Skip to main content

Advertisement

Log in

Evolving therapies for lower-risk myelodysplastic syndromes

Annals of Hematology Aims and scope Submit manuscript

Abstract

The development in the therapeutic landscape of myelodysplastic syndromes (MDS) has substantially lagged behind other hematologic malignancies with no new drug approvals for MDS for 13 years since the approval of decitabine in the United States in 2006. While therapeutic concepts for MDS patients continue to be primarily defined by clinical-pathologic risk stratification tools such as the International Prognostic Scoring System (IPSS) and its revised version IPSS-R, our understanding of the genetic landscape and the molecular pathogenesis of MDS has greatly evolved over the last decade. It is expected that the therapeutic approach to MDS patients will become increasingly individualized based on prognostic and predictive genetic features and other biomarkers. Herein, we review the current treatment of lower-risk MDS patients and discuss promising agents in advanced clinical testing for the treatment of symptomatic anemia in lower-risk MDS patients such as luspatercept and imetelstat. Lastly, we review the clinical development of new agents and the implications of the wider availability of mutational analysis for the management of individual MDS patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Greenberg PL, Stone RM, Al-Kali A, Barta SK, Bejar R, Bennett JM, Carraway H, De Castro CM, Deeg HJ, DeZern AE, Fathi AT, Frankfurt O, Gaensler K, Garcia-Manero G, Griffiths EA, Head D, Horsfall R, Johnson RA, Juckett M, Klimek VM, Komrokji R, Kujawski LA, Maness LJ, O'Donnell MR, Pollyea DA, Shami PJ, Stein BL, Walker AR, Westervelt P, Zeidan A, Shead DA, Smith C (2017) Myelodysplastic syndromes, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw 15(1):60–87

    Article  Google Scholar 

  2. Bewersdorf JP, Zeidan AM (2019) Transforming growth factor (TGF)-beta pathway as a therapeutic target in lower risk myelodysplastic syndromes. Leukemia. 33(6):1303–1312

  3. Zeidan AM, Shallis RM, Wang R, Davidoff A, Ma X (2019) Epidemiology of myelodysplastic syndromes: why characterizing the beast is a prerequisite to taming it. Blood Rev 34:1–15. https://doi.org/10.1016/j.blre.2018.09.001

    Article  PubMed  Google Scholar 

  4. Santini V (2019) How I treat MDS after hypomethylating agent failure. Blood 133(6):521–529. https://doi.org/10.1182/blood-2018-03-785915

    Article  CAS  PubMed  Google Scholar 

  5. Platzbecker U (2019) Treatment of MDS. Blood 133(10):1096–1107. https://doi.org/10.1182/blood-2018-10-844696

    Article  CAS  PubMed  Google Scholar 

  6. Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstocker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D (2012) Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120(12):2454–2465. https://doi.org/10.1182/blood-2012-03-420489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chokr N, Pine AB, Bewersdorf JP, Shallis RM, Stahl M, Zeidan AM (2019) Getting personal with myelodysplastic syndromes: is now the right time? Expert Rev Hematol 12(4):215–224. https://doi.org/10.1080/17474086.2019.1592673

    Article  CAS  PubMed  Google Scholar 

  8. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR, International Vidaza High-Risk MDSSSG (2009) 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 10(3):223–232. https://doi.org/10.1016/S1470-2045(09)70003-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J, Faderl S, Bueso-Ramos C, Ravandi F, Estrov Z, Ferrajoli A, Wierda W, Shan J, Davis J, Giles F, Saba HI, Issa JP (2007) Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109(1):52–57. https://doi.org/10.1182/blood-2006-05-021162

    Article  CAS  PubMed  Google Scholar 

  10. Steensma DP (2018) Myelodysplastic syndromes current treatment algorithm 2018. Blood Cancer J 8(5):47. https://doi.org/10.1038/s41408-018-0085-4

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lee EJ, Podoltsev N, Gore SD, Zeidan AM (2016) The evolving field of prognostication and risk stratification in MDS: recent developments and future directions. Blood Rev 30(1):1–10. https://doi.org/10.1016/j.blre.2015.06.004

    Article  CAS  PubMed  Google Scholar 

  12. Zeidan AM, Sekeres MA, Garcia-Manero G, Steensma DP, Zell K, Barnard J, Ali NA, Zimmerman C, Roboz G, DeZern A, Nazha A, Jabbour E, Kantarjian H, Gore SD, Maciejewski JP, List A, Komrokji R, Consortium MDSCR (2016) Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides. Leukemia 30(3):649–657. https://doi.org/10.1038/leu.2015.283

    Article  CAS  PubMed  Google Scholar 

  13. Zeidan AM, Sekeres MA, Wang XF, Al Ali N, Garcia-Manero G, Steensma DP, Roboz G, Barnard J, Padron E, DeZern A, Maciejewski JP, List AF, Komrokji RS, Consortium MDSCR (2015) Comparing the prognostic value of risk stratifying models for patients with lower-risk myelodysplastic syndromes: is one model better? Am J Hematol 90(11):1036–1040. https://doi.org/10.1002/ajh.24173

    Article  PubMed  Google Scholar 

  14. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, Schnittger S, Sanada M, Kon A, Alpermann T, Yoshida K, Roller A, Nadarajah N, Shiraishi Y, Shiozawa Y, Chiba K, Tanaka H, Koeffler HP, Klein HU, Dugas M, Aburatani H, Kohlmann A, Miyano S, Haferlach C, Kern W, Ogawa S (2014) Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 28(2):241–247. https://doi.org/10.1038/leu.2013.336

    Article  CAS  PubMed  Google Scholar 

  15. Bejar R, Papaemmanuil E, Haferlach T, Garcia-Manero G, Maciejewski JP, Sekeres MA, Walter MJ, Graubert TA, Cazzola M, Malcovati L, Ogawa S, Fenaux P, Hellstrom-Lindberg E, Kern W, Boultwood J, Pellagatti A, Bowen D, Tauro S, Groves MJ, Vyas P, Quek L, Nazha A, Thol F, Heuser M, Shih L-Y, Padron E, Sallman D, Komrokji RS, List AF, Santini V, Fontenay M, Campbell PJ, Tüchler H, Stevenson K, Neuberg DS, Greenberg P, Ebert BL (2015) Somatic mutations in MDS patients are associated with clinical features and predict prognosis independent of the IPSS-R: analysis of combined datasets from the international working group for Prognosis in MDS-Molecular Committee. Blood 126(23):907

    Article  Google Scholar 

  16. Steensma DP (2018) How i use molecular genetic tests to evaluate patients who have or may have myelodysplastic syndromes. Blood 132(16):1657–1663. https://doi.org/10.1182/blood-2018-06-860882

    Article  CAS  PubMed  Google Scholar 

  17. Malcovati L, Hellström-Lindberg E, Bowen D, Adès L, Cermak J, Del Cañizo C, Della Porta MG, Fenaux P, Gattermann N, Germing U, Jansen JH, Mittelman M, Mufti G, Platzbecker U, Sanz GF, Selleslag D, Skov-Holm M, Stauder R, Symeonidis A, van de Loosdrecht AA, de Witte T, Cazzola M, European Leukemia N (2013) Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 122(17):2943–2964. https://doi.org/10.1182/blood-2013-03-492884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Girmenia C, Candoni A, Delia M, Latagliata R, Molteni A, Oliva EN, Palumbo GA, Poloni A, Salutari P, Santini V, Voso MT, Musto P (2019) Infection control in patients with myelodysplastic syndromes who are candidates for active treatment: expert panel consensus-based recommendations. Blood Rev 34:16–25. https://doi.org/10.1016/j.blre.2018.10.002

