Lenalidomide (Revlimid) induced at least 8 consecutive weeks of red blood cell transfusion independence (RBC-TI) in 26.9% of transfusion-dependent patients with lower-risk myelodysplastic syndromes (MDS) without a 5q deletion in an international randomized trial.
For placebo, the rate was 2.5% (P<0.001) and was likely due to resolution of anemia rather than MDS, according to Valeria Santini, MD, of the University of Florence, Italy, and colleagues writing in the Journal of Clinical Oncology.
Median onset of RBC-TI with treatment occurred at 10.1 weeks, with 90% responding within 16 weeks. The median duration of response was almost 31 weeks.
Measures of health-related quality of life at 3 months, however, showed no significant inter-arm difference across the five domains of fatigue, dyspnea, physical functioning, emotional functioning, and global quality of life.
In those who maintained RBC-TI for >8 weeks, however, treatment was associated with significant improvements in HRQoL (P<0.01). But at week 24 only emotional functioning was statistically significant: 0.8 versus 27.1 (P=0.047). In patients on lenalidomide after week 24, a trend to improved scores emerged across all domains.
"Prior RBC transfusion burden and prior ESA [erythropoiesis-stimulating agent], and possibly endogenous EPO [erythropoietin] levels, may be used to select patients who are more sensitive to lenalidomide," Santini and colleagues wrote. "The subgroup of patients with MDS who responded to lenalidomide needs further characterization, and molecular studies are ongoing."
Lenalidomide is already FDA-approved for the minority (5%-10%) of lower-risk, transfusion-dependent MDS patients who carry the del(5q) cytogenetic abnormality.
During 2010-2013, the 72-center study enrolled 239 adult patients: median age 71 (range 43-87), 67.8% male, median time from diagnosis 2.6 years (range 0.1-29.6). At baseline 70.3% had ring sideroblasts of >15%.
Participants, who were ineligible for or refractory to ESAs, were randomly assigned 2:1 to lenalidomide (n=160) or placebo (n=79) once daily on 28-day cycles. Median duration of treatment was 164 days (range 7.0-1158.0 days) in the lenalidomide group and 168 days (range 14.0-449.0 days) in the placebo group.
With intended follow-up of 5 years, the primary endpoint was the rate of RBC-TI at >8 weeks, with secondary endpoints of RBC-TI at >24 weeks, RBC-TI duration, erythroid response, health-related quality of life (HRQoL), and safety.
For those who achieved RBC-TI lasting >8 weeks, the median duration of RBC-TI with lenalidomide was 30.9 weeks (95% CI 20.7-59.1). And a post-hoc analysis found a transfusion reduction of >4 units of packed RBCs, based on a 112-day assessment, of 21.8% in the lenalidomide group versus 0% in the placebo group.
These findings are consistent with a phase II study in which 26.2% of patients with lower-risk non-del(5q) MDS achieved 8-week transfusion independence.
Higher response rates occurred in patients with serum levels of endogenous EPO of <500 mU/mL at baseline: 34.0% versus 15.5% for >500 mU/mL.
Regarding safety, the most frequent lenalidomide-related adverse events of any grade were myelosuppressive and were consistent with the drug's known safety profile. Discontinuations due to adverse events occurred in 31.9% and 11.4% patients in the lenalidomide and placebo groups, respectively.
Lenalidomide did not appear to affect transformation to acute myeloid leukemia: the incidence of progression was 1.91 (95% CI 0.80-4.59) per 100 person-years and 2.46 (95% CI 0.79 to 7.64) per 100 person-years for the lenalidomide and placebo arms, respectively.
The authors cautioned that since the median overall survival has not yet been reached, the data do not permit a definitive analysis. Collection of long-term follow-up data is ongoing.
"Overall, these data support the possible clinical benefits of lenalidomide in lower-risk non-del(5q) MDS," Santini and associates wrote.
The investigators also noted that adding EPO to lenalidomide EPO may benefit this patient population, citing a study in which the combination induced erythroid response in 39.4% of patients with lower-risk non-del(5q)MDS versus 23.1% in a lenalidomide-only arm.
In an accompanying editorial, Mikkael A. Sekeres, MD, MS, of the Cleveland Clinic, called the study's findings "reassuringly consistent" with the previous phase II trial in a similar population, with nearly identical rates of transfusion independence but a 25% longer duration time.
But for the vast majority with non-del (5q) MDS "lenalidomide will continue to be relegated to the off-label realm," Sekeres said. He pointed out that for the majority of study patients neither quality of life nor transfusion requirements substantially improved.
For "a tantalizing few," the drug is extremely effective, he wrote, "and it is now our responsibility, as clinical and translational scientists, to determine how we can better identify those people, and make the long day's journey into night [for lower-risk MDS] even longer."
This study was sponsored by Celgene, which markets lenalidomide. The majority of study authors as well as the editorial commentator reported financial relationships with industry.
Aucun commentaire:
Enregistrer un commentaire