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Personalized management of MDS
the interaction between p53 and endogenous inhibitors thereby reactivating p53-mediated tumor suppression in AML cells.187 Phase I/II clinical testing with these drugs is ongoing.
Telomerase inhibition
Defective maintenance of telomere integrity is a hall- mark of cancer and is implicated in the pathogenesis of MDS. In MDS, telomere erosion and dysfunction potenti- ate persistent DNA damage and accumulation of molecu- lar alterations.188,189 Evidence suggests that telomere ero- sion can suppress hematopoietic stem cell self-renewal, repopulating capacity, and differentiation. Imetelstat is a telomerase inhibitor that targets cells with short telomeres and highly active telomerase, and has been shown in early clinical studies to have activity in myeloid malignancies.190 Initial data on the use of imetelstat in lower-risk MDS patients resistant to ESA has shown encouraging erythroid responses.191
Luspatercept
ease refractory to or were unlikely to respond to ESA (38% of patients achieved transfusion independence).195 This drug is currently undergoing USA FDA review for therapeutic use in MDS-RS.
Future considerations
Given the stem cell origin and the multiplicity of molec- ular abnormalities in MDS, it is difficult to identify poten- tially effective drugs that can be used to treat a high propor- tion of patients. Recent studies have demonstrated the fea- sibility of ex vivo drug cytotoxicity platforms to screen effec- tively for multiple, potentially useful and novel drugs in myeloid neoplasms, including MDS, to provide functional data to guide personalized therapy for treatment-refractory patients with myeloid malignancies and to accurately pre- dict clinical responses in vivo.196-198 Such studies will likely synergize with molecular data and emerging genomics- and cellular-based precision medicine approaches such as in silico computational biology modeling.199,200 Ultimately, combin- ing both genomics-based and ex vivo functional data may further refine precision therapy in myeloid neoplasms such as MDS and translate into improved patients’ outcomes.
Acknowledgment
This work is part of the MDS-RIGHT activities, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 634789 - “Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time”.
Increased levels of the transforming growth factor β (TGFβ) superfamily inhibitors of erythropoiesis (predomi- nantly growth and differentiation factor-11) occur within MDS erythroid cells.192 Luspatercept, a recombinant fusion protein, is considered to bind TGFβ superfamily ligands and reduce SMAD2 and SMAD3 signaling, reduce erythroid hyperplasia, and enhance erythroid maturation and hemo- globin levels in MDS.193,194 In a recent phase III trial, luspa- tercept was shown to reduce the severity of anemia in transfusion-dependent patients with MDS-RS who had dis-
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