The myelodysplastic syndromes (MDS) are a heterogeneous collection of clonal, hematopoietic disorders primarily affecting an older population, making successful drug development a complicated process. A sole focus on response rate in clinical trials is likely not clinically meaningful if not accompanied by substantive response duration, improvement in quality of life, and ideally prolongation of survival. The process of receiving a new therapy should not be more burdensome than the MDS sequela it is intended to ameliorate. We review challenges in drug development in MDS with respect to aligning trial endpoints for lower and higher risk patients with treatment goals meaningful to patients.
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Foran JM, Shammo JM. Clinical presentation, diagnosis, and prognosis of myelodysplastic syndromes. Am J Med. 2012;125(7 Suppl):S6–13.
Naqvi K, Jabbour E, Bueso-Ramos C, Pierce S, Borthakur G, Estrov Z, et al. Implications of discrepancy in morphologic diagnosis of myelodysplastic syndrome between referral and tertiary care centers. Blood. 2011;118:4690–3.
Vardiman J, Thiele J, Arber D, Brunning R, Borowitz M, Porwit A, et al. The 2008 Revisions of the WHO classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.
Makishima H, Yoshizato T, Yoshida K, Sekeres MA, Radivoyevitch T, Suzuki H, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet. 2017;49:204–12.
Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson Br, Garcia-Manero G, et al. Clinical Effect of Point Mutations in Myelodysplastic Syndromes. N Eng J Med. 2011;364:2496–506.
Zhao X, Yang F, Li S, Liu M, Ying S, Jia X, et al. CpG island methylator phenotype of myelodysplastic syndrome identified through genome-wide profiling of DNA methylation and gene expression. Br J Haematol. 2014;165:649–58.
Taskesen E, Havermans M, van Lom K, Sanders MA, van Norden Y, Bindels E, et al. Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling. Blood. 2014;123:3327–35.
Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16.
Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32.
Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–803.
List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456–65.
Steensma DP, Baer MR, Slack JL, Buckstein R, Godley LA, Garcia-Manero G, et al. Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol. 2009;27:3842–8.
Sekeres MA. Epidemiology, natural history, and practice patterns of patients with myelodysplastic syndromes in 2010. J Natl Compr Canc Netw. 2011;9:57–63.
Sekeres MA, Schoonen WM, Kantarjian H, List A, Fryzek J, Paquette R, et al. Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. J Natl Cancer Inst. 2008;100:1542–51.
Zipperer E, Tanha N, Strupp C, Kundgen A, Nachtkamp K, Neukirchen J, et al. The myelodysplastic syndrome-comorbidity index provides additional prognostic information on patients stratified according to the revised international prognostic scoring system. Haematologica. 2014;99:e31–2.
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.
Sekeres MA, Gerds AT. Established and novel agents for myelodysplastic syndromes. Hematol Am Soc Hematol Educ Program. 2014;2014:82–9.
Platzbecker U, Symeonidis A, Oliva EN, Goede JS, Delforge M, Mayer J, et al. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017;31:1944–50.
Gabrilove J, Paquette R, Lyons RM, Mushtaq C, Sekeres MA, Tomita D, et al. Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for correcting anaemia in patients with myelodysplastic syndromes. Br J Haematol. 2008;142:379–93.
Raza A, Galili N, Smith SE, Godwin J, Boccia RV, Myint H, et al. A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome. Cancer. 2012;118:2138–47.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–25. Epub 2006 Apr 11.
Gale RP, Barosi G, Barbui T, Cervantes F, Dohner K, Dupriez B, et al. What are RBC-transfusion-dependence and -independence? Leuk Res. 2011;35:8–11.
Steensma DP, Gattermann N. When is iron overload deleterious, and when and how should iron chelation therapy be administered in myelodysplastic syndromes? Best Pract Res Clin Haematol. 2013;26:431–44.
Sekeres MA. How to manage lower-risk myelodysplastic syndromes. Leukemia. 2012;26:390–4.
Steensma DP. Myelodysplasia paranoia: iron as the new radon. Leuk Res. 2009;33:1158–63.
Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017;18:1338–47.
Komrokji R, Garcia-Manero G, Ades L, Prebet T, Steensma DP, Jurcic JG, et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018;5:e63–e72.
