Virus Reactivation Profile as Assessed by PCR and Serology Pattern Following First-Line Alemtuzumab (Anti-CD52 Monoclonal Antibody, Campath®) Therapy in Patients with B-CLL.

Abstract

Alemtuzumab (Campath®) has shown promising results in the treatment of B-cell chronic lymphocytic leukemia (B-CLL) as first-line therapy and in fludarabine-refractory disease (Lundin, Blood 2002; Keating, Blood 2002). Alemtuzumab induces depletion of all lymphoid subsets, which may persist for a prolonged period of time (Lundin, Leukemia 2004). As a result, an increased risk of infection has been associated with alemtuzumab therapy, in particular cytomegalovirus (CMV) reactivation causing symptomatic disease in 10%–30% of patients. It is of importance, therefore, to study the incidence of clinical and subclinical reactivation of not only CMV but also other pathogenic viruses, as well as serology patterns, in order to better understand the consequences of the induced immunosuppression and to further evaluate the safety of alemtuzumab therapy in B-CLL patients. In this study, serum samples were analyzed from 18 patients with B-CLL who achieved long-lasting unmaintained remissions following first-line alemtuzumab SC therapy (Lundin, Blood 2002). Quantitative real time PCR was used to detect and measure the presence of CMV, Ebstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), and parvovirus B19. Analyses were conducted at the following timepoints: baseline; Months 1, 2, and 3 of alemtuzumab therapy; end of treatment; 6 and 12 months post-alemtuzumab therapy. The presence of serum immunoglobulin G (IgG) antibodies against CMV, varicella-zoster (VZV), Morbillivirus, Epstein-Barr Nuclear Antigen-1 (EBNA1) protein of EBV, and Streptococcus pneumoniae were detected by Enzyme-Linked Immunosorbent Assay (ELISA), and EBV viral capsid antigen (VCA) IgG by immunofluorescence (IF). All 18 patients with B-CLL responded (PR or CR) to alemtuzumab therapy. Median time to treatment failure was 34 months (range, 9–71+). There were 9 episodes of viral reactivation (5 CMV after 1–2 months of therapy; 3 EBV at baseline; 1 HHV-6 after 1 month of therapy) measured by PCR in 8 patients (44%) during the study period. The median number of genome equivalents/mL was 2,600 (range, 1,300–81,400). A retrospective analysis of the case records revealed that 3/5 episodes of CMV reactivation correlated to discrete clinical symptoms (transient, grade I fever or temporary cough), which were not diagnosed as viremia during the clinical part of the study. All 9 episodes of viral reactivation resolved spontaneously, except for 1 patient (in stable unmaintained PR) who had a late recurrence of symptomatic EBV infection 20 months after completion of alemtuzumab therapy. The viral load and symptoms responded to rituximab (anti-CD20 monoclonal antibody, Rituxan®) therapy, but repeated treatment episodes have been required. Most patients had stable IgG reactivities during and after alemtuzumab therapy; however, 6 patients (35%) had a significant decrease in antibody titers: 4 against Morbillivirus and 2 against EBV. These results suggest that virus reactivation is not uncommon in patients receiving alemtuzumab therapy for B-CLL. Notably, most reactivations occurred early during therapy, were asymptomatic or caused discrete symptoms, and usually resolved spontaneously without specific therapy. Additional studies on virus reactivation and long-term studies of virus serology to evaluate the need for vaccination are warranted also in patients with fludarabine-refractory B-CLL receiving alemtuzumab.