The Non-transplant Treatment of Myelodysplastic Syndromes—What’s on the Horizon? Austin G. Kulasekararaj a,b and Ghulam J. Mufti a,b The therapeutic advance in the field of myelodysplastic syndromes (MDS) has evolved over the last decade with efficacy of hypomethylating agents and immunomodulatory drugs. Currently, several promising agents with diverse mechanisms of actions are in various stages of clinical development and will expand the therapeutic armamentarium for MDS. The advent of next generation sequenc- ing technologies has improved the understanding of disease biology and this will drive further activity in the near future with new targeted therapies, like exploitation of newly identified molecular aberrations, such as SF3BI and STAG2, as a therapeutic target and also further refinement of existing treatments. Semin Hematol 49:350 –360. © 2012 Published by Elsevier Inc. T he treatment of a clinically and genetically het- erogeneous disease like myelodysplastic syn- dromes (MDS) involves a complex algorithm that incorporates multiple disease-specific and host- related factors such as performance status, but is ulti- mately aimed at improving the quality of life, delaying leukemic progression, and improving survival. A disease that was considered a “provincial backwa- ter,” predominantly due to the lack of effective therapy except allogeneic hematopoietic stem cell transplanta- tion (HSCT), was given a therapeutic boost by the efficacy of azacitidine, lenalidomide, and decitabine and their subsequent approval by the US Food and Drug Administration (FDA) between 2004 and 2006. The obvious buoyancy triggered by FDA approvals re- sulted in a burst of activity, not only in clinical trials but also in drug development for novel therapeutic agents. The lack of complete understanding of the pathogenesis of MDS, and its evolution and progres- sion, has largely hindered targeted therapy until now. However, the advent of high-throughput se- quencing technologies to sequence the MDS genome is beginning to transform the molecular paradigms that are relevant to MDS therapeutics. Equipped with this biological knowledge, the field of MDS therapeutics should see a flurry of activity in the near future, with new targeted therapies and refinement of existing treat- ments. The need for novel therapy is predominantly, but not exclusively, for patients with high-risk MDS failing azanucleoside therapy who are ineligible for HSCT, for del(5q) MDS refractory to lenalidomide, and for non- del(5q) MDS patients who fail or do not benefit from growth factor therapy. An increasingly unmet clinical need is for therapeutics to target patients relapsing following reduced-intensity conditioned HSCT (30%– 40%), either pre-emptively or after relapse. There are approximately 200 clinical trials recruiting MDS patients with investigational agents in the non- transplant setting and this list is rapidly increasing. This review will assess the preclinical and clinical data avail- able for compounds with proven efficacy in non-hema- tologic malignancies but with an emerging role in my- eloid neoplasms, and also therapies altering the stromal microenvironment of MDS. This list summarized below is not comprehensive, but rather describes a represen- tative class of medications with a possible role in MDS therapeutics in the near future. This review does not address novel therapeutics in the context of HSCT for MDS. PARP INHIBITORS The search for targeted therapy in cancer is a rapidly developing field and synthetic lethality remains a prom- ising avenue for selectively killing tumor cells. The a Department of Haematological Medicine, King’s College London School of Medicine, London, UK. b Department of Haematology, King’s College Hospital, London, UK. Conflicts of interest: none. Address correspondence to Ghulam J. Mufti, King’s College London, Department of Haematological Medicine, The Rayne Institute, 123 Coldharbour La, London, SE5 9NU United Kingdom. E-mail: ghulam.mufti@kcl.ac.uk 0037-1963/$ - see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1053/j.seminhematol.2012.07.005 Seminars in Hematology, Vol 49, No 4, October 2012, pp 350 –360 350