Myelodysplastic syndrome

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 Sanjay R. Mohan, MD, MSCI
Vanderbilt University
Nashville, TN
24 regimens on this page
43 variants on this page

Note: this page has historically been focused on disease-modifying regimens, as opposed to regimens intended to decrease transfusion requirements such as erythropoietin. As such, most regimens are for higher-risk MDS. For patients with bone marrow blast percentage greater than 10%, there is a large overlap with acute myeloid leukemia regimens; please see the AML page for regimens.


Guidelines

ELN

ESMO

"How I treat"

International expert panel

NCCN

Lower-risk MDS, all lines of therapy

Erythropoietin monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Fenaux et al. 2018 (EPOANE3021) 2011-2014 Phase III (E-esc) Placebo Superior erythroid response through week 24

Growth factor therapy

References

  1. 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 PubMed

Erythropoetin & Lenalidomide

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Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Toma et al. 2015 (GFM-Len-Epo-08) 2010-2012 Phase III (E-esc) Lenalidomide Seems to have superior erythroid response per IWG 2006 criteria

Targeted therapy

Growth factor therapy

28-day cycles

Regimen variant #2

Study Evidence
Komrokji et al. 2012 (CC-5013-PK-002) Phase II

Note: this regimen is for erythroid nonresponders or those with relapsed anemia after 16 weeks of lenalidomide monotherapy.

Targeted therapy

Growth factor therapy

28-day cycles

References

  1. CC-5013-PK-002: Komrokji RS, Lancet JE, Swern AS, Chen N, Paleveda J, Lush R, Saba HI, List AF. Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood. 2012 Oct 25;120(17):3419-24. Epub 2012 Aug 30. link to original article contains protocol PubMed
  2. GFM-Len-Epo-08: 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. Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. Leukemia. 2016 Apr;30(4):897-905. Epub 2015 Oct 26. link to original article contains protocol PubMed NCT01718379

Lenalidomide monotherapy

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Regimen variant #1, 5 mg continuous

Study Years of enrollment Evidence Comparator Comparative Efficacy
Fenaux et al. 2011 (CC-5013-MDS-004) 2005-2007 Phase III (E-esc) Placebo Superior primary endpoint
Santini et al. 2016 (MDS-005) 2010-2013 Phase III (E-esc) Placebo Superior RBC transfusion independence ≥ 8 weeks

Note: in MDS-005, this was the dose used for patients with CrCl 40 to 60 mL/min/1.73m2.

Targeted therapy

28-day cycles

Regimen variant #2, 10 mg/day continuous

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
List et al. 2005 (CC-5013-MDS-001) 2002-2003 Phase II, <20 pts
List et al. 2006 (CC-5013-MDS-003) 2003-2004 Phase II (RT)
Raza et al. 2008 (CC-5013-MDS-002) 2003-NR Phase II
Santini et al. 2016 (MDS-005) 2010-2013 Phase III (E-esc) Placebo Superior RBC transfusion independence ≥ 8 weeks

Targeted therapy

28-day cycles

Regimen variant #3, 10 mg 21/28

Study Years of enrollment Evidence Comparator Comparative Efficacy
List et al. 2005 (CC-5013-MDS-001) 2002-2003 Phase II, <20 pts
Fenaux et al. 2011 (CC-5013-MDS-004) 2005-2007 Phase III (E-esc) Placebo Superior primary endpoint
Toma et al. 2015 (GFM-Len-Epo-08) 2010-2012 Phase III (C) Epoetin & Lenalidomide Seems to have inferior erythroid response per IWG 2006 criteria

Targeted therapy

28-day cycles

References

  1. CC-5013-MDS-001: List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. link to original article PubMed
  2. CC-5013-MDS-003: 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 Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006 Oct 5;355(14):1456-65. link to original article contains protocol PubMed
  3. CC-5013-MDS-002: 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. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008 Jan 1;111(1):86-93. Epub 2007 Sep 24. link to original article contains protocol PubMed NCT00064974
  4. 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 PubMed NCT00179621
  5. 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 PubMed NCT01029262
  6. GFM-Len-Epo-08: 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. Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. Leukemia. 2016 Apr;30(4):897-905. Epub 2015 Oct 26. link to original article contains protocol PubMed NCT01718379

Luspatercept monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Fenaux et al. 2020 (MEDALIST) 2016-2017 Phase III (E-esc) Placebo Superior transfusion independence

Growth factor therapy

21-day cycle for 8 cycles

References

  1. 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 contains verified protocol PubMed

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Fenaux et al. 2011 (CC-5013-MDS-004) 2005-2007 Phase III (C) Lenalidomide Inferior primary endpoint
Santini et al. 2016 (MDS-005) 2010-2013 Phase III (C) Lenalidomide Inferior RBC transfusion independence ≥ 8 weeks

No active antineoplastic treatment.

