Aplastic anemia

Section editor
	Benjamin Tillman, MD Vanderbilt University Nashville, TN, USA LinkedIn

9 regimens on this page 12 variants on this page

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.

BSH

• 2024: Kulasekararaj et al. Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline PubMed
• 2017: Samarasinghe et al. Paediatric amendment to adult BSH Guidelines for aplastic anaemia PubMed

Initial therapy

ATG (Horse) & Cyclosporine

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tichelli et al. 2011 (SAA-G-CSF)	2002-01 to 2008-07	Phase 3 (C)	ATG (Horse), Cyclosporine, G-CSF	Did not meet co-primary endpoints of EFS/OS
Scheinberg et al. 2009 (NHLBI 03-H-0193)	2003-06 to 2005-11	Phase 3 (C)	ATG (Horse), Cyclosporine, Sirolimus	Did not meet primary endpoint of hematologic RR
Scheinberg et al. 2011 (NHLBI 06-H-0034)	2005-12 to 2010-07	Phase 3 (C)	ATG (Rabbit) & Cyclosporine	Superior OS

Immunosuppressive therapy

• Antithymocyte globulin, horse ATG (Atgam) 40 mg/kg IV once per day on days 1 to 4
• Cyclosporine A (type not specified) by the following age-based criteria:
  • 12 years old or older: 5 mg/kg (route not specified) every 12 hours, starting on day 1, then dose adjusted to keep trough blood level of 200 to 400 ng/ml
  • Younger than 12 years old: 7.5 mg/kg (route not specified) every 12 hours, starting on day 1, then dose adjusted to keep trough blood level of 200 to 400 ng/ml

Supportive therapy

• Per NHLBI 03-H-0193:
• Prednisone (Sterapred) 1 mg/kg/day PO on days 1 to 10, then tapered over the next week, to prevent serum sickness
• Pentamidine (Nebupent) (dose not specified) once per month for at least 6 months
• Per others:
• Valacyclovir (Valtrex) (dose not specified) once per day

One course; CsA duration at least 6 months; among responders, CsA was tapered after 6 months with a 25% reduction in dose every 3 months for 18 more months, totaling 2 years of oral CsA (per NHLBI 03-H-0193)

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Teramura et al. 2007	1996-06 to 2000-06	Phase 3 (C)	ATG (Horse), Cyclosporine, G-CSF	Seems to have inferior hematologic response rate at 6 months

Immunosuppressive therapy

• Horse ATG (Lymphoglobuline; Merieux, Lyon, France) 15 mg/kg IV over 12 hours once per day on days 1 to 5
• Cyclosporine A (type not specified) 6 mg/kg/day

Supportive therapy

• Prednisolone (Millipred) to prevent serum sickness, as follows:
  • Days 1 to 9: 1 mg/kg/day PO
  • Days 10 to 15: 0.5 mg/kg/day PO
  • Days 16 to 21: 0.2 mg/kg/day PO

At least 28-week course

Dose and schedule modifications

• Cyclosporine dose adjusted to keep trough blood level of 150 to 250 ng/ml

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Marsh et al. 1999	1993-04 to 1997-03	Phase 3 (E-esc)	Cyclosporine	Seems to have superior ORR (primary endpoint)

Note: if blood cell count continued to increase at 6 months, cyclosporine continued at the therapeutic dose until the blood cell count plateaued, then reduced gradually to help prevent a relapse of the aplasia, per individual clinician discretion.

Immunosuppressive therapy

• Horse ATG (Lymphoglobuline; Merieux, Lyon, France) 15 mg/kg IV once per day on days 1 to 5
• Cyclosporine A (type not specified) 2.5 mg/kg (route not specified) twice per day

Supportive therapy

• Prednisolone (Millipred) to prevent serum sickness, as follows:
  • Days 5 to 13: 1 mg/kg/day PO
  • Days 14 to 20: reduced to zero over one week (tapering schedule not provided)

One at least 6-month course (see note)

