Myelodysplastic syndrome

Section editor
	Sanjay R. Mohan, MD, MSCI Vanderbilt University Nashville, TN, USA

For placebo or observational studies in this condition, please visit this page.

24 regimens on this page 43 variants on this page

Note: 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.

• We have moved How I Treat articles to a dedicated page.

Note: regimens tested in specific populations are located on dedicated pages:

• MDS, IDH-mutated

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ELN

• 2013: Malcovati et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet PubMed

ESMO

• 2014: Fenaux et al. Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

International expert panel

• 2017: de Witte et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel PubMed

NCCN

• NCCN Guidelines - Myelodysplastic Syndromes
  • 2017: Greenberg et al. Myelodysplastic Syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology PubMed
  • 2015: Greenberg et al. Myelodysplastic Syndromes, Version 2.2015 PubMed
  • 2013: Greenberg et al. Myelodysplastic syndromes: clinical practice guidelines in oncology. PubMed
  • 2011: Greenberg et al. NCCN Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. PubMed
  • 2008: Greenberg et al. Myelodysplastic syndromes. PubMed
  • 2006: Greenberg et al. Myelodysplastic syndromes clinical practice guidelines in oncology. PubMed

Lower-risk MDS, all lines of therapy

Azacitidine oral monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garcia-Manero et al. 2021 (AZA-MDS-003)	2013-2018	Phase 3 (E-esc)	Placebo	Superior transfusion independence (primary endpoint)

Chemotherapy

• Azacitidine oral (Onureg) 300 mg PO once per day on days 1 to 21

28-day cycles

References

1. AZA-MDS-003: Garcia-Manero G, Santini V, Almeida A, Platzbecker U, Jonasova A, Silverman LR, Falantes J, Reda G, Buccisano F, Fenaux P, Buckstein R, Diez Campelo M, Larsen S, Valcarcel D, Vyas P, Giai V, Olíva EN, Shortt J, Niederwieser D, Mittelman M, Fianchi L, La Torre I, Zhong J, Laille E, Lopes de Menezes D, Skikne B, Beach CL, Giagounidis A. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes. J Clin Oncol. 2021 May 1;39(13):1426-1436. Epub 2021 Mar 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01566695

Darbepoetin alfa monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Platzbecker et al. 2017 (Amgen 20090160)	2011-12 to 2014-08	Phase 3 (E-esc)	Placebo	Superior transfusion incidence from weeks 5 to 24 (primary endpoint)

Growth factor therapy

• Darbepoetin alfa (Aranesp) 500 mcg SC once on day 1

21-day cycles

References

1. 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 contains dosing details in manuscript PubMed NCT01362140

Erythropoietin alfa monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fenaux et al. 2018 (EPOANE3021)	2011-2014	Phase 3 (E-esc)	Placebo	Superior erythroid response through week 24 (primary endpoint)
Platzbecker et al. 2023 (COMMANDS)	2019-01-02 to 2022-08-31	Phase 3 (C)	Luspatercept	Inferior red blood cell transfusion independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL in weeks 1 to 24

Growth factor therapy

• Epoetin alfa (Procrit) 450 IU/kg (maximum dose of 40,000 IU) SC once on day 1

7-day cycles

Dose and schedule modifications

• Dose could be increased to 1050 IU/kg (maximum dose of 80,000 IU) at week 8 for patients not achieving an erythroid response

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 contains dosing details in manuscript PubMed NCT01381809
2. COMMANDS: Platzbecker U, Della Porta MG, Santini V, Zeidan AM, Komrokji RS, Shortt J, Valcarcel D, Jonasova A, Dimicoli-Salazar S, Tiong IS, Lin CC, Li J, Zhang J, Giuseppi AC, Kreitz S, Pozharskaya V, Keeperman KL, Rose S, Shetty JK, Hayati S, Vodala S, Prebet T, Degulys A, Paolini S, Cluzeau T, Fenaux P, Garcia-Manero G. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023 Jul 29;402(10399):373-385. Epub 2023 Jun 10. link to original article PubMed NCT03682536

Erythropoetin alfa & Lenalidomide

Regimen

Study	Dates of enrollment	Evidence
Komrokji et al. 2012 (CC-5013-PK-002)	2005-01 to 2007-10	Phase 2

Note: this regimen was intended for patients with non-response to erythroid growth factors or those with relapsed anemia after 16 weeks of lenalidomide monotherapy.