    Article  PubMed  Google Scholar 

  19. Nachtkamp K, Stark R, Strupp C, Kündgen A, Giagounidis A, Aul C, Hildebrandt B, Haas R, Gattermann N, Germing U (2016) Causes of death in 2877 patients with myelodysplastic syndromes. Ann Hematol 95(6):937–944. https://doi.org/10.1007/s00277-016-2649-3

    Article  PubMed  Google Scholar 

  20. Shenoy N, Vallumsetla N, Rachmilewitz E, Verma A, Ginzburg Y (2014) Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome. Blood 124(6):873–881. https://doi.org/10.1182/blood-2014-03-563221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zeidan AM, Giri S, DeVeaux M, Ballas SK, Duong VH (2018) Systematic review and meta-analysis of the effect of iron chelation therapy on overall survival and disease progression in patients with lower-risk myelodysplastic syndromes. Ann Hematol. https://doi.org/10.1007/s00277-018-3539-7

  22. Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, Giagounidis A, Hildebrandt B, Bernasconi P, Knipp S, Strupp C, Lazzarino M, Aul C, Cazzola M (2007) Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25(23):3503–3510. https://doi.org/10.1200/JCO.2006.08.5696

    Article  PubMed  Google Scholar 

  23. Jin X, He X, Cao X, Xu P, Xing Y, Sui S, Wang L, Meng J, Lu W, Cui R, Ni H, Zhao M (2018) Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice. Haematologica 103(10):1627–1634. https://doi.org/10.3324/haematol.2018.193128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chacko J, Pennell DJ, Tanner MA, Hamblin TJ, Wonke B, Levy T, Thomas PW, Killick SB (2007) Myocardial iron loading by magnetic resonance imaging T2* in good prognostic myelodysplastic syndrome patients on long-term blood transfusions. Br J Haematol 138(5):587–593. https://doi.org/10.1111/j.1365-2141.2007.06695.x

    Article  CAS  PubMed  Google Scholar 

  25. Jensen PD, Jensen FT, Christensen T, Nielsen JL, Ellegaard J (2003) Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: a study in adult patients with acquired anemias. Blood 101(1):91–96. https://doi.org/10.1182/blood-2002-06-1704

    Article  CAS  PubMed  Google Scholar 

  26. Ghoti H, Fibach E, Merkel D, Perez-Avraham G, Grisariu S, Rachmilewitz EA (2010) Changes in parameters of oxidative stress and free iron biomarkers during treatment with deferasirox in iron-overloaded patients with myelodysplastic syndromes. Haematologica 95(8):1433–1434. https://doi.org/10.3324/haematol.2010.024992

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zeidan AM, Griffiths EA (2018) To chelate or not to chelate in MDS: that is the question! Blood Rev 32(5):368–377. https://doi.org/10.1016/j.blre.2018.03.002

    Article  CAS  PubMed  Google Scholar 

  28. Fenaux P, Santini V, Spiriti MAA, Giagounidis A, Schlag R, Radinoff A, Gercheva-Kyuchukova L, Anagnostopoulos A, Oliva EN, Symeonidis A, Berger MH, Götze KS, Potamianou A, Haralampiev H, Wapenaar R, Milionis I, Platzbecker U (2018) A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia 32(12):2648–2658. https://doi.org/10.1038/s41375-018-0118-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Platzbecker U, Symeonidis A, Oliva EN, Goede JS, Delforge M, Mayer J, Slama B, Badre S, Gasal E, Mehta B, Franklin J (2017) A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia 31(9):1944–1950. https://doi.org/10.1038/leu.2017.192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Terpos E, Mougiou A, Kouraklis A, Chatzivassili A, Michalis E, Giannakoulas N, Manioudaki E, Lazaridou A, Bakaloudi V, Protopappa M, Liapi D, Grouzi E, Parharidou A, Symeonidis A, Kokkini G, Laoutaris NP, Vaipoulos G, Anagnostopoulos NI, Christakis JI, Meletis J, Bourantas KL, Zoumbos NC, Yataganas X, Viniou NA (2002) Prolonged administration of erythropoietin increases erythroid response rate in myelodysplastic syndromes: a phase II trial in 281 patients. Br J Haematol 118(1):174–180. https://doi.org/10.1046/j.1365-2141.2002.03583.x

    Article  CAS  PubMed  Google Scholar 

  31. Greenberg PL, Sun Z, Miller KB, Bennett JM, Tallman MS, Dewald G, Paietta E, van der Jagt R, Houston J, Thomas ML, Cella D, Rowe JM (2009) Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the eastern cooperative oncology group (E1996). Blood 114(12):2393–2400. https://doi.org/10.1182/blood-2009-03-211797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jadersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellstrom-Lindberg E (2005) Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood 106(3):803–811. https://doi.org/10.1182/blood-2004-10-3872

    Article  CAS  PubMed  Google Scholar 

  33. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl IMS, Dybedal I, Grimfors G, Hesse-Sundin E, Hjorth M, Kanter-Lewensohn L, Linder O, Luthman M, Löfvenberg E, Öberg G, Porwit-MacDonald A, Rådlund A, Samuelsson J, Tangen JM, Winquist I, Wisloff F, Group ftSM (2003) A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol 120(6):1037–1046. https://doi.org/10.1046/j.1365-2141.2003.04153.x

    Article  PubMed  Google Scholar 

  34. Buckstein R, Balleari E, Wells R, Santini V, Sanna A, Salvetti C, Crisa E, Allione B, Danise P, Finelli C, Clavio M, Poloni A, Salvi F, Cilloni D, Oliva EN, Musto P, Houston B, Zhu N, Geddes M, Leitch H, Leber B, Sabloff M, Nevill TJ, Yee KW, Storring JM, Francis J, Maurillo L, Latagliata R, Spiriti MAA, Andriani A, Piccioni AL, Fianchi L, Fenu S, Gumenyuk S, Buccisano F (2017) ITACA: a new validated international erythropoietic stimulating agent-response score that further refines the predictive power of previous scoring systems. Am J Hematol 92(10):1037–1046. https://doi.org/10.1002/ajh.24842

    Article  PubMed  Google Scholar 

  35. Santini V, Schemenau J, Levis A, Balleari E, Sapena R, Adès L, Guerci A, Beyne-Rauzy O, Gourin M-P, Cheze S, Stamatoullas A, Sanna A, Gioia D, Cametti G, Ferrero D, Raffoux E, Rose C, Poloni A, Prebet T, Legros L, Natarajan-Amé S, Fenaux P, Germing U, Dreyfus F, Park S (2013) Can the revised IPSS predict response to erythropoietic-stimulating agents in patients with classical IPSS low or intermediate-1 MDS? Blood 122(13):2286–2288. https://doi.org/10.1182/blood-2013-07-512442

    Article  CAS  PubMed  Google Scholar 

  36. Oelschlaegel U, Alexander Röhnert M, Mohr B, Sockel K, Herold S, Ehninger G, Bornhäuser M, Thiede C, Platzbecker U (2016) Clonal architecture of del(5q) myelodysplastic syndromes: aberrant CD5 or CD7 expression within the myeloid progenitor compartment defines a subset with high clonal burden. Leukemia 30(2):517–520. https://doi.org/10.1038/leu.2015.158

