Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 02Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.comblood from 3 years earlier, excluding the presence of the malignant T-cell clone at an earlier stage of disease.This case demonstrated that a large-cell T-cell lymphoma had developed in a patient with a chronic B-cell leukemia. In the classical Richter’s syndrome, CLL cells are believed to transform into a large cell B-cell lymphoma, after acquisition of additional molecular lesions [5]. Rarely, in large cellular lymphomas complicating CLL, there is any clonal relationship with CLL. There have been case reports of Hodgkin’s disease [6-8] and T-cell lymphoma [9-11] found in CLL patients.Cohort studyTo estimate the incidence of T-cell lymphomas among CLL patients, we performed a retrospective study within the Netherlands Cancer Registry (NCR) database. We retrieved all cancer cases diagnosed in the Netherlands between 1989 and 2008 and included patients diagnosed with a first primary invasive cancer (n =1,270,595). Patients were followed until the occurrence of T-cell lymphoma, death, or end of follow-up (December 31, 2008). The order of the cancer diagnosis was determined according to the International Rules for Multiple Primary Cancers (ICD-O, [12]). All T-cell malignancies diagnosed after CLL diagnosis were included, using ICD-O-2 codes 9700-9702, 9705, 9708, 9714, 9716-9719, 9827, 9831, 9834, 9948 and ICD-O-3 codes 9591, 9593, 9675, 9680, 9684, 9702-9704, 9713, 9823, 9825 combined with type=T-cell. As a measure of excess risk, Standardized Incidence Ratio (SIR) was calculated as the ratio of the observed number of cases in the cohort to the expected number of cases. The number of expected cases was calculated by multiplying the person-years at risk by the age-, gender-, and calendar year-specific incidence rates in the background population. 95% Confidence Intervals (95% CI) for SIRs were calculated based on a Poisson distribution. SAS software (SAS system 9.3, SAS Institute, Cary, NC) was used to perform the statistical analyses.As shown in Table 1, Dutch CLL patients exhibited a threefold excess risk of developing a T-cell malignancy when compared with the entire Dutch population (SIR 3.0; 95% CI, 1.3-5.8). To correct for possible increased detection among cancer survivors, we also compared CLL patients with all Dutch cancer survivors. This yielded a SIR of 1.7, however statistically non-significant (95% CI, 0.71-3.3). As this might be due to the small size of the cohort, we performed the same analysis on the Surveillance, Epidemiology and End Results (SEER) database. We retrieved all registered cancer cases diagnosed in the United States (US) of America between 1973 and 2010 and included patients diagnosed with a first primary invasive cancer (n =6,316,679). End of follow-up date was December 31, 2010. We found that US CLL patients exhibited a more than two-fold risk for T-cell malignancies compared with all US cancer survivors (SIR 2.1; 95% CI, 1.7-2.7).DiscussionWe here presented a patient with therapy-refractory CLL who died from multi-organ failure, in whom a T-cell lymphoma was detected at post-mortem examination. Within the Dutch NCR and larger US SEER databases, the epidemiological data corroborate the hypothesis that CLL predisposes patients for the development of T-cell malignancies. Indeed, there is a biologic rationale for increased incidence of clonal T-cell disorders in CLL. In CLL, there is an expansion of T-cells with a globally impaired function characterized by a pseudo-exhausted phenotype [13]. Also, microarray and functional studies showed that T-cells from CLL patients undergo significant changes on a molecular and structural level [14]. Clearly, CLL cells and T-cells have reciprocal interactions, inducing both expansion and intrinsic changes, and possibly facilitating malignant transformation. Of note, other factors may play a role in the pathogenesis of T-cell malignancies in CLL patients. We cannot exclude that previous treatment and/or immunosuppression would contribute to the pathogenesis of T-cell malignancies. In previous case reports, treatment with Chlorambucil, Fludarabine, and various immunosuppressive agents were described [10,11]. Compared with untreated follicular lymphoma patients, untreated CLL patients have a two-fold increased risk of second malignancies, as shown in a large Canadian cohort study [3]. Prolonged Chlorambucil treatment was not associated with an increase in second malignancies in a cohort of CLL patients [15], whereas most recently Benjamini et al. demonstrated that frontline treatment with Fludarabine, Cyclophosphamide, and Rituximab was associated with an increased risk of therapy related acute myeloid leukemia and Richter’s syndrome [16]. In these cohort studies, no cases of T-cell malignancy were described.In conclusion, albeit the low incidence, CLL patients have an increased risk of developing T-cell malignancies. It remains to be established whether malignant transformation of T-cells is facilitated by interactions with CLL cells, direct mutations induced by chemotherapy, or deficiency in adequate immunosurveillance related to CLL and/or use of immunomodulating agents.References1. Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, Garcia-Manero G . Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009; 27: 1637-1643.2. Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leuk Lymphoma. 2005; 46: 49-54.3. Beiggi S, Johnston JB, Seftel MD, Pitz MW, Kumar R, Banerji V, et al. Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study. Br J Cancer. 2013; 109: 1287–1290. 4. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011; 2011: 96-103.5. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical perspectives. Hematol Oncol. 2009; 27: 1-10.6. Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol. 1990; 93: 333-339.Compared withCLL patients all cancers general populationn Time at risk (PY) n (TCM) SIR 95% CI SIR 95% CINCR 13,504 61,631 8 1.7 (0.71-3.3) 3.0 (1.3-5.8)SEER 90,721 443,802 72 2.1 (1.7-2.7) n/aTable 1: Increased rates of T-Cell Lymphoma (TCL) as a second primary malignancy in patients with Chronic Lymphocytic Leukemia (CLL) as compared with all cancer patients and the general population in the Netherlands (NCR) or United States of America (SEER). CI, confidence interval; n, number of patients; n/a, not available; PY, patient-years; SIR, standardized-incidence ratio.Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 03Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.com7. Fayad L, Robertson LE, O’Brien S, Manning JT, Wright S, Hagemeister F, et al. Hodgkin’s disease variant of Richter’s syndrome: experience at a single institution. Leuk Lymphoma. 1996; 23: 333-337.8. Weisenberg E, Anastasi J, Adeyanju M, Variakojis D, Vardiman JW. Hodgkin’s disease associated with chronic lymphocytic leukemia. Eight additional cases, including two of the nodular lymphocyte predominant type. Am J Clin Pathol. 1995; 103: 479-484.9. Lee A, Skelly ME, Kingma DW, Medeiros LJ. B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter’s syndrome. Am J Clin Pathol. 1995; 103: 348-352.10. Martinez A, Pittaluga S, Villamor N, Colomer D, Rozman M, Raffeld M, et al. Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. Am J Surg Pathol. 2004; 28: 849-858.11. Novogrudsky A, Amorosi EL, Gottesman SR. High-grade T-cell lymphoma complicating B-cell chronic lymphocytic leukemia: an unusual manifestation of “Richter’s syndrome”. Am J Hematol. 2001; 66: 203-206.12. Working Group Report. International rules for multiple primary cancers (ICD-0 third edition). Eur J Cancer Prev. 2005; 14: 307-308.13. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013; 121: 1612-1621.14. Görgün G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005; 115: 1797-1805.15. Callea V, Brugiatelli M, Stelitano C, Gentile M, Nobile F, Morabito F. Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy. Leuk Lymphoma. 2006; 47: 2314-2320.16. Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. Leuk Lymphoma. Informa Clin Med. 2014; 1–8. Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reserved

University of Groningen Research Database

  
 University of Groningen
Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia
Choi, Goda ; van den Broek, Esther C; Stam, Olga CG; van Noesel, C.J.M.; Tonino, Sanne
H.; Kater, Armon P.
Published in:
Annals of Hematology & Oncology
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Publication date:
2015
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Choi, G., van den Broek, E. C., Stam, O. C. G., van Noesel, C. J. M., Tonino, S. H., & Kater, A. P. (2015).
Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Annals of
Hematology & Oncology, 2(2), 1023.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
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Download date: 11-02-2018
Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence 
of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.
Ann Hematol Oncol - Volume 2 Issue 2 - 2015
ISSN : 2375-7965 | www.austinpublishinggroup.com 
Choi et al. © All rights are reserved
Annals of Hematology & Oncology
Open Access
Abstract
We present a patient with chemotherapy-refractory Chronic Lymphocytic 
Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, 
with both multiple small-cellular CLL lesions and large-cellular, monoclonal 
T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and 
CLL was studied using Dutch and American cancer registry databases. Analysis 
showed an excess risk for T-cell malignancies in CLL patients, with increased 
standardized incidence ratios compared with the general population and all 
cancer survivors in the databases. We hypothesize that CLL cells interact with 
T-cells in the microenvironment, facilitating malignant transformation.
