First-line Lenalidomide for Elderly CLL Patients
ABSTRACT & COMMENTARY
By William B.Ershler, MD
Synopsis:In a single institutional study (M.D. Anderson), 60 older patients with chronic lymphocytic leukemia were treated with lenalidomide. Thirty-five of the 60 patients had a response lasting > 36 months, and compared with those who did not have such a durable response, those who did had lower pretreatment ß-2 microglobulin levels and were more likely to have favorable cytogenetics. Lenalidomide treatment was associated with improvement in circulating immunoglobulin levels and T-lymphocyte numbers.
Source: Strati P, et al. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 2013;122:734-737.
Recent data from NCI SEER indicate the median age at diagnosis for chronic lymphocytic leukemia (CLL) is 71 years.1 Whereas a wide range of therapeutic approaches have been generally recommended for newly diagnosed patients ranging from observation alone, to single or combination chemotherapy, to allogeneic stem cell transplantation under various circumstances, optimal initial therapy for older CLL patients has yet to be established.2 Agents such as chlorambucil, fludarabine, and bendamustine have been explored with reasonably good response rates and tolerability. Recently, lenolidomide has proven effective for patients with both relapsed/refractory disease3,4 and in the first-line setting.5
To examine the safety and efficacy of single-agent lenolidomide in elderly patients with CLL, Strati and colleagues from the M.D. Anderson Cancer Center performed a Phase 2 trial in which they enrolled 60 treatment-naïve elderly CLL patients (median age 71 years, range 66-85 years). Treatment consisted of lenolidomide (5 mg, orally) administered continuously. After 2 months, treatment doses were escalated by 5 mg to a maximum dose of 25 mg/day. Patients remained on treatment until there was evidence for disease progression.
At a median follow-up of 4 years, time-to-treatment failure had not been reached and overall survival was 82%. Thirty-five (58%) patients had a response lasting > 36 months (long-term responders [LTRs]) and the clinical features and results for these patients were compared to those who did not meet criteria for LTR (short-term responders [STRs]). Among the LTRs, the best responses consisted of 25 (71%) complete remissions and 10 (29%) partial remissions. In addition to clinical responses, an increase in IgA, IgG, and IgM levels of > 50% from baseline was reported in 61%, 45%, and 42% of LTRs. Normalization in the percentage of CD4 and CD8 T cells and overall T-cell numbers were observed in 48%, 71%, and 99% of LTRs. Compared with STRs, LTRs had lower baseline plasma levels of ß-2-microglobulin, were more likely to have trisomy 12, and less likely to have deletion 17p. The median daily dose of lenalidomide was 5 mg (range, 2.5-10 mg).
COMMENTARY
In an earlier study out of Toronto, Chen and colleagues5 used lenalidomide as initital treatment for patients with CLL. The plan was to use lenalidomide at 10 mg/d for 21 days of a 28-day cycle with weekly 5 mg dose escalations to a target of 25 mg. However, they encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg. Twenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common.
In the current M.D. Anderson trial, 40% of those considered LTRs needed a dose reduction within 18 months of treatment, and this was most commonly due to hematologic toxicity. Of the 35 LTRs, 10 discontinued lenalidomide for a variety of reasons including neurotoxicity (n = 2), deep vein thrombosis (n = 1), infection (n = 1), weight loss (n = 1), thrombocytopenia (n = 1), and the development of squamous cell skin cancer (n = 1). Only one patient discontinued because of evidence for disease progression, and that was after 43 months of treatment.
Thus, lenalidomide was shown to be effective in the initial management of elderly patients with CLL. A number of questions remain to be addressed regarding the optimal use of this drug, including when to start treatment and at what dose. For patients with more favorable presentations (e.g., asymptomatic, favorable biochemical markers and cytogenetics, etc.), delaying treatment until clear progression is evident remains a reasonable approach, and initial treatment at 2.5 mg/day may also prove to be effective and with less toxicity. These, of course, are questions to be most satisfactorily addressed by clinical trial.
References
1.Howlader N, et al. SEER Cancer Statistics Review, 1975-2010, National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/csr/1975_2010/, based on November 2012 SEER data submission, posted to the SEER web site, 2013.
2.Lamanna N. Treatment of older patients with chronic lymphocytic leukemia. Curr Hematol Malig Rep 2012;7:21-25.
3.Chanan-Khan A, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: Results of a phase II study. J Clin Oncol 2006;24:5343-5349.
4.Wendtner CM, et al. Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia. Leuk Lymphoma 2012;53:417-423.
5.Chen CI, et al. Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol 2011;29:1175-1181.