References

  1. 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 PubMed NCT00179621
  2. 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 PubMed NCT01029262
  3. 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 PubMed
  4. 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 contains verified protocol PubMed

First-line therapy

Alemtuzumab monotherapy

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Regimen

Study Evidence
Sloand et al. 2010 Phase II

Indication: Intermediate-1 MDS (RAEB-I, RA, or RARS)

Targeted therapy

Supportive medications

11-day course

References

  1. Sloand EM, Olnes MJ, Shenoy A, Weinstein B, Boss C, Loeliger K, Wu CO, More K, Barrett AJ, Scheinberg P, Young NS. Alemtuzumab treatment of intermediate-1 myelodysplasia patients is associated with sustained improvement in blood counts and cytogenetic remissions. J Clin Oncol. 2010 Dec 10;28(35):5166-73. Epub 2010 Nov 1. link to original article contains verified protocol link to PMC article PubMed

ATG (Horse) monotherapy

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ATG: AntiThymocyte Globulin

Regimen

Study Evidence
Molldrem et al. 1997 Phase II

Note: Molldrem et al. 2002 is a larger cohort that includes the patients reported in Molldrem et al. 1997.

Immunosuppressive therapy

Supportive medications

  • Prednisone (Sterapred) 1 mg/kg/day (minimum of 40 mg) PO on days 1 to 10, then tapered to off during days 11 to 17

17-day course

References

  1. Molldrem JJ, Caples M, Mavroudis D, Plante M, Young NS, Barrett AJ. Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol. 1997 Dec;99(3):699-705. link to original article PubMed
    1. Update: Molldrem JJ, Leifer E, Bahceci E, Saunthararajah Y, Rivera M, Dunbar C, Liu J, Nakamura R, Young NS, Barrett AJ. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med. 2002 Aug 6;137(3):156-63. link to original article contains protocol PubMed
  2. Retrospective: Sloand EM, Wu CO, Greenberg P, Young N, Barrett J. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol. 2008 May 20;26(15):2505-11. Epub 2008 Apr 14. link to original article PubMed

ATG (Rabbit) monotherapy

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ATG: AntiThymocyte Globulin

Regimen

Study Evidence
Komrokji et al. 2014 (RDCRN 5406) Phase II

Immunosuppressive therapy

Supportive medications

  • Prednisone (Sterapred) 1 mg/kg/day PO, started 2 days before first dose and continued at full dose during the 4 days, then tapered over the subsequent 14 days (tapering schedule not described)
  • Antibiotics per local practices

18-day course

References

  1. RDCRN 5406: Komrokji RS, Mailloux AW, Chen DT, Sekeres MA, Paquette R, Fulp WJ, Sugimori C, Paleveda-Pena J, Maciejewski JP, List AF, Epling-Burnette PK. A phase 2 multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction. Haematologica. 2014 Jul;99(7):1176-83. Epub 2014 Jan 31. link to original article contains verified protocol link to PMC article PubMed

ATG (Horse) & Cyclosporine

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ATG & Cyclosporine: AntiThymocyte Globulin & Cyclosporine
ATG & CsA: AntiThymocyte Globulin & Cyclosporine A

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Passweg et al. 2010 (SAKK 33/99) 2000-2006 Phase III (E-esc) Best supportive care Seems to have superior hematologic RR at 6 mo

Immunosuppressive therapy

6-month course

References

  1. 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 contains partial protocol PubMed NCT00004208

Azacitidine monotherapy

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Regimen variant #1, 60 mg/m2, 5 days/cycle

Study Evidence
Grövdal et al. 2010 Phase II

Intended to be used for high-risk MDS patients in remission after induction therapy

