Lenalidomide in non-deletion 5q lower-risk myelodysplastic syndromes: a glass quarter full or three quarters empty?

Myelodysplastic syndromes (MDS) are a group of clonal bone marrow failure disorders characterized by disorganized, unproductive as well as malignant hematopoiesis. MDS typically manifest with varying degree of cytopenias, mostly anemia, requiring regular red blood cell transfusions in many patients. In comparison to higher-risk MDS for which allogeneic stem cell transplantation and azacitidine provide a survival advantage, no therapy to date has provided such for patients with lower-risk (LR)-MDS (International Prognostic Scoring System low and intermediate-1 risk groups or International Prognostic Scoring SystemRevised very low, low and intermediate risk groups) and the goals of care focus on improving (or maintaining) the quality of life [1]. Anemic patients with LR-MDS are often treated with erythropoiesis-stimulating agents (ESAs) with a response rate of only 22–42% in unselected patients, and among responders a median response duration of 2 years [2–4]. Therefore, most patients with LR-MDS require additional therapies beyond ESAs [5,6]. In transfusion-dependent LR-MDS with deletion in the long arm of chromosome 5 (del5q), lenalidomide is approved for first-line use given its impressive clinical activity leading to transfusion independence (TI) in approximately 65% of patients with a median response duration of 2.1 years [7,8]. Unfortunately, del5q is found in only 10% of MDS patients and only 1% of these patients are categorized as LR-MDS [9]. Phase 2 and 3 studies of lenalidomide in non-del5q LR-MDS reported TI in 25% of patients and a response duration of 40 weeks [10,11]. A retrospective analysis of the largest cohort of non-del5q LR-MDS patients to date showed that only 39% of patients after ESA failure trial second-line therapies with the majority (67%) receiving the hypomethylating agents (HMAs) azacitidine and decitabine. It is only in the third-line setting, and thus usually in the face of HMA-failure when the majority of patients (55%) trial lenalidomide therapy [12]. MDS-005 is a recent phase III study which evaluated the use of lenalidomide 10mg daily on a 28-day cycle in non-del5q LR-MDS patients’ refractory to ESAs or for whom an elevated EPO level indicated likely ESA failure. The study demonstrated that TI was achieved by 27% of subjects in the lenalidomide arm compared with 2.5% in the placebo arm. In addition to this modest response rate, the median response duration was only 31 weeks [11]. In the accompanying article, Almeida et al. [13] provide a more detailed analysis of the safety data from this phase 3 trial. As reported originally, lenalidomide was associated with a higher incidence of Grade 3–4 neutropenia (62 versus 11%), thrombocytopenia (36 versus 4%) when compared to placebo [13]. These findings mirror the observed incidences noted in previous phase 2 and phase 3 data of lenalidomide use in del5q LR-MDS after ESA failure or ineligibility, a population in which lenalidomide use is approved [7,8,10]. Dose interruption occurred in 19–29% of patients because of these Grade 3–4 hematologic toxicities and ultimately triggered lenalidomide discontinuation in 32% of patients, compared to 11% in the placebo group [13]. It is worth noting that lower doses (5mg) and abbreviated schedules (e.g. 21 days in 28-day cycles) have previously shown fairly similar rates of TI, lesser incidence of Grade 3 or 4 toxicities and thus lesser subsequent dose interruptions or adjustments [7,8]. Studies with higher doses of lenalidomide in AML and MDS have demonstrated