A Genetic Risk-Stratified Phase 2 Study of Fludarabine/Antibody Combinations in Symptomatic, Untreated CLL: Results from Cancer and Leukemia Group B (CALGB) 10404 (Alliance)

In this randomized phase 2 study, researchers seek to define the optimal foundational chemoimmunotherapy regimen in patients with non-del(11q) disease and to ascertain the role of lenalidomide (L) in symptomatic, untreated CLL.

Patients with untreated CLL requiring therapy were randomized to the following treatment arms: fludarabine plus rituximab (FR) for 6 cycles (all cycles were 28 days), including only non-del(11q) patients; FR for 6 cycles followed by L at 5 mg on days 1 to 21 of the first cycle, then 10 mg on days 1 to 21 of the next 5 cycles, including only non-del(11q) patients; FR plus cyclophosphamide (FCR) for 6 cycles, including patients with and without del(11q); and FCR for 6 cycles followed by L at 5 mg on days 1 to 21 of the first cycle, then 10 mg on days 1 to 21 of the next 5 cycles, including only del(11q) patients.

Patients with del(11q22.3) in at least 20% of cells were excluded from the primary analysis, so that only those patients without del(11q) were evaluated to determine whether the 2-year progression-free survival (PFS) rate improved.

A total of 342 non-del(11q) patients with CLL were randomized to treatment with FR (n = 123), FR+L (n = 109), or FCR (n = 110). Baseline characteristics were similar across arms. At 2 years, 64% of patients in the FR arm achieved PFS, compared with 71% in the FR+L arm and 74% in the FCR arm. Median PFS was 43 months, 66 months, and 78 months for FR, FR+L, and FCR, respectively, and the difference between FR versus FR+L (P = 0.03) and FR versus FCR (P <0.01) was statistically significant. Median overall survival (OS) has not been reached for any arm. OS at 1, 2, and 3 years was similar across the 3 arms, although there was a plateau in OS, with no events beyond 41 months, in the FR+L arm, as opposed to FR/FCR, in which events continued to occur. The most common adverse events were cytopenias and infections.

The researchers concluded that both FR+L and FCR met the primary end point. Moreover, FR+L extended PFS relative to FR, and a plateau in survival differentiated this arm from the FR/FCR arms. As demonstrated by these results, L appears to increase long-term survival and warrants further studies comparing FR+L with FCR, or studies incorporating L into other novel treatment regimens.

Ruppert AS, et al. ASCO Abstract 7503.

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