Defining prior therapy in myelodysplastic syndromes and criteria for relapsed and refractory disease: implications for clinical trial design and enrollment

Abstract

The recent approval of 3 drugs for the treatment of myelodysplastic syndromes (MDSs) has resulted in a revolution in therapeutic options that was absent a decade ago. At the same time, the changing MDS environment is raising new challenges in clinical trial design and defining new indications for MDS drugs. Many current trials still rely on IPSS-based enrollment criteria, despite the wellrecognized limitations of the IPSS. Clinical trialists designing studies struggle with several important trial design challenges, including which patients constitute the "previously treated" and "relapsed/refractory" MDS populations, and how specifically to define disease "progression." This article considers some of these issues as they relate to study design, including how to identify certain MDS populations and define disease progression. (Blood. 2009;114:2575-2580) IntroductionThe myelodysplastic syndromes (MDSs) are a collection of clonal bone marrow disorders that, in their most severe forms, approximate acute leukemia, with a predicted survival measured in months. Available treatment options for patients with MDS have increased considerably over the last decade, and our knowledge of the molecular underpinnings of these diseases is beginning to catch up. The recent expansion in therapeutic choices and biologic understanding is clearly demonstrated when one considers that among the 816 patients included in the 1997 International Prognostic Scoring System (IPSS), who were enrolled in 7 registries assembled from the mid-1980s through the mid-1990s, 92% had received no therapy for their MDS other than transfusions, and the IPSS's cytogenetic risk categorization was based on just 6 common karyotypic results (normal, 5qϪ, 20qϪ, ϪY, Ϫ7/7qϪ, and complex; the dozens of other less common but recurrent MDSassociated cytogenetic patterns were lumped together unhelpfully as "other"). 1 Now, in the year 2009, 3 drugs-azacitidine, lenalidomide, and decitabine 2-4 -are approved by the US Food and Drug Administration (FDA) specifically for MDS-related indications, along with at least 5 hematopoietic growth factors licensed for other indications that can potentially be used for patients with MDS (epoetin, darbepoetin, filgrastim, sargramostim, and pegfilgrastim [5][6][7] ; whereas the thrombopoietin agonists romiplostim and eltrombopag have activity in MDS,8,9 their use is currently restricted to patients with immune thrombocytopenia). "Disease-modulating" therapies used off-label for treating MDS include cytotoxic agents (such as cytarabine and clofarabine) and those with immune-modulating mechanisms of action (such as thalidomide and antithymocyte globulin). [10][11][12][13] The growing number of available therapies makes it more difficult to design clinical trials for the untreated MDS population.With respect to biologic understanding, although the mechanisms of disease in MDS remain largely obscure, we now understand the prognostic implications of a much broader range of karyotypes than the small number included in the IPSS. The largest...

Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure

“…This raises interesting issues regarding possible effects of AZA, including, as suggested by others, a possible modification of the MDS natural history. 11,24 …”

Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion

“…Second line treatments after relapse or resistance to ESA include hypomethylating agents, yielding response rates between 25 to 35% (9) , while various other agents are currently being evaluated, including lenalidomide (LEN).…”

IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis

“…15 Isocitrate dehydrogenase 1 gene (IDH1) encodes for the protein isocitrate dehydrogenase 1, an enzyme that participates in the citric acid cycle. It catalyzes the carboxylation of isocitrate to alpha-ketoglutarate.…”