Keywords: Chronic lymphocytic leukemia; T-cell lymphoma; Neoplastic cell 
transformation; Cohort studies
Introduction
Chronic Lymphocytic Leukemia (CLL) is a chronic 
lymphoproliferative disorder characterized by progressive 
accumulation of mature B-cells in peripheral blood and secondary 
lymphoid organs. Primary causes of death include infections and 
secondary malignancies [1], suggesting an immunodeficiency in 
CLL patients [2]. Recent epidemiological data demonstrated that 
the increased risk of other primary malignancies in CLL patients is 
independent of treatment or surveillance bias [3]. Most likely, CLL is 
not a disease limited to B-cells only, but also affects other components 
of the immune system due to extensive crosstalk between CLL cells 
and their microenvironment [4]. In this report, we present a patient 
with therapy-refractory CLL in whom post-mortem examination 
revealed the presence of a T-cell lymphoma. We further studied the 
coincidence of T-cell malignancies and CLL within two population-
based cancer registries, and found an excess risk of T-cell malignancies 
in patients with CLL. 
Case Presentation
A 75-year-old male patient with therapy-refractory CLL was 
referred to our hospital. CLL had been diagnosed 7 years earlier 
(initially Rai 0) and during the last 3 years, he was intermittently 
treated with Chlorambucil. One month before admission, he had a 
painful cervical node, from which a biopsy revealed CD5 positive, 
cycline-D1 negative B-cells, compatible with CLL and without 
signs of transformation. Upon admission, patient presented with 
fever, dysphagia, and general malaise. His blood counts showed 
a pancytopenia with hemoglobin 7.9 g/dL (12.1 a month before), 
leukocytes 2,300/μl (50% lymphocytes), and platelets 10,000/μl 
(80,000 before). Without clinical signs of a specific infection, he was 
treated with broad-spectrum antibiotics. A bone marrow biopsy was 
performed, showing80% CLL cells (positive for CD5/CD19/CD23/
CD20dim) and dysplasia in the myeloid and erythroid lineages. 
Within hours, he had progressive respiratory failure due to either 
sepsis or transfusion-related lung injury. Despite ventilatory support, 
Case Report
Increased Incidence of T-Cell Malignancies in Patients 
with Chronic Lymphocytic Leukemia
Choi G1*, van den Broek EC3*, Stam OCG2, van 
Noesel CJM2, Tonino SH1 and Kater AP1
1Department of Hematology, University of Amsterdam, 
Netherlands
2Department of Pathology, University of Amsterdam, 
Netherlands
3Integraal Kankercentrum Zuid, Eindhoven, Netherlands
*Corresponding author: G Choi, University 
Medical Center Groningen, Department of Hematology 
(HPC DA21) Hanzeplein 1, 9713 GZ Groningen, The 
Netherlands, Tel: 31 50 361 2354; Fax: 31 50 361 5960; 
Email: c.w.choi@umcg.nl
Received: December 04, 2014; Accepted: January 16, 
2015; Published: January 19, 2015
patient’s condition rapidly deteriorated and he died within a few 
hours.
Post-mortem examination showed signs of multi-organ failure, 
including congested lungs without microbial infiltrates. There was 
hepatosplenomegaly and lymphadenopathy. Immunohistochemistry 
studies showed diffuse infiltrates of small, basophilic cells, positive 
for CD5, CD20 and CD23 (in liver, spleen, and bone marrow). 
Remarkably, the spleen contained, apart from CLL, areas with large 
cells with atypical nuclei positive for CD3, CD8, and Granzyme B, 
and negative for CD4, CD5, CD20, CD23, CD30, ALK1, CD79a, 
PAX-5, EBV, and keratin.Ki67 showed a high proliferation index 
in these areas. Altogether, this patient was found to have CLL and a 
high-grade peripheral T-cell lymphoma NOS (Figure 1). Molecular 
analyses of both spleen and liver lesions demonstrated clonal B-cell 
receptor and clonal T-cell receptor rearrangements, confirming both 
malignancies. Analysis was also performed on banked peripheral 
Figure 1: Spleen section with T-cell lymphoma (*) and CLL, stained 
with (A) H&E, (B) CD79a, (C) CD3, (D) CD5 monoclonal antibodies (50x 
magnification). 
Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 02
Choi G Austin Publishing Group
Submit your Manuscript | www.austinpublishinggroup.com
blood from 3 years earlier, excluding the presence of the malignant 
T-cell clone at an earlier stage of disease.