    Article  CAS  PubMed  Google Scholar 

  37. Park S, Hamel JF, Toma A, Kelaidi C, Thepot S, Campelo MD, Santini V, Sekeres MA, Balleari E, Kaivers J, Sapena R, Gotze K, Muller-Thomas C, Beyne-Rauzy O, Stamatoullas A, Kotsianidis I, Komrokji R, Steensma DP, Fensterl J, Roboz GJ, Bernal T, Ramos F, Calabuig M, Guerci-Bresler A, Bordessoule D, Cony-Makhoul P, Cheze S, Wattel E, Rose C, Vey N, Gioia D, Ferrero D, Gaidano G, Cametti G, Pane F, Sanna A, Germing U, Sanz GF, Dreyfus F, Fenaux P (2017) Outcome of lower-risk patients with myelodysplastic syndromes without 5q deletion after failure of erythropoiesis-stimulating agents. J Clin Oncol 35(14):1591–1597. https://doi.org/10.1200/jco.2016.71.3271

    Article  PubMed  Google Scholar 

  38. Jadersten M, Malcovati L, Dybedal I, Della Porta MG, Invernizzi R, Montgomery SM, Pascutto C, Porwit A, Cazzola M, Hellstrom-Lindberg E (2008) Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol 26(21):3607–3613. https://doi.org/10.1200/jco.2007.15.4906

    Article  PubMed  Google Scholar 

  39. Affentranger L, Bohlius J, Hallal M, Bonadies N (2019) Efficacy of granulocyte colony stimulating factor in combination with erythropoiesis stimulating agents for treatment of anemia in patients with lower risk myelodysplastic syndromes: a systematic review. Crit Rev Oncol Hematol 136:37–47. https://doi.org/10.1016/j.critrevonc.2019.01.021

    Article  PubMed  Google Scholar 

  40. Balleari E, Rossi E, Clavio M, Congiu A, Gobbi M, Grosso M, Secondo V, Spriano M, Timitilli S, Ghio R (2006) Erythropoietin plus granulocyte colony-stimulating factor is better than erythropoietin alone to treat anemia in low-risk myelodysplastic syndromes: results from a randomized single-centre study. Ann Hematol 85(3):174–180. https://doi.org/10.1007/s00277-005-0044-6

    Article  CAS  PubMed  Google Scholar 

  41. Gotlib J, Lavori P, Quesada S, Stein RS, Shahnia S, Greenberg PL (2009) A phase II intra-patient dose-escalation trial of weight-based darbepoetin alfa with or without granulocyte-colony stimulating factor in myelodysplastic syndromes. Am J Hematol 84(1):15–20. https://doi.org/10.1002/ajh.21316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kelaidi C, Park S, Sapena R, Beyne-Rauzy O, Coiteux V, Vey N, Stamatoullas A, Choufi B, Delaunay J, Gourin MP, Cheze S, Ravoet C, Ferrant A, Escoffre-Barbe M, Aljassem L, Raffoux E, Itzykson R, Ades L, Dreyfus F, Fenaux P (2013) Long-term outcome of anemic lower-risk myelodysplastic syndromes without 5q deletion refractory to or relapsing after erythropoiesis-stimulating agents. Leukemia 27(6):1283–1290. https://doi.org/10.1038/leu.2013.16

    Article  CAS  PubMed  Google Scholar 

  43. Leitch HA, Parmar A, Wells RA, Chodirker L, Zhu N, Nevill TJ, Yee KWL, Leber B, Keating MM, Sabloff M, St Hilaire E, Kumar R, Delage R, Geddes M, Storring JM, Kew A, Shamy A, Elemary M, Lenis M, Mamedov A, Ivo J, Francis J, Zhang L, Buckstein R (2017) Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient-related factors and measuring from time of first red blood cell transfusion dependence: an MDS-CAN analysis. Br J Haematol 179(1):83–97. https://doi.org/10.1111/bjh.14825

    Article  CAS  PubMed  Google Scholar 

  44. Raptis A, Duh MS, Wang ST, Dial E, Fanourgiakis I, Fortner B, Paley C, Mody-Patel N, Corral M, Scott J (2010) Treatment of transfusional iron overload in patients with myelodysplastic syndrome or severe anemia: data from multicenter clinical practices. Transfusion 50(1):190–199. https://doi.org/10.1111/j.1537-2995.2009.02361.x

    Article  CAS  PubMed  Google Scholar 

  45. Remacha AF, Arrizabalaga B, Villegas A, Duran MS, Hermosin L, de Paz R, Garcia M, Diez Campelo M, Sanz G (2015) Evolution of iron overload in patients with low-risk myelodysplastic syndrome: iron chelation therapy and organ complications. Ann Hematol 94(5):779–787. https://doi.org/10.1007/s00277-014-2274-y

    Article  CAS  PubMed  Google Scholar 

  46. Rose C, Brechignac S, Vassilief D, Pascal L, Stamatoullas A, Guerci A, Larbaa D, Dreyfus F, Beyne-Rauzy O, Chaury MP, Roy L, Cheze S, Morel P, Fenaux P (2010) Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myelodysplasies). Leuk Res 34(7):864–870. https://doi.org/10.1016/j.leukres.2009.12.004

    Article  CAS  PubMed  Google Scholar 

  47. Angelucci E, Li J, Greenberg PL, Depei W, Hou M, Montaño Figueroa E, Rodriguez G, Dong X, Ghosh J, Bornstein O, Garcia-Manero G (2018) Safety and efficacy, including event-free survival, of deferasirox versus placebo in iron-overloaded patients with low- and int-1-risk myelodysplastic syndromes (MDS): outcomes from the randomized, double-blind Telesto study. Blood 132(supplement 1):234. https://doi.org/10.1182/blood-2018-99-111134

    Article  Google Scholar 

  48. Stahl M, Bewersdorf JP, Giri S, Wang R, Zeidan AM (2020) Use of immunosuppressive therapy for management of myelodysplastic syndromes: a systematic review and meta-analysis. Haematologica 105(1):102–111. https://doi.org/10.3324/haematol.2019.219345

    Article  PubMed  PubMed Central  Google Scholar 

  49. Xiao L, Qi Z, Qiusheng C, Li X, Luxi S, Lingyun W (2012) The use of selective immunosuppressive therapy on myelodysplastic syndromes in targeted populations results in good response rates and avoids treatment-related disease progression. Am J Hematol 87(1):26–31. https://doi.org/10.1002/ajh.22184

    Article  PubMed  Google Scholar 

  50. Stahl M, DeVeaux M, de Witte T, Neukirchen J, Sekeres MA, Brunner AM, Roboz GJ, Steensma DP, Bhatt VR, Platzbecker U, Cluzeau T, Prata PH, Itzykson R, Fenaux P, Fathi AT, Smith A, Germing U, Ritchie EK, Verma V, Nazha A, Maciejewski JP, Podoltsev NA, Prebet T, Santini V, Gore SD, Komrokji RS, Zeidan AM (2018) The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort. Blood Adv 2(14):1765–1772. https://doi.org/10.1182/bloodadvances.2018019414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Komrokji RS, Mailloux AW, Chen DT, Sekeres MA, Paquette R, Fulp WJ, Sugimori C, Paleveda-Pena J, Maciejewski JP, List AF, Epling-Burnette PK (2014) A phase II multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction. Haematologica 99(7):1176–1183. https://doi.org/10.3324/haematol.2012.083345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sloand EM, Wu CO, Greenberg P, Young N, Barrett J (2008) Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 26(15):2505–2511. https://doi.org/10.1200/JCO.2007.11.9214