Chemotherapy

28-day cycles

Regimen variant #2, 75 mg/m2, 3 days/cycle

Study Evidence Comparator Comparative Efficacy
Jabbour et al. 2017 (MDA 2012-0507) Randomized Phase II (E-switch-ic) Decitabine Seems to have inferior ORR

Chemotherapy

28-day cycles

Regimen variant #3, 75 mg/m2, 5 days/cycle

Study Evidence Comparator Comparative Efficacy
Fili et al. 2013 Phase II
Thépot et al. 2016 (GFM-Aza-Epo-2008-01) Randomized Phase II (C) Azacitidine & Epoetin Did not meet primary endpoint of RBC transfusion independence after 6 cycles

Intended to be used for low-risk MDS patients who are symptomatic or intolerant to erythropoietin (Fili et al. 2013) or resistant to erythropoietin (GFM-Aza-Epo-2008-01).

Chemotherapy

Supportive medications

  • G-CSF or GM-CSF was allowed if ANC less than 200/uL and/or systemic infection
  • Erythropoiesis-stimulating agents were not allowed
  • Antimicrobial and antifungal prophylaxis (agents not specified) given if ANC less than 500/uL

28-day cycle for 8 cycles (Fili et al. 2013) or up to 18 cycles (GFM-Aza-Epo-2008-01)

Regimen variant #4, 75 mg/m2, 7 days/cycle (uninterrupted)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Silverman et al. 2002 (CALGB 9221) 1994-1996 Phase III (E-RT-esc) Best supportive care Seems to have superior OS
Fenaux et al. 2009 (AZA-001) 2004-2006 Phase III (E-RT-esc) Best supportive care Superior OS
Sekeres et al. 2017 (SWOG S1117) 2012-2014 Randomized Phase II (C) 1. Azacitidine & Lenalidomide Did not meet primary endpoint of ORR
2. Azacitidine & Vorinostat Did not meet primary endpoint of ORR
Dickinson et al. 2018 (SUPPORT) 2014-2015 Phase III (C) Azacitidine & Eltrombopag Superior primary endpoint

Chemotherapy

28-day cycles

Depending on the study, given for at least 4 cycles, continued for 3 cycles beyond complete remission, or continued indefinitely

Regimen variant #5, 75 mg/m2, 7 days/cycle (5-2-2)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sekeres et al. 2017 (SWOG S1117) 2012-2014 Randomized Phase II (C) 1. Azacitidine & Lenalidomide Did not meet primary endpoint of ORR
2. Azacitidine & Vorinostat Did not meet primary endpoint of ORR

Chemotherapy

28-day cycles

References

  1. 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 contains verified protocol PubMed
    1. QoL 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 PubMed
    2. 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 contains protocol PubMed
  2. 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 contains protocol link to PMC article PubMed
  3. Grövdal M, Karimi M, Khan R, Aggerholm A, Antunovic P, Astermark J, Bernell P, Engström LM, Kjeldsen L, Linder O, Nilsson L, Olsson A, Holm MS, Tangen JM, Wallvik J, Oberg G, Hokland P, Jacobsen SE, Porwit A, Hellström-Lindberg E. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol. 2010 Aug;150(3):293-302. Epub 2010 May 20. link to original article contains verified protocol PubMed
  4. Filì C, Malagola M, Follo MY, Finelli C, Iacobucci I, Martinelli G, Cattina F, Clissa C, Candoni A, Fanin R, Gobbi M, Bocchia M, Defina M, Spedini P, Skert C, Manzoli L, Cocco L, Russo D. Prospective phase II Study on 5-days azacitidine for treatment of symptomatic and/or erythropoietin unresponsive patients with low/INT-1-risk myelodysplastic syndromes. Clin Cancer Res. 2013 Jun 15;19(12):3297-308. link to original article contains verified protocol PubMed
  5. GFM-Aza-Epo-2008-01: Thépot S, Ben Abdelali R, Chevret S, Renneville A, Beyne-Rauzy O, Prébet T, Park S, Stamatoullas A, Guerci-Bresler A, Cheze S, Tertian G, Choufi B, Legros L, Bastié JN, Delaunay J, Chaury MP, Sanhes L, Wattel E, Dreyfus F, Vey N, Chermat F, Preudhomme C, Fenaux P, Gardin C; Groupe Francophone des Myélodysplasies. A randomized phase II trial of azacitidine +/- epoetin-β in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents. Haematologica. 2016 Aug;101(8):918-25. Epub 2016 May 26. link to original article contains verified protocol link to PMC article PubMed
  6. SWOG S1117: Sekeres MA, Othus M, List AF, Odenike O, Stone RM, Gore SD, Litzow MR, Buckstein R, Fang M, Roulston D, Bloomfield CD, Moseley A, Nazha A, Zhang Y, Velasco MR, Gaur R, Atallah E, Attar EC, Cook EK, Cull AH, Rauh MJ, Appelbaum FR, Erba HP. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol. 2017 Aug 20;35(24):2745-2753. Epub 2017 May 9. link to original article contains verified protocol PubMed NCT01522976
  7. MDA 2012-0507: Jabbour E, Short NJ, Montalban-Bravo G, Huang X, Bueso-Ramos C, Qiao W, Yang H, Zhao C, Kadia T, Borthakur G, Pemmaraju N, Sasaki K, Estrov Z, Cortes J, Ravandi F, Alvarado Y, Komrokji R, Sekeres MA, Steensma DP, DeZern A, Roboz G, Kantarjian H, Garcia-Manero G. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood. 2017 Sep 28;130(13):1514-1522. Epub 2017 Aug 3. link to original article contains verified protocol PubMed
  8. SUPPORT: Dickinson M, Cherif H, Fenaux P, Mittelman M, Verma A, Portella MSO, Burgess P, Ramos PM, Choi J, Platzbecker U; SUPPORT study investigators. Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood. 2018 Dec 20;132(25):2629-2638. Epub 2018 Oct 10. link to original article contains protocol PubMed NCT02158936