Targeted therapy

• Lenalidomide (Revlimid) 10 to 15 mg PO once per day on days 1 to 7

Growth factor therapy

• Epoetin alfa (Procrit) 40,000 units SC once on day 1

7-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 dosing details in abstract PubMed NCT00910858

Erythropoetin beta & Lenalidomide

Regimen variant #1, dose-reduced lenalidomide

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
List et al. 2021 (ECOG E2905)	2009-2016	Phase 3 (E-esc)	Lenalidomide	Superior major erythroid response (primary endpoint)

Note: patients in ECOG E2905 were reassessed after cycle 4 and discontinued treatment if they did not have a MER. This dose was intended for patients with a pre-treatment platelet count of 50 x 10⁹ to 99 x 10⁹ or an ANC of 500/μL to 999/μL.

Targeted therapy

• Lenalidomide (Revlimid) 5 mg PO once per day on days 1 to 21

Growth factor therapy

• Epoetin beta (Recormon) 60,000 units SC once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
List et al. 2021 (ECOG E2905)	2009-2016	Phase 3 (E-esc)	Lenalidomide	Superior major erythroid response (primary endpoint)
Toma et al. 2015 (GFM-Len-Epo-08)	2010-2012	Phase 3 (E-esc)	Lenalidomide	Seems to have superior erythroid response per IWG 2006 criteria (primary endpoint)

Note: patients in ECOG E2905 were reassessed after cycle 4 and discontinued treatment if they did not have a MER.

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

Growth factor therapy

• Epoetin beta (Recormon) 60,000 units SC once per day on days 1, 8, 15, 22

28-day cycles

References

1. 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 dosing details in abstract PubMed NCT01718379
2. ECOG E2905: List AF, Sun Z, Verma A, Bennett JM, Komrokji RS, McGraw K, Maciejewski J, Altman JK, Cheema PS, Claxton DF, Luger SM, Mattison RJ, Wassenaar TR, Artz AS, Schiffer CA, Litzow MR, Tallman MS. Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin. J Clin Oncol. 2021 Mar 20;39(9):1001-1009. Epub 2021 Jan 13. link to original article contains dosing details in supplement link to PMC article PubMed NCT00843882

Lenalidomide monotherapy

Regimen variant #1, 5 mg continuous

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fenaux et al. 2011 (CC-5013-MDS-004)	2005-2007	Phase 3 (E-esc)	1. Placebo	Superior primary endpoint
			2. Lenalidomide; 10 mg 21/28	Not reported
Santini et al. 2016 (MDS-005)	2010-2013	Phase 3 (E-esc)	Placebo	Superior RBC transfusion independence at 8 or more weeks (primary endpoint)

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

Targeted therapy

• Lenalidomide (Revlimid) 5 mg PO once per day on days 1 to 28

28-day cycles

Regimen variant #2, 10 mg/day continuous

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
List et al. 2005 (CC-5013-MDS-001)	2002-2003	Phase 2, fewer than 20 pts
List et al. 2006 (CC-5013-MDS-003)	2003-2004	Phase 2 (RT)
Raza et al. 2008 (CC-5013-MDS-002)	2003-NR	Phase 2
Santini et al. 2016 (MDS-005)	2010-2013	Phase 3 (E-esc)	Placebo	Superior RBC transfusion independence at 8 or more weeks (primary endpoint)

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 28

28-day cycles

Regimen variant #3, 10 mg 21/28

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
List et al. 2005 (CC-5013-MDS-001)	2002-2003	Phase 2, fewer than 20 pts
Fenaux et al. 2011 (CC-5013-MDS-004)	2005-2007	Phase 3 (E-esc)	1. Placebo	Superior primary endpoint
			2. Lenalidomide; 5 mg	Not reported
Toma et al. 2015 (GFM-Len-Epo-08)	2010-2012	Phase 3 (C)	Erythropoetin beta & Lenalidomide	Seems to have inferior erythroid response per IWG 2006 criteria