    Article  PubMed  PubMed Central  Google Scholar 

  53. Lim ZY, Killick S, Germing U, Cavenagh J, Culligan D, Bacigalupo A, Marsh J, Mufti GJ (2007) Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia 21(7):1436–1441. https://doi.org/10.1038/sj.leu.2404747

    Article  CAS  PubMed  Google Scholar 

  54. Saunthararajah Y, Nakamura R, Wesley R, Wang QJ, Barrett AJ (2003) A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood 102(8):3025–3027. https://doi.org/10.1182/blood-2002-11-3325

    Article  CAS  PubMed  Google Scholar 

  55. Passweg JR, Giagounidis AA, Simcock M, Aul C, Dobbelstein C, Stadler M, Ossenkoppele G, Hofmann WK, Schilling K, Tichelli A, Ganser A (2011) Immunosuppressive therapy for patients with myelodysplastic syndrome: a prospective randomized multicenter phase III trial comparing antithymocyte globulin plus cyclosporine with best supportive care--SAKK 33/99. J Clin Oncol 29(3):303–309. https://doi.org/10.1200/JCO.2010.31.2686

    Article  CAS  PubMed  Google Scholar 

  56. Network NCC (2019) NCCN guidelines version 2.2019: myelodysplastic syndromes. https://www.nccn.org/store/login/login.aspx?ReturnURL=https%3a%2f%2fwww.nccn.org%2fprofessionals%2fphysician_gls%2fPDF%2fmds.pdf. Accessed 20.12.2018 2018

  57. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R, Myelodysplastic Syndrome-003 Study I (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355(14):1456–1465. https://doi.org/10.1056/NEJMoa061292

    Article  CAS  PubMed  Google Scholar 

  58. Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Canizo C, Guerci-Bresler A, Nilsson L, Platzbecker U, Lubbert M, Quesnel B, Cazzola M, Ganser A, Bowen D, Schlegelberger B, Aul C, Knight R, Francis J, Fu T, Hellstrom-Lindberg E, Group MDSLdqS (2011) A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with del5q. Blood 118(14):3765–3776. https://doi.org/10.1182/blood-2011-01-330126

    Article  CAS  PubMed  Google Scholar 

  59. Schuler E, Giagounidis A, Haase D, Shirneshan K, Busche G, Platzbecker U, Nolte F, Gotze K, Schlenk RF, Ganser A, Letsch A, Braulke F, Lubbert M, Bug G, Schafhausen P, Bacher U, Gattermann N, Wulfert M, Haas R, Germing U (2016) Results of a multicenter prospective phase II trial investigating the safety and efficacy of lenalidomide in patients with myelodysplastic syndromes with isolated del(5q) (LE-MON 5). Leukemia 30(7):1580–1582. https://doi.org/10.1038/leu.2015.340

    Article  CAS  PubMed  Google Scholar 

  60. Giagounidis A, Mufti GJ, Mittelman M, Sanz G, Platzbecker U, Muus P, Selleslag D, Beyne-Rauzy O, te Boekhorst P, del Cañizo C, Guerci-Bresler A, Nilsson L, Lübbert M, Quesnel B, Ganser A, Bowen D, Schlegelberger B, Göhring G, Fu T, Benettaib B, Hellström-Lindberg E, Fenaux P (2014) Outcomes in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study. Eur J Haematol 93(5):429–438. https://doi.org/10.1111/ejh.12380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mossner M, Jann JC, Nowak D, Platzbecker U, Giagounidis A, Gotze K, Letsch A, Haase D, Shirneshan K, Braulke F, Schlenk RF, Haferlach T, Schafhausen P, Bug G, Lubbert M, Ganser A, Busche G, Schuler E, Nowak V, Pressler J, Oblander J, Fey S, Muller N, Lauinger-Lorsch E, Metzgeroth G, Weiss C, Hofmann WK, Germing U, Nolte F (2016) Prevalence, clonal dynamics and clinical impact of TP53 mutations in patients with myelodysplastic syndrome with isolated deletion (5q) treated with lenalidomide: results from a prospective multicenter study of the German MDS study group (GMDS). Leukemia 30(9):1956–1959. https://doi.org/10.1038/leu.2016.111

    Article  CAS  PubMed  Google Scholar 

  62. Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, Hedlund A, Hast R, Schlegelberger B, Porwit A, Hellström-Lindberg E, Mufti GJ (2011) TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 29(15):1971–1979. https://doi.org/10.1200/JCO.2010.31.8576

    Article  PubMed  Google Scholar 

  63. Mallo M, Del Rey M, Ibanez M, Calasanz MJ, Arenillas L, Larrayoz MJ, Pedro C, Jerez A, Maciejewski J, Costa D, Nomdedeu M, Diez-Campelo M, Lumbreras E, Gonzalez-Martinez T, Marugan I, Such E, Cervera J, Cigudosa JC, Alvarez S, Florensa L, Hernandez JM, Sole F (2013) Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and mutations. Br J Haematol 162(1):74–86. https://doi.org/10.1111/bjh.12354

    Article  CAS  PubMed  Google Scholar 

  64. Santini V, Almeida A, Giagounidis A, Gropper S, Jonasova A, Vey N, Mufti GJ, Buckstein R, Mittelman M, Platzbecker U, Shpilberg O, Ram R, Del Canizo C, Gattermann N, Ozawa K, Risueno A, MacBeth KJ, Zhong J, Seguy F, Hoenekopp A, Beach CL, Fenaux P (2016) 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 34(25):2988–2996. https://doi.org/10.1200/JCO.2015.66.0118

    Article  CAS  PubMed  Google Scholar 

  65. Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, Dreisbach L, Schiffer CA, Stone RM, Greenberg PL, Curtin PT, Klimek VM, Shammo JM, Thomas D, Knight RD, Schmidt M, Wride K, Zeldis JB, List AF (2008) Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 111(1):86–93. https://doi.org/10.1182/blood-2007-01-068833

    Article  CAS  PubMed  Google Scholar 

  66. Toma A, Kosmider O, Chevret S, Delaunay J, Stamatoullas A, Rose C, Beyne-Rauzy O, Banos A, Guerci-Bresler A, Wickenhauser S, Caillot D, Laribi K, De Renzis B, Bordessoule D, Gardin C, Slama B, Sanhes L, Gruson B, Cony-Makhoul P, Chouffi B, Salanoubat C, Benramdane R, Legros L, Wattel E, Tertian G, Bouabdallah K, Guilhot F, Taksin AL, Cheze S, Maloum K, Nimuboma S, Soussain C, Isnard F, Gyan E, Petit R, Lejeune J, Sardnal V, Renneville A, Preudhomme C, Fontenay M, Fenaux P, Dreyfus F (2016) Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. Leukemia 30(4):897–905. https://doi.org/10.1038/leu.2015.296