Azacitidine & Lenalidomide

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Regimen variant #1, 7 days of azacitidine

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sekeres et al. 2017 (SWOG S1117) 2012-2014 Randomized Phase II (E-esc) 1. Azacitidine Did not meet primary endpoint of ORR
2. Azacitidine & Vorinostat Not reported

Chemotherapy

Targeted therapy

28-day cycles

Regimen variant #2, 5-2-2 azacitidine

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sekeres et al. 2017 (SWOG S1117) 2012-2014 Randomized Phase II (E-esc) 1. Azacitidine Did not meet primary endpoint of ORR
2. Azacitidine & Vorinostat Not reported

Chemotherapy

Targeted therapy

28-day cycles

Regimen variant #3, 5 days of azacitidine

Study Evidence
Sekeres et al. 2012 (CASE17Z05) Phase II

Chemotherapy

Targeted therapy

28-day cycle for up to 7 cycles

Subsequent treatment

  • Option to continue single agent azacitidine per MD discretion

References

  1. CASE17Z05: Sekeres MA, Tiu RV, Komrokji R, Lancet J, Advani AS, Afable M, Englehaupt R, Juersivich J, Cuthbertson D, Paleveda J, Tabarroki A, Visconte V, Makishima H, Jerez A, Paquette R, List AF, Maciejewski JP. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood. 2012 Dec 13;120(25):4945-51. Epub 2012 Aug 22. link to original article contains protocol link to PMC article PubMed
  2. SWOG S1117: Sekeres MA, Othus M, List AF, Odenike O, Stone RM, Gore SD, Litzow MR, Buckstein R, Fang M, Roulston D, Bloomfield CD, Moseley A, Nazha A, Zhang Y, Velasco MR, Gaur R, Atallah E, Attar EC, Cook EK, Cull AH, Rauh MJ, Appelbaum FR, Erba HP. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol. 2017 Aug 20;35(24):2745-2753. Epub 2017 May 9. link to original article contains verified protocol PubMed NCT01522976

Azacitidine & Vorinostat

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Regimen variant #1, 7 days of azacitidine

Study Years of enrollment Evidence Comparator Comparative Efficacy
Verma et al. 2013 (Study 6898) NR in abstract Phase II
Sekeres et al. 2017 (SWOG S1117) 2012-2014 Randomized Phase II (E-esc) 1. Azacitidine Did not meet primary endpoint of ORR
2. Azacitidine & Lenalidomide Not reported

Note: this was schedule two from Study 6898, except that vorinostat was once per day in the phase II trial.

