A combination of fludarabine and alemtuzumab (FluCam) was shown to improve outcomes for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) in a single-arm pilot study and in a phase II trial. To validate these observations and assess the efficacy and safety of FluCam versus fludarabine monotherapy as second-line therapy for patients with relapsed or refractory CLL, researchers conducted a phase III, multicenter, open-label, randomized trial, the results of which were released at the 51st ASH Annual Meeting.
New Orleans, LA — A combination of fludarabine and alemtuzumab (FluCam) was shown to improve outcomes for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) in a single-arm pilot study and in a phase II trial. To validate these observations and assess the efficacy and safety of FluCam versus fludarabine monotherapy as second-line therapy for patients with relapsed or refractory CLL, researchers conducted a phase III, multicenter, open-label, randomized trial, the results of which were released at the 51st ASH Annual Meeting.
Study Design and Findings
The study randomized 335 patients (median age, 60 y) with CLL (Rai stages I—IV) to FluCam (n = 168) or fludarabine (n = 167) using the minimization method to ensure both treatment arms were balanced in terms of study center, Rai stage, disease status, age, sex, prior fludarabine therapy, and maximum lymph node size. Patients in the FluCam arm received escalating doses of intravenous alemtuzumab until a dose of 30 mg was tolerated, after which they received FluCam as 30 mg/mintravenous fludarabine followed immediately by 30 mg of intravenous alemtuzumab on days 1 to 3 of a 28-day cycle. Patients in the fludarabine-only arm received 25 mg/mofintravenous fludarabine on days 1 to 5 of a 28-day cycle. Patients in both arms could receive up to 6 cycles, depending on response and toxicity, and all patients received prophylaxis with trimethoprim/sulfamethoxazole double strength and famciclovir (Famvir) until CD4+ counts were ≥200 cells/µL.
In the FluCam arm, 60% of patients received all 6 cycles of treatment compared with 64% in the fludarabine monotherapy arm. The
independent response review panel (IRRP) determined that the median progression-free survival (PFS) for patients in the FluCam arm was significantly prolonged compared with that for patients in the fludarabine arm (Table 1), at 29.6 months versus 20.7 months, respectively (P =.005; hazard ratio, 1.63; 95% confidence interval, 1.16—2.28). Median PFS for patients with Rai stage I to II disease was 27.4 months in the FluCam arm (n = 105) versus 21.3 months in the fludarabine arm (n = 103; P =.215), and for stage III to IV disease, PFS was 26.1 months in the FluCam arm (n = 61) versus 12.1 months in the fludarabine arm (n = 62; P = .003). FluCam was also found to result in significantly higher overall response (OR) and complete response (CR) rates compared with fludarabine, with an OR of
84.8% versus 67.9%, respectively (P <.001); and a CR of 30.4% versus 16.4%, respectively (P = .002).
Table 1. Efficacy of Fludarabine
with or without Alemtuzumab
(n = 168)
(n = 167)
Median PFS, mo
Rai stage I-II
Rai stage III-IV
CR indicates complete response; FluCam, fludarabine plus alemtuzumab; OR, overall response; PFS, progression-free survival.
At a median follow up of 17 months, no differences in survival were observed between cohorts, with 37 deaths occurring in the combination arm and 41 in the monotherapy arm. Adverse events (Table 2) observed in >10% of patients included pyrexia, neutropenia, leukopenia, thrombocytopenia, anemia, chills, lymphopenia, rash, infusion-related reactions, nausea, and urticaria in the FluCam arm; and neutropenia, thrombocytopenia, anemia, and leucopenia in the fludarabine-only arm. Both the FluCam arm and the fludarabine monotherapy arm had comparable rates of treatment-emergent grade 3-4 neutropenia (60% vs 66%, respectively), thrombocytopenia (18% vs 22%, respectively), and anemia (13% vs 22%, respectively). Overall, 33% (n = 54) of patients receiving FluCam experienced a serious adverse event compared with 26% (n = 42) taking fludarabine alone. The rate of serious neutropenia was higher in the FluCam arm, at 4.9% compared with 1.8% in the fludarabine group, but the incidence of febrile neutropenia was similar in both groups, occurring in 3.7% and 3.6% of patients, respectively. Infections, including cytomegalovirus (CMV), occurred in 47% of patients receiving combination therapy and 35% of patients on monotherapy. Only patients in the FluCam arm experienced symptomatic CMV infection, observed in 8% of patients, of which 1% were considered serious (none >grade 3).
Table 2. Adverse Effects of Fludarabine
with or without Alemtuzumab
Adverse Effect, %
(n = 168)
(n = 167)
CMV indicates cytomegalovirus; FluCam, fludarabine plus alemtuzumab.
Based on the interim analysis, the investigators concluded that combination of fludarabine and alemtuzumab is superior to fludarabine alone as a second-line therapy for patients with relapsed or refractory CLL, including those with advanced disease. They noted that because FluCam results in a significantly longer PFS, is associated with higher rates of OR and CR, has an acceptable safety profile, and is convenient to administer, it may be an additional second-line treatment option for patients with relapsed or refractory CLL. ASH Abstract 537.
Disclosure: Authors received support and funding from Genzyme Corporation.