Myelodysplastic syndrome - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main MDS page for regimens that include active anticancer treatment.
=Lower-risk MDS, all lines of therapy=
==Placebo==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Fenaux et al. 2011 (CC-5013-MDS-004) 	2005-2007 	Phase 3 (C)	1. Lenalidomide; 5 mg2. Lenalidomide; 10 mg 21/28	Lower RBC-TI for at least 26 weeks (primary endpoint)
Santini et al. 2016 (MDS-005) 	2010-2013 	Phase 3 (C)	Lenalidomide 	Lower RBC-TI for at least 8 weeks
Platzbecker et al. 2017 (Amgen 20090160)	2011-12 to 2014-08 	Phase 3 (C)	Darbepoetin alfa 	Higher transfusion incidence from weeks 5 to 24
Fenaux et al. 2020 (MEDALIST) 	2016-03 to 2017-06 	Phase 3 (C)	Luspatercept 	Worse RBC-TI
Platzbecker et al. 2023 (IMerge) 	2019-09-11 to 2021-10-13	Phase 3 (C)	Imetelstat 	Lower RBC-TI at 8 or more weeks
No active antineoplastic treatment.
===References===
# CC-5013-MDS-004: Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Cañizo C, Guerci-Bresler A, Nilsson L, Platzbecker U, Lübbert M, Quesnel B, Cazzola M, Ganser A, Bowen D, Schlegelberger B, Aul C, Knight R, Francis J, Fu T, Hellström-Lindberg E; MDS-004 Lenalidomide del5q Study Group. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011 Oct 6;118(14):3765-76. Epub 2011 Jul 13. link to original article EuroPMC NCT00179621
##HRQoL analysis: Revicki DA, Brandenburg NA, Muus P, Yu R, Knight R, Fenaux P. Health-related quality of life outcomes of lenalidomide in transfusion-dependent patients with Low- or Intermediate-1-risk myelodysplastic syndromes with a chromosome 5q deletion: results from a randomized clinical trial. Leuk Res. 2013 Mar;37(3):259-65. Epub 2012 Dec 27. link to original article EuroPMC
# MDS-005: Santini V, Almeida A, Giagounidis A, Gröpper S, Jonasova A, Vey N, Mufti GJ, Buckstein R, Mittelman M, Platzbecker U, Shpilberg O, Ram R, Del Cañizo C, Gattermann N, Ozawa K, Risueño A, MacBeth KJ, Zhong J, Séguy F, Hoenekopp A, Beach CL, Fenaux P. 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 Sep 1;34(25):2988-96. Epub 2016 Jun 27. link to original article EuroPMC NCT01029262
#Amgen 20090160: Platzbecker U, Symeonidis A, Oliva EN, Goede JS, Delforge M, Mayer J, Slama B, Badre S, Gasal E, Mehta B, Franklin J. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017 Sep;31(9):1944-1950. Epub 2017 Jun 19. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01362140
# EPOANE3021: 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. A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia. 2018 Dec;32(12):2648-2658. Epub 2018 Mar 30. link to original article link to PMC article EuroPMC NCT01381809
# MEDALIST: 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, Adès L, Verma A, Savona MR, Laadem A, Benzohra A, Zhang J, Rampersad A, Dunshee DR, Linde PG, Sherman ML, Komrokji RS, List AF. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 2020 Jan 9;382(2):140-151. link to original article EuroPMC NCT02631070
##HRQoL analysis: Oliva EN, Platzbecker U, Garcia-Manero G, Mufti GJ, Santini V, Sekeres MA, Komrokji RS, Shetty JK, Tang D, Guo S, Liao W, Zhang G, Ha X, Ito R, Lord-Bessen J, Backstrom JT, Fenaux P. Health-Related Quality of Life Outcomes in Patients with Myelodysplastic Syndromes with Ring Sideroblasts Treated with Luspatercept in the MEDALIST Phase 3 Trial. J Clin Med. 2021 Dec 22;11(1):27. link to original article link to PMC article EuroPMC
#IMerge: Platzbecker U, Santini V, Fenaux P, Sekeres MA, Savona MR, Madanat YF, Díez-Campelo M, Valcárcel D, Illmer T, Jonášová A, Bělohlávková P, Sherman LJ, Berry T, Dougherty S, Shah S, Xia Q, Sun L, Wan Y, Huang F, Ikin A, Navada S, Feller F, Komrokji RS, Zeidan AM. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024 Jan 20;403(10423):249-260. Epub 2023 Dec 1. Erratum in: Lancet. 2024 Jan 20;403(10423):248. link to original article EuroPMC NCT02598661
=First-line therapy=
==Best supportive care==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Silverman et al. 2002 (CALGB 9221) 	1994-1996 	Phase 3 (C)	Azacitidine 	Seems to have shorter OS
Greenberg et al. 2009 (ECOG E1996) 	1997-2004 	Phase 3 (C)	Epoetin +/- G-CSF	Lower erythroid ORR
Passweg et al. 2010 (SAKK 33/99) 	2000-2006 	Phase 3 (C)	ATG & CSA 	Seems to have lower hematologic RR at 6 mo
Kantarjian et al. 2006 (D-0007) 	2001-2004 	Phase 3 (C)	Decitabine 	Lower ORR
Lübbert et al. 2011 (EORTC LSG/GMDSSG 06011)	2002-2007 	Phase 3 (C)	Decitabine 	Did not meet primary endpoint of OS
Fenaux et al. 2009 (AZA-001) 	2004-2006 	Phase 3 (C)	Azacitidine 	Shorter OSMedian OS: 15 vs 24.5 mo(HR 1.72, 95% CI 1.30-2.33)
Note: although EORTC LSG/GMDSSG 06011 had a significantly different PFS, it did not meet the primary endpoint of OS. No active antineoplastic therapy; included here because it was a comparator arm in several studies.