    Article  CAS  PubMed  Google Scholar 

  67. Sibon D, Cannas G, Baracco F, Prebet T, Vey N, Banos A, Besson C, Corm S, Blanc M, Slama B, Perrier H, Fenaux P, Wattel E (2012) Lenalidomide in lower-risk myelodysplastic syndromes with karyotypes other than deletion 5q and refractory to erythropoiesis-stimulating agents. Br J Haematol 156(5):619–625. https://doi.org/10.1111/j.1365-2141.2011.08979.x

    Article  CAS  PubMed  Google Scholar 

  68. Stahl M, Zeidan AM (2017) Lenalidomide use in myelodysplastic syndromes: insights into the biologic mechanisms and clinical applications. Cancer 123(10):1703–1713. https://doi.org/10.1002/cncr.30585

    Article  CAS  PubMed  Google Scholar 

  69. Kubasch AS, Schulze F, Giagounidis A, Götze KS, Krönke J, Sockel K, Middeke JM, Chermat F, Gloaguen S, Puttrich M, Weigt C, William D, Fenaux P, Schlenk RF, Thiede C, Stasik S, Mies A, Adès L, Oelschlägel U, Platzbecker U (2019) Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents. Leukemia. https://doi.org/10.1038/s41375-019-0645-z

  70. Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, Radsak M, Wolff T, Zhang X, Laadem A, Sherman ML, Attie KM, Giagounidis A (2017) 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 18(10):1338–1347. https://doi.org/10.1016/S1470-2045(17)30615-0

    Article  CAS  PubMed  Google Scholar 

  71. Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi F, Giai V, Vyas P, Bowen D, Selleslag D, DeZern AE, Jurcic JG, Germing U, Götze KS, Quesnel B, Beyne-Rauzy O, Cluzeau T, Voso MT, Mazure D, Vellenga E, Greenberg PL, Hellström-Lindberg E, Zeidan AM, Laadem A, Benzohra A, Zhang J, Rampersad A, Linde PG, Sherman ML, Komrokji RS, List AF (2018) The Medalist trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood 132(Suppl 1):1–1. https://doi.org/10.1182/blood-2018-99-110805

    Article  Google Scholar 

  72. Komrokji R, Garcia-Manero G, Ades L, Prebet T, Steensma DP, Jurcic JG, Sekeres MA, Berdeja J, Savona MR, Beyne-Rauzy O, Stamatoullas A, DeZern AE, Delaunay J, Borthakur G, Rifkin R, Boyd TE, Laadem A, Vo B, Zhang J, Puccio-Pick M, Attie KM, Fenaux P, List AF (2018) 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 5(2):e63–e72. https://doi.org/10.1016/S2352-3026(18)30002-4

    Article  PubMed  Google Scholar 

  73. Mies A, Platzbecker U (2017) Increasing the effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis-stimulating agents and transforming growth factor-beta superfamily inhibitors. Semin Hematol 54(3):141–146. https://doi.org/10.1053/j.seminhematol.2017.06.004

    Article  PubMed  Google Scholar 

  74. Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Diez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi F, Giai V, Vyas P, Bowen D, Selleslag D, DeZern AE, Jurcic JG, Germing U, Gotze KS, Quesnel B, Beyne-Rauzy O, Cluzeau T, Voso MT, Mazure D, Vellenga E, Greenberg PL, Hellstrom-Lindberg E, Zeidan AM, Ades L, Verma A, Savona MR, Laadem A, Benzohra A, Zhang J, Rampersad A, Dunshee DR, Linde PG, Sherman ML, Komrokji RS, List AF (2020) Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med 382(2):140–151. https://doi.org/10.1056/NEJMoa1908892

    Article  CAS  PubMed  Google Scholar 

  75. Platzbecker U, Dunshee D, Komrokji RS, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, Sekeres MA, See WL, Tsai K, Risueño A, Ma J, Schwickart M, Rampersad A, Zhang J, Laadem A, Menezes D, MacBeth K, Linde PG, Reynolds JG, List AF, Fenaux P (2019) Luspatercept significantly reduces red blood cell (RBC) transfusion burden, regardless of gene mutation frequency, spectrum, and prognostic significance, among patients (pts) with LR-MDS enrolled in the MEDALIST trial. Blood 134(Supplement_1):2999. https://doi.org/10.1182/blood-2019-123655

    Article  Google Scholar 

  76. Garcia-Manero G, Mufti GJ, Fenaux P, Buckstein R, Santini V, Díez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, List AF, Laadem A, Ito R, Zhang J, Rampersad A, Sinsimer D, Linde PG, Platzbecker U, Komrokji R (2019) Hematologic improvement-neutrophil and -platelet in the MEDALIST trial: multilineage data from a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood 134(Supplement_1):4243. https://doi.org/10.1182/blood-2019-123048

    Article  Google Scholar 

  77. Platzbecker U (2019) Treatment of MDS. Blood:blood-2018-2010-844696. doi:https://doi.org/10.1182/blood-2018-10-844696

  78. Santini V, Valcarcel D, Platzbecker U, Komrokji RS, Cleverly A, Lahn MM, Janssen J, Zhao Y, Chiang A, Giagounidis A, Guba SC, Sridharan A, Gueorguieva I, Girvan A, da Silva FM, Bhagat TD, Pradhan K, Steidl U, Will B, Verma A (2019) Phase 2 study of the ALK5 inhibitor Galunisertib in very low-, low-, and intermediate-risk myelodysplastic syndromes. Clin Cancer Res. https://doi.org/10.1158/1078-0432.Ccr-19-1338

  79. Muench DE, Ferchen K, Velu CS, Pradhan K, Chetal K, Chen X, Weirauch MT, Colmenares C, Verma A, Salomonis N, Grimes HL (2018) SKI controls MDS-associated chronic TGF-beta signaling, aberrant splicing, and stem cell fitness. Blood 132(21):e24–e34. https://doi.org/10.1182/blood-2018-06-860890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kubasch AS, Platzbecker U (2019) Setting fire to ESA and EMA resistance: new targeted treatment options in lower risk myelodysplastic syndromes. Int J Mol Sci 20(16):3853. https://doi.org/10.3390/ijms20163853

    Article  CAS  PubMed Central  Google Scholar 

  81. Chen N, Hao C, Peng X, Lin H, Yin A, Hao L, Tao Y, Liang X, Liu Z, Xing C, Chen J, Luo L, Zuo L, Liao Y, Liu BC, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP (2019) Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med 381(11):1001–1010. https://doi.org/10.1056/NEJMoa1813599

    Article  PubMed  Google Scholar 

  82. Chen N, Hao C, Liu BC, Lin H, Wang C, Xing C, Liang X, Jiang G, Liu Z, Li X, Zuo L, Luo L, Wang J, Zhao MH, Liu Z, Cai GY, Hao L, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP (2019) Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med 381(11):1011–1022. https://doi.org/10.1056/NEJMoa1901713

    Article  PubMed  Google Scholar 

  83. Henry DH, Glaspy J, Harrup RA, Mittelman M, Zhou A, Bradley C, Saha G, Bartels P, Robert L, Yu K-HP (2019) Roxadustat (FG4592; ASP1517; AZD9941) in the treatment of anemia in patients with lower risk myelodysplastic syndrome (LR-MDS) and low red blood cell (RBC) transfusion burden (LTB). Blood 134(Supplement_1):843. https://doi.org/10.1182/blood-2019-128714

