Alan List, MD
Clinical experience with lenalidomide (Revlimid) in myelodysplastic syndromes (MDS) has provided evidence of potential to improve survival and reduce the leukemic progression in patients with 5q-deletion (del[5q]), according to a review of the evidence.
“Treatment with lenalidomide in 5q-deletion MDS yields high rates of transfusion independence and cytogenetic response,” Alan List, MD, CEO of Moffitt Cancer Center, said during a keynote address at the 2016 Society of Hematologic Oncology annual meeting. “The frequency of both hematologic response and cytogenetic response to lenalidomide is dose dependent.
“Improvement in overall survival and freedom from [leukemic] progression are dependent upon the depth of cytogenetic response and clonal suppression,” added List.
A decade ago, lenalidomide received FDA approval on the basis of phase II trial data. Since then, clinical investigators and practitioners have addressed lingering questions about the drug’s safety and efficacy.
The phase II MDS-003 study evaluated lenalidomide in 148 patients with transfusion-dependent del(5q), low/intermediate-risk MDS. Patients received 1 of 2 doses of the drug: 10 mg/day continuously or 10 mg/day in 21-day cycles. Combined results from the 2 groups showed that 99 (67%) patients achieved the primary endpoint of transfusion independence, and 81 (71%) had cytogenetic responses.
The FDA granted approval but with the stipulation that a phase III trial would be conducted to compare the safety and efficacy of the approved dose versus a lower dose (5 mg/day). The randomized MDS-004 trial involved 276 patients with del(5q) MDS treated with lenalidomide 5 mg/day continuously, lenalidomide 10 mg/day in 21-day cycles, or continuous placebo.
The trial had a primary endpoint of transfusion independence for at least 26 weeks in association with serum hemoglobin increase >1 g/dL versus baseline. The 10-mg dose of lenalidomide demonstrated superiority versus the lower dose in both the intention-to-treat (ITT) population (54% vs 33%) and modified ITT population (56% vs 41%). The higher dose also resulted in a higher rate of complete and partial cytogenetic response (41.5% vs 17.4%).
The frequency of grade ≥3 hematologic adverse events was similar with the 2 doses of lenalidomide, as was the rate of dose reduction, and more patients in the 5-mg arm discontinued treatment than in the 10-mg arm (16% vs 9%).
“Clearly, dose matters—not in the way that the FDA was concerned—as a higher dose was better,” said List. “Do we have the right dose? For the time being, we have the only dose that we know is going to be relatively effective. The question now is whether we need to go higher.”
Results of a combined analysis of the phase II and III trials suggested that the rate of cytogenetic response (complete, partial, and combined) increased with the planned dose (ASCO 2011, Abst. 6522a). However, an analysis of patients who achieved transfusion independence for more than 26 weeks showed a similar but attenuated dose association, suggesting the potential benefit might be less than expected, said List.
Treatment-induced transfusion independence has implications for 2 hard endpoints in MDS: overall survival (OS) and progression to acute myelogenous leukemia (AML). A recent analysis of patients with del(5q) MDS showed that patients who were transfusion independent at the start of follow-up had significantly better OS and a significantly lower risk of progression to AML (Leukemia
Lenalidomide also appeared superior in an analysis involving a historical control group. The comparison yielded a hazard ratio of 0.597 for OS in favor of lenalidomide (P
= .012) and a 2-year AML risk of 6.9% versus 12.1% (Leukemia
“The only way we’re going to know for sure is in a randomized trial, which will never occur,” said List.
More recently, evidence has emerged suggesting that lenalidomide favorably affects somatic gene mutation clonal architecture in del(5q) MDS (Blood. 2016;127:749-760). A comparison of patients who responded to lenalidomide versus those who did not showed about a 20% difference in suppression of somatic mutations in the patients who responded to treatment.
Studies of mutations that interfere with response to lenalidomide suggest TP53 may have particular significance in del(5q) MDS. Recent studies from Spain and France showed significantly lower rates of transfusion independence and cytogenetic response in patients with TP53
mutations versus wild-type TP53.
Another line of research has uncovered another possible mechanism by which lenalidomide affects outcomes in del(5q) MDS. The data suggested that the del(5q) accelerates telomere shortening and that response to lenalidomide is associated with restoration of telomere length in del(5q) MDS (Leuk Res