Incidence of cytomegalovirus infection and disease in

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Incidence of cytomegalovirus infection and disease in patients with lymphoproliferative disorders treated with alemtuzumab Expert Rev. Hematol. 4(1), 9–16 (2011)

Carlos Vallejo, Eduardo Ríos, Javier de la Serna, Isidro Jarque, Christelle Ferrá, Pedro Sánchez-Godoy, Carlos Solano, Rafael de la Cámara, Ana Isabel Rosell, Rosario Varela, María Dolores García, Eva González-Barca, Javier López, Elena Pérez, Secundino Ferrer, Luis Felipe Casado, Lourdes Vázquez, Lucía Villalón and José A García-Marco† Author for correspondence: Service of Hematology, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain [email protected]

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The aim of this study was to assess the incidence of cytomegalovirus (CMV) infection and disease in patients with hematologic malignancies treated with alemtuzumab. The outcome of CMV infection in hematologic patients treated with alemtuzumab in 19 hospitals throughout Spain was assessed retrospectively. Data were collected from the medical records of patients over a period of 6 months following initiation of alemtuzumab therapy. We studied 102 patients (89 with B-cell chronic lymphocytic leukemia and 13 with other lymphoproliferative diseases, with a median age of 63 years [range 29–81 years]). Alemtuzumab was administered for a mean of 11.2 (standard deviation: 13.8) weeks, with a median total dose of 423 mg (range: 59–1440 mg). Alemtuzumab as a single agent was administered in 92.2% of patients and was associated with chemotherapy in 7.8% of cases. Prophylactic antivirals included famcyclovir (47%), acyclovir (34%), valacyclovir (14%) and valgancyclovir (5%). CMV viremia testing was performed a mean of 6.3 times (range: 1–19). The incidence of CMV infection was 38.9% (46% in patients treated with steroids and 75% in patients receiving ≥1000 mg of alemtuzumab). Treatment of CMV infection included gancyclovir or valgancyclovir in 94% of cases. Viremia became negative after a median of 20 days (95% CI: 13.4–26.6). CMV disease occurred in five patients. The incidence of CMV infection in alemtuzumab-treated patients was 38.9%. The incidence increased in patients treated concomitantly with steroids and in those treated with high doses of alemtuzumab, although only eight patients received 1000 mg or more, systematic monitoring of CMV viremia and early treatment of infection resulted in a favorable outcome of CMV reactivation. Keywords : alemtuzumab • antiviral therapy • chronic lymphocytic leukemia • cytomegalovirus disease • cytomegalovirus infection • lymphoproliferative diseases

Alemtuzumab (MabCampath® ) has been shown to be an effective therapy in lympho­ proliferative disorders and autoimmune cytopenias  [1–4] . Clinical experience with alemtuzumab has grown significantly in recent years especially regarding its efficacy and safety, as well as the identification of patient subgroups likely to benefit from alemtuzumab therapy [5] . These advances have resulted in the wide acceptance and incorporation of alemtuzumab into the treatment armamentarium of B-cell chronic lymphocytic leukemia (B-CLL) [6] , with promising results in front-line therapy [7,8] . Besides the efficacy of this monoclonal antibody in fludarabine-refractory patients  [9–11] , alemtuzumab 10.1586/EHM.10.77

is able to eradicate minimal residual disease in bone marrow [12] and achieve clinical responses in high-risk relapsed patients, including those with del(17)(p13.1) where the TP53 gene resides [13,14] . The ability of alemtuzumab to induce a dramatic depletion of lymphocytes is associated with increased susceptibility to certain opportunistic infections. Cytomegalovirus (CMV) reactivation is now a well-documented complication in patients receiving alemtuzumab [15,16] . CMV reactivation can lead to uncontrolled viral replication and subsequent development of overt disease. The incidence of CMV reactivation is variable, ranging from 4 to 29% when the incidence

© 2011 Expert Reviews Ltd

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Vallejo, Ríos, de la Serna et al.

refers to symptomatic CMV infection [7,11,12,15,17] , and as high as 67% among patients with previously treated B-CLL when CMV reactivation is defined on the basis of positive results for sensitive antigenemia assays or DNA PCR testing [16–18] . The wide range of reported incidences might be the result of several important differences between the studies in terms of design, patient population and viral detection methods. However, knowledge of the CMV reactivation rate is still incomplete and it is necessary to add data from studies carried out in different countries to gain an overall picture of the incidence of this complication in patients receiving alemtuzumab in daily practice conditions. Therefore, the aim of the present study was to estimate the incidence of CMV infection and disease in a retrospective Spanish cohort of patients with lymphoproliferative diseases receiving alemtuzumab-based therapy. Design & methods

A retrospective, observational and multicenter study was conducted between June and August 2007 in which the outcome of patients with hematologic diseases treated with alemtuzumab was investigated. The primary end point of the study was to determine the incidence of CMV infection and disease. Secondary end points were as follows: time of appearance of CMV infection and time to progression to CMV disease after the beginning of alemtuzumab treatment; time of CMV viremia negativization from the onset of antiviral treatment and number of relapses in relation to the individual antiviral agents administered; patient survival from the onset of alemtuzumab to the last visit or up to 180 days after the initiation of alemtuzumab therapy (whichever came first); CMV disease-related mortality; and safety of antivirals against CMV infection. The study was carried out in a routine clinical setting. Patients were attended to in the Services of Hematology and Medical Oncology of 19 acute-care university-affiliated hospitals throughout Spain in daily practice conditions. Data were collected from the patients’ medical records over a 6‑month period after the initiation of alemtuzumab treatment. The study protocol was reviewed and approved by the Ethics Committee of Hospital Universitario Puerta de Hierro (Madrid, Spain). Despite the retro­spective nature of the study, all patients signed an informed consent form at the time of becoming eligible to participate in this study. Patients of 18 years of age or older with lymphoproliferative diseases who had received treatment with alemtuzumab (intravenous or subcutaneous route) during the past 36 months, either as a single agent or in combination with other cytotoxic drugs according to the clinical practice protocols of the center, were enrolled onto the study. Patients who had received less than three doses of alemtuzumab were excluded from the study, as were those with documented active CMV infection or disease upon initiation of treatment with alemtuzumab, HIV infection and recipients of allogeneic hematopoietic stem cell transplantation. Once the investigators had verified that the patients were eligible for inclusion in the study, the medical records were examined in detail for 6 months after the initiation of alemtuzumab treatment and the following data were recorded: age; sex; type 10