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

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 dosing details in abstract PubMed NCT00065156
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 dosing details in abstract 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 dosing details in abstract PubMed NCT01718379
7. ECOG E2905: List AF, Sun Z, Verma A, Bennett JM, Komrokji RS, McGraw K, Maciejewski J, Altman JK, Cheema PS, Claxton DF, Luger SM, Mattison RJ, Wassenaar TR, Artz AS, Schiffer CA, Litzow MR, Tallman MS. Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin. J Clin Oncol. 2021 Mar 20;39(9):1001-1009. Epub 2021 Jan 13. link to original article link to PMC article PubMed NCT00843882

Luspatercept monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fenaux et al. 2020 (MEDALIST)	2016-03 to 2017-06	Phase 3 (E-RT-esc)	Placebo	Superior transfusion independence (primary endpoint)
Platzbecker et al. 2023 (COMMANDS)	2019-01-02 to 2022-08-31	Phase 3 (E-switch-ooc)	Erythropoietin alfa	Superior red blood cell transfusion independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL in weeks 1 to 24 (primary endpoint)

Prior treatment criteria

• MEDALIST: Disease refractory to ESAs or unlikely to respond to ESAs (erythroppoietin level of 200 U/L or more) or prior intolerance to ESAs due to an adverse event

Growth factor therapy

• Luspatercept (Reblozyl) 1 mg/kg SC once on day 1

21-day cycle for 8 cycles

Dose and schedule modifications

• Luspatercept dose can be increased based upon response (see paper for details)

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 dosing details in manuscript PubMed NCT02631070
2. COMMANDS: Platzbecker U, Della Porta MG, Santini V, Zeidan AM, Komrokji RS, Shortt J, Valcarcel D, Jonasova A, Dimicoli-Salazar S, Tiong IS, Lin CC, Li J, Zhang J, Giuseppi AC, Kreitz S, Pozharskaya V, Keeperman KL, Rose S, Shetty JK, Hayati S, Vodala S, Prebet T, Degulys A, Paolini S, Cluzeau T, Fenaux P, Garcia-Manero G. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023 Jul 29;402(10399):373-385. Epub 2023 Jun 10. link to original article PubMed NCT03682536

First-line therapy

Alemtuzumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Sloand et al. 2010 (NHLBI 05-H-0206)	2005-2010	Phase 1/2

Eligibility criteria

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

Targeted therapy

• Alemtuzumab (Campath) 1 mg IV once on day 1, then 10 mg IV once per day on days 2 to 11

Supportive therapy

• PCP prophylaxis: Pentamidine (Nebupent) (dose not specified) INH once per month for at least 6 months
• Valacyclovir (Valtrex) (dose/schedule not specified) until CD4 count greater than 200/μL
• Ciprofloxacin (Cipro) (dose/schedule not specified) if ANC less than 500/μL
• Erythropoietin permitted for severe anemia
• G-CSF permitted for severe neutropenia

11-day course

References

1. NHLBI 05-H-0206: 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 dosing details in manuscript link to PMC article PubMed NCT00217594

ATG (Horse) monotherapy

ATG: AntiThymocyte Globulin

Regimen

Study	Dates of enrollment	Evidence
Molldrem et al. 1997	NR	Phase 2

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

Immunosuppressive therapy

• Antithymocyte globulin, horse ATG (Atgam) 40 mg/kg IV over 4 to 8 hours once per day on days 1 to 4

Supportive therapy

• 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 dosing details in abstract 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 link to PMC article PubMed

ATG (Rabbit) monotherapy

ATG: AntiThymocyte Globulin

Regimen

Study	Dates of enrollment	Evidence
Komrokji et al. 2014 (RDCRN 5406)	2007-2009	Phase 2

Immunosuppressive therapy

• Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2.5 mg/kg IV over at least 6 hours once per day on days 1 to 4

Supportive therapy

• 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 dosing details in manuscript link to PMC article PubMed NCT00466843

ATG (Horse) & Cyclosporine

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Passweg et al. 2010 (SAKK 33/99)	2000-2006	Phase 3 (E-esc)	Best supportive care	Seems to have superior hematologic RR at 6 mo (primary endpoint)

Immunosuppressive therapy

• Antithymocyte globulin, horse ATG (Lymphoglobuline) 15 mg/kg IV once per day on days 1 to 5
• Cyclosporine (formulation/route/dose/schedule not specified) on days 1 to 180

