Biomarkers of minimal residual disease in rituximab‐treated patients with mixed cryoglobulinemia

Abstract

Hepatitis C virus (HCV) represents the major risk factor for mixed cryoglobulinemia (MC), a small‐vessel vasculitis that may evolve into an overt B‐cell non‐Hodgkin's lymphoma. Here, we aimed to identify a biomarker signature for the early diagnosis of minimal residual disease (MRD). We assessed free light chains (FLCs), IgM k,and IgM λ heavy/light chain (HLC) pairs, and vascular endothelial growth factor (VEGF) in sera from 34 patients with MC vasculitis (32 HCV‐ and 2 HBV‐related), treated with low‐dose rituximab (RTX). FLCs and IgM HLCs were measured by turbidimetric assay; VEGF by an enzyme‐linked immunosorbent assay. After RTX, the positive (complete + partial) clinical and laboratory responses were of 85.29% and 50%, respectively; in contrast, the mean levels of FLCs, IgM HLCs, and VEGF were substantially unaffected in most patients and still above the normal range. In those achieving a reduction of FLCs and IgM k and λ chains values within the range of normality, we found that post‐treatment free λ chains and IgM k values correlated with clinical and laboratory response. Our results suggest that high levels of FLCs, IgM HLCs, and VEGF could represent the signature of “dormant” B cell clones’ activity that could be very useful to identify MRD indicative of possible relapse or worsening outcome.

The Role of B Cells in Adult and Paediatric Liver Injury

“…Rituximab has been shown to be the most widely used treatment for HCV patients with cryoglobulinemia vasculitis ( 148 , 228 ). One cycle of low-dose rituximab achieved a complete clinical response in 22 out of 31 (70.96%) of MC patients ( 229 ). Clinical manifestations of cryoglobulinemia such as skin ulcers, renal manifestations and sensitive-motor neuropathy have improved through the use of rituximab ( 228 ).…”

Cryoglobulins: Identification, classification, and novel biomarkers of mysterious proteins

“…Different mechanisms are involved in the beneficial therapeutic response to RTX observed in the course of different antibody-dependent and cell-mediated autoimmune diseases [40] . Assessment of circulating biomarker levels represents a promising tool for a more accurate evaluation of both disease activity and response to RTX treatment [41] , [42] , [43] . For the best strategy of personalized medicine, therapeutic monitoring of biological drugs represents an important effort in the diagnostic-therapeutic pathway to improve overall patient management and favor an appropriate clinical approach.…”

“…FLCs could represent the signature of “dormant” B-cell clone activity and be very useful for identifying the minimal residual disease indicative of a possible relapse or worsening outcome in HCV-MC patients after rituximab treatment, despite positive (complete + partial) clinical and laboratory responses of 85% and 50%, respectively, suggesting that a better clinical endpoint for drug administration could be widely useful [42] .…”

“…The correlation between post-treatment HLC values and clinical and laboratory responses demonstrated their reliability as markers of clonality and their utility in the evaluation of MRD and therapeutic response to RTX. Their employment could be useful for recognizing patients who could benefit from additional anti-CD20 therapy, with an improvement in patient-tailored treatments [42] .…”

“…The development of a dangerous immune complex-mediated glomerulonephritis represents worsening evolution of the immunologic disorder initially triggered by HCV infection [119] that could impair renal function. In this setting, the evaluation of a minimal residual disease in rituximab-treated patients with MC through the assessment of FLCs, heavy/light chains pairs or vascular endothelial growth factor (VEGF) may be crucial to improve the prognosis [42] .…”