Can adding alemtuzumab to fludarabine improve survival for people with previously treated advanced chronic lymphocytic leukemia?

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Patients with Rai Stage III/IV chronic lymphocytic leukemia (CLL) have shorter median survival than those with Rai Stage I/II disease. The researchers had previously reported significantly improved progression-free survival (PFS) with fludarabine plus alemtuzumab (FluCam) compared with fludarabine alone (Flu) in previously treated CLL, citing Engert ASH 2009 and EHA 2010. This report examined efficacy and safety in the advanced-stage subset of those patients.

This was a Phase 3, multicenter, controlled trial in which patients with relapsed/refractory CLL were randomized to intravenous Flu, 25 mg/m² on days 1–5 every 28 days, or intravenous alemtuzumab (Cam) plus intravenous Flu (FluCam). Before cycle 1, FluCam patients underwent Cam dose escalation through 3 mg, 10 mg and 30 mg; once 30 mg was tolerated, they received Flu 30 mg/m² IV and Cam 30 mg IV on days 1–3 every 28 days. Either treatment could be given for up to 6 cycles, depending on response and toxicity. Randomization used the minimization method to balance study center, disease status, prior therapy, Rai stage, age, gender and lymph node size between arms. All patients received prophylactic cotrimoxazole and famciclovir until their CD4+ counts were >200 cells/mcL.

The primary endpoint was PFS with FluCam compared with Flu. A pre-specified Rai Stage III/IV subgroup analysis compared PFS, overall response rate (ORR, complete plus partial responses), complete response rate (CR), overall survival (OS) and safety. PFS differences between arms were tested using the log-rank test.

Of 335 enrolled patients, 123 (37%) had Rai Stage III/IV disease: 61 received FluCam and 62 received Flu. In the overall study population, FluCam significantly prolonged PFS: 24.1 versus 15.4 months with Flu (p = 0.002; hazard ratio [HR] 0.618; 95% confidence interval [CI] 0.46–0.83). The remaining results focus on the Rai Stage III/IV subgroup. In this subgroup, FluCam versus Flu patients had median ages of 65 years (range 36–80) versus 64 years (46–80), were 70% versus 61% male, and had prior Flu exposure in 10% versus 8%. The median number of treatment cycles was 6 with FluCam and 5 with Flu.

In the advanced-stage subgroup, FluCam significantly prolonged PFS compared with Flu: 24.5 versus 11.8 months (p < 0.001; HR 0.46; 95% CI 0.29–0.73). ORR was 77% versus 56% (p = 0.016), and CR was 16% versus 3% (p = 0.014), both significantly favoring FluCam. At a median follow-up of 21 months, median OS had not been reached with FluCam versus 23.5 months with Flu (p = 0.005; HR 0.44; 95% CI 0.24–0.79), representing a reported 56% reduction in the risk of death.

Treatment-related adverse events occurred in 97% of the FluCam arm (n = 59) and 88% of the Flu arm (n = 60) in the Rai Stage III/IV subgroup. The researchers reported no clinically relevant differences in the adverse-event profile between arms. Infusion-related events and leukopenia were among the adverse events occurring in ≥10% of patients and more frequently with FluCam than with Flu. All-cause grade 3/4 hematologic adverse events with FluCam versus Flu were neutropenia, 47% versus 48%; leukopenia, 29% versus 8%; thrombocytopenia, 15% versus 20%; and anemia, 7% versus 23%. Treatment-emergent infections occurred in 42% with FluCam versus 52% with Flu. No cytomegalovirus (CMV) infections were reported in either arm of this subgroup.

All-cause serious adverse events occurred in 37% with FluCam and 45% with Flu. The most commonly reported all-cause serious adverse events occurring in ≥5% of either arm were fever, 5% versus 2%; neutropenia, 3% versus 5%; febrile neutropenia, 2% versus 8%; and anemia, 0% versus 8%, respectively. Deaths during treatment or within 30 days after the last dose occurred in 3% with FluCam versus 8% with Flu.

The researchers concluded that this Rai Stage III/IV subgroup analysis demonstrated an overall survival advantage, longer PFS and improved ORR and CR with FluCam compared with Flu. They described FluCam’s safety profile in advanced-stage disease as acceptable and, in most respects, comparable to Flu alone. They considered FluCam a compelling treatment option for previously treated advanced CLL.

Disclosures: Engert reported Genzyme honoraria, board or advisory committee membership, and research funding. The off-label-use disclosure stated that alemtuzumab (Campath, MabCampath) is indicated for CLL. This trial examined alemtuzumab in combination with fludarabine monophosphate. Gercheva reported Genzyme honoraria, board or advisory committee membership, and research funding. Pilipenko reported Genzyme honoraria, board or advisory committee membership, and research funding. Robak reported Genzyme honoraria, board or advisory committee membership, and research funding. Wu reported Genzyme employment and equity ownership. Sirard reported Genzyme employment and equity ownership. Elter reported Genzyme honoraria, board or advisory committee membership, and research funding.