    Article  Google Scholar 

  84. Calado RT, Young NS (2009) Telomere diseases. N Engl J Med 361(24):2353–2365. https://doi.org/10.1056/NEJMra0903373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gurkan E, Tanriverdi K, Baslamisli F (2005) Telomerase activity in myelodysplastic syndromes. Leuk Res 29(10):1131–1139. https://doi.org/10.1016/j.leukres.2005.03.006

    Article  CAS  PubMed  Google Scholar 

  86. Gohring G, Lange K, Hofmann W, Nielsen KV, Hellstrom-Lindberg E, Roy L, Morgan M, Kreipe H, Busche G, Giagounidis A, Schlegelberger B (2012) Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide. Leukemia 26(2):356–358. https://doi.org/10.1038/leu.2011.193

    Article  CAS  PubMed  Google Scholar 

  87. Lange K, Holm L, Vang Nielsen K, Hahn A, Hofmann W, Kreipe H, Schlegelberger B, Gohring G (2010) Telomere shortening and chromosomal instability in myelodysplastic syndromes. Genes Chromosomes Cancer 49(3):260–269. https://doi.org/10.1002/gcc.20737

    Article  CAS  PubMed  Google Scholar 

  88. Park HS, Choi J, See CJ, Kim JA, Park SN, Im K, Kim SM, Lee DS, Hwang SM (2017) Dysregulation of telomere lengths and telomerase activity in myelodysplastic syndrome. Ann Lab Med 37(3):195–203. https://doi.org/10.3343/alm.2017.37.3.195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Baerlocher GM, Oppliger Leibundgut E, Ottmann OG, Spitzer G, Odenike O, McDevitt MA, Roth A, Daskalakis M, Burington B, Stuart M, Snyder DS (2015) Telomerase inhibitor imetelstat in patients with essential thrombocythemia. N Engl J Med 373(10):920–928. https://doi.org/10.1056/NEJMoa1503479

    Article  CAS  PubMed  Google Scholar 

  90. Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, Laborde RR, Wassie E, Schimek L, Hanson CA, Gangat N, Wang X, Pardanani A (2015) A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med 373(10):908–919. https://doi.org/10.1056/NEJMoa1310523

    Article  CAS  PubMed  Google Scholar 

  91. Fenaux P, Steensma D, Van Eygen K, Raza A, Santini V, Germing U, Font P, Díez-Campelo M, Thepot S, Vellenga E, Patnaik M, Jang J, Sherman J, Sun L, Varsos H, Rizo A, Wan Y, Huang F, Bussolari J, Rose E, Platzbecker U (2019) Treatment with imetelstat provides durable transfusion independence (TI) in heavily transfused non-del(5q) lower risk MDS (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESAS). EHA library Jun 15, 2019; 267420; S837

  92. Fenaux P, Raza A, Vellenga E, Platzbecker U, Santini V, Samarina I, Van Eygen K, Díez-Campelo M, Patnaik MM, Sherman L, Sun L, Varsos H, Rose E, Rizo A, Steensma DP (2017) Efficacy and safety of imetelstat in RBC transfusion-dependent (TD) IPSS low/Int-1 MDS relapsed/refractory to erythropoiesis-stimulating agents (ESA) (IMerge). Blood 130(Suppl 1):4256

    Google Scholar 

  93. Steensma DP, Platzbecker U, Van Eygen K, Raza A, Santini V, Germing U, Font P, Samarina I, Díez-Campelo M, Thepot S, Vellenga E, Patnaik MM, Jang JH, Bussolari J, Sherman L, Sun L, Varsos H, Rose E, Fenaux P (2018) Imetelstat treatment leads to durable transfusion independence (TI) in RBC transfusion-dependent (TD), non-del(5q) lower risk MDS relapsed/refractory to erythropoiesis-stimulating agent (ESA) who are Lenalidomide (LEN) and HMA naive. Blood 132(Suppl 1):463. https://doi.org/10.1182/blood-2018-99-114877

    Article  Google Scholar 

  94. Houwerzijl EJ, Blom NR, van der Want JJ, Louwes H, Esselink MT, Smit JW, Vellenga E, de Wolf JT (2005) Increased peripheral platelet destruction and caspase-3-independent programmed cell death of bone marrow megakaryocytes in myelodysplastic patients. Blood 105(9):3472–3479. https://doi.org/10.1182/blood-2004-06-2108

    Article  CAS  PubMed  Google Scholar 

  95. Tamura H, Ogata K, Luo S, Nakamura K, Yokose N, Dan K, Tohyama K, Yoshida Y, Hamaguchi H, Sakamaki H, Kuwaki T, Tahara T, Kato T, Nomura T (1998) Plasma thrombopoietin (TPO) levels and expression of TPO receptor on platelets in patients with myelodysplastic syndromes. Br J Haematol 103(3):778–784. https://doi.org/10.1046/j.1365-2141.1998.01054.x

    Article  CAS  PubMed  Google Scholar 

  96. Kantarjian H, Fenaux P, Sekeres MA, Becker PS, Boruchov A, Bowen D, Hellstrom-Lindberg E, Larson RA, Lyons RM, Muus P, Shammo J, Siegel R, Hu K, Franklin J, Berger DP (2010) Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol 28(3):437–444. https://doi.org/10.1200/jco.2009.24.7999

    Article  CAS  PubMed  Google Scholar 

  97. Sekeres MA, Kantarjian H, Fenaux P, Becker P, Boruchov A, Guerci-Bresler A, Hu K, Franklin J, Wang YM, Berger D (2011) Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower risk myelodysplastic syndromes. Cancer 117(5):992–1000. https://doi.org/10.1002/cncr.25545

    Article  CAS  PubMed  Google Scholar 

  98. Fenaux P, Muus P, Kantarjian H, Lyons RM, Larson RA, Sekeres MA, Becker PS, Orejudos A, Franklin J (2017) Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long-term safety and efficacy. Br J Haematol 178(6):906–913. https://doi.org/10.1111/bjh.14792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sekeres MA, Giagounidis A, Kantarjian H, Mufti GJ, Fenaux P, Jia C, Yang AS, Platzbecker U (2014) Development and validation of a model to predict platelet response to romiplostim in patients with lower-risk myelodysplastic syndromes. Br J Haematol 167(3):337–345. https://doi.org/10.1111/bjh.13037

    Article  CAS  PubMed  Google Scholar 

  100. Oliva EN, Alati C, Santini V, Poloni A, Molteni A, Niscola P, Salvi F, Sanpaolo G, Balleari E, Germing U, Fenaux P, Stamatoullas A, Palumbo GA, Salutari P, Impera S, Avanzini P, Cortelezzi A, Liberati AM, Carluccio P, Buccisano F, Voso MT, Mancini S, Kulasekararaj A, Morabito F, Bocchia M, Cufari P, Spiriti MA, Santacaterina I, D'Errigo MG, Bova I, Zini G, Latagliata R (2017) Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol 4(3):e127–e136. https://doi.org/10.1016/s2352-3026(17)30012-1

    Article  PubMed  Google Scholar 

  101. Mittelman M, Platzbecker U, Afanasyev B, Grosicki S, Wong RSM, Anagnostopoulos A, Brenner B, Denzlinger C, Rossi G, Nagler A, Garcia-Delgado R, Portella MSO, Zhu Z, Selleslag D (2018) Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial. Lancet Haematol 5(1):e34–e43. https://doi.org/10.1016/s2352-3026(17)30228-4