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

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

Study	Dates of enrollment	Evidence
Grövdal et al. 2010	2004-2006	Phase 2

Note: this regimen was intended to be used for high-risk MDS patients in remission after induction therapy

Chemotherapy

• Azacitidine (Vidaza) 60 mg/m² SC once per day on days 1 to 5

28-day cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jabbour et al. 2017 (MDA 2012-0507)	2012-2016	Randomized Phase 2 (E-switch-ic)	Decitabine	Seems to have inferior ORR (primary endpoint)

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² IV or SC once per day on days 1 to 3

28-day cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fili et al. 2013 (MDSAZA0706)	2008-2010	Phase 2
Thépot et al. 2016 (GFM-Aza-Epo-2008-01)	2009-2010	Randomized Phase 2 (C)	Azacitidine & Epoetin	Did not meet primary endpoint of RBC transfusion independence after 6 cycles

Note: This regimen was intended to be used for low-risk MDS patients who were symptomatic or intolerant to erythropoietin (MDSAZA0706) or resistant to erythropoietin (GFM-Aza-Epo-2008-01).

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² SC once per day on days 1 to 5

Supportive therapy

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

28-day cycle for 8 cycles (MDSAZA0706) or up to 18 cycles (GFM-Aza-Epo-2008-01)

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Silverman et al. 2002 (CALGB 9221)	1994-1996	Phase 3 (E-RT-esc)	Best supportive care	Seems to have superior OS
Fenaux et al. 2009 (AZA-001)	2004-2006	Phase 3 (E-RT-esc)	Best supportive care	Superior OS (primary endpoint) Median OS: 24.5 vs 15 mo (HR 0.58, 95% CI 0.43-0.77)
Sekeres et al. 2017 (SWOG S1117)	2012-2014	Randomized Phase 2 (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)	2014-06 to 2015-12	Phase 3 (C)	Azacitidine & Eltrombopag	Superior primary endpoint
Awaiting publication (A18-15331)	2019-2021	Phase 3 (C)	Azacitidine & Eprenetapopt	TBD if different primary endpoint of CR rate
Awaiting publication (SELECT-MDS-1)	2021-2023	Phase 3 (C)	Azacitidine & Tamibarotene	TBD if different primary endpoint of CR rate

Biomarker eligibility criteria

• SELECT-MDS-1: RARA positive

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² IV or SC once per day on days 1 to 7

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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sekeres et al. 2017 (SWOG S1117)	2012-2014	Randomized Phase 2 (C)	1. Azacitidine & Lenalidomide	Did not meet primary endpoint of ORR
			2. Azacitidine & Vorinostat	Did not meet primary endpoint of ORR
Adès et al. 2022 (PANTHERMDS)	2017-2019	Phase 3 (C)	Azacitidine & Pevonedistat	Did not meet primary endpoint of EFS
Awaiting publication (VERONA)	2020-2025	Phase 3 (C)	Azacitidine & Venetoclax	TBD if different primary endpoint of OS
Awaiting publication (SELECT-MDS-1)	2021-2023	Phase 3 (C)	Azacitidine & Tamibarotene	TBD if different primary endpoint of CR rate

Biomarker eligibility criteria

• SELECT-MDS-1: RARA positive

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² IV or SC once per day on days 1 to 5, 8 & 9

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 dosing details in manuscript PubMed
   1. 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 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 dosing details in abstract 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 dosing details in abstract link to PMC article PubMed NCT00071799
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 dosing details in manuscript PubMed
4. MDSAZA0706: 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. Epub 2013 Apr 17. link to original article contains dosing details in manuscript PubMed NCT00897130
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 dosing details in manuscript link to PMC article PubMed NCT01015352
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 dosing details in manuscript link to PMC article 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 dosing details in manuscript link to PMC article PubMed NCT01720225
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 dosing details in abstract link to PMC article PubMed NCT02158936
9. PANTHER_MDS: Adès L, Girshova L, Doronin VA, Díez-Campelo M, Valcárcel D, Kambhampati S, Viniou NA, Woszczyk D, De Paz Arias R, Symeonidis A, Anagnostopoulos A, Munhoz EC, Platzbecker U, Santini V, Fram RJ, Yuan Y, Friedlander S, Faller DV, Sekeres MA. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML. Blood Adv. 2022 Sep 13;6(17):5132-5145. link to original article link to PMC article PubMed NCT03268954
10. A18-15331: NCT03745716
11. SELECT-MDS-1: contains dosing details on CT.gov NCT04797780
12. VERONA: contains dosing details on CT.gov NCT04401748