Dose and schedule modifications

• Cyclosporine dose adjusted to keep trough blood level of 75 to 200 ng/ml

References

1. Marsh J, Schrezenmeier H, Marin P, Ilhan O, Ljungman P, McCann S, Socie G, Tichelli A, Passweg J, Hows J, Raghavachar A, Locasciulli A, Bacigalupo A. Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. Blood. 1999 Apr 1;93(7):2191-5. link to original article contains dosing details in manuscript PubMed
2. Teramura M, Kimura A, Iwase S, Yonemura Y, Nakao S, Urabe A, Omine M, Mizoguchi H. Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan. Blood. 2007 Sep 15;110(6):1756-61. Epub 2007 May 25. link to original article contains dosing details in manuscript PubMed
3. NHLBI 03-H-0193: Scheinberg P, Wu CO, Nunez O, Scheinberg P, Boss C, Sloand EM, Young NS. Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Haematologica. 2009 Mar;94(3):348-54. Epub 2009 Jan 30. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00061360
4. SAA-G-CSF: Tichelli A, Schrezenmeier H, Socié G, Marsh J, Bacigalupo A, Dührsen U, Franzke A, Hallek M, Thiel E, Wilhelm M, Höchsmann B, Barrois A, Champion K, Passweg JR; EBMT. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2011 Apr 28;117(17):4434-41. Epub 2011 Jan 13. link to original article PubMed NCT01163942
   1. Update: Tichelli A, Peffault de Latour R, Passweg J, Knol-Bout C, Socié G, Marsh J, Schrezenmeier H, Höchsmann B, Bacigalupo A, Samarasinghe S, Rovó A, Kulasekararaj A, Röth A, Eikema DJ, Bosman P, Bader P, Risitano A, Dufour C; Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation. Long-term outcome of a randomized controlled study in patients with newly diagnosed severe aplastic anemia treated with antithymocyte globuline, cyclosporine, with or without G-CSF: a Severe Aplastic Anemia Working Party Trial from the European Group of Blood and Marrow Transplantation. Haematologica. 2020 May;105(5):1223-1231. Epub 2019 Oct 3. link to original article link to PMC article PubMed
5. NHLBI 06-H-0034: Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, Young NS. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011 Aug 4;365(5):430-8. link to original article link to PMC article PubMed NCT00260689

ATG (Horse), Cyclosporine, Eltrombopag

Regimen variant #1, with pediatric dosing

Study	Dates of enrollment	Evidence
Townsley et al. 2017 (NHLBI 12-H-0150)	NR	Phase 1/2

Note: This is the eltrombopag dosing used in cohort 3, which had the highest response rate. ATG and CsA dosing was not described in Townsley et al. 2017 but was based on NHLBI 06-H-0034.

Immunosuppressive therapy

• Antithymocyte globulin, horse ATG (Atgam) 40 mg/kg IV once per day on days 1 to 4
• Cyclosporine A (type not specified) by the following age-based criteria:
  • 12 years old or older: 5 mg/kg (route not specified) every 12 hours
  • Younger than 12 years old: 7.5 mg/kg (route not specified) every 12 hours

Growth factor therapy

• Eltrombopag (Promacta) by the following age- and race-based criteria:
  • 2 to 5 years old AND East or Southeast Asian: 1.25 mg/kg PO once per day
  • 2 to 5 years old AND not East or Southeast Asian: 2.5 mg/kg PO once per day
  • 6 to 11 years old AND East or Southeast Asian: 37.5 mg PO once per day
  • 6 to 11 years old AND not East or Southeast Asian: 75 mg PO once per day
  • 12 years old or older AND East or Southeast Asian: 75 mg PO once per day
  • 12 years old or older AND not East or Southeast Asian: 150 mg PO once per day

Supportive therapy

• Pentamidine (Nebupent) (dose not specified) once per month
• Valacyclovir (Valtrex) (dose not specified) once per day

6-month course

Dose and schedule modifications

• Cyclosporine A dose adjusted to keep trough blood level of 200 to 400 ng/ml

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Peffault de Latour et al. 2022 (RACE)	2015-2019	Phase 3 (E-esc)	ATG (horse) & Cyclosporine	Superior CHR at 3 months (primary endpoint)