This case demonstrated that a large-cell T-cell lymphoma had 
developed in a patient with a chronic B-cell leukemia. In the classical 
Richter’s syndrome, CLL cells are believed to transform into a large 
cell B-cell lymphoma, after acquisition of additional molecular lesions 
[5]. Rarely, in large cellular lymphomas complicating CLL, there is 
any clonal relationship with CLL. There have been case reports of 
Hodgkin’s disease [6-8] and T-cell lymphoma [9-11] found in CLL 
patients.
Cohort study
To estimate the incidence of T-cell lymphomas among CLL 
patients, we performed a retrospective study within the Netherlands 
Cancer Registry (NCR) database. We retrieved all cancer cases 
diagnosed in the Netherlands between 1989 and 2008 and included 
patients diagnosed with a first primary invasive cancer (n =1,270,595). 
Patients were followed until the occurrence of T-cell lymphoma, 
death, or end of follow-up (December 31, 2008). The order of the 
cancer diagnosis was determined according to the International Rules 
for Multiple Primary Cancers (ICD-O, [12]). All T-cell malignancies 
diagnosed after CLL diagnosis were included, using ICD-O-2 codes 
9700-9702, 9705, 9708, 9714, 9716-9719, 9827, 9831, 9834, 9948 
and ICD-O-3 codes 9591, 9593, 9675, 9680, 9684, 9702-9704, 9713, 
9823, 9825 combined with type=T-cell. As a measure of excess risk, 
Standardized Incidence Ratio (SIR) was calculated as the ratio of the 
observed number of cases in the cohort to the expected number of 
cases. The number of expected cases was calculated by multiplying the 
person-years at risk by the age-, gender-, and calendar year-specific 
incidence rates in the background population. 95% Confidence 
Intervals (95% CI) for SIRs were calculated based on a Poisson 
distribution. SAS software (SAS system 9.3, SAS Institute, Cary, NC) 
was used to perform the statistical analyses.
As shown in Table 1, Dutch CLL patients exhibited a threefold 
excess risk of developing a T-cell malignancy when compared with 
the entire Dutch population (SIR 3.0; 95% CI, 1.3-5.8). To correct 
for possible increased detection among cancer survivors, we also 
compared CLL patients with all Dutch cancer survivors. This yielded 
a SIR of 1.7, however statistically non-significant (95% CI, 0.71-3.3). 
As this might be due to the small size of the cohort, we performed 
the same analysis on the Surveillance, Epidemiology and End Results 
(SEER) database. We retrieved all registered cancer cases diagnosed 
in the United States (US) of America between 1973 and 2010 and 
included patients diagnosed with a first primary invasive cancer 
(n =6,316,679). End of follow-up date was December 31, 2010. We 
found that US CLL patients exhibited a more than two-fold risk for 
T-cell malignancies compared with all US cancer survivors (SIR 2.1; 
95% CI, 1.7-2.7).
Discussion
We here presented a patient with therapy-refractory CLL who 
died from multi-organ failure, in whom a T-cell lymphoma was 
detected at post-mortem examination. Within the Dutch NCR and 
larger US SEER databases, the epidemiological data corroborate the 
hypothesis that CLL predisposes patients for the development of 
T-cell malignancies. Indeed, there is a biologic rationale for increased 
incidence of clonal T-cell disorders in CLL. In CLL, there is an 
expansion of T-cells with a globally impaired function characterized 
by a pseudo-exhausted phenotype [13]. Also, microarray and 
functional studies showed that T-cells from CLL patients undergo 
significant changes on a molecular and structural level [14]. Clearly, 
CLL cells and T-cells have reciprocal interactions, inducing both 
expansion and intrinsic changes, and possibly facilitating malignant 
transformation. Of note, other factors may play a role in the 
pathogenesis of T-cell malignancies in CLL patients. We cannot 
exclude that previous treatment and/or immunosuppression would 
contribute to the pathogenesis of T-cell malignancies. In previous 
case reports, treatment with Chlorambucil, Fludarabine, and various 
immunosuppressive agents were described [10,11]. Compared with 
untreated follicular lymphoma patients, untreated CLL patients have 
a two-fold increased risk of second malignancies, as shown in a large 
Canadian cohort study [3]. Prolonged Chlorambucil treatment was not 
associated with an increase in second malignancies in a cohort of CLL 
patients [15], whereas most recently Benjamini et al. demonstrated 
that frontline treatment with Fludarabine, Cyclophosphamide, and 
Rituximab was associated with an increased risk of therapy related 
acute myeloid leukemia and Richter’s syndrome [16]. In these cohort 
studies, no cases of T-cell malignancy were described.