Azacitidine & Lenalidomide

Regimen variant #1, 7 days of azacitidine

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

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² IV or SC once per day on days 1 to 7

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

28-day cycles

Regimen variant #2, 5-2-2 azacitidine

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

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² IV or SC once per day on days 1 to 5, 8 & 9

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

28-day cycles

Regimen variant #3, 5 days of azacitidine

Study	Dates of enrollment	Evidence
Sekeres et al. 2012 (CASE17Z05)	2009-03 to 2011-04	Phase 2

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² IV once per day on days 1 to 5

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

28-day cycle for up to 7 cycles

Subsequent treatment

• Option to continue single agent azacitidine maintenance 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 dosing details in abstract link to PMC article PubMed NCT00352001
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 dosing details in manuscript link to PMC article PubMed NCT01522976

Azacitidine & Vorinostat

Regimen variant #1, 7 days of azacitidine

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (Study 6898)	NR in abstract	Phase 2
Sekeres et al. 2017 (SWOG S1117)	2012-2014	Randomized Phase 2 (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 2 trial.

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² IV or SC once per day on days 1 to 7

Targeted therapy

• Vorinostat (Zolinza) 300 mg PO twice per day on days 3 to 9

28-day cycles

Regimen variant #2, 5-2-2 azacitidine

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

Chemotherapy

• Azacitidine (Vidaza) 75 mg/m² IV or SC once per day on days 1 to 5, 8 & 9

Targeted therapy

• Vorinostat (Zolinza) 300 mg PO twice per day on days 3 to 9

28-day cycles

References

1. Study 6898: link to original abstract NCT00392353
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 dosing details in manuscript link to PMC article PubMed NCT01522976

Clofarabine monotherapy

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Faderl et al. 2011b	NR	Randomized Phase 2 (E-de-esc)	Clofarabine; 30 mg/m2 dosing	Did not meet primary endpoint of ORR

Note: 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

• Clofarabine (Clolar) 15 mg/m² IV over 60 minutes once per day on days 1 to 5

Supportive therapy

• "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	Dates of enrollment	Evidence
Faderl et al. 2010 (MDACC 2005-0536)	NR	Non-randomized

Note: The initial dose was too toxic; 20 mg/m² was the final dose level

Chemotherapy

• Clofarabine (Clolar) 20 mg/m² PO once per day on days 1 to 5

Supportive therapy

• "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 dosing details in manuscript link to PMC article PubMed NCT00299156
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 dosing details in manuscript link to PMC article PubMed

Cyclosporine monotherapy

Regimen

Study	Dates of enrollment	Evidence
Jonásova et al. 1998	NR	Pilot, fewer than 20 pts

Immunosuppressive therapy

• Cyclosporine 2.5 to 3 mg/kg PO twice per day, adjusted to maintain therapeutic cyclosporine level of 100 to 300 ng/mL

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 dosing details in abstract 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 link to PMC article PubMed

Decitabine monotherapy

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2007	NR	Randomized Phase 2, fewer than 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

• Decitabine (Dacogen) 10 mg/m² IV over 60 minutes once per day on days 1 to 10

28-day cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2006 (D-0007)	2001-2004	Phase 3 (E-RT-esc)	Best supportive care	Superior ORR (co-primary endpoint)
Lübbert et al. 2011 (EORTC LSG/GMDSSG 06011)	2002-2007	Phase 3 (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

• Decitabine (Dacogen) 15 mg/m² IV over 3 to 4 hours every 8 hours on days 1 to 3

42-day cycle for up to 10 cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jabbour et al. 2017 (MDA 2012-0507)	2012-2016	Randomized Phase 2 (E-switch-ic)	Azacitidine	Seems to have superior ORR (primary endpoint)

