Alemtuzumab has shown significant activity in chronic lymphocytic leukemia (CLL). However its use has been associated to profound immune suppression leading to high rates of severe infechaematologica tions. We have previously reported that alemtuzumab given at lower doses may be equally effective and less toxic in refractory CLL. Aim. We conducted a multicenter retrospective study on the routine clinical use of low-dose alemtuzumab in relapsed/refractory CLL. Methods. One hundred and eight patients from 11 Italian centers were included in the analysis. Low-dose alemtuzumab was defined as a total weekly dose <45 mg and a cumulative dose <600 mg up to eighteen weeks of therapy; both subcutaneous (SC) and intravenous (IV) administrations were allowed. The other inclusion criterion was that patients had to be treated with at least one previous line not containing alemtuzumab as single agent or in combination. Biological prognostic factors including CD38 and ZAP70 expression, as well as FISH analysis were available for 97 patients; the IGHV mutational status was known for 49 patients. Results. Median age was 68 years (range 40-84). No patients had an ECOG PS >2. Fifty patients (46%) were in Binet stage C, the median WBC count was 54.900/mmc (2.100-288.000), while bulky lymph nodes (>5 cm) were present in 17 patients. Forty-three patients (44%) showed an unfavorable cytogenetic profile, including 27 patients with del(17p) and 18 patients carrying del(11q); CD38 and ZAP70 were expressed by 47 and 48 patients, respectively; 33 of the 49 patients studied (67%) were characterized by an unmutated IGHV configuration. The median number of previous lines of therapy was 2 (1-6); 75% of patients were previously exposed to chlorambucil (60% being refractory) and 60% to fludarabine (74% being refractory). Different treatment schedules of alemtuzumab were employed; most patients (92%) received a weekly dose of 30 mg either divided into three 10 mg administrations (51%) or given as a single dose (41%). In 14 cases, alemtuzumab was given IV. The overall response rate (ORR) was 56%, including 22% of CRs. After a median follow-up of 42.2 months (2.1- 91.9), the median OS and PFS were 39 months (95% CI 29.8-58.4) and 19.4 months (95% CI 15.9-23.6), respectively. In univariate analysis, response was inversely associated to lymph node (p=.01) and spleen (p=.02) size, fludarabine-refractoriness (p=.01), previous treatment lines (p=.01), presence of del(11q) (p=.009). Presence of del(17p) was not associated to a worse outcome. Response occurred regardless of the cumulative dose of alemtuzumab administered, both in the whole cohort and in the biologically-determined high risk subsets of patients. Hematologic toxicities were frequent but manageable: grade 3-4 neutropenia, thrombocytopenia and anemia were reported in 29%, 6% and 6% of patients, respectively. Severe (grade 3-4) infections occurred in 7 patients (7%) during therapy. CMV reactivation was documented in 37 patients (34%), with only one case of CMV infection. Conclusions. This retrospective analysis shows that alemtuzumab given at lower doses is a valid and currently used therapeutic option for the treatment of relapsed/refractory CLL, in particular in elderly and frail patients.

A RETROSPECTIVE MULTICENTER TRIAL WITH LOW-DOSE ALEMTUZUMAB IN RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS. ON BEHALF OF THE GIMEMA CHRONIC LYMPHOPROLIFERATIVE DISORDERS WORKING PARTY

CUNEO, Antonio;
2011

Abstract

Alemtuzumab has shown significant activity in chronic lymphocytic leukemia (CLL). However its use has been associated to profound immune suppression leading to high rates of severe infechaematologica tions. We have previously reported that alemtuzumab given at lower doses may be equally effective and less toxic in refractory CLL. Aim. We conducted a multicenter retrospective study on the routine clinical use of low-dose alemtuzumab in relapsed/refractory CLL. Methods. One hundred and eight patients from 11 Italian centers were included in the analysis. Low-dose alemtuzumab was defined as a total weekly dose <45 mg and a cumulative dose <600 mg up to eighteen weeks of therapy; both subcutaneous (SC) and intravenous (IV) administrations were allowed. The other inclusion criterion was that patients had to be treated with at least one previous line not containing alemtuzumab as single agent or in combination. Biological prognostic factors including CD38 and ZAP70 expression, as well as FISH analysis were available for 97 patients; the IGHV mutational status was known for 49 patients. Results. Median age was 68 years (range 40-84). No patients had an ECOG PS >2. Fifty patients (46%) were in Binet stage C, the median WBC count was 54.900/mmc (2.100-288.000), while bulky lymph nodes (>5 cm) were present in 17 patients. Forty-three patients (44%) showed an unfavorable cytogenetic profile, including 27 patients with del(17p) and 18 patients carrying del(11q); CD38 and ZAP70 were expressed by 47 and 48 patients, respectively; 33 of the 49 patients studied (67%) were characterized by an unmutated IGHV configuration. The median number of previous lines of therapy was 2 (1-6); 75% of patients were previously exposed to chlorambucil (60% being refractory) and 60% to fludarabine (74% being refractory). Different treatment schedules of alemtuzumab were employed; most patients (92%) received a weekly dose of 30 mg either divided into three 10 mg administrations (51%) or given as a single dose (41%). In 14 cases, alemtuzumab was given IV. The overall response rate (ORR) was 56%, including 22% of CRs. After a median follow-up of 42.2 months (2.1- 91.9), the median OS and PFS were 39 months (95% CI 29.8-58.4) and 19.4 months (95% CI 15.9-23.6), respectively. In univariate analysis, response was inversely associated to lymph node (p=.01) and spleen (p=.02) size, fludarabine-refractoriness (p=.01), previous treatment lines (p=.01), presence of del(11q) (p=.009). Presence of del(17p) was not associated to a worse outcome. Response occurred regardless of the cumulative dose of alemtuzumab administered, both in the whole cohort and in the biologically-determined high risk subsets of patients. Hematologic toxicities were frequent but manageable: grade 3-4 neutropenia, thrombocytopenia and anemia were reported in 29%, 6% and 6% of patients, respectively. Severe (grade 3-4) infections occurred in 7 patients (7%) during therapy. CMV reactivation was documented in 37 patients (34%), with only one case of CMV infection. Conclusions. This retrospective analysis shows that alemtuzumab given at lower doses is a valid and currently used therapeutic option for the treatment of relapsed/refractory CLL, in particular in elderly and frail patients.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1506925
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