Tefferi A, Al-Ali HK, Barosi G, Devos T, Gisslinger H, Jiang Q, et al. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. Leukemia. 2017;31:1252.
Ramsey SD, McCune JS, Blough DK, McDermott CL, Beck SJ, Lopez JA, et al. Patterns of blood product use among patients with myelodysplastic syndrome. Vox Sang. 2012;102:331–7.
Kantarjian H, Giles F, List A, Lyons R, Sekeres MA, Pierce S, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007;109:1705–14.
Platzbecker U, Sekeres MA, Kantarjian H, Giagounidis A, Mufti GJ, Jia C, et al. Relationship of different platelet response criteria and patient outcomes in a romiplostim myelodysplastic syndromes trial. Leukemia. 2014;28:2418–21.
Kantarjian H, Fenaux P, Sekeres MA, Becker PS, Boruchov A, Bowen D, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2009;28:437–44.
Giagounidis A, Mufti GJ, Fenaux P, Sekeres MA, Szer J, Platzbecker U, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014;120:1838–46.
Bailey RA, Reardon G, Wasserman MR, McKenzie RS, Hord RS. Association of anemia with worsened activities of daily living and health-related quality of life scores derived from the Minimum Data Set in long-term care residents. Health Qual Life Outcomes. 2012;10:129.
Platzbecker U, Hofbauer LC, Ehninger G, Holig K. The clinical, quality of life, and economic consequences of chronic anemia and transfusion support in patients with myelodysplastic syndromes. Leuk Res. 2012;36:525–36.
Casadevall N, Durieux P, Dubois S, Hemery F, Lepage E, Quarre MC, et al. Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial. Blood. 2004;104:321–7.
Steensma DP, Heptinstall KV, Johnson VM, Novotny PJ, Sloan JA, Camoriano JK, et al. Common troublesome symptoms and their impact on quality of life in patients with myelodysplastic syndromes (MDS): results of a large internet-based survey. Leuk Res. 2008;32:691–8.
Santini V, Almeida A, Giagounidis A, Platzbecker U, Buckstein R, Beach CL, et al. The Effect of Lenalidomide on Health-Related Quality of Life in Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes: Results From the MDS-005 Study. Clin Lymphoma Myeloma Leuk. 2018;18:136–44.e7.
Abel GA, Efficace F, Buckstein RJ, Tinsley S, Jurcic JG, Martins Y, et al. Prospective international validation of the Quality of Life in Myelodysplasia Scale (QUALMS). Haematologica. 2016;101:781–8.
List AF, Bennett JM, Sekeres MA, Skikne B, Fu T, Shammo JM, et al. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. Leukemia. 2015;29:2452.
Santini V, Almeida A, Giagounidis A, Gropper S, Jonasova A, Vey N, et al. Randomized Phase III Study of Lenalidomide Versus Placebo in RBC Transfusion-Dependent Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes and Ineligible for or Refractory to Erythropoiesis-Stimulating Agents. J Clin Oncol. 2016;34:2988–96.
Nazha A, Al-Issa K, Hamilton BK, Radivoyevitch T, Gerds AT, Mukherjee S, et al. Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes. Leukemia. 2017;31:2848–50.
Nazha A, Komrokji RS, Garcia-Manero G, Barnard J, Roboz GJ, Steensma DP, et al. The efficacy of current prognostic models in predicting outcome of patients with myelodysplastic syndromes at the time of hypomethylating agent failure. Haematologica. 2016;101:e224–7.
Zeidan AM, Sekeres MA, Garcia-Manero G, Steensma DP, Zell K, Barnard J, et al. Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides. Leukemia. 2016;30:649–57.
Komrokji RS, DeZern AE, Zell K, Al Ali NH, Estling C, Zimmerman C, et al. Validation of International Working Group (IWG) Response Criteria in Higher-Risk Myelodysplastic Syndromes (MDS): A Report on Behalf of the MDS Clinical Research Consortium (MDSCRC). Blood. 2015;126:909.
Garcia-Manero G, Fenaux P, Al-Kali A, Baer MR, Sekeres MA, Roboz GJ, et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17:496–508.