Fludarabine plus alemtuzumab provides another treatment option for CLL
MedWire News: Fludarabine combined with alemtuzumab improves the outcome of patients with previously treated chronic lymphocytic leukemia (CLL) compared with fludarabine alone, results of an international phase III trial show.
The combined regimen also had an acceptable toxicity profile, report Thomas Elter (University of Cologne, Germany) and colleagues in the Lancet Oncology journal.
Despite the increasing number of treatment options, CLL remains an incurable disease, the researchers remark.
Preclinical data and early clinical trials suggested that the addition of alemtuzumab to fludarabine-based regimens could have a synergistic effect due to their complementary modes of action that may improve patient outcome.
Elter and team therefore compared the efficacy and safety of this combination treatment with that of fludarabine monotherapy in a phase III trial among 335 patients with relapsed or refractory CLL.
The patients were all aged 18 years and over with CLL Binet stage A, B, or C, or Rai stages I-IV and had received one previous line of treatment. They were randomly assigned in a 1:1 ratio to combination treatment (fludarabine 30 mg/m2 per day plus alemtuzumab 30 mg per day on days 1-3) or monotherapy (fludarabine 25 mg/m2 on days 1-5) for a maximum of six 28-day cycles.
The researchers report that the primary endpoint of progression-free survival (PFS) was significantly greater in the combination therapy group compared with the monotherapy group, at a median of 23.7 versus 16.5 months. Median overall survival was not reached in the combination therapy group and was 52.9 months in the monotherapy group, a difference that was also statistically significant.
Of note, the significantly improved PFS in patients who received combination treatment compared with monotherapy was consistent in subgroup analyses that looked at older patients and those with advanced disease - groups that are judged to be high-risk.
The majority of patients in both groups (98% for combination therapy, 90% for monotherapy) experienced at least one adverse event (AE).
Patients in the fludarabine plus alemtuzumab group had more cytomegalovirus infections (14% vs 0.6%) and grade 1 or 2 infusion-related adverse reactions (62% vs 13%) than those in the monotherapy group.
Grade 3 or 4 leukopenia and lymphopenia rates were also higher in the combination treatment group compared with the monotherapy group at 74% and 94% versus 34% and 33%, respectively.
Conversely, neutropenia, thrombocytopenia, and anemia were all higher in the monotherapy group than in combined treatment group, at 68%, 17%, and 17% versus 59%, 11%, and 9%, respectively.
The incidence of serious adverse events was higher in the combination treatment group (33% vs 25%) but deaths due to adverse events were similar between the two groups (6% vs 7%).
The researchers point out that "although there was a discrepancy in grade 3 or 4 adverse events between treatment groups, most of these events were anticipated and they were related to the mechanism of action of alemtuzumab (particularly lymphopenia or leukopenia and infusion-associated reactions)."
Despite these differences, the proportion of patients who completed all six treatment cycles was similar, at around 65%, in both groups.
"The fludarabine plus alemtuzumab combination provides clinical benefits with an acceptable safety profile in previously treated patients with CLL when compared with single-agent fludarabine. This combination might become an important additional treatment option for patients with relapsed or refractory CLL," Elter and co-authors concude.
By Laura Dean