In conclusion, albeit the low incidence, CLL patients have 
an increased risk of developing T-cell malignancies. It remains 
to be established whether malignant transformation of T-cells is 
facilitated by interactions with CLL cells, direct mutations induced by 
chemotherapy, or deficiency in adequate immunosurveillance related 
to CLL and/or use of immunomodulating agents.
References
1. Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, Garcia-Manero 
G . Characteristics associated with important clinical end points in patients 
with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009; 
27: 1637-1643.
2. Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence 
and pathogenesis with emphasis on the role of different therapies. Leuk 
Lymphoma. 2005; 46: 49-54.
3. Beiggi S, Johnston JB, Seftel MD, Pitz MW, Kumar R, Banerji V, et al. 
Increased risk of second malignancies in chronic lymphocytic leukaemia 
patients as compared with follicular lymphoma patients: a Canadian 
population-based study. Br J Cancer. 2013; 109: 1287–1290. 
4. Burger JA. Nurture versus nature: the microenvironment in chronic 
lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011; 
2011: 96-103.
5. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical 
perspectives. Hematol Oncol. 2009; 27: 1-10.
6. Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome. 
Report of eight cases. Am J Clin Pathol. 1990; 93: 333-339.
Compared with
CLL patients all cancers general population
n Time at risk (PY) n (TCM) SIR 95% CI SIR 95% CI
NCR 13,504 61,631 8 1.7 (0.71-3.3) 3.0 (1.3-5.8)
SEER 90,721 443,802 72 2.1 (1.7-2.7) n/a
Table 1: Increased rates of T-Cell Lymphoma (TCL) as a second primary 
malignancy in patients with Chronic Lymphocytic Leukemia (CLL) as compared 
with all cancer patients and the general population in the Netherlands (NCR) or 
United States of America (SEER). CI, confidence interval; n, number of patients; 
n/a, not available; PY, patient-years; SIR, standardized-incidence ratio.
Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 03
Choi G Austin Publishing Group
Submit your Manuscript | www.austinpublishinggroup.com
7. Fayad L, Robertson LE, O’Brien S, Manning JT, Wright S, Hagemeister F, et 
al. Hodgkin’s disease variant of Richter’s syndrome: experience at a single 
institution. Leuk Lymphoma. 1996; 23: 333-337.
8. Weisenberg E, Anastasi J, Adeyanju M, Variakojis D, Vardiman JW. 
Hodgkin’s disease associated with chronic lymphocytic leukemia. Eight 
additional cases, including two of the nodular lymphocyte predominant type. 
Am J Clin Pathol. 1995; 103: 479-484.
9. Lee A, Skelly ME, Kingma DW, Medeiros LJ. B-cell chronic lymphocytic 
leukemia followed by high grade T-cell lymphoma. An unusual variant of 
Richter’s syndrome. Am J Clin Pathol. 1995; 103: 348-352.
10. Martinez A, Pittaluga S, Villamor N, Colomer D, Rozman M, Raffeld M, et al. 
Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in 
B-CLL patients: clinicopathologic observations and molecular analysis. Am J 
Surg Pathol. 2004; 28: 849-858.
11. Novogrudsky A, Amorosi EL, Gottesman SR. High-grade T-cell lymphoma 
complicating B-cell chronic lymphocytic leukemia: an unusual manifestation 
of “Richter’s syndrome”. Am J Hematol. 2001; 66: 203-206.
12. Working Group Report. International rules for multiple primary cancers (ICD-0 
third edition). Eur J Cancer Prev. 2005; 14: 307-308.
13. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. 
T cells from CLL patients exhibit features of T-cell exhaustion but retain 
capacity for cytokine production. Blood. 2013; 121: 1612-1621.
14. Görgün G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic 
lymphocytic leukemia cells induce changes in gene expression of CD4 and 
CD8 T cells. J Clin Invest. 2005; 115: 1797-1805.
15. Callea V, Brugiatelli M, Stelitano C, Gentile M, Nobile F, Morabito F. Incidence 
of second neoplasia in patients with B-cell chronic lymphocytic leukemia 
treated with chlorambucil maintenance chemotherapy. Leuk Lymphoma. 
