Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study

Abstract

This study investigated the efficacy, safety, and clinical benefit of alemtuzumab (Campath-1H) for patients with relapsed or refractory B-cell chronic lymphocytic leukemia exposed to alkylating agents and having failed fludarabine therapy. Ninety-three patients received alemtuzumab in 21 centers worldwide, with the aim to obtain an overall response rate of at least 20%. Dosage was increased gradually (target 30 mg, 3 times weekly, for a maximum of 12 weeks). Infection prophylaxis was mandatory, beginning on day 8, and continuing for a minimum of 2 months after treatment. Responses were assessed at weeks 4, 8, and 12, and patients were followed for 34 months. Overall objective response in the intent-to-treat population (n ‫؍‬ 93) was 33% (CR 2%, PR 31%). Median time to response was 1.5 months (range, 0.4-3.7 months). Median time to progression was 4.7 months overall, 9.5 months for responders. At data cut-off, 27 patients (29%) were alive; overall median survival was 16 months (95% CI: 11.8-21.9) and 32 months for responders. Nineteen responders survived more than 21 months. Clinical benefit was observed both in responders and in patients with stable disease. The most common adverse events were related to infusion, generally grade 1 or 2 in severity, occurring mainly in the first week. Grade 3 or 4 infections were reported in 25 patients (26.9%). However, only 3 (9.7%) of 31 patients who responded to alemtuzumab treatment developed grade 3 or 4 infections on the study. Alemtuzumab induced significant responses in these patients with clinical benefit in the majority and with acceptable toxicity in a high-risk group. (Blood. 2002; 99:3554-3561)

Management of infections in patients with chronic lymphocytic leukemia treated with alemtuzumab

“…Seven of eight non-responders developed major infections during treatment and within 35 days following treatment completion, and two of them died from infections [49]. Similarly, in the pivotal study of 93 relapsed/refractory CLL patients, 25 patients (27%) experienced grade 3/4 infectious events (27%), which occurred more frequently in non-responders than in responders (36% versus 9.7%) [30]. In a recent study, 91 patients with relapsed/refractory CLL were treated with alemtuzumab until maximum response, which included achievement of minimal residual disease (MRD)-negative remission [38].…”

“…In the pivotal study of alemtuzumab in patients with relapsed/refractory disease, CD19 + /CD5 + B cells and CD3 + /CD4 + and CD3 + /CD8 + T cells were significantly depressed after 4 weeks of treatment [30]; these findings were confirmed by another study that also noted a decrease in CD16 + natural killer (NK) cells [49]. The T-cell population gradually recovered to baseline levels by 36 weeks after therapy initiation [30]. Similar results on the recovery of CD4 + cells in alemtuzumab combination therapy were reported [12].…”

“…Importantly, several studies have shown that infectious events typically occur around the time of T-cell and neutrophil nadirs (Fig. 1) [13,30,38,40,49].…”

“…Alemtuzumab therapy is also known to cause transient neutropenia, anemia, and thrombocytopenia that resolve in most patients by a 2-month follow-up [30]. The effect of alemtuzumab on other blood cells such as macrophages has not been reported.…”

“…Its mechanism of action includes complementdependent cytotoxicity and antibody-dependent cellmediated cytotoxicity, and probably apoptosis [41,50,55,63]. Single-agent alemtuzumab is highly effective as both first-line treatment for CLL and treatment for relapsed/ fludarabine-refractory CLL, and has been approved for both indications [24,30]. Alemtuzumab is also being evaluated intensively in the settings of combination therapy [12], consolidation therapy [14,32,37,43,61], and as part of the conditioning regimen for patients undergoing autologous [37] or allogeneic stem cell transplantation (SCT) [10].…”