Clonal evolution in hematological malignancies and therapeutic implications.

The ability of cancer to evolve and adapt is a principal challenge to therapy in general and to the paradigm of targeted therapy in particular. This ability is fueled by the co-existence of multiple, genetically heterogeneous subpopulations within the cancer cell population. Increasing evidence has supported the idea that these subpopulations are selected in a Darwinian fashion, by which the genetic landscape of the tumor is continuously reshaped. Massively parallel sequencing has enabled a recent surge in our ability to study this process, adding to previous efforts using cytogenetic methods and targeted sequencing. Altogether, these studies reveal the complex evolutionary trajectories occurring across individual hematological malignancies. They also suggest that while clonal evolution may contribute to resistance to therapy, treatment may also hasten the evolutionary process. New insights into this process challenge us to understand the impact of treatment on clonal evolution and inspire the development of novel prognostic and therapeutic strategies.

The B lymphocyte stimulator receptor-ligand system in hepatitis C virus-induced B cell clonal disorders.

OBJECTIVE: The study aim was to examine the B lymphocyte stimulator (BLyS) receptor-ligand system in hepatitis C virus (HCV)-induced B lymphocyte clonal disorders. METHODS: 94 patients with chronic HCV (including 35 with HCV+ mixed cryoglobulinaemia (MC)-vasculitis and nine with HCV+ B cell non-Hodgkin's lymphoma (B-NHL)) and 15 healthy volunteers were included. RESULTS: A twofold serum BLyS increase was associated with HCV-induced MC-vasculitis, and a threefold increase with HCV-induced B-NHL, compared with patients that were HCV+, but without vasculitis, or healthy controls (p<0.05). Lower membrane BLyS expression in HCV-induced MC-vasculitis was observed. CD19+ BLyS binding and BLyS receptor 3 (BR3) staining showed a stepwise decrease with highest values in healthy controls and who were HCV+ without MC, and lowest in B-NHL (p<0.05, p<0.0001, respectively) with a further decrease in VH1-69+ clonal B cells. BLyS anti-apoptotic effects were maintained despite this decrease in BR3 staining. Complete clinical remission after antiviral treatment was associated with a decrease in serum BLyS, and an increase in BR3 staining. Rituximab treatment was associated with a fivefold increase in serum BLyS (p<0.001), mirroring the depletion of CD19+ cells. BR3 staining in repopulating B cells was significantly decreased (p<0.005). CONCLUSIONS: The BLyS ligand-receptor activity is increased in HCV-induced B cell clonal disorders, indicating a possible role for treatment targeting the BLyS receptor-ligand system.

Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand?

Mixed cryoglobulinemia (MC) vasculitis represents a complication of the B cell response to a variety of chronic inflammatory diseases. Recent reports describe the use of monoclonal antibodies directed to CD20 antigen (rituximab), a transmembrane protein expressed on pre-B lymphocytes and mature lymphocytes. The goal of this article is therefore to review published data in order to better analyse the efficacy and tolerance of rituximab treatment in patients with MC vasculitis. After systematic review of the literature and exclusion of review papers, 13 manuscripts were identified that reported on a total number of 57 cases of MC secondary to hepatitis C virus (HCV) infection (75.4%) or essential mixed cryoglobulinemia (24.6%). Previous treatments failed to control the main signs of vasculitis; these were either HCV (n = 37) or immunomodulating treatments. Most patients (48 out of 57) received four weekly consecutive intravenous infusions of 375 mg/m(2) of rituximab. The duration of follow-up after rituximab therapy was 9.7 months. Rituximab infusions had great efficacy on the main vasculitis signs, with a clinical response in 80-93% patients. A relapse of MC was noted in 14 out of 36 (39%) patients. A relatively small number of side effects were reported. We conclude that rituximab therapy for patients with mixed cryoglobulinemia vasculitis, HCV-induced or essential, shows great efficacy on the main vasculitis signs in the majority of reported patients. A relapse of cryoglobulinemia vasculitis was frequently noted. Randomised controlled trials with long-term study are needed to form definitive conclusions on the benefit/risk ratio of rituximab therapy in such patients.

Hepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferation.

Hepatitis C virus (HCV) infection is the second most cocmmon chronic viral infection in the world with a global prevalence of about 2%. Chronic HCV infection is commonly associated with a number of extrahepatic complications. Circulating mixed cryoglobulins (MCs) are detected in 40-60% of HCV-infected patients whereas overt cryoglobulinaemia vasculitis develops in only 5-10% of the cases. MC reflects the expansion of B cells producing a pathogenic IgM with rheumatoid factor (RF) activity. Because cryoglobulin-producing B cells in HCV are mostly monoclonal, HCV-associated MC can be viewed as a benign B cell lymphoproliferative condition. The disease expression of MC vasculitis is variable, ranging from mild clinical symptoms (purpura, arthralgia) to fulminant life-threatening complications (glomerulonephritis, widespread vasculitis). The overall risk of non-Hodgkin's lymphoma in patients with HCV-MC is estimated to be 35 times higher than that in the general population. This review will focus on recent advances in our understanding of the clinical course, complications, pathophysiology and treatment of those immune-mediated disorders.