Immunosuppressive therapy

• Antithymocyte globulin, horse ATG (Atgam) 40 mg/kg IV once per day on days 1 to 4
• Cyclosporine 5 mg/kg/day, starting on day 1, continued for a minimum of 12 months, then tapered over the next 12 months

Growth factor therapy

• Eltrombopag (Promacta) 150 mg PO once per day, started on day 14, continued for at least 3 and up to 6 months

24-month course

References

1. NHLBI 12-H-0150: Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, Weinstein B, Valdez J, Lotter J, Feng X, Desierto M, Leuva H, Bevans M, Wu C, Larochelle A, Calvo KR, Dunbar CE, Young NS. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017 Apr 20;376(16):1540-1550. link to original article contains partial protocol link to PMC article PubMed NCT01623167
2. RACE: Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, Halkes CJM, Recher C, Barraco F, Forcade E, Vallejo JC, Drexler B, Mear JB, Smith AE, Angelucci E, Raymakers RAP, de Groot MR, Daguindau E, Nur E, Barcellini W, Russell NH, Terriou L, Iori AP, La Rocca U, Sureda A, Sánchez-Ortega I, Xicoy B, Jarque I, Cavenagh J, Sicre de Fontbrune F, Marotta S, Munir T, Tjon JML, Tavitian S, Praire A, Clement L, Rabian F, Marano L, Hill A, Palmisani E, Muus P, Cacace F, Frieri C, van Lint MT, Passweg JR, Marsh JCW, Socié G, Mufti GJ, Dufour C, Risitano AM; Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med. 2022 Jan 6;386(1):11-23. link to original article contains dosing details in manuscript PubMed NCT02099747

ATG (Horse), Cyclosporine, Methylprednisolone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Frickhofen et al. 1991	1986-05 to 1989-06	Phase 3 (E-esc)	ATG & Methylprednisolone	Seems to have superior ORR

Note: See paper for details about duration and tapering of cyclosporine.

Immunosuppressive therapy

• Antithymocyte globulin, horse ATG (Atgam) 0.75 ml/kg IV over 8 to 12 hours once per day on days 1 to 8
• Cyclosporine by the following age-specific criteria:
  • Adults: 6 mg/kg PO twice per day
  • Children: 500 mg/m² PO twice per day
• Methylprednisolone (Solumedrol) 5 mg/kg IV or PO once per day on days 1 to 8, then 1 mg/kg IV or PO once per day on days 9 to 14, then tapered off over the next 15 days

One course

Dose and schedule modifications

• Cyclosporine dose adjusted to keep trough blood level of 500 to 800 ng/ml during days 1 to 28, then 200 to 500 ng/ml subsequently

References

1. Frickhofen N, Kaltwasser JP, Schrezenmeier H, Raghavachar A, Vogt HG, Herrmann F, Freund M, Meusers P, Salama A, Heimpel H; German Aplastic Anemia Study Group. Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. N Engl J Med. 1991 May 9;324(19):1297-304. link to original article contains dosing details in manuscript PubMed

ATG (Horse), Cyclosporine, G-CSF

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Teramura et al. 2007	1996-06 to 2000-06	Phase 3 (E-esc)	ATG (Horse) & Cyclosporine	Seems to have superior hematologic response rate at 6 months
Tichelli et al. 2011 (SAA-G-CSF)	2002-01 to 2008-07	Phase 3 (E-esc)	ATG (Horse) & Cyclosporine	Did not meet co-primary endpoints of EFS/OS

Immunosuppressive therapy

• Horse ATG (Lymphoglobuline; Merieux, Lyon, France) 15 mg/kg IV over 12 hours once per day on days 1 to 5
• Cyclosporine A (type not specified) 6 mg/kg/day (route not specified)

Growth factor therapy

• ONE of the following:
  • Filgrastim (Neupogen) as follows:
    • Days 1 to 28: 400 mcg/m² IV once every other day
    • Days 29 to 84: 400 mcg/m² IV once or twice per week
  • Lenograstim (Granocyte) as follows:
    • Days 1 to 28: 50 mcg/kg IV once every other day
    • Days 29 to 84: 50 mcg/kg IV once or twice per week