Chemotherapy

• Decitabine (Dacogen) 20 mg/m² IV over 60 minutes once per day on days 1 to 3

28-day cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garcia-Manero et al. 2013 (DACO-026)	2008-2009	Randomized Phase 2 (E-switch-ic)	Decitabine; SC weekly	Did not meet primary endpoint of OIR

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

Chemotherapy

• Decitabine (Dacogen) 20 mg/m² SC once per day on days 1 to 3

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

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2007	NR	Randomized Phase 2 (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	NR	Randomized Phase 2 (C)	Decitabine & Valproate	Did not meet efficacy endpoint
Garcia-Manero et al. 2020 (ASTX727-01-B)	2014-NR	Randomized Phase 2, fewer than 20 pts in this subgroup (C)	Oral decitabine	Not reported
Garcia-Manero et al. 2024 (ASCERTAIN)	2018-02-08 to 2021-06-07	Phase 3 (C)	PO Decitabine	Equivalent pharmacokinetic exposure (primary endpoint)

Note: ASTX727-01-B was a randomized crossover trial examining PK/PD, and was not designed to compare efficacy.

Chemotherapy

• Decitabine (Dacogen) 20 mg/m² IV over 60 minutes once per day on days 1 to 5

4- to 6-week cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kantarjian et al. 2007	NR	Randomized Phase 2, fewer than 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

• Decitabine (Dacogen) 10 mg/m² SC twice per day on days 1 to 5

28-day cycles

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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garcia-Manero et al. 2013 (DACO-026)	2008-2009	Randomized Phase 2 (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

• Decitabine (Dacogen) 20 mg/m² SC once per day on days 1, 8, 15

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

References

1. 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 contains dosing details in abstract PubMed NCT00043381
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 dosing details in abstract 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 dosing details in manuscript 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 dosing details in manuscript link to PMC article PubMed NCT00619099
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 dosing details in manuscript 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 dosing details in manuscript link to PMC article PubMed NCT01720225
7. ASTX727-01-B: Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells R, McCloskey J, Odenike O, DeZern AE, Yee K, Busque L, O'Connell C, Michaelis LC, Brandwein J, Kantarjian H, Oganesian A, Azab M, Savona MR. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020 Aug 6;136(6):674-683. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02103478
8. ASCERTAIN: Garcia-Manero G, McCloskey J, Griffiths EA, Yee KWL, Zeidan AM, Al-Kali A, Deeg HJ, Patel PA, Sabloff M, Keating MM, Zhu N, Gabrail NY, Fazal S, Maly J, Odenike O, Kantarjian H, DeZern AE, O'Connell CL, Roboz GJ, Busque L, Buckstein R, Amin H, Randhawa J, Leber B, Shastri A, Dao KH, Oganesian A, Hao Y, Keer HN, Azab M, Savona MR. Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study. Lancet Haematol. 2024 Jan;11(1):e15-e26. link to original article contains dosing details in abstract PubMed NCT03306264

Decitabine and cedazuridine monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garcia-Manero et al. 2020 (ASTX727-01-B)	2014-NR	Randomized Phase 2 (E-RT-switch-ic)	Decitabine	Not reported
Garcia-Manero et al. 2024 (ASCERTAIN)	2018-02-08 to 2021-06-07	Phase 3 (E-RT-switch-ic)	Decitabine	Equivalent pharmacokinetic exposure (primary endpoint)

Note: ASTX727-01-B was a randomized crossover trial examining PK/PD, and was not designed to compare efficacy.

Chemotherapy

• Decitabine and cedazuridine (Inqovi) 35/100 mg PO once per day on days 1 to 5

28-day cycles

References

1. ASTX727-01-B: Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells R, McCloskey J, Odenike O, DeZern AE, Yee K, Busque L, O'Connell C, Michaelis LC, Brandwein J, Kantarjian H, Oganesian A, Azab M, Savona MR. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020 Aug 6;136(6):674-683. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02103478
2. ASCERTAIN: Garcia-Manero G, McCloskey J, Griffiths EA, Yee KWL, Zeidan AM, Al-Kali A, Deeg HJ, Patel PA, Sabloff M, Keating MM, Zhu N, Gabrail NY, Fazal S, Maly J, Odenike O, Kantarjian H, DeZern AE, O'Connell CL, Roboz GJ, Busque L, Buckstein R, Amin H, Randhawa J, Leber B, Shastri A, Dao KH, Oganesian A, Hao Y, Keer HN, Azab M, Savona MR. Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study. Lancet Haematol. 2024 Jan;11(1):e15-e26. link to original article contains dosing details in abstract PubMed NCT03306264