2006; 47: 2314-2320.
16. Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second 
cancers in patients with chronic lymphocytic leukemia who received frontline 
fludarabine, cyclophosphamide and rituximab therapy: distribution and 
clinical outcomes. Leuk Lymphoma. Informa Clin Med. 2014; 1–8. 
Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence 
of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.
Ann Hematol Oncol - Volume 2 Issue 2 - 2015
ISSN : 2375-7965 | www.austinpublishinggroup.com 
Choi et al. © All rights are reserved


   University of GroningenIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi, Goda; van den Broek, Esther C; Stam, Olga CG; van Noesel, C.J.M.; Tonino, Sanne H.;Kater, Armon P.Published in:Annals of Hematology & OncologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Choi, G., van den Broek, E. C., Stam, O. CG., van Noesel, C. J. M., Tonino, S. H., & Kater, A. P. (2015).Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Annals ofHematology & Oncology, 2(2), [1023 ].CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 13-02-2023Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reservedAnnals of Hematology & OncologyOpen AccessAbstractWe present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compared with the general population and all cancer survivors in the databases. We hypothesize that CLL cells interact with T-cells in the microenvironment, facilitating malignant transformation.Keywords: Chronic lymphocytic leukemia; T-cell lymphoma; Neoplastic cell transformation; Cohort studiesIntroductionChronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by progressive accumulation of mature B-cells in peripheral blood and secondary lymphoid organs. Primary causes of death include infections and secondary malignancies [1], suggesting an immunodeficiency in CLL patients [2]. Recent epidemiological data demonstrated that the increased risk of other primary malignancies in CLL patients is independent of treatment or surveillance bias [3]. Most likely, CLL is not a disease limited to B-cells only, but also affects other components of the immune system due to extensive crosstalk between CLL cells and their microenvironment [4]. In this report, we present a patient with therapy-refractory CLL in whom post-mortem examination revealed the presence of a T-cell lymphoma. We further studied the coincidence of T-cell malignancies and CLL within two population-based cancer registries, and found an excess risk of T-cell malignancies in patients with CLL. Case PresentationA 75-year-old male patient with therapy-refractory CLL was referred to our hospital. CLL had been diagnosed 7 years earlier (initially Rai 0) and during the last 3 years, he was intermittently treated with Chlorambucil. One month before admission, he had a painful cervical node, from which a biopsy revealed CD5 positive, cycline-D1 negative B-cells, compatible with CLL and without signs of transformation. Upon admission, patient presented with fever, dysphagia, and general malaise. His blood counts showed a pancytopenia with hemoglobin 7.9 g/dL (12.1 a month before), leukocytes 2,300/μl (50% lymphocytes), and platelets 10,000/μl (80,000 before). Without clinical signs of a specific infection, he was treated with broad-spectrum antibiotics. A bone marrow biopsy was performed, showing80% CLL cells (positive for CD5/CD19/CD23/CD20dim) and dysplasia in the myeloid and erythroid lineages. Within hours, he had progressive respiratory failure due to either sepsis or transfusion-related lung injury. Despite ventilatory support, Case ReportIncreased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic LeukemiaChoi G1*, van den Broek EC3*, Stam OCG2, van Noesel CJM2, Tonino SH1 and Kater AP11Department of Hematology, University of Amsterdam, Netherlands2Department of Pathology, University of Amsterdam, Netherlands3Integraal Kankercentrum Zuid, Eindhoven, Netherlands*Corresponding author: G Choi, University Medical Center Groningen, Department of Hematology (HPC DA21) Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Tel: 31 50 361 2354; Fax: 31 50 361 5960; Email: c.w.choi@umcg.nlReceived: December 04, 2014; Accepted: January 16, 2015; Published: January 19, 2015patient’s condition rapidly deteriorated and he died within a few hours.Post-mortem examination showed signs of multi-organ failure, including congested lungs without microbial infiltrates. There was hepatosplenomegaly and lymphadenopathy. Immunohistochemistry studies showed diffuse infiltrates of small, basophilic cells, positive for CD5, CD20 and CD23 (in liver, spleen, and bone marrow). Remarkably, the spleen contained, apart from CLL, areas with large cells with atypical nuclei positive for CD3, CD8, and Granzyme B, and negative for CD4, CD5, CD20, CD23, CD30, ALK1, CD79a, PAX-5, EBV, and keratin.Ki67 showed a high proliferation index in these areas. Altogether, this patient was found to have CLL and a high-grade peripheral T-cell lymphoma NOS (Figure 1). Molecular analyses of both spleen and liver lesions demonstrated clonal B-cell receptor and clonal T-cell receptor rearrangements, confirming both malignancies. Analysis was also performed on banked peripheral Figure 1: Spleen section with T-cell lymphoma (*) and CLL, stained with (A) H&E, (B) CD79a, (C) CD3, (D) CD5 monoclonal antibodies (50x magnification). Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 02Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.comblood from 3 years earlier, excluding the presence of the malignant T-cell clone at an earlier stage of disease.This case demonstrated that a large-cell T-cell lymphoma had developed in a patient with a chronic B-cell leukemia. In the classical Richter’s syndrome, CLL cells are believed to transform into a large cell B-cell lymphoma, after acquisition of additional molecular lesions [5]. Rarely, in large cellular lymphomas complicating CLL, there is any clonal relationship with CLL. There have been case reports of Hodgkin’s disease [6-8] and T-cell lymphoma [9-11] found in CLL patients.Cohort studyTo estimate the incidence of T-cell lymphomas among CLL patients, we performed a retrospective study within the Netherlands Cancer Registry (NCR) database. We retrieved all cancer cases diagnosed in the Netherlands between 1989 and 2008 and included patients diagnosed with a first primary invasive cancer (n =1,270,595). Patients were followed until the occurrence of T-cell lymphoma, death, or end of follow-up (December 31, 2008). The order of the cancer diagnosis was determined according to the International Rules for Multiple Primary Cancers (ICD-O, [12]). All T-cell malignancies diagnosed after CLL diagnosis were included, using ICD-O-2 codes 9700-9702, 9705, 9708, 9714, 9716-9719, 9827, 9831, 9834, 9948 and ICD-O-3 codes 9591, 9593, 9675, 9680, 9684, 9702-9704, 9713, 9823, 9825 combined with type=T-cell. As a measure of excess risk, Standardized Incidence Ratio (SIR) was calculated as the ratio of the observed number of cases in the cohort to the expected number of cases. The number of expected cases was calculated by multiplying the person-years at risk by the age-, gender-, and calendar year-specific incidence rates in the background population. 95% Confidence Intervals (95% CI) for SIRs were calculated based on a Poisson distribution. SAS software (SAS system 9.3, SAS Institute, Cary, NC) was used to perform the statistical analyses.As shown in Table 1, Dutch CLL patients exhibited a threefold excess risk of developing a T-cell malignancy when compared with the entire Dutch population (SIR 3.0; 95% CI, 1.3-5.8). To correct for possible increased detection among cancer survivors, we also compared CLL patients with all Dutch cancer survivors. This yielded a SIR of 1.7, however statistically non-significant (95% CI, 0.71-3.3). As this might be due to the small size of the cohort, we performed the same analysis on the Surveillance, Epidemiology and End Results (SEER) database. We retrieved all registered cancer cases diagnosed in the United States (US) of America between 1973 and 2010 and included patients diagnosed with a first primary invasive cancer (n =6,316,679). End of follow-up date was December 31, 2010. We found that US CLL patients exhibited a more than two-fold risk for T-cell malignancies compared with all US cancer survivors (SIR 2.1; 95% CI, 1.7-2.7).DiscussionWe here presented a patient with therapy-refractory CLL who died from multi-organ failure, in whom a T-cell lymphoma was detected at post-mortem examination. Within the Dutch NCR and larger US SEER databases, the epidemiological data corroborate the hypothesis that CLL predisposes patients for the development of T-cell malignancies. Indeed, there is a biologic rationale for increased incidence of clonal T-cell disorders in CLL. In CLL, there is an expansion of T-cells with a globally impaired function characterized by a pseudo-exhausted phenotype [13]. Also, microarray and functional studies showed that T-cells from CLL patients undergo significant changes on a molecular and structural level [14]. Clearly, CLL cells and T-cells have reciprocal interactions, inducing both expansion and intrinsic changes, and possibly facilitating malignant transformation. Of note, other factors may play a role in the pathogenesis of T-cell malignancies in CLL patients. We cannot exclude that previous treatment and/or immunosuppression would contribute to the