Lenalidomide maintenance extends PFS in CLL
Lenalidomide, when used as maintenance therapy, extends progression-free survival (PFS) in patients with previously treated chronic lymphocytic leukaemia (CLL), according to results of the phase III CONTINUUM* trial.
Participants in this multicentre (111 centres in 21 countries) trial were adults (n=314, median age 63 years, 72 percent male) who had previously undergone two lines of therapy for CLL (with purine analogue, bendamustine, anti-CD20 antibody, chlorambucil, or alemtuzumab as first- or second-line treatment) with at least a partial response to second-line therapy and with an ECOG score of 0–2. They were randomized to receive oral doses of lenalidomide (2.5 mg/day, n=160) or placebo (n=154) for 28-day cycles until disease progression or unacceptable toxicity. Patients were followed-up for a median 31.5 months. Treatment dose escalation to 5 mg/day, and from 5 to 10 mg/day was allowed from cycle two and six, respectively, if well-tolerated.
Median time to improved response was 12.2 and 76.3 weeks in the lenalidomide and placebo arms, respectively, while duration of improved response was not estimable in either group.
Patients on lenalidomide had significantly longer PFS compared with those on placebo (median 33.9 vs 9.2 months; hazard ratio [HR], 0.40, 95 percent confidence interval [CI], 0.29–0.55; p<0.0001) as well as PFS2 (time from randomization to second disease progression, death, or initiation of CLL treatment following next-line therapy; median 57.5 vs 32.7 months; HR, 0.46, 95 percent CI, 0.29–0.70; p=0.0003). [Lancet Haematol 2017;doi:10.1016/S2352-3026(17)30168-0]
“PFS2 is useful to rule out any potentially adverse effect of first-line therapy on the efficacy of subsequent therapeutic regimens. In this study, lenalidomide significantly prolonged PFS2 compared with placebo, suggesting that lenalidomide maintenance had no negative effects on the efficacy of subsequent treatments,” said the researchers.
The primary endpoint, overall survival, was comparable between patients on lenalidomide and placebo (median 70.4 months vs not estimable; HR, 0.96, 95 percent CI, 0.63–1.48; p=0.86), though the researchers suggested that a longer follow-up period may affect the OS outcome.
A post hoc analysis showed that patients on lenalidomide who had a dose escalation had better PFS over those on placebo (18.2 vs 4.6 months; HR, 0.43; p=0.0006 and 48.0 vs 14.8 months; HR, 0.26; p<0.0001 for maximum dose 5 and 10 mg, respectively).
The most frequent grade 3–4 treatment-emergent adverse events (TEAEs) experienced by patients on lenalidomide vs placebo were neutropenia (60 percent vs 23 percent), thrombocytopenia (17 percent vs 6 percent), and diarrhoea (8 percent vs <1 percent). Seven and two patients on lenalidomide and placebo, respectively, experienced haematological invasive second primary malignancies.
Fatal TEAEs occurred in three and two patients on lenalidomide and placebo, respectively). A larger proportion of patients on lenalidomide than placebo discontinued treatment due to TEAEs (34 percent vs 9 percent).
“[A]chievement of complete response with no minimal residual disease [MRD in CLL] is rare,” said the researchers. “Given that current therapies do not always lead to MRD-negativity, the ability of lenalidomide to prolong duration of response after treatment in patients with CLL is an important clinical achievement.”
“As the treatment landscape progresses, lenalidomide therapy might present an alternative treatment option for those patients who cannot achieve MRD-negativity with other therapies, or those who do not have access to newer treatment options,” they said.
With its ability to improve PFS, delay time to third-line therapy, and not reduce subsequent treatment efficacy, coupled with an acceptable toxicity profile, lenalidomide could also potentially be positioned as maintenance therapy following first-line chemoimmunotherapy, said the researchers.
The study was not designed to determine comparative dose-specific outcomes. Furthermore, the role of lenalidomide maintenance therapy following CLL treatment with newer drugs has not been established.
According to Dr Julie Chang from the University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, US, another limitation was the lack of cytogenetic testing and heavy-chain-mutation analysis data among study participants.
“Subgroups of patients with 11q deletion, unmutated heavy-chain gene, and complex cytogenetics have consistently been shown to have less favourable PFS after first-line therapy, and are a population in which maintenance therapy could be particularly attractive,” she said in a commentary. [Lancet Haematol 2017;doi:10.1016/S2352-3026(17)30180-1]