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The therapeutic goal for patients with lower-risk myelodysplastic syndrome (MDS) is to improve bone marrow function and reduce the requirement for red blood cell transfusions. Lenalidomide has been shown to offer clinical benefit for lower-risk patients with 5q deletion [del(5q)] but is currently only approved for patients with transfusion dependency due to toxicity concerns. It is proposed that early treatment with lenalidomide at a low dose may prolong the time to transfusion dependency, and ultimately improve outcomes.1
The interim results of the phase III Sintra-REV study (NCT01243476; data cut-off, July 2020), investigating the efficacy and safety of early treatment with low-dose lenalidomide in patients with lower-risk MDS and del(5q), were presented by Maria Diez-Campelo during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.1 Here we summarize the findings.
A phase III, multicenter, double-blind, randomized, placebo-controlled study, with the following patient inclusion criteria:
A summary of the study design is shown in Figure 1.
Figure 1. Sintra-REV trial design1
R, randomization.
Primary endpoint:
Secondary objectives included:
Selected patient characteristics are shown in Table 1. There were no significant differences observed between the lenalidomide and placebo arms.
Table 1. Selected patient characteristics1
IPSS, international prognostic scoring system. *Additional cytogenetic abnormalities: +8, t(1;13), -Y, -7 (lenalidomide arm), and del(11q), -Y (placebo arm). |
||
Lenalidomide |
Placebo |
|
---|---|---|
Sex, female, % |
80.0 |
85.7 |
Median age, years |
72.2 |
71.9 |
IPSS low, % |
87.5 |
81.0 |
IPSS intermediate-1, % |
12.5 |
19.0 |
Isolated del(5q) abnormality, % |
90.0 |
90.5 |
Additional cytogenetic abnormality*, % |
10.0 |
9.5 |
Hemoglobin, g/dL |
9.8 |
9.8 |
Absolute neutrophil count, ×109/L |
2.1 |
2.2 |
Platelets, ×109/L |
238 |
272 |
Peripheral blood blasts, % |
0 |
0 |
Bone marrow blasts, % |
1.5 |
2.0 |
Time to Sintra-REV, months |
2.7 |
4.0 |
At the time of reporting, >80% of patients had completed the trial protocol. The median time on treatment was higher in the lenalidomide arm compared with the placebo arm (23.9 vs 10.6 months). Lenalidomide treatment was discontinued in 52.5% of patients, mainly due to progressive disease and need for transfusion (38%), rejection of informed consent (28.5%), or physician decision (23.8%). In the placebo arm, treatment was discontinued in 66.6% of patients; progressive disease and transfusion need accounted for 71.4% of these cases.
Low-dose lenalidomide was considered safe and well-tolerated. Grade 3–4 adverse events are summarized in Table 2. Although almost half of patients in the lenalidomide arm developed neutropenia, only one developed febrile neutropenia and there were no neutropenia-related complications requiring hospitalization.
There were nine deaths in total, none related to study treatment, and acute myeloid leukemia was diagnosed in three patients, of which two (5%) were in the lenalidomide arm and one (5%) in the placebo arm.
Table 2. Grade 3–4 adverse events1
AE, adverse event; DVT, deep vein thrombosis; PE, pulmonary embolism. |
||
|
Lenalidomide |
Placebo |
---|---|---|
Non-hematologic Grade 3–4 AE, % |
||
Vascular (PE/DVT) |
2.6 |
0 |
Rash |
2.6 |
0 |
Second neoplasm |
5.3 |
0 |
Hematologic Grade 3–4 AE, % |
||
Anemia |
2.6 |
0 |
Thrombocytopenia |
5.3 |
0 |
Neutropenia |
46.8 |
4.8 |
Febrile neutropenia |
2.6 |
0 |
In this interim analysis of the phase III Sintra-REV trial, early treatment with low-dose lenalidomide delayed the time to and reduced the risk of transfusion dependency for patients with lower-risk, del(5q) MDS. Erythroid and cytogenetic responses were observed in 72.5% and 80% of patients, respectively, and the low-dose treatment had an acceptable safety profile. Since the follow-up data is not yet mature, the impact of this regimen on long-term outcome is still to be determined.
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