Supportive therapy

• Prednisolone (Millipred) to prevent serum sickness, as follows:
  • Days 1 to 9: 1 mg/kg/day PO
  • Days 10 to 15: 0.5 mg/kg/day PO
  • Days 16 to 21: 0.2 mg/kg/day PO

One course of at least 28 weeks

Dose and schedule modifications

• Cyclosporine dose adjusted to keep trough blood level of 150 to 250 ng/ml

References

1. Teramura M, Kimura A, Iwase S, Yonemura Y, Nakao S, Urabe A, Omine M, Mizoguchi H. Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan. Blood. 2007 Sep 15;110(6):1756-61. Epub 2007 May 25. link to original article contains dosing details in manuscript PubMed
2. SAA-G-CSF: Tichelli A, Schrezenmeier H, Socié G, Marsh J, Bacigalupo A, Dührsen U, Franzke A, Hallek M, Thiel E, Wilhelm M, Höchsmann B, Barrois A, Champion K, Passweg JR; EBMT. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2011 Apr 28;117(17):4434-41. Epub 2011 Jan 13. link to original article PubMed NCT01163942

ATG (Horse), Cyclosporine, Sirolimus

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Scheinberg et al. 2009 (NHLBI 03-H-0193)	2003-06 to 2005-11	Phase 3 (E-switch-ic)	ATG (Horse) & Cyclosporine	Did not meet primary endpoint of hematologic RR

Immunosuppressive therapy

• Antithymocyte globulin, horse ATG (Atgam) 40 mg/kg IV once per day on days 1 to 4
• Cyclosporine A (type not specified) by the following age-based criteria:
  • 12 years old or older: 5 mg/kg (route not specified) every 12 hours, starting on day 1, then dose adjusted to keep trough blood level of 200 to 400 ng/ml
  • Younger than 12 years old: 7.5 mg/kg (route not specified) every 12 hours, starting on day 1, then dose adjusted to keep trough blood level of 200 to 400 ng/ml
• Sirolimus (Rapamune) by the following weight-based criteria:
  • 40 kg or more: 2 mg/day PO, starting on day 1, then dose adjusted to keep levels between 5 to 15 ng/ml
  • Less than 40 kg: 1 mg/m²/day PO, starting on day 1, then dose adjusted to keep levels between 5 to 15 ng/ml

Supportive therapy

• Prednisone (Sterapred) 1 mg/kg/day PO on days 1 to 10, then tapered over the next week, to prevent serum sickness
• Pentamidine (Nebupent) (dose not specified) once per month for at least 6 months
• Valacyclovir (Valtrex) 500 mg PO once per day for at least 8 weeks

6-month course

References

1. NHLBI 03-H-0193: Scheinberg P, Wu CO, Nunez O, Scheinberg P, Boss C, Sloand EM, Young NS. Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Haematologica. 2009 Mar;94(3):348-54. Epub 2009 Jan 30. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00061360

ATG (Rabbit) & Cyclosporine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Scheinberg et al. 2011 (NHLBI 06-H-0034)	2005-12 to 2010-07	Phase 3 (E-switch-ic)	ATG (Horse) & Cyclosporine	Inferior OS (secondary endpoint)

Immunosuppressive therapy

• Antithymocyte globulin, rabbit ATG (Thymoglobulin) 3.5 mg/kg IV once per day on days 1 to 5
• Cyclosporine A (type not specified) by the following age-based criteria:
  • 12 years old or older: 5 mg/kg (route not specified) every 12 hours
  • Younger than 12 years old: 7.5 mg/kg (route not specified) every 12 hours

Supportive therapy

• Pentamidine (Nebupent) (dose not specified) once per month
• Valacyclovir (Valtrex) (dose not specified) once per day

One course

Dose and schedule modifications

• Cyclosporine dose adjusted to keep trough blood level of 200 to 400 ng/ml

References

1. NHLBI 06-H-0034: Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, Young NS. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011 Aug 4;365(5):430-8. link to original article link to PMC article PubMed NCT00260689

