Prognostic role of CD4 T-cell depletion after frontline fludarabine, cyclophosphamide and rituximab in chronic lymphocytic leukaemia

Martin Gauthier,Michael Peres,Loic Ysebaert,Françoise Durrieu,Anne Quillet Mary,Anne Quillet Mary,Elodie Martin,Thomas Filleron,Lucie Obéric,François Vergez,Fontanet Bijou

doi:10.1186/s12885-019-5971-z

Abstract

BackgroundEradication of minimal residual disease (MRD), at the end of Fludarabine-Cyclophosphamide-Rituximab (FCR) treatment, is a validated surrogate marker for progression-free and overall survival in chronic lymphocytic leukaemia. But such deep responses are also associated with severe immuno-depletion, leading to infections and the development of secondary cancers.MethodsWe assessed, blood MRD and normal immune cell levels at the end of treatment, in 162 first-line FCR patients, and analysed survival and adverse event.ResultsMultivariate Landmark analysis 3 months after FCR completion identified unmutated IGHV status (HR, 2.03, p = 0.043), the level of MRD reached (intermediate versus low, HR, 2.43, p = 0.002; high versus low, HR, 4.56, p = 0.002) and CD4 > 200/mm3 (HR, 3.30, p < 0.001) as factors independently associated with progression-free survival (PFS); neither CD8 nor NK counts were associated with PFS. The CD4 count was associated with PFS irrespective of IGHV mutational status, but only in patients with detectable MRD (HR, 3.51, p = 0.0004, whereas it had no prognostic impact in MRD < 10− 4 patients: p = 0.6998). We next used a competitive risk model to investigate whether immune cell subsets could be associated with the risk of infection and found no association between CD4, CD8 and NK cells and infection.ConclusionsConsolidation/maintenance trials based on detectable MRD after FCR should investigate CD4 T-cell numbers both as a selection and a response criterion, and consolidation treatments should target B-cell/T-cell interactions.

Highlights

Eradication of minimal residual disease (MRD), at the end of Fludarabine-Cyclophosphamide-Rituximab (FCR) treatment, is a validated surrogate marker for progression-free and overall survival in chronic lymphocytic leukaemia
Since bystander immune cells such as CD4 T-cells promote chronic lymphocytic leukaemia (CLL) survival/proliferation in tumour niches before FCR [16], we hypothesised that normal lymphocyte levels may influence the duration of progression-free survival (PFS) independently of the MRD status achieved after completion of therapy
In the univariate Cox model, baseline characteristics associated with shorter PFS were unmutated IGHV status (IGHV-UM) (HR, 2.55 [1.42–4.59], p = 0.0012), del17p and/or TP53 mutation (HR, 3.87 [1.34–11.22], p = 0.0072) and del11q (HR, 2.19 [1.35–3.56], p = 0.0012) (Table 2)

Summary

Introduction

Eradication of minimal residual disease (MRD), at the end of Fludarabine-Cyclophosphamide-Rituximab (FCR) treatment, is a validated surrogate marker for progression-free and overall survival in chronic lymphocytic leukaemia. Such deep responses are associated with severe immuno-depletion, leading to infections and the development of secondary cancers. Since bystander immune cells such as CD4 T-cells promote CLL survival/proliferation in tumour niches before FCR [16], we hypothesised that normal lymphocyte levels may influence the duration of PFS independently of the MRD status achieved after completion of therapy. Since FCR induces profound and durable lymphopenia, we correlated these measurements to the well-described risk of developing secondary malignancies and/or serious infectious events [17]

Methods

Results

Conclusion