and status of hematologic disease necessitating alemtuzumab treatment (Rai  [19] and Binet stage system  [20]); salient features of antineoplastic therapy including alemtuzumab; concomitant treatments including steroids; use of prophylactic antiviral treatment; surveillance of CMV viremia; presence of CMV infection, CMV disease and other opportunistic infections; antiviral treatment for CMV infection and disease; response to treatment; adverse events; and outcome. Testing for CMV viremia included a variety of diagnostic tests, such as pp65 antigenemia assay, qualitative and quantitative PCR and hybridization procedures that detect CMV DNA in blood leukocytes or plasma, viral culture and/or leukocyte shell vial culture assay. Positive results were considered in the presence of an antigenemia level of one or more positive cells per slide (100,000 cells/slide) and/or a viral load of 500 or more CMV DNA copies/ml in the PCR assay. Reactivation was defined as asymptomatic CMV positivity, infection as fever in association with CMV positivity in the absence of other causative conditions for elevated temperature, and disease as fever with organic involvement according to standard clinical criteria [21] . Response to alemtuzumab was assessed according to criteria established by the National Cancer Institute-sponsored Working Group [22] and defined as complete response, partial response, refractory disease, progressive disease and stable disease. A sample of 70 evaluable patients was anticipated, with the participation of approximately 17 investigators and a recruitment target of approximately five patients per physician. Quantitative variables are expressed as mean and standard deviation (SD) or median with the corresponding 95% confidence interval (CI). Categorical variables are expressed as absolute numbers and percentages. The chi-square test or the Fisher exact test were used for the comparison of percentages. Survival curves were obtained by the Kaplan–Meier method. Results

The study population included 102  patients; 79 men and 23 women, with a median age of 63 years (range: 29–81 years). The diagnosis of the hematologic disease was B-CLL in 87% of the patients and other lymphoproliferative syndromes in 13% (T-cell prolymphocytic leukemia in six cases, T-cell nonHodgkin’s lymphoma in three, B-cell non-Hodgkin’s lymphoma in two, lymphoma in two, mycosis fungoides in three, Sezary syndrome in one and hairy cell leukemia in one). Risk categories of the Rai classification system  [19] included stage 0 in 13.8% of patients, stage I in 17.2%, stage II in 27.6%, stage III in 9.2% and stage IV in 32.2%. Patients classified as stage 0 were treated because of the presence of symptomatic disease with associated p53 deletion or because they were refractory to other therapies. Binet disease stages [20] were as follows: 26.4% of patients in stage A, 34.5% in stage B and 39.1% in stage C. Constitutional B symptoms were present in 21 (20.6%) patients. Cytogenetic abnormalities were present in 43 (42.2%) patients, with trisomy 12, complex karyotypes and abnormalities of 13q being the most frequent. In addition, p53 dysfunction was detected in 18 (17.6%) patients. Expert Rev. Hematol. 4(1), (2011)

Incidence of CMV infection & disease in patients with lymphoproliferative disorders

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Alemtuzumab was administered for a mean of 11.2 (SD: 13.8) The characteristics of these five patients with CMV disease are weeks, with a median total dose of 423 mg (range: 59–1440 mg). shown in Table 2 . Eight patients received 1000 mg or more of alemtuzumab. In patients with asymptomatic reactivation, the mean Alemtuzumab as a single agent was given to 92.2% of patients (SD) level of antigenemia was 7.1 (10.8) positive cells and combined with other agents in 7.8% of cases. The most (range: 0.8–42.5) and mean CMV DNA 9557.8 (21,112.5) copfrequently used cytotoxic drugs were fludarabine (alone or ies/ml (range: 0.3–67,799.3). In patients with CMV disease, in various combinations with cyclophosphamide, rituximab, the mean level of antigenemia was 26.4 (34.8) positive cells vincristine, adriamycin or mitoxantrone), pentostatin alone (range: 1.8–51.0) and mean CMV DNA 17,045.8 (29,516.1) and rituximab alone. Concomitant treatment with steroids copies/ml (range: 0.3–51,128). was recorded in 37 (36.3%) patients. Prophylactic antiviral Other opportunistic infections were recorded in 48.9% of the treatment was administered to 95 (93.1%) patients, including patients. A total of 142 adverse events, 111 (84.7%) of which famcyclovir in 45 (47.4%), acyclovir in 32 (33.7%), valacyclo- were in relation to treatment with alemtuzumab, were recorded vir in 13 (13.7%) and valgancyclovir in five patients (5.3%). in 68 patients. Most adverse events were of mild or moderate Details of treatment are shown in Table 1. Response to alemtu- intensity. Severe adverse events occurred in 17 (12.1%) cases. zumab included complete remission in 41.2% of cases, partial The incidence of CMV infection was significantly higher response in 29.5% and nonresponse in 28.9%. In comparison in patients treated concomitantly with steroids as compared with disease status before treatment with alemtuzumab, there with those untreated (46 vs 25%; p