pathogenesis of T-cell malignancies. In previous case reports, treatment with Chlorambucil, Fludarabine, and various immunosuppressive agents were described [10,11]. Compared with untreated follicular lymphoma patients, untreated CLL patients have a two-fold increased risk of second malignancies, as shown in a large Canadian cohort study [3]. Prolonged Chlorambucil treatment was not associated with an increase in second malignancies in a cohort of CLL patients [15], whereas most recently Benjamini et al. demonstrated that frontline treatment with Fludarabine, Cyclophosphamide, and Rituximab was associated with an increased risk of therapy related acute myeloid leukemia and Richter’s syndrome [16]. In these cohort studies, no cases of T-cell malignancy were described.In conclusion, albeit the low incidence, CLL patients have an increased risk of developing T-cell malignancies. It remains to be established whether malignant transformation of T-cells is facilitated by interactions with CLL cells, direct mutations induced by chemotherapy, or deficiency in adequate immunosurveillance related to CLL and/or use of immunomodulating agents.References1. Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, Garcia-Manero G . Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009; 27: 1637-1643.2. Molica S. Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leuk Lymphoma. 2005; 46: 49-54.3. Beiggi S, Johnston JB, Seftel MD, Pitz MW, Kumar R, Banerji V, et al. Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study. Br J Cancer. 2013; 109: 1287–1290. 4. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011; 2011: 96-103.5. Rossi D, Gaidano G. Richter syndrome: molecular insights and clinical perspectives. Hematol Oncol. 2009; 27: 1-10.6. Brecher M, Banks PM. Hodgkin’s disease variant of Richter’s syndrome. Report of eight cases. Am J Clin Pathol. 1990; 93: 333-339.Compared withCLL patients all cancers general populationn Time at risk (PY) n (TCM) SIR 95% CI SIR 95% CINCR 13,504 61,631 8 1.7 (0.71-3.3) 3.0 (1.3-5.8)SEER 90,721 443,802 72 2.1 (1.7-2.7) n/aTable 1: Increased rates of T-Cell Lymphoma (TCL) as a second primary malignancy in patients with Chronic Lymphocytic Leukemia (CLL) as compared with all cancer patients and the general population in the Netherlands (NCR) or United States of America (SEER). CI, confidence interval; n, number of patients; n/a, not available; PY, patient-years; SIR, standardized-incidence ratio.Ann Hematol Oncol 2(2): id1023 (2015)  - Page - 03Choi G Austin Publishing GroupSubmit your Manuscript | www.austinpublishinggroup.com7. Fayad L, Robertson LE, O’Brien S, Manning JT, Wright S, Hagemeister F, et al. Hodgkin’s disease variant of Richter’s syndrome: experience at a single institution. Leuk Lymphoma. 1996; 23: 333-337.8. Weisenberg E, Anastasi J, Adeyanju M, Variakojis D, Vardiman JW. Hodgkin’s disease associated with chronic lymphocytic leukemia. Eight additional cases, including two of the nodular lymphocyte predominant type. Am J Clin Pathol. 1995; 103: 479-484.9. Lee A, Skelly ME, Kingma DW, Medeiros LJ. B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter’s syndrome. Am J Clin Pathol. 1995; 103: 348-352.10. Martinez A, Pittaluga S, Villamor N, Colomer D, Rozman M, Raffeld M, et al. Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis. Am J Surg Pathol. 2004; 28: 849-858.11. Novogrudsky A, Amorosi EL, Gottesman SR. High-grade T-cell lymphoma complicating B-cell chronic lymphocytic leukemia: an unusual manifestation of “Richter’s syndrome”. Am J Hematol. 2001; 66: 203-206.12. Working Group Report. International rules for multiple primary cancers (ICD-0 third edition). Eur J Cancer Prev. 2005; 14: 307-308.13. Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S, Agrawal S, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013; 121: 1612-1621.14. Görgün G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest. 2005; 115: 1797-1805.15. Callea V, Brugiatelli M, Stelitano C, Gentile M, Nobile F, Morabito F. Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy. Leuk Lymphoma. 2006; 47: 2314-2320.16. Benjamini O, Jain P, Trinh L, Qiao W, Strom SS, Lerner S, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes. Leuk Lymphoma. Informa Clin Med. 2014; 1–8. Citation: Choi G, van den Broek EC, Stam OCG, van Noesel CJM, Tonino SH and Kater AP. Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia. Ann Hematol Oncol. 2015;2(2): 1023.Ann Hematol Oncol - Volume 2 Issue 2 - 2015ISSN : 2375-7965 | www.austinpublishinggroup.com Choi et al. © All rights are reserved

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Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia

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