Chemotherapy

Targeted therapy

28-day cycles

Regimen variant #2, 5-2-2 azacitidine

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sekeres et al. 2017 (SWOG S1117) 2012-2014 Randomized Phase II (E-esc) 1. Azacitidine Did not meet primary endpoint of ORR
2. Azacitidine & Lenalidomide Not reported

Chemotherapy

Targeted therapy

28-day cycles

References

  1. Abstract: Amit Verma, Rosalie Odchimar-Reissig, Eric J. Feldman, Shyamala C. Navada, Erin P Demakos, Maria R. Baer, Vesna Najfeld, Joseph A Sparano, Richard Piekarz. A Phase II Trial Of Epigenetic Modulators Vorinostat In Combination With Azacitidine (azaC) In Patients With The Myelodysplastic Syndrome (MDS): Initial Results Of Study 6898 Of The New York Cancer Consortium. Blood Nov 2013,122(21)386 link to original abstract
  2. SWOG S1117: Sekeres MA, Othus M, List AF, Odenike O, Stone RM, Gore SD, Litzow MR, Buckstein R, Fang M, Roulston D, Bloomfield CD, Moseley A, Nazha A, Zhang Y, Velasco MR, Gaur R, Atallah E, Attar EC, Cook EK, Cull AH, Rauh MJ, Appelbaum FR, Erba HP. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol. 2017 Aug 20;35(24):2745-2753. Epub 2017 May 9. link to original article contains verified protocol PubMed NCT01522976

Best supportive care

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Silverman et al. 2002 (CALGB 9221) 1994-1996 Phase III (C) Azacitidine Seems to have inferior OS
Greenberg et al. 2009 (ECOG E1996) 1997-2004 Phase III (C) Epoietin +/- G-CSF Inferior erythroid ORR
Passweg et al. 2010 (SAKK 33/99) 2000-2006 Phase III (C) ATG & CSA Seems to have inferior hematologic RR at 6 mo
Kantarjian et al. 2006MDS 2001-2004 Phase III (C) Decitabine Inferior ORR
Lübbert et al. 2011 (EORTC LSG/GMDSSG 06011) 2002-2007 Phase III (C) Decitabine Did not meet primary endpoint of OS
Fenaux et al. 2009 (AZA-001) 2004-2006 Phase III (C) Azacitidine Inferior OS

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

  1. 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 contains verified protocol PubMed
    1. QoL 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 PubMed
    2. 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 contains protocol PubMed
  2. 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 contains protocol PubMed
  3. 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 contains protocol link to PMC article PubMed content property of HemOnc.org
  4. 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 PubMed
  5. 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 contains partial protocol PubMed NCT00004208
  6. 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 contains verified protocol PubMed NCT00043134
    1. 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 PubMed
  7. 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 PubMed

Clofarabine monotherapy

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Regimen variant #1

Study Evidence Comparator Comparative Efficacy
Faderl et al. 2012 Randomized Phase II (E-de-esc) Clofarabine 30 mg/m2 dosing Did not meet primary endpoint of ORR

This randomized trial tested two doses of clofarabine, 15 mg/m2 and 30 mg/m2. Lower dose was less toxic and clinical activity was comparable

Chemotherapy

Supportive medications

  • "Supportive care measures such as antibiotic prophylaxis (eg, levofloxacin, valacyclovir, and itraconazole or voriconazole), hematopoietic growth factors, and transfusions were provided as necessitated for optimal medical care of the patients." In order to decrease risk of liver function abnormalities, no antifungals were given on the days where clofarabine was given.

4- to 8-week cycle for up to 12 cycles

Regimen variant #2

Study Evidence
Faderl et al. 2010 (MDACC 2005-0536) Non-randomized

Initial dose was too toxic; 20 mg/m2 was final dose level

Chemotherapy

Supportive medications

  • "Supportive care included anti-infectious prophylaxis (eg, levaquin, valacyclovir, and itraconazole or voriconazole), hematopoietic growth factors, and transfusions as judged indicated by the treating physician." In order to decrease risk of liver function abnormalities, no antifungals were given on the days where clofarabine was given.

