Cladribine and fludarabine equally helpful for progressive CLL

NEW YORK (Reuters Health) - As first-line treatment for progressive chronic lymphocytic leukemia (CLL), cladribine and fludarabine are equally effective and safe in combination with cyclophosphamide, according to phase III trial results.

Purine nucleoside analogs such as cladribine and fludarabine are among the most active drugs against CLL, hematologists in Poland note in the March 8 online issue of the Journal of Clinical Oncology. They had theorized that functional differences between the two agents would result in different treatment outcomes for CLL.

Indeed, they note, a 2007 interim report on a phase III trial comparing the two agents as monotherapy had found significantly higher complete response rates and longer progression-free survival in the cladribine arm.

In the current randomized multicenter trial, 192 subjects received cladribine, 0.12 mg/kg plus cyclophosphamide, 250 mg/m2 for 3 days, as first-line therapy. Another 203 received fludarabine, 25 mg/m2 plus the same dose of cyclophosphamide. Patients received up to six 28-day cycles.

According to first author Dr. Tadeusz Robak from the Medical University of Lodz and colleagues, 47% in the cladribine group and 46% in the fludarabine group had complete responses, at a median follow-up of 3.2 years. The cladribine and fludarabine groups, respectively, had overall response rates of 88% and 82%, median progression-free survival of 2.34 years and 2.27 years, and estimated 4-year survival of 62.4% and 60.6%. None of these differences was statistically significant.

The investigators continued to see similar complete response rates when they stratified patients by demographic, clinical or cytogenetic factors.

Dr. Robak and colleagues can't explain the discrepancy between their findings and those of the 2007 report, although they suggest it's possible that "the increase of an antitumor effect after combination with cyclophosphamide is greater for fludarabine" than for cladribine.

On multivariate analyses, diffuse bone marrow infiltration pattern and the presence of 17p13 or 11q22 deletions were independent negative predictors of survival. The authors note that either deletion can cause a defective apoptotic response by way of the p53 pathway, a leading cause of poor prognosis in CLL.

They acknowledge that they lacked complete prognostic information in a significant proportion of patients, however.

"Further development of p53-independent agents and cytogenetic risk-adapted treatment strategy seem essential to improve CLL patients' survival," the researchers write. They also suggest trials in which chemotherapy is boosted by incorporating rituximab or other monoclonal antibodies.

Both agents were generally well tolerated, with no significant differences in acute hematologic and nonhematologic complications, the authors report. The most common grade 3 and 4 complications were infections, cytopenias, and autoimmune hemolytic anemia.

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