Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia

Abstract

The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873.

Figure 1

PFS and OS for elderly patients on lenalidomide frontline therapy. (A) PFS and OS for all patients on frontline lenalidomide therapy. At 24 months of follow-up, the median PFS was 60% and OS was 88%. (B) PFS for all patients according to achievement of PR or better compared with patients who did not achieve an objective response. (C) OS according to achievement of PR or better compared with no response.

Figure 2

Correlative studies of peripheral blood lymphocyte populations and serum Ig levels. *P < .001, compared with pretreatment values. (A) Serum IgG measurements as a percentage change from baseline. There is a significant increase in serum IgG from 3-9 cycles of therapy. Lines represent median percentage change in serum IgG; boxes, interquartile range; and outer spread lines, 10th to 90th percentiles. (B) Serum IgM measurements as a percentage change from baseline. There is a significant increase in serum IgM from by 3 cycles and from 3-9 cycles of therapy. Lines represent median percentage change in serum IgM; boxes, interquartile range; and outer spread lines, 10th to 90th percentiles. (C) Peripheral blood total lymphocyte and CD3⁺ T-lymphocyte counts for patients who completed at least 15 cycles of therapy (n = 38), including 31 patients who have completed 21 cycles. Range bars represent the interquartile range.

Figure 3

CCL3 and CCL4 serum levels before and during therapy with lenalidomide. CCL3 and CCL4 plasma levels were measured by enzyme-linked immunosorbent assay in peripheral blood samples of patients before therapy and after 3, 9, and 15 cycles of lenalidomide. (A) CCL3 levels (pg/mL) measured before therapy according to NCI response: NR, CR, and PR (mean ± SEM, 102.8 ± 42.6, 53.9 ± 10.5, and 75.6 ± 19.5, respectively) and (B) CCL4 levels (pg/mL) according to response: NR, CR, and PR (mean ± SEM, 411.5 ± 172.9, 261.4 ± 71.1, and 302.0 ± 94, respectively). There was no significant difference in CCL3 or CCL4 levels before therapy between response groups. CCL3 and CCL4 levels were also measured during therapy. (C) Although there was an increase in CCL3 levels by 3 cycles of therapy regardless of response, by 9 cycles of therapy significantly higher levels of CCL3 were noted in nonresponders compared with responders (P < .05). There were insufficient data to assess the difference between responders and nonresponders after 15 cycles of therapy. (D) Similarly, CCL4 levels increased both in responders and nonresponders after 3 cycles of therapy, but there were significantly higher CCL4 levels occurring in responders to therapy after 9 cycles of therapy with lenalidomide (P < .05). Insufficient data were available after 15 cycles of therapy for comparison. NR indicates no response (stable or progressive disease); PR, partial response; CR, complete response; and R, responders (PR or CR).