4- to 8-week cycle for up to 12 cycles

References

  1. MDACC 2005-0536: Faderl S, Garcia-Manero G, Estrov Z, Ravandi F, Borthakur G, Cortes JE, O'Brien S, Gandhi V, Plunkett W, Byrd A, Kwari M, Kantarjian HM. Oral clofarabine in the treatment of patients with higher-risk myelodysplastic syndrome. J Clin Oncol. 2010 Jun 1;28(16):2755-60. Epub 2010 Apr 26. link to original article contains verified protocol link to PMC article PubMed
  2. Faderl S, Garcia-Manero G, Jabbour E, Ravandi F, Borthakur G, Estrov Z, Gandhi V, Byrd AL, Kwari M, Cortes J, Kantarjian HM. A randomized study of 2 dose levels of intravenous clofarabine in the treatment of patients with higher-risk myelodysplastic syndrome. Cancer. 2012 Feb 1;118(3):722-8. Epub 2011 Jul 12. link to original article contains verified protocol link to PMC article PubMed

Cyclosporine monotherapy

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Regimen

Study Evidence
Jonásova et al. 1998 Pilot, <20 pts

Immunosuppressive therapy

References

  1. Jonásova A, Neuwirtová R, Cermák J, Vozobulová V, Mociková K, Sisková M, Hochová I. Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol. 1998 Feb;100(2):304-9. link to original article contains protocol PubMed
  2. Retrospective: Sloand EM, Wu CO, Greenberg P, Young N, Barrett J. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol. 2008 May 20;26(15):2505-11. Epub 2008 Apr 14. link to original article PubMed

Decitabine monotherapy

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Regimen variant #1, 10 mg/m2, 10 days per cycle (IV)

Study Evidence Comparator Comparative Efficacy
Kantarjian et al. 2007 Randomized Phase II, <20 pts in this arm (E-esc) 1. Decitabine IV x 5 days per cycle Seems to have inferior CR rate
2. Decitabine SC x 5 days per cycle Not reported

Chemotherapy

28-day cycles

Regimen variant #2, 15 mg/m2, 3 days per cycle (IV)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kantarjian et al. 2006MDS 2001-2004 Phase III (E-RT-esc) Best supportive care Superior ORR
Lübbert et al. 2011 (EORTC LSG/GMDSSG 06011) 2002-2007 Phase III (E-esc) Best supportive care Did not meet primary endpoint of OS

Note: although EORTC LSG/GMDSSG 06011 had a significantly different PFS, it did not meet the primary endpoint of OS.

Chemotherapy

42-day cycle for up to 10 cycles

Regimen variant #3, 20 mg/m2, 3 days per cycle (IV)

Study Evidence Comparator Comparative Efficacy
Jabbour et al. 2017 (MDA 2012-0507) Randomized Phase II (E-switch-ic) Azacitidine Seems to have superior ORR

Chemotherapy

28-day cycles

Regimen variant #4, 20 mg/m2, 3 days per cycle (SC)

Study Evidence Comparator Comparative Efficacy
Garcia-Manero et al. 2013 Randomized Phase II (E-switch-ic) Decitabine SC weekly Did not meet primary endpoint of OIR

Note: cycle length was allowed to vary by +/- 3 days.

Chemotherapy

28-day cycle for up to 13 cycles (1 year)

Regimen variant #5, 20 mg/m2, 5 days per cycle (IV)

Study Evidence Comparator Comparative Efficacy
Kantarjian et al. 2007 Randomized Phase II (E-switch-ic) 1. Decitabine IV x 10 days per cycle Seems to have superior CR rate
2. Decitabine SC x 5 days per cycle Seems to have superior CR rate
Issa et al. 2014 Randomized Phase II (C) Decitabine & Valproic acid Did not meet efficacy endpoint

Chemotherapy

4- to 6-week cycles

Regimen variant #6, 20 mg/m2, 5 days per cycle (SC)

Study Evidence Comparator Comparative Efficacy
Kantarjian et al. 2007 Randomized Phase II, <20 pts in this arm (E-switch-ic) 1. Decitabine IV x 5 days per cycle Seems to have inferior CR rate
2. Decitabine IV x 10 days per cycle Not reported

Chemotherapy

28-day cycles

Regimen variant #7, 20 mg/m2, weekly (SC)

Study Evidence Comparator Comparative Efficacy
Garcia-Manero et al. 2013 (DACO-026) Randomized Phase II (E-switch-ic) Decitabine SC x 3 days per cycle Did not meet primary endpoint of OIR

Note: cycle length was allowed to vary by +/- 3 days.

