Background
Phase 2, single-arm, open-label trial. 148 patients with transfusion-dependent myelodysplastic syndrome associated with chromosome 5q31 deletion (del5q), regardless of additional cytogenetic abnormalities. Patients with IPSS Low/Int-1 risk received lenalidomide aiming to reduce transfusion requirements and suppress the del5q clone.
Interventions and follow up
Regimen: Lenalidomide 10 mg orally once daily (28-day cycles) — transfusion-dependent low/intermediate-1 risk MDS with del(5q)
Primary endpoint: RBC transfusion independence (TI) and cytogenetic response at 24 weeks (ITT)
mFollow up: Median 104 weeks
Primary endpoint: RBC transfusion independence (TI) and cytogenetic response at 24 weeks (ITT)
mFollow up: Median 104 weeks
Results
RBC-TI: 67% (99/148)
Reduced transfusion need (any reduction): 76% (112/148)
Median time to response: 4.6 weeks
Median duration of TI: Not reached at median 104-week follow-up
Cytogenetic improvement: 73% (62/85 evaluable)
Complete cytogenetic remission: 45% (38/85)
Complete cytologic normalization: 36% (38/106 evaluable)
Reduced transfusion need (any reduction): 76% (112/148)
Median time to response: 4.6 weeks
Median duration of TI: Not reached at median 104-week follow-up
Cytogenetic improvement: 73% (62/85 evaluable)
Complete cytogenetic remission: 45% (38/85)
Complete cytologic normalization: 36% (38/106 evaluable)
Adverse events
Hematologic: Grade 3–4 neutropenia 55%; grade 3–4 thrombocytopenia 44% — most common reasons for dose interruption or reduction
Other: No treatment-related deaths reported
Other: No treatment-related deaths reported
Conclusions
Lenalidomide produced rapid, durable transfusion independence in two-thirds of transfusion-dependent del5q MDS patients, with concurrent cytogenetic and cytologic remissions in the majority of evaluable patients, establishing lenalidomide as a disease-modifying therapy in del5q LR-MDS.
Key Limitations
Single-arm, non-randomized phase 2 design without a control group limits causal interpretation. Marked grade 3–4 myelosuppression required frequent dose modification. Follow-up, while substantial, was insufficient to characterize long-term AML transformation risk in del5q clones; subsequent concern about TP53-mutated subclones was addressed only later. Applicability to non-del5q MDS is absent.
Clinical Context
MDS-003 was the pivotal study supporting FDA approval of lenalidomide for transfusion-dependent del5q LR-MDS in 2005. It established lenalidomide as standard first- or second-line therapy in del5q LR-MDS, later confirmed by the randomized MDS-004 trial. ELN MDS guidance recommends molecular screening for TP53 mutation prior to initiation given concern about clonal evolution in a subset of patients.
References