    Article  PubMed  Google Scholar 

  102. Corazza F, Hermans C, D'Hondt S, Ferster A, Kentos A, Benoit Y, Sariban E (2006) Circulating thrombopoietin as an in vivo growth factor for blast cells in acute myeloid leukemia. Blood 107(6):2525–2530. https://doi.org/10.1182/blood-2005-06-2552

    Article  CAS  PubMed  Google Scholar 

  103. Kantarjian HM, Fenaux P, Sekeres MA, Szer J, Platzbecker U, Kuendgen A, Gaidano G, Wiktor-Jedrzejczak W, Carpenter N, Mehta B, Franklin J, Giagounidis A (2018) Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial. Lancet Haematol 5(3):e117–e126. https://doi.org/10.1016/S2352-3026(18)30016-4

    Article  PubMed  Google Scholar 

  104. Dodillet H, Kreuzer KA, Monsef I, Skoetz N (2017) Thrombopoietin mimetics for patients with myelodysplastic syndromes. Cochrane Database Syst Rev 9:CD009883. https://doi.org/10.1002/14651858.CD009883.pub2

    Article  PubMed  Google Scholar 

  105. Prica A, Sholzberg M, Buckstein R (2014) Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials. Br J Haematol 167(5):626–638. https://doi.org/10.1111/bjh.13088

    Article  CAS  PubMed  Google Scholar 

  106. Platzbecker U, Wong RS, Verma A, Abboud C, Araujo S, Chiou TJ, Feigert J, Yeh SP, Gotze K, Gorin NC, Greenberg P, Kambhampati S, Kim YJ, Lee JH, Lyons R, Ruggeri M, Santini V, Cheng G, Jang JH, Chen CY, Johnson B, Bennett J, Mannino F, Kamel YM, Stone N, Dougherty S, Chan G, Giagounidis A (2015) Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial. Lancet Haematol 2(10):e417–e426. https://doi.org/10.1016/s2352-3026(15)00149-0

    Article  PubMed  Google Scholar 

  107. Kantarjian HM, Giles FJ, Greenberg PL, Paquette RL, Wang ES, Gabrilove JL, Garcia-Manero G, Hu K, Franklin JL, Berger DP (2010) Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood 116(17):3163–3170. https://doi.org/10.1182/blood-2010-03-274753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Dickinson M, Cherif H, Fenaux P, Mittelman M, Verma A, Portella MSO, Burgess P, Ramos PM, Choi J, Platzbecker U, investigators Ss (2018) Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood 132(25):2629–2638. https://doi.org/10.1182/blood-2018-06-855221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Greenberg PL, Garcia-Manero G, Moore M, Damon L, Roboz G, Hu K, Yang AS, Franklin J (2013) A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma 54(2):321–328. https://doi.org/10.3109/10428194.2012.713477

    Article  CAS  PubMed  Google Scholar 

  110. Wang ES, Lyons RM, Larson RA, Gandhi S, Liu D, Matei C, Scott B, Hu K, Yang AS (2012) A randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide. J Hematol Oncol 5:71. https://doi.org/10.1186/1756-8722-5-71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bewersdorf JP, Shallis RM, Stahl M, Zeidan AM (2019) Epigenetic therapy combinations in acute myeloid leukemia: what are the options? Ther Adv Hematol 10:2040620718816698. https://doi.org/10.1177/2040620718816698

  112. Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, Harb W, Kantarjian H, Lowder J, Oganesian A, Azab M, Garcia-Manero G (2019) An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol 6(4):e194–e203. https://doi.org/10.1016/s2352-3026(19)30030-4

    Article  PubMed  Google Scholar 

  113. Garcia-Manero G, Griffiths EA, Roboz GJ, Busque L, Wells RA, Odenike O, Steensma DP, Yee KWL, Faderl S, Amrein PC, Michaelis LC, Kantarjian HM, Oganesian A, Lowder JN, Azab M, Savona MR (2017) A phase 2 dose-confirmation study of oral ASTX727, a combination of oral decitabine with a cytidine deaminase inhibitor (CDAi) cedazuridine (E7727), in subjects with myelodysplastic syndromes (MDS). Blood 130(Suppl 1):4274

    Google Scholar 

  114. Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, Ravandi F, Sayar H, Jang JH, Porkka K, Selleslag D, Sandhu I, Turgut M, Giai V, Ofran Y, Kizil Cakar M, Botelho de Sousa A, Rybka J, Frairia C, Borin L, Beltrami G, Cermak J, Ossenkoppele GJ, La Torre I, Skikne B, Kumar K, Dong Q, Beach C, Roboz GJ (2019) The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (Oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission. Blood 134(Supplement_2):LBA-3. https://doi.org/10.1182/blood-2019-132405

    Article  Google Scholar 

  115. Savona MR, Kolibaba K, Conkling P, Kingsley EC, Becerra C, Morris JC, Rifkin RM, Laille E, Kellerman A, Ukrainskyj SM, Dong Q, Skikne BS (2018) Extended dosing with CC-486 (oral azacitidine) in patients with myeloid malignancies. Am J Hematol. https://doi.org/10.1002/ajh.25216

  116. Garcia-Manero G, Gore SD, Kambhampati S, Scott B, Tefferi A, Cogle CR, Edenfield WJ, Hetzer J, Kumar K, Laille E, Shi T, MacBeth KJ, Skikne B (2016) Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia 30(4):889–896. https://doi.org/10.1038/leu.2015.265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Garcia-Manero G, Scott BL, Cogle CR, Boyd TE, Kambhampati S, Hetzer J, Dong Q, Kumar K, Ukrainskyj SM, Beach CL, Skikne BS (2018) CC-486 (oral azacitidine) in patients with myelodysplastic syndromes with pretreatment thrombocytopenia. Leuk Res 72:79–85. https://doi.org/10.1016/j.leukres.2018.08.001

    Article  CAS  PubMed  Google Scholar 

  118. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, Ebert BL (2011) Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 364(26):2496–2506. https://doi.org/10.1056/NEJMoa1013343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bejar R, Stevenson KE, Caughey B, Lindsley RC, Mar BG, Stojanov P, Getz G, Steensma DP, Ritz J, Soiffer R, Antin JH, Alyea E, Armand P, Ho V, Koreth J, Neuberg D, Cutler CS, Ebert BL (2014) Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J Clin Oncol 32(25):2691–2698. https://doi.org/10.1200/JCO.2013.52.3381

    Article  PubMed  PubMed Central  Google Scholar 

  120. Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, Yoon CJ, Ellis P, Wedge DC, Pellagatti A, Shlien A, Groves MJ, Forbes SA, Raine K, Hinton J, Mudie LJ, McLaren S, Hardy C, Latimer C, Della Porta MG, O'Meara S, Ambaglio I, Galli A, Butler AP, Walldin G, Teague JW, Quek L, Sternberg A, Gambacorti-Passerini C, Cross NC, Green AR, Boultwood J, Vyas P, Hellstrom-Lindberg E, Bowen D, Cazzola M, Stratton MR, Campbell PJ, Chronic Myeloid Disorders Working Group of the International Cancer Genome C (2013) Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122(22):3616–3627; quiz 3699. https://doi.org/10.1182/blood-2013-08-518886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bewersdorf JP, Stahl M, Zeidan AM (2019) Are we witnessing the start of a therapeutic revolution in acute myeloid leukemia? Leuk Lymphoma:1–16. https://doi.org/10.1080/10428194.2018.1546854

