Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission – experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG)

Abstract

Patients with CLL responding to initial chemotherapy with fludarabine alone (F) or in combination with cyclophosphamide (FC) were randomized for treatment with alemtuzumab (30 mg i.v. TIW, 12 weeks) or observation. Of 21 evaluable patients, 11 were randomized to alemtuzumab before the study was stopped due to severe infections in seven of 11 patients. These infections (one life-threatening pulmonary aspergillosis IV; four CMV reactivations III requiring i.v. ganciclovir; one pulmonary tuberculosis III; one herpes zoster III) were successfully treated and not associated with cumulative dose of alemtuzumab. In the observation arm, one herpes zoster infection II and one sinusitis I were documented. At 6 months after randomization, two patients in the alemtuzumab arm converted to CR, while three patients in the observation arm progressed. After alemtuzumab treatment, five of six patients achieved a molecular remission in peripheral blood while all patients in the observation arm remained MRD-positive (P ¼ 0.048). At 21.4 months median follow-up, patients receiving alemtuzumab showed a significant longer progression-free survival (no progression vs mean 24.7 months; P ¼ 0.036). In conclusion, a consolidation therapy with alemtuzumab is able to achieve molecular remissions and longer survival in CLL, but a safe treatment regimen needs to be determined.

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

“…The rationale is that reduction in residual disease by alemtuzumab may improve patient response and survival. Indeed, an impressive improvement in progressionfree survival was demonstrated with alemtuzumab consolidation [54,61]. However, elevated infectious complications have also been noted in some studies [32,61].…”

“…Indeed, an impressive improvement in progressionfree survival was demonstrated with alemtuzumab consolidation [54,61]. However, elevated infectious complications have also been noted in some studies [32,61]. For example, the earlier CLL4B trial of the German CLL Study Group had to be stopped due to severe infection in seven of 11 patients [61].…”

“…However, elevated infectious complications have also been noted in some studies [32,61]. For example, the earlier CLL4B trial of the German CLL Study Group had to be stopped due to severe infection in seven of 11 patients [61]. In particular, the CALGB 10101 study reported six infection-related deaths in patients receiving alemtuzumab consolidation after fludarabine/rituximab induction therapy [32].…”

“…In particular, the CALGB 10101 study reported six infection-related deaths in patients receiving alemtuzumab consolidation after fludarabine/rituximab induction therapy [32]. It is not immediately clear why infection-related mortality is higher in this trial than in other consolidation trials [37,43,61]. An open issue concerning alemtuzumab consolidation therapy is whether the alemtuzumab dosage should be adjusted according to the level of residual disease after induction therapy.…”

“…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].…”