===References===
# CALGB 9221: Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2002 May 15;20(10):2429-40. link to original article EuroPMC
## HRQoL analysis: Kornblith AB, Herndon JE 2nd, Silverman LR, Demakos EP, Odchimar-Reissig R, Holland JF, Powell BL, DeCastro C, Ellerton J, Larson RA, Schiffer CA, Holland JC. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002 May 15;20(10):2441-52. link to original article EuroPMC
## Pooled update: Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, Larson RA; CALGB. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006 Aug 20;24(24):3895-903. link to original article EuroPMC
# D-0007: Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R 3rd, Shen L, Nimer SD, Leavitt R, Raza A, Saba H. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006 Apr 15;106(8):1794-803. link to original article EuroPMC NCT00043381
# AZA-001: 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 MDS Survival Study Group. 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 Mar;10(3):223-32. Epub 2009 Feb 21. link to original article link to PMC article EuroPMC content property of HemOnc.org NCT00071799
# ECOG E1996: 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. 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. 2009 Sep 17;114(12):2393-400. Epub 2009 Jun 29. link to original article link to PMC article EuroPMC NCT00003138
# SAKK 33/99: Passweg JR, Giagounidis AA, Simcock M, Aul C, Dobbelstein C, Stadler M, Ossenkoppele G, Hofmann WK, Schilling K, Tichelli A, Ganser A. 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. 2011 Jan 20;29(3):303-9. Epub 2010 Dec 13. link to original article EuroPMC NCT00004208
# EORTC LSG/GMDSSG 06011: Lübbert M, Suciu S, Baila L, Rüter BH, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, Beeldens F, Muus P, Pflüger KH, Coens C, Hagemeijer A, Eckart Schaefer H, Ganser A, Aul C, de Witte T, Wijermans PW; European Organisation for Research and Treatment of Cancer Leukemia Group; German MDS Study Group. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011 May 20;29(15):1987-96. Epub 2011 Apr 11. link to original article EuroPMC NCT00043134
## Subgroup analysis: Becker H, Suciu S, Rüter BH, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, Muus P, Pflüger KH, Hagemeijer A, Schaefer HE, Fiaccadori V, Baron F, Ganser A, Aul C, de Witte T, Wijermans PW, Lübbert M. Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG). Ann Hematol. 2015 Dec;94(12):2003-13. Epub 2015 Sep 24. link to original article EuroPMC
# MDS-005: Santini V, Almeida A, Giagounidis A, Gröpper S, Jonasova A, Vey N, Mufti GJ, Buckstein R, Mittelman M, Platzbecker U, Shpilberg O, Ram R, Del Cañizo C, Gattermann N, Ozawa K, Risueño A, MacBeth KJ, Zhong J, Séguy F, Hoenekopp A, Beach CL, Fenaux P. 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 Sep 1;34(25):2988-96. Epub 2016 Jun 27. link to original article EuroPMC NCT01029262
=Relapsed or refractory=
==Best supportive care==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Garcia-Manero et al. 2016 (ONTIME)	2010-2013 	Phase 3 (C)	Rigosertib	Did not meet primary endpoint of OS
No active antineoplastic therapy; considered the standard of care for MDS relapsed/refractory to hypomethylating agents.
===References===
# ONTIME: Garcia-Manero G, Fenaux P, Al-Kali A, Baer MR, Sekeres MA, Roboz GJ, Gaidano G, Scott BL, Greenberg P, Platzbecker U, Steensma DP, Kambhampati S, Kreuzer KA, Godley LA, Atallah E, Collins R Jr, Kantarjian H, Jabbour E, Wilhelm FE, Azarnia N, Silverman LR; ONTIME study investigators. 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 Apr;17(4):496-508. Epub 2016 Mar 8. link to original article EuroPMC NCT01241500
Category:Myelodysplastic syndrome regimens
Category:Null regimens
Category:Disease-specific pages
Category:Bone marrow failure syndromes