We read with interest the article by Cortelezzi et al.1 published in a recent issue of this journal. They report their experience with low-dose subcutaneous alemtuzumab (10 mg three times per week for 18 weeks) in 49 patients with pretreated B-cell chronic lymphocytic leukemia (B-CLL). The rationale for the use of subcutaneous low-dose alemtuzumab was to reduce the profound lymphopenia and high risk of infections when using the conventional intravenous schedule (30 mg three times a week for 12 weeks), which are serious problems particularly in older chronic lymphocytic leukemia patients and those already severely immunocompromised by advanced disease and earlier therapies. The authors show interesting data regarding the efficacy of low-dose alemtuzumab in terms of response rate, progression-free survival, time to retreatment, and a favorable toxicity profile in a group of poor prognosis patients.
We now report our clinical experience with low-dose alemtuzumab in 19 heavily pretreated chronic lymphocytic leukemia patients. Twelve of these patients, who have been previously reported, received intravenous low-dose alemtuzumab (10 mg three times a week) in ten weeks.2 Seven additional patients were subsequently treated with the same schedule, except that alemtuzumab was administered subcutaneously to reduce infusion related toxicity.3, 4
All patients had progressive disease according to NCI-WG criteria at the time when treatment with low-dose alemtuzumab was started. Eighteen patients had previously received alkylating agents-based therapy, 15 fludarabine-containing regimen, 4 rituximab-containing regimen and 2 autologous PBSCT (median number of previous treatments 2, range 1–6). Eight patients were fludarabine refractory. Median age of the patients was 62 years (range 50–78 years), 13 were male and 6 female.
Sixteen patients completed the planned treatment. Two patients discontinued the treatment prematurely for documented progressive disease and 1 because of the development of a second malignancy. Assessment of response, according to NCI-WG criteria and including a BM biopsy in all responding patients, was performed 2 months after the end of the treatment. Overall survival, time to progression and time to retreatment were calculated from the start of alemtuzumab treatment to the event.
Three patients (16%) obtained a complete response (CR) and 6 (31%) obtained a partial response (PR), with an overall response rate of 47% (Table 1). Two of the remaining patients experienced progressive disease shortly after the end of the treatment, whereas 5 patients had stable disease. Of the 5 patients with 17p-karyotype, 1 obtained a complete response and another a partial response, whereas only 1 of the 8 fludarabine-refractory patients achieved a partial response. The response rate according to other clinical and biological features is reported in Table 1.
Except for grade IV neutropenia requiring G-CSF in 4 patients and grade IV anemia requiring red blood cell transfusions in 2 patients, therapy was well tolerated both by patients who received subcutaneous and patients who received intravenous alemtuzumab. Other hematological and extra-haematological side effects were relatively mild and consisted of fever, itching, rigor, headache and hypotension. No episode of febrile neutropenia or bacterial/fungal infection occurred during treatment. Nine patients (47%) showed cytomegalovirus (CMV) reactivation after a median of 6 weeks of treatment, when the median lymphocyte counts were 140/mmc. Treatment was temporarily interrupted and patients were successfully treated with oral ganciclovir for a median of 14 days.
After a median follow-up of 33 months, 10 patients (52%) died with a median overall survival of 29 months. Only 2 of these patients responded to the treatment. The other 7 responding patients experienced progression of the disease. The median progression-free survival was 11 months (range 5–45 months). Thirteen patients, 5 responders and 8 nonresponders, received further treatment. The median treatment-free survival was 20 months (range 6–70 months).
Our results are similar to the results of Cortelezzi et al. in terms of Overall Response Rate (ORR) (47 vs 53%), median overall survival (29 vs 30 months) and fatal events (52 vs 55%, with median follow-up of 33 and 25 months, respectively). Regarding safety and tolerability, in both studies alemtuzumab therapy was well tolerated and most of the adverse events were transient, although we observed more cases of grade III–IV anemia (21 vs 3.3%), grade III–IV neutropenia (52 vs 36%), low grade fever (36 vs 14%) and CMV reactivation (47 vs 25%). A possible explanation for the last discrepancy could be the different threshold values and application of the CMV–DNA assay to define CMV reactivation.5 However, it is important to note that in both series none of the patients developed clinically relevant CMV disease.
In conclusion, we confirm the data of Cortelezzi et al. regarding the efficacy and tolerability of low-dose alemtuzumab, although some noteworthy differences emerged between the two studies. Their data showed an increased complete response rate (27 vs 16%) and a longer median time to alternative treatment (9 vs 7 months), but also a higher rate of infectious complications during and after treatment (0.6 vs 0.0 episodes per patient) and a smaller proportion of patients who completed the planned treatment (38/49 vs 16/19). These differences are probably because of the higher cumulative dose of alemtuzumab in their study (480 vs 300 mg), which translated into somewhat greater efficacy but also a greater incidence of infectious complications, among which one third were severe or life threatening. Thus, we agree with Cortelezzi et al. that low-dose alemtuzumab is an effective therapeutic option in refractory chronic lymphocytic leukemia, especially in the setting of elderly and poor prognosis patients, but believe that additional studies are required to define the optimal duration of treatment.
Cortelezzi A, Pasquini MC, Gardellini A, Gianelli U, Bossi A, Reda G et al. Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study. Leukemia 2009; 23: 2027–2033.
Laurenti L, Piccioni P, Tarnani M, Efremov DG, Fiorini A, Garzia M et al. Low-dose intravenous alemtuzumab therapy in pretreated patients affected by chronic lymphocytic leukemia. A single center experience. Haematologica 2005; 90: 1143–1145.
Christian BA, Lin TS . Antibody therapy for chronic lymphocytic leukemia. Semin Hematol 2008; 45: 95–103.
Stilgenbauer S, Zenz T, Winkler D, Bühler A, Schlenk RF, Groner S et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2 H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2009; 27: 3994–4001.
Laurenti L, Piccioni P, Cattani P, Cingolani A, Efremov D, Chiusolo P et al. Cytomegalovirus reactivation during alemtuzumab therapy for chronic lymphocytic leukemia: incidence and treatment with oral ganciclovir. Haematologica 2004; 89: 1248–1252.
The authors declare no conflict of interest.