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

BMC Cancer. 2019 Aug 14;19(1):809. doi: 10.1186/s12885-019-5971-z.

Abstract

Background: 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. But such deep responses are also associated with severe immuno-depletion, leading to infections and the development of secondary cancers.

Methods: We 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.

Results: Multivariate 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.

Conclusions: Consolidation/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.

Keywords: CD4 T-cells; Chemo-immunotherapy; Chronic lymphocytic Leukaemia; Immunosuppression; Minimal residual disease.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / pathology*
  • Cyclophosphamide / adverse effects
  • Cyclophosphamide / therapeutic use
  • Female
  • Follow-Up Studies
  • Humans
  • Immunoglobulin Variable Region / genetics
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use
  • Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Lymphocyte Count
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm, Residual
  • Prognosis
  • Rituximab / adverse effects
  • Rituximab / therapeutic use
  • Survival Analysis
  • Treatment Outcome
  • Vidarabine / adverse effects
  • Vidarabine / analogs & derivatives
  • Vidarabine / therapeutic use

Substances

  • Immunoglobulin Variable Region
  • Immunosuppressive Agents
  • Rituximab
  • Cyclophosphamide
  • Vidarabine
  • fludarabine