The availability of the oral iron-chelating agent deferasirox has led to its widespread use in MDS patients. While some consensus panels advocate prophylactic iron chelation in patients with ongoing transfusion needs and substantial transfusion history, the impact of iron chelation on survival and disease progression is unknown.
Lower-risk patients (conventionally defined as International Prognostic Scoring System (IPSS) low-risk and intermediate-1–risk groups) who have failed to respond or have ceased responding to ESAs may be treated with one of several disease-modifying agents. The impact of this practice on survival in lower-risk patients is unknown. Whether these drugs should be used following an ESA failure or as up-front therapy has never been determined. In contrast, in higher-risk patients, azacitidine has been shown to improve survival. (Refer to the DNA methyltransferase inhibitors section of this summary for more information.)
Lenalidomide is FDA-approved for the treatment of lower-risk, transfusion-dependent MDS patients who harbor a del(5q) cytogenic abnormality. In a phase II registration study of 148 transfusion-dependent low-risk and intermediate-1–risk patients with del(5q) chromosomal abnormalities (alone, or associated with other abnormalities), lenalidomide induced transfusion independence in 67%, with a median time to response of 4 to 5 weeks. The median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. Of 62 evaluable patients, 38 patients developed complete cytogenetic remission.
Lenalidomide administration is limited by dose-limiting neutropenia and thrombocytopenia.[Level of evidence: 3iiiDiv] Treatment-related thrombocytopenia also correlated with cytogenetic responses, emphasizing the importance of successful suppression of the del(5q) clone with lenalidomide to achieve meaningful responses.
A subsequent phase III study randomly assigned lower-risk del(5q) MDS patients to receive placebo and lenalidomide at either 5 mg daily for 28 days or 10 mg daily for 21 days of a 28-day cycle. Transfusion independence responses lasting longer than 6 months occurred in 43% to 52% of subjects treated on the lenalidomide arms, compared with 6% of controls. The cytogenetic response rate was 25% to 50% on the active treatment arms, and the 3-year risk of AML transformation was 25%.
Lenalidomide has limited activity in lower-risk, red blood cell transfusion–dependent MDS patients who do not harbor the del(5q) lesion. In a phase II study similar in design to the registration study, 56 of 215 patients (26%) achieved transfusion independence. Median duration of response was 41 weeks (range, 8–136 weeks). Grade 3 or 4 myelosuppression occurred in only 20% to 25% of patients, and unlike for del(5q) patients, was not associated with subsequent attainment of a transfusion independence response to therapy.
Antithymocyte globulin (ATG) has shown activity in MDS patients in several small series. The National Heart, Lung, and Blood Institute conducted a phase II trial including 25 MDS patients with less than 20% blasts. Of all the patients studied, 11 (or 44%) responded and became transfusion-independent after ATG (three complete responses, six partial responses, and two minimal responses). Multivariate analysis identified HLA-DR-15 (phenotype) expression, briefer period of red cell transfusion dependence, and younger age as predictors of response to ATG. One study used alemtuzumab to treat a heavily preselected population of lower-risk MDS patients, in whom the response rate was 80%.