Combination Therapy Increases Response Rates in Chronic Lymphocytic Leukemia

July 26, 2007 — In patients with chronic lymphocytic leukemia (CLL), combined therapy with fludarabine and cyclophosphamide substantially improves both response rates and progression-free survival compared with fludarabine alone or chlorambucil alone. These findings, which are published in the July 21 issue of The Lancet, could become the basis for emerging protocols that incorporate monoclonal antibodies, write the authors.
Although CLL is the most common leukemia diagnosed in developed nations and it remains incurable, effective treatments continue to evolve. "The primary point of our study is that the combination fludarabine plus cyclophosphamide should now become the standard treatment in CLL, as opposed to fludarabine or chlorambucil alone," lead author Daniel Catovsky, FRCP, from the Institute of Cancer Research in Sutton, United Kingdom, told Medscape. "The reason is that it has more effective response rates and better progression-free survival."
"Progression-free survival is now considered the best measure of success of a drug in CLL, as it reflects quality and duration of remission," he added. "Overall survival may improve later on, but the problem with overall survival in CLL is that second line treatments change," Dr. Catovsky commented. "The combination of fludarabine plus cyclophosphamide should be the basis of better and newer combination which incorporates monoclonal antibodies."
Trials Adds Considerably to Current Knowledge
"This trial has added considerably to our knowledge of combination therapies in CLL," comment Tait D. Shanafelt, MD, and Neil E. Kay, MD, from Mayo Clinic in Rochester, Minnesota, in an accompanying editorial. The superiority of combination therapy, as demonstrated by this trial, has been previously reported in similar studies by the German CLL Study Group and the North American Intergroup.
Drs. Shanafelt and Kay point out that, aside from the primary outcome, the results are important for several reasons. This was a large trial that examined response rates in relation to both traditional clinical variables and more recently defined molecular risk variables.
"Second, the response analysis provides valuable information about the efficacy and tolerability of the treatment regimens for elderly patients," they write. Third, the researchers assessed the important and often neglected issue of how treatment affects quality of life during long-term follow-up.
"Pilot data suggest the addition of rituximab to fludarabine-based treatment may further improve patients' outcomes, and we eagerly await the results of the ongoing randomized trials that are comparing the fludarabine and cyclophosphamide regimen with the same combination with rituximab," the editorialists write.
In the current phase 3 trial, combination fludarabine and cyclophosphamide therapy was compared with either fludarabine alone or high-dose chlorambucil (70 mg/m² in each cycle) in treatment-naïve patients with CLL. The study involved 777 patients who were randomized into 3 groups: 196 received fludarabine plus chlorambucil, 194 received fludarabine only, and 38 received chlorambucil only. The median follow-up time was 3 years and 5 months, and nearly one third of the cohort was older than 70 years.
At follow-up, there was no significant difference in overall survival among patients in any of the study groups. However, both complete and overall response rates were superior with combined fludarabine and cyclophosphamide therapy as opposed to fludarabine alone (complete response rate, 38% vs 15%, respectively; overall response rate, 94% vs 80%, respectively) or chlorambucil alone (complete response rate, 7%; overall response rate, 72%).
The researchers also observed that patients who received the combination protocol had significantly better progression-free survival (36%) than those who received monotherapy with either fludarabine (10%) or chlorambucil (10%). The median length of progression-free survival for all treatment groups was 1 year and 8 months; for fludarabine or chlorambucil given alone, 1 year and 11 months; and for fludarabine plus cyclophosphamide, 3 years and 7 months.
Patients who received the combination protocol had a higher rate of neutropenia and hospital admissions compared with those who received chlorambucil, but there was less incidence of hemolytic anemia with fludarabine plus cyclophosphamide (5%) than with either fludarabine (11%) or chlorambucil (12%) alone. Global health status scores that measured quality of life were lower in patients assigned to fludarabine plus cyclophosphamide during treatment (at 3 and 6 months), but their scores were higher later. The differences in quality-of-life scores did not differ significantly among the treatment groups.
This study was funded by a core grant from Leukaemia Research UK. Laboratory studies were funded by an educational grant from Schering Health Care (United Kingdom) and Schering AG (Germany). Daniel Catovsky has disclosed receiving consulting and lecture fees from Schering AG, Roche, and Genmab.
Lancet. 2007;370:197-198, 230-239.