  122. Stein EM, Fathi AT, DiNardo CD, Pollyea DA, Swords RT, Roboz GJ, Collins R, Sekeres MA, Stone RM, Attar EC, Tosolini A, Xu Q, Amatangelo M, Gupta I, Knight RD, De Botton S, Tallman MS, Kantarjian HM (2016) Enasidenib (AG-221), a potent oral inhibitor of mutant Isocitrate dehydrogenase 2 (<em>IDH2</em>) enzyme, induces hematologic responses in patients with myelodysplastic syndromes (MDS). Blood 128(22):343

    Article  Google Scholar 

  123. Richard-Carpentier G, DeZern AE, Takahashi K, Konopleva MY, Loghavi S, Masarova L, Alvarado Y, Ravandi F, Montalban Bravo G, Naqvi K, Sasaki K, Delumpa R, Kwari M, Sekeres MA, Nazha A, Roboz GJ, Kantarjian HM, Garcia-Manero G, DiNardo CD (2019) Preliminary results from the phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS). Blood 134(Supplement_1):678. https://doi.org/10.1182/blood-2019-130501

    Article  Google Scholar 

  124. DiNardo CD, Watts JM, Stein EM, de Botton S, Fathi AT, Prince GT, Stein AS, Foran JM, Stone RM, Patel PA, Tallman MS, Choe S, Wang H, Zhang V, Dai D, Fan B, Yen KE, Kapsalis SM, Hickman D, Agresta SV, Liu H, Wu B, Attar EC, Kantarjian HM (2018) Ivosidenib (AG-120) induced durable remissions and transfusion independence in patients with IDH1-mutant relapsed or refractory myelodysplastic syndrome: results from a phase 1 dose escalation and expansion study. Blood 132(Suppl 1):1812. https://doi.org/10.1182/blood-2018-99-111264

    Article  Google Scholar 

  125. Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R (2017) Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia 31(2):272–281. https://doi.org/10.1038/leu.2016.275

    Article  CAS  PubMed  Google Scholar 

  126. Lin CC, Hou HA, Chou WC, Kuo YY, Liu CY, Chen CY, Lai YJ, Tseng MH, Huang CF, Chiang YC, Lee FY, Liu MC, Liu CW, Tang JL, Yao M, Huang SY, Ko BS, Wu SJ, Tsay W, Chen YC, Tien HF (2014) IDH mutations are closely associated with mutations of DNMT3A, ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution. Am J Hematol 89(2):137–144. https://doi.org/10.1002/ajh.23596

    Article  CAS  PubMed  Google Scholar 

  127. Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann M, Gohring G, Schumann C, Bug G, Ottmann O, Hofmann WK, Schlegelberger B, Ganser A, Heuser M (2010) IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica 95(10):1668–1674. https://doi.org/10.3324/haematol.2010.025494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bejar R, Lord A, Stevenson K, Bar-Natan M, Perez-Ladaga A, Zaneveld J, Wang H, Caughey B, Stojanov P, Getz G, Garcia-Manero G, Kantarjian H, Chen R, Stone RM, Neuberg D, Steensma DP, Ebert BL (2014) TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124(17):2705–2712. https://doi.org/10.1182/blood-2014-06-582809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Traina F, Visconte V, Elson P, Tabarroki A, Jankowska AM, Hasrouni E, Sugimoto Y, Szpurka H, Makishima H, O'Keefe CL, Sekeres MA, Advani AS, Kalaycio M, Copelan EA, Saunthararajah Y, Olalla Saad ST, Maciejewski JP, Tiu RV (2014) Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia 28(1):78–87. https://doi.org/10.1038/leu.2013.269

    Article  CAS  PubMed  Google Scholar 

  130. Takahashi K, Wang F, Sahil S, Zhang J, Gumbs C, Issa GC, Benton CB, Pierce S, Jabbour E, Daver N, Kadia T, DiNardo C, Kantarjian HM, Futreal A, Garcia-Manero G (2015) Presence of 4 or more driver mutations predicts poor response to hypomethylating agent (HMA) therapy and poor overall survival in MDS. Blood 126(23):1663

    Article  Google Scholar 

  131. Bejar R (2017) CHIP, ICUS, CCUS and other four-letter words. Leukemia 31(9):1869–1871. https://doi.org/10.1038/leu.2017.181

    Article  CAS  PubMed  Google Scholar 

  132. Bewersdorf JP, Ardasheva A, Podoltsev NA, Singh A, Biancon G, Halene S, Zeidan AM (2019) From clonal hematopoiesis to myeloid leukemia and what happens in between: will improved understanding lead to new therapeutic and preventive opportunities? Blood Rev 37:100587. https://doi.org/10.1016/j.blre.2019.100587

  133. Malcovati L, Galli A, Travaglino E, Ambaglio I, Rizzo E, Molteni E, Elena C, Ferretti VV, Catricala S, Bono E, Todisco G, Bianchessi A, Rumi E, Zibellini S, Pietra D, Boveri E, Camaschella C, Toniolo D, Papaemmanuil E, Ogawa S, Cazzola M (2017) Clinical significance of somatic mutation in unexplained blood cytopenia. Blood 129(25):3371–3378. https://doi.org/10.1182/blood-2017-01-763425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, Kluk MJ, Henderson B, Kinnunen L, Koistinen HA, Ladenvall C, Getz G, Correa A, Banahan BF, Gabriel S, Kathiresan S, Stringham HM, McCarthy MI, Boehnke M, Tuomilehto J, Haiman C, Groop L, Atzmon G, Wilson JG, Neuberg D, Altshuler D, Ebert BL (2014) Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371(26):2488–2498. https://doi.org/10.1056/NEJMoa1408617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, McConkey M, Gupta N, Gabriel S, Ardissino D, Baber U, Mehran R, Fuster V, Danesh J, Frossard P, Saleheen D, Melander O, Sukhova GK, Neuberg D, Libby P, Kathiresan S, Ebert BL (2017) Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 377(2):111–121. https://doi.org/10.1056/NEJMoa1701719

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

AMZ is a Leukemia and Lymphoma Society Scholar in Clinical Research and is also supported by a NCI’s Cancer Clinical Investigator Team Leadership Award (CCITLA). This research was partly funded by the Dennis Cooper Hematology Young Investigator Award (AMZ) and was in part supported by the National Cancer Institute of the National Institutes of Health under Award Number P30 CA016359.

Funding

This research was partly funded by the Dennis Cooper Hematology Young Investigator Award (AMZ) and was in part supported by the National Cancer Institute of the National Institutes of Health under Award Number P30 CA016359.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amer M. Zeidan.

Ethics declarations

Declaration of conflicts of interest

AMZ received research funding (institutional) from Celgene, Acceleron, Abbvie, Otsuka, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, and ADC Therapeutics. AMZ had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene, Ariad, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Trovagene, BeyondSpring, and Takeda. JPB declares that he has no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bewersdorf, J.P., Zeidan, A.M. Evolving therapies for lower-risk myelodysplastic syndromes. Ann Hematol 99, 677–692 (2020). https://doi.org/10.1007/s00277-020-03963-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-020-03963-1

Keywords

Navigation