Chemotherapy

28-day cycle for up to 13 cycles (1 year)

References

  1. 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 contains protocol PubMed
  2. 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. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007 Jan 1;109(1):52-7. Epub 2006 Aug 1. link to original article contains protocol PubMed
  3. 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 contains verified protocol PubMed NCT00043134
    1. 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 PubMed
  4. DACO-026: Garcia-Manero G, Jabbour E, Borthakur G, Faderl S, Estrov Z, Yang H, Maddipoti S, Godley LA, Gabrail N, Berdeja JG, Nadeem A, Kassalow L, Kantarjian H. Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes. J Clin Oncol. 2013 Jul 10;31(20):2548-53. Epub 2013 Jun 3. link to original article contains verified protocol link to PMC article PubMed
  5. Issa JP, Garcia-Manero G, Huang X, Cortes J, Ravandi F, Jabbour E, Borthakur G, Brandt M, Pierce S, Kantarjian HM. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015 Feb 15;121(4):556-61. Epub 2014 Oct 21. link to original article contains verified protocol link to PMC article PubMed
  6. MDA 2012-0507: Jabbour E, Short NJ, Montalban-Bravo G, Huang X, Bueso-Ramos C, Qiao W, Yang H, Zhao C, Kadia T, Borthakur G, Pemmaraju N, Sasaki K, Estrov Z, Cortes J, Ravandi F, Alvarado Y, Komrokji R, Sekeres MA, Steensma DP, DeZern A, Roboz G, Kantarjian H, Garcia-Manero G. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood. 2017 Sep 28;130(13):1514-1522. Epub 2017 Aug 3. link to original article contains verified protocol PubMed

LoDAC

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LoDAC: Low Dose Ara-C (Cytarabine)
LDAC: Low-dose Ara-C (Cytarabine)

Regimen variant #1, SC

Study Evidence Comparator Comparative Efficacy
Miller et al. 1992 Phase III (E-esc) Best supportive care Did not meet efficacy endpoints
Zwierzina et al. 2005 (EORTC 06903) Phase III (C) 1. LoDAC & GM-CSF
2. LoDAC & IL-3 		Did not meet primary endpoints of ORR/PFS

Note: the cycle length is not explicitly defined in EORTC 06903. This is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Chemotherapy

21-day cycle for up to 6 cycles

Regimen variant #2, CI

Study Evidence
Wisch et al. 1983 Non-randomized, <20 pts

Note: this regimen is for historic reference.

Chemotherapy

  • Cytarabine (Ara-C) 20 mg/m2/day IV continuous infusion over 7 to 21 days, started on day 1

4- to 6-week cycle for up to 2 cycles

References

  1. Wisch JS, Griffin JD, Kufe DW. Response of preleukemic syndromes to continuous infusion of low-dose cytarabine. N Engl J Med. 1983 Dec 29;309(26):1599-602. link to original article contains verified protocol PubMed
  2. Miller KB, Kim K, Morrison FS, Winter JN, Bennett JM, Neiman RS, Head DR, Cassileth PA, O'Connell MJ. The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: a phase-III intergroup study. Ann Hematol. 1992 Oct;65(4):162-8. Erratum in: Ann Hematol 1993 Mar;66(3):164. Kyungmann K [corrected to Kim K]. link to original article contains protocol PubMed
  3. EORTC 06903: Zwierzina H, Suciu S, Loeffler-Ragg J, Neuwirtova R, Fenaux P, Beksac M, Harousseau J, Nuessler V, Cermak J, Solbu G, Willemze R, de Witte T, Amadori S; EORTC Leukemia Cooperative Group. Low-dose cytosine arabinoside (LD-AraC) vs LD-AraC plus granulocyte/macrophage colony stimulating factor vs LD-AraC plus interleukin-3 for myelodysplastic syndrome patients with a high risk of developing acute leukemia: final results of a randomized phase III study (06903) of the EORTC Leukemia Cooperative Group. Leukemia. 2005 Nov;19(11):1929-33. link to original article contains verified protocol PubMed

Temozolomide monotherapy

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Regimen

Study Evidence
Brandwein et al. 2014 Phase II

Patient selection was based on MGMT expression by Western blot. See article for details.

