The automated monocyte count is independently predictive of overall survival from diagnosis in chronic lymphocytic leukaemia and of survival following first-line chemotherapy
Introduction
Chronic lymphocytic leukaemia (CLL) is a clinically heterogeneous disorder which can vary from an indolent condition, with a prognosis similar to that of age-matched controls, to an aggressive disorder with a markedly shortened survival. Numerous methods for prognostication exist with some of the most robust including the assessment of clinical stage at diagnosis using the Binet or Rai systems, the detection of adverse cytogenetic abnormalities (deletions of 17p, 11q and the presence of trisomy 12), the extent of immunoglobulin VH gene (IgVH) somatic hypermutation and the strength of CD38 and zeta-associated protein of 70 kDa (ZAP70) expression by CLL-cells [1].
The survival of CLL-cells in vivo is critically dependent upon interactions with the microenvironments of the bone marrow and secondary lymphoid tissues and this dependency contributes to the poor survival of CLL-cells cultured in vitro where extrinsic signals important for the maintenance of CLL-cell viability are lacking. The addition of cultured stromal cells such as nurse-like cells, monocytes or macrophages to ex vivo tissue culture systems improves the viability of cultured CLL-cells [2].
Infiltration of tumour microenvironments by monocytes and macrophages has been identified in a variety of malignancies [3] with the extent of such infiltration being associated with an adverse prognosis in Hodgkin's lymphoma and other tumours [4]. In CLL the malignant B-cells are protected from apoptosis by monocytes in a process mediated by monocyte-derived CD14 which is present in elevated levels in the serum of patients with CLL when compared to normal controls [5]. This suggests that monocyte-derived survival signals may be important for the maintenance of the malignant clone in CLL.
We hypothesised that an elevated monocyte count at diagnosis would be associated with an adverse prognosis in CLL due to the possible tumour-promoting effects of these cells.
Section snippets
Methods
CLL was diagnosed according to National Cancer Institute (NCI) guidelines [6]. All patients had typical CLL with lymphocytes expressing CD5, CD19, CD23 and weak, clonally restricted, surface immunoglobulin. Data recorded for each patient included age, sex, date of diagnosis, date of first therapy, date of death and duration of follow-up. CLL-patients were identified from patients referred to a dedicated CLL-clinic within Hull and East Yorkshire Trust, the sole tertiary referral unit for a
Validation of automated monocyte counts in CLL-patients
We utilised the automated Sysmex XE2100™ to assess monocyte counts in CLL-patients at diagnosis. This device has been demonstrated to produce white cell differentials which display a high level of concordance with cell counts obtained using flow cytometry [13], however, the alternative Coulter S Plus instruments have been reported as detecting a falsely high monocyte count in patients with CLL [14]. Therefore we performed 500-cell manual differential counts in 50 patients with CLL. The mean
Discussion
In this paper we demonstrate that assessment of the monocyte count at the time of diagnosis of CLL provides useful prognostic information. A monocytosis at diagnosis is associated with a shortened OS and TFS with this abnormality being associated with the presence of high-risk cytogenetic abnormalities and also with ALC. In a multivariate analysis that included age, Binet stage, CD38 expression, high-risk cytogenetics, ALC and monocyte count only age and monocyte count were independently
Acknowledgements
Contributions. R.M. collated and analysed data. J.B. undertook data collection and analysis. P.E. performed IgVH analysis. R.C. analysed data. D.A. initiated the project, analysed data and wrote the manuscript.
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