Management of Cytomegalovirus (CMV) Reactivation in B-CLL Patients Receiving Sequential Treatment with Fludarabine (FAMP) Including Regimens and Alemtuzumab.

Background: Monoclonal antibodies directed towards specific cell surface antigens on neoplastic cells have been increasingly used in lymphoid malignancies in the last few years. Alemtuzumab is a humanized monoclonal antibody which binds the CD52 antigen highly expressed on B-CLL cells. Alemtuzumab significantly depletes both B and T lymphocytes increasing the risk of opportunistic infections. Cytomegalovirus (CMV) infection causes significant morbidity and mortality in the setting of immunodeficiency. CMV reactivation has been described in most of the reported series in which alemtuzumab has been administered.

Aim: We investigated the incidence and management of CMV reactivation in a population of B-CLL patients treated with FAMP including regimens, followed by Alemtuzumab as consolidation.

Methods: 35 B-CLL patients, 22 males and 13 females, median age 55 (range 39–64), responding to FAMP including regimens (32 FAMP alone, 3 FAMP+cyclophosphamide) received subcutaneous Campath-1H three times a week for six weeks in escalating doses up to 10 mg in order to treat residual disease. Monitoring of CMV reactivation by CMV pp65 antigenemia test was weekly performed, starting from the first week of alemtuzumab treatment until 4 weeks after discontinuation.

Results: CMV pp65 antigenemia positive test was detected in 20 patients (57%). The median time for reactivation was 43 days (range 23–61) from the beginning of therapy. Among those twenty pts, 11 showed less than 10 positive cells. All the 9 pts (25.7%) showing positive test with more than 10 cells [median positive cells 44.5 (range 12–751) ] received pre-emptive treatment with oral Gancyclovir 1g thrice daily (oGCV). Only three of this group of 9 pts presented mild symptoms (fever and/or epigastric pain). Among the 11 pts presenting with positive antigenemia in less than 10 cells, seven received oGCV as pre-emptive therapy while the remaining four were not treated. Only one of the seven pts given pre-emptive therapy was symptomatic, presenting fever. The four pts not receiving treatment with oGCV showed a negativity at the subsequent test within a week from the first positive detection. Negativity of antigenemia test was obtained in all the pts receiving pre-emptive oGCV treatment. After short-time of discontinuation, alemtuzumab was restarted in all 20 cases tested positive for pp65 antigenemia. Organ involvement was never seen.

Conclusion: Our survey shows that pp65 antigenemia is a sensitive test for monitoring CMV reactivation in pts treated with alemtuzumab. We suggest that the combination of FAMP and alemtuzumab is permissive to a higher risk of CMV reactivation in B-CLL pts. Pre-emptive treatment with oGCV is able to prevent the severe manifestations of CMV such as pneumonia and colitis and to permit the completion of the therapeutic program. To improve the cost-effectiveness of this strategy we propose: antigenemia monitoring not before the 4^th week of treatment; closely repeating the test in case of positivity less than 10 cells; treating only in case of increase of the number of positive cells.