Nowhere has the notion of personalized medicine been more realized than in oncology therapeutics. Within MDS, the use of lenalidomide for lower-risk patients with the del (5q) cytogenetic abnormality is emblematic of this approach. But is the drug personalized enough to be used in any patient whose cancer expresses del (5q)?
Therapy for myelodysplastic syndromes (MDS) has undergone a revolution of sorts in the past 5 years, with the approval by the US Food and Drug Administration of 3 drugs specifically for this collection of diseases: azacitidine in 2004,1 lenalidomide in 2005,2 and decitabine in 2006.3 Only 1 of these, lenalidomide, is approved for an MDS subgroup: patients with lower-risk (International Prognostic Scoring System [IPSS] scores ≤ 1.0), transfusion-dependent disease who harbor the del (5q) cytogenetic abnormality. In this narrowly defined group, who comprise approximately 8% to 9% of all MDS patients, lenalidomide is a wonder drug, yielding transfusion independence responses in 67% of patients, complete cytogenetic remissions in 44%, and a duration of transfusion independence lasting a median of 2.2 years.4 One question that arises frequently is whether the drug can be used with equal efficacy, and as front-line therapy, for those MDS patients with higher-risk (IPSS scores ≥ 1.5) disease and a del (5q) abnormality.
In this issue of Blood, Adès and colleagues report the results from a phase 2 study, exploring the safety and efficacy of lenalidomide in 29 del (5q) patients with higher risk MDS and 18 del (5q) patients with acute myeloid leukemia (AML) and 20% to 30% myeloblasts.5 Among the MDS patients, 6 (21%) achieved a complete remission (CR), 2 (7%) a marrow CR, and 4 (14%) hematologic improvement in erythropoiesis. Among AML patients, 1 (6%) achieved a CR. Median response duration was 6.5 months for all patients, 11.5 months for those with an isolated del (5q) abnormality, and median overall survival was 272 days (∼ 9 months). CR was more likely to occur in those with an isolated del (5q) lesion (in 6 of 9 patients, or 67%) compared with those with additional cytogenetic abnormalities (P < .001). It was also more likely to occur in those with an initial platelet count greater than 100 000/mm3 (in 6 of 13 patients, or 46%), compared with those with lower platelet counts (P = .001). A majority of patients experienced severe neutropenia and/or thrombocytopenia, and 30 patients (64%) required hospitalization during their treatment course.
Compare these results to those presented by Fenaux and colleagues of a phase 3 study of azacitidine versus conventional care in patients with higher-risk MDS (AZA-001) at the American Society of Hematology Annual Meeting 1 year ago.6 Median survival in the azacitidine arm was 24.4 months (a full 15 months greater than the present study), though CR rates were similar (17%), and partial remission and hematologic improvements were higher (12% and 49%, respectively). It is unclear whether these advantages translated to AZA-001 patients with the del (5q) abnormality, either in isolation or with additional cytogenetic abnormalities, though a preliminary report suggests that a combination of MDS and AML patients with the del (5q) lesion had a median survival of 9 months, significantly lower than similar patients without this abnormality (15 months, P = .007).7
Why the inferior responses to single-agent lenalidomide in the study by Adès et al, when presumably therapy is “targeted” more to a distinct, identifiable lesion for which this therapy has demonstrated presumed cytotoxicity (with cytogenetic response rates) in lower-risk disease? We may be witnessing a recapitulation of the FMS-like tyrosine kinase 3 (flt3) internal tandem duplication story, in which flt3 inhibitors demonstrated only a modicum of activity in flt3 positive leukemias when used as single agents, likely because patients with more advanced disease (such as higher-risk MDS or frank AML) have additional genetic abnormalities that promote proliferation and impair differentiation.8 This may bespeak the need to optimize dosing or to combine lenalidomide with additional therapy. Ongoing studies are investigating the use of lenalidomide as a single agent at higher doses for AML patients with the del (5q) abnormality (Southwest Oncology Group study S0605); lenalidomide in combination with azacitidine in higher-risk MDS9 ; and lenalidomide in combination with traditional cytotoxic chemotherapy for AML.
Returning to our question, what to do with the higher risk MDS patient with the del (5q) abnormality, either in isolation or in addition to other chromosome abnormalities? Given the superior (or, in the case of an isolated del (5q) lesion, lack of data indicating inferior) response rates and overall survival compared with single agent lenalidomide, the firstline treatment of choice still must be a hypomethylating agent or combination therapy that includes lenalidomide as part of a clinical trial. The study by Adès et al further illuminates lenalidomide's specificity for the del (5q) clone and provides unequivocal justification for exploring dosing modification or combination strategies.
Conflict-of-interest disclosure: M.A.S. has received research funding and honoraria for participating in advisory boards from Celgene. ■