Low-dose Cytarabine monotherapy (LoDAC)

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

Regimen variant #1, SC

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

Note: the cycle length was not explicitly defined in EORTC 06903. This was 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

• Cytarabine (Ara-C) 10 mg/m² SC twice per day on days 1 to 14

21-day cycle for up to 6 cycles

Regimen variant #2, CI

Historic variant

Study	Dates of enrollment	Evidence
Wisch et al. 1983	1982-07 to 1983-03	Non-randomized, fewer than 20 pts

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 dosing details in manuscript PubMed
2. Miller KB, Kim K, Morrison FS, Winter JN, Bennett JM, Neiman RS, Head DR, Cassileth PA, O'Connell MJ; ECOG; SWOG. 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 dosing details in abstract 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 dosing details in manuscript PubMed

Temozolomide monotherapy

Regimen

Study	Dates of enrollment	Evidence
Brandwein et al. 2014	NR	Phase 2

Note: 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

28-day cycle for up to 12 cycles

Dose and schedule modifications

• Patients with complete response could receive 200 mg/m²/day PO on days 1 to 5

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 dosing details in abstract PubMed

Consolidation after first-line therapy

Busulfan & Cyclophosphamide, then allo HSCT

BuCy: Busulfan & Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kröger et al. 2017 (RICMAC)	2004-2012	Phase 3 (C)	Bu/Flu RIC allo HSCT	Might have inferior OS
Xuan et al. 2023	2016-04-18 to 2019-09-30	Phase 3 (C)	Busulfan, Cyclophosphamide, Decitabine, G-CSF	Inferior CIR24

Chemotherapy

• Busulfan (Myleran) 3.2 mg/kg IV once per day on days -7 to -4 (total dose: 12.8 mg/kg)
• Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 and -2 (total dose: 120 mg/kg)

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• Cyclosporine
• Methotrexate (MTX) "according to the discretion of the attending physician"

Supportive therapy

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

One course

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 NCT01203228
2. Xuan L, Dai M, Jiang E, Wang Y, Huang F, Fan Z, Xu N, Nie D, Liang X, Chen H, Ye J, Shi P, Liu H, Jin H, Lin R, Yan C, Zhang Y, Sun J, Han M, Liu Q. The effect of granulocyte-colony stimulating factor, decitabine, and busulfan-cyclophosphamide versus busulfan-cyclophosphamide conditioning on relapse in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2023 Mar;10(3):e178-e190. Epub 2023 Jan 23. link to original article contains dosing details in abstract PubMed NCT02744742

Busulfan & Fludarabine, then allo HSCT

BuFlu: Busulfan & Fludarabine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Beelen et al. 2019 (MC-FludT.14/L)	2013-2016	Phase 3 (C)	Fludarabine & Treosulfan	Non-inferior EFS24

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV over 30 minutes once per day on days -7 to -3
  • MC-FludT.14/L gave the doses on days -6 to -2
• Busulfan (Myleran) 0.8 mg/kg IV over 2 hours every 6 hours on days -4 & -3 (total dose: 6.4 mg/kg)

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• ATG (Rabbit) 2.5 mg/kg IV over 6 hours once per day on days -4 to -2
• Tacrolimus (Prograf) with doses adjusted to maintain levels of 5 to 10 ng/mL, tapered on day +90 to off by day +180 (if no GVHD)
• Methotrexate (MTX) 5 mg/m² IV once per day on days +1, +3, +6, +11