Chemotherapy

  • Temozolomide (Temodar) 200 mg/m2/day PO on days 1 to 7
    • Complete responders could receive: 200 mg/m2/day PO on days 1 to 5

28-day cycle for up to 12 cycles

References

  1. Brandwein JM, Kassis J, Leber B, Hogge D, Howson-Jan K, Minden MD, Galarneau A, Pouliot JF. Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for low O(6) -methylguanine DNA methyltransferase expression. Br J Haematol. 2014 Dec;167(5):664-70. Epub 2014 Aug 27. link to original article contains protocol PubMed

Consolidation after first-line therapy

Busulfan & Cyclophosphamide, then allo HSCT

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BuCy: Busulfan & Cyclophosphamide

Regimen

Study Evidence Comparator Comparative Efficacy
Kröger et al. 2017 (RICMAC) Phase III (C) Bu/Flu RIC allo HSCT Might have inferior OS

Chemotherapy

Immunotherapy

GVHD prophylaxis

Supportive therapy

  • Filgrastim (Neupogen) 450 mcg SC once per day, starting on day +5 and continued until ANC greater than 3000/μL

One course

Immunotherapy

Stem cells transfused on day 0

References

  1. RICMAC: Kröger N, Iacobelli S, Franke GN, Platzbecker U, Uddin R, Hübel K, Scheid C, Weber T, Robin M, Stelljes M, Afanasyev B, Heim D, Deliliers GL, Onida F, Dreger P, Pini M, Guidi S, Volin L, Günther A, Bethge W, Poiré X, Kobbe G, van Os M, Brand R, de Witte T. Dose-Reduced Versus Standard Conditioning Followed by Allogeneic Stem-Cell Transplantation for Patients With Myelodysplastic Syndrome: A Prospective Randomized Phase III Study of the EBMT (RICMAC Trial). J Clin Oncol. 2017 Jul 1;35(19):2157-2164. Epub 2017 May 2. link to original article PubMed

Relapsed or refractory

Best supportive care

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Regimen

Study Evidence Comparator Comparative Efficacy
Garcia-Manero et al. 2016 (ONTIME) Phase III (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

  1. 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 PubMed

Erlotinib monotherapy

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Regimen

Study Evidence
Komrokji et al. 2014 (MCC-15961) Phase II
Thepot et al. 2014 (GFM-ERLOTINIB-08) Phase I/II

This is the MTD in GFM-ERLOTINIB-08.

Targeted therapy

References

  1. MCC-15961: Komrokji RS, Padron E, Yu D, Fulp WJ, Rodriguez Y, Tinsley S, List AF, Lancet JE. Phase II clinical study of erlotinib for treatment of myelodysplastic syndromes. Am J Hematol. 2014 Aug;89(8):809-12. Epub 2014 May 16. link to full article link to PMC article PubMed
  2. GFM-ERLOTINIB-08: Thepot S, Boehrer S, Seegers V, Prebet T, Beyne-Rauzy O, Wattel E, Delaunay J, Raffoux E, Hunault M, Jourdan E, Chermat F, Sebert M, Kroemer G, Fenaux P, Adès L; Groupe Francophone des Myelodysplasies. A phase I/II trial of erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure. Leuk Res. 2014 Dec;38(12):1430-4. Epub 2014 Oct 7. link to original article PubMed

Midostaurin monotherapy

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Regimen variant #1

Study Evidence Comparator
Fischer et al. 2010 Randomized Phase II, <20 pts in this subgroup (E-de-esc) Midostaurin; 100 mg twice per day

Targeted therapy

Continued indefinitely

Regimen variant #2

Study Evidence Comparator
Fischer et al. 2010 Randomized Phase II, <20 pts in this subgroup (E-esc) Midostaurin; 50 mg twice per day

Targeted therapy

Continued indefinitely

References

  1. Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010 Oct 1;28(28):4339-45. Epub 2010 Aug 23. link to original article link to PMC article contains verified protocol PubMed

Response criteria

WHO International Working Group criteria (2000, modified in 2006)

  1. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Löwenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL; World Health Organization (WHO) international working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000 Dec 1;96(12):3671-4. link to original article PubMed
  2. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. Epub 2006 Apr 11. link to original article PubMed

Prognosis

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