Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia.

Helen Marie Parry,Christopher Hudson,Annette Pachnio,Jusnara Begum,Paul A H Moss,James R Cerhan,Susan L Slager,Tait D Shanafelt,Matthew J Maurer,Guy Pratt,Sarah Damery,Stephen Man,Christopher Pepper,Christopher Fegan

doi:10.1002/ajh.24403

Abstract

Human cytomegalovirus (HCMV) is a widely prevalent herpes virus which establishes a state of chronic infection. The establishment of CMV‐specific immunity controls viral reactivation and leads to the accumulation of very large numbers of virus‐specific T cells which come to dominate the immune repertoire. There is concern that this may reduce the immune response to heterologous infections and HCMV infection has been associated with reduced survival in elderly people. Patients with chronic lymphocytic leukemia (B‐CLL) suffer from a state of immune suppression but have a paradoxical increase in the magnitude of the CMV‐specific T cell and humoral immune response. As such, there is now considerable interest in how CMV infection impacts on the clinical outcome of patients with B‐CLL. Utilizing a large prospective cohort of patients with B‐CLL (n = 347) we evaluated the relationship between HCMV seropositivity and patient outcome. HCMV seropositive patients had significantly worse overall survival than HCMV negative patients in univariate analysis (HR = 2.28, 95% CI: 1.34–3.88; P = 0.002). However, CMV seropositive patients were 4 years older than seronegative donors and this survival difference was lost in multivariate modeling adjusted for age and other validated prognostic markers (P = 0.34). No significant difference was found in multivariate modeling between HCMV positive and negative patients in relation to the time to first treatment (HR = 1.12, 95% CI: 0.68–1.84; P = 0.65). These findings in a second independent cohort of 236 B‐CLL patients were validated. In conclusion no evidence that HCMV impacts on the clinical outcome of patients with B‐CLL was found. Am. J. Hematol. 91:776–781, 2016. © 2016 Wiley Periodicals, Inc.

Highlights

Human Cytomegalovirus (HCMV) is a prevalent beta-herpes virus that is usually asymptomatic upon primary infection
The discovery cohort consisted of 390 patients, of which 347 patients were identified as having serum available for CMV testing and were used to explore the relationship between CMV and clinical outcome in B-CLL
CMV is recognized as an important pathogen in patients who are immune suppressed and viral reactivation is a common occurrence in patients with B-CLL who undergo treatment with alemtuzumab

Summary

Introduction

Human Cytomegalovirus (HCMV) is a prevalent beta-herpes virus that is usually asymptomatic upon primary infection. HCMV maintains lifelong latency within cells of the myeloid lineage and its prevalence increases with age [1,2]. A significant proportion of both CD41 and CD81 T cells are required to maintain viral latency and prevent HCMV viral reactivation [5,6]. This extreme expansion of HCMV-specific T cells, which is most marked in the CD81 T cell repertoire, contributes to a reduction in the number of na€ıve T cells and leads to an inversion of the CD4:CD8 T cell ratio [7]. There is increasing concern that the burden of CMV infection can lead to health problems, in older people, and CMV seropositivity has been associated with impaired responses to vaccination [8], increasing levels of inflammatory cytokines [9] and an increase in overall morbidity and mortality in several studies [10,11]

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Conclusion