One course

References

1. MC-FludT.14/L: Beelen DW, Trenschel R, Stelljes M, Groth C, Masszi T, Reményi P, Wagner-Drouet EM, Hauptrock B, Dreger P, Luft T, Bethge W, Vogel W, Ciceri F, Peccatori J, Stölzel F, Schetelig J, Junghanß C, Grosse-Thie C, Michallet M, Labussiere-Wallet H, Schaefer-Eckart K, Dressler S, Grigoleit GU, Mielke S, Scheid C, Holtick U, Patriarca F, Medeot M, Rambaldi A, Micò MC, Niederwieser D, Franke GN, Hilgendorf I, Winkelmann NR, Russo D, Socié G, Peffault de Latour R, Holler E, Wolff D, Glass B, Casper J, Wulf G, Menzel H, Basara N, Bieniaszewska M, Stuhler G, Verbeek M, Grass S, Iori AP, Finke J, Benedetti F, Pichlmeier U, Hemmelmann C, Tribanek M, Klein A, Mylius HA, Baumgart J, Dzierzak-Mietla M, Markiewicz M. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol. 2020 Jan;7(1):e28-e39. Epub 2019 Oct 9. link to original article contains dosing details in abstract PubMed NCT00822393
2. MDACC 2011-0628: Andersson BS, Thall PF, Ma J, Valdez BC, Bassett R Jr, Chen J, Ahmed S, Alousi A, Bashir Q, Ciurea S, Gulbis A, Cool R, Kawedia J, Hosing C, Kebriaei P, Kornblau S, Myers A, Oran B, Rezvani K, Shah N, Shpall E, Parmar S, Popat UR, Nieto Y, Champlin RE. A randomized phase III study of pretransplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in allogeneic stem cell transplantation. Bone Marrow Transplant. 2022 Aug;57(8):1295-1303. Epub 2022 May 24. link to original article link to PMC article PubMed NCT01471444

Relapsed or refractory

Erlotinib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Komrokji et al. 2014 (MCC-15961)	2009-2011	Phase 2
Thepot et al. 2014 (GFM-ERLOTINIB-08)	2010-07 to 2012-07	Phase 1/2

Note: This was the MTD in GFM-ERLOTINIB-08.

Targeted therapy

• Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 28

28-day cycles

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 contains dosing details in manuscript PubMed NCT00977548
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 contains dosing details in manuscript PubMed

Midostaurin monotherapy

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fischer et al. 2010 (CPKC412A2104)	2002-NR	Randomized phase 2b, fewer than 20 pts in this subgroup (E-de-esc)	Midostaurin; 100 mg twice per day	Not reported

Targeted therapy

• Midostaurin (Rydapt) 50 mg PO twice per day on days 1 to 28

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fischer et al. 2010 (CPKC412A2104)	2002-NR	Randomized phase 2b, fewer than 20 pts in this subgroup (E-esc)	Midostaurin; 50 mg twice per day	Not reported

Targeted therapy

• Midostaurin (Rydapt) 100 mg PO twice per day on days 1 to 28

28-day cycles

References

1. CPKC412A2104: 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 dosing details in manuscript PubMed NCT00045942

Response criteria

WHO International Working Group criteria

1. 2023: Zeidan AM, Platzbecker U, Bewersdorf JP, Stahl M, Adès L, Borate U, Bowen D, Buckstein R, Brunner A, Carraway HE, Daver N, Díez-Campelo M, de Witte T, DeZern AE, Efficace F, Garcia-Manero G, Garcia JS, Germing U, Giagounidis A, Griffiths EA, Hasserjian RP, Hellström-Lindberg E, Iastrebner M, Komrokji R, Kulasekararaj AG, Malcovati L, Miyazaki Y, Odenike O, Santini V, Sanz G, Scheinberg P, Stauder R, van de Loosdrecht AA, Wei AH, Sekeres MA, Fenaux P. Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes. Blood. 2023 Apr 27;141(17):2047-2061. link to original article PubMed
   1. 2018: Platzbecker U, Fenaux P, Adès L, Giagounidis A, Santini V, van de Loosdrecht AA, Bowen D, de Witte T, Garcia-Manero G, Hellström-Lindberg E, Germing U, Stauder R, Malcovati L, Sekeres MA, Steensma DP, Gloaguen S. Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials. Blood. 2019 Mar 7;133(10):1020-1030. Epub 2018 Nov 7. link to original article link to PMC article PubMed
   2. 2006: 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
   3. 2000: 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

Prognosis

• IPSS (Medscape)
• IPSS-R calculator, Revised International Prognostic Scoring System calculator (mds-foundation.org)
• Advanced IPSS-R calculator, Revised International Prognostic Scoring System calculator (mds-foundation.org)