Cyclosporine monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gluckman et al. 1992	1986-01 to 1989-12	Phase 3 (E-switch-ic)	ATG (Horse) & Prednisone	Did not meet primary endpoint of hematologic RR
Marsh et al. 1999	1993-04 to 1997-03	Phase 3 (C)	ATG (Horse) & Cyclosporine	Seems to have inferior ORR

Note: if blood cell count continued to increase at 6 months, cyclosporine was continued at the therapeutic dose until the blood cell count plateaued, then reduced gradually to help prevent a relapse of the aplasia, per individual clinician discretion.

Immunosuppressive therapy

• Cyclosporine A (type not specified)

Supportive therapy

• Prednisolone (Millipred) to prevent serum sickness, as follows:
  • Days 5 to 13: 1 mg/kg/day PO
  • Days 14 to 20: reduced to zero over one week (tapering schedule not provided)

One course of at least 6 months (see note)

Dose and schedule modifications

• Cyclosporine dose adjusted to keep trough blood level of 75 to 200 ng/ml

References

1. Gluckman E, Esperou-Bourdeau H, Baruchel A, Boogaerts M, Briere J, Donadio D, Leverger G, Leporrier M, Reiffers J, Janvier M, Michallet M, Stryckmans P; Cooperative Group on the Treatment of Aplastic Anemia. Multicenter randomized study comparing cyclosporine-A alone and antithymocyte globulin with prednisone for treatment of severe aplastic anemia. Blood. 1992 May 15;79(10):2540-6. link to original article PubMed
2. Marsh J, Schrezenmeier H, Marin P, Ilhan O, Ljungman P, McCann S, Socie G, Tichelli A, Passweg J, Hows J, Raghavachar A, Locasciulli A, Bacigalupo A. Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. Blood. 1999 Apr 1;93(7):2191-5. link to original article contains dosing details in manuscript PubMed

Relapsed or refractory

ATG (Rabbit), Cyclosporine, Methylprednisolone

Regimen

Study	Dates of enrollment	Evidence
Di Bona et al. 1999	1991-10-01 to 1997-08	Phase 2
Scheinberg et al. 2006	2000-01 to 2005-05	Retrospective

Immunosuppressive therapy

• Antithymocyte globulin, rabbit ATG (Thymoglobulin) 3.5 mg/kg IV over 6 to 8 hours once per day on days 1 to 5
• Cyclosporine A 5 mg/kg PO once per day on days 1 to 180, then tapered (schedule not specified)
• Methylprednisolone (Solumedrol) 2 mg/kg IV once per day on days 1 to 5, then 1 mg/kg IV once per day on days 6 to 10, then tapered off by day 30

Supportive therapy

• Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 1 to 90

One course

References

1. Di Bona E, Rodeghiero F, Bruno B, Gabbas A, Foa P, Locasciulli A, Rosanelli C, Camba L, Saracco P, Lippi A, Iori AP, Porta F, De Rossi G, Comotti B, Iacopino P, Dufour C, Bacigalupo A; GITMO. Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Br J Haematol. 1999 Nov;107(2):330-4. Erratum in: Br J Haematol 2000 Feb;108(2):461. De Rossi V [corrected to De Rossi G]. link to original article contains dosing details in manuscript PubMed
2. Retrospective: Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol. 2006 Jun;133(6):622-7. link to original article PubMed

Eltrombopag monotherapy

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Olnes et al. 2012 (NHLBI 09-H-0154)	2009-2011	Phase 2	RR: 44%

Growth factor therapy

• Eltrombopag (Promacta) 50 mg PO once per day, increased by 25 mg every 2 weeks until platelet count greater than 20 x 10⁹/L or maximum of 150 mg per day

Continued indefinitely

References

1. NHLBI 09-H-0154: Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, Parikh AR, Soto S, Biancotto A, Feng X, Lozier J, Wu CO, Young NS, Dunbar CE. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012 Jul 5;367(1):11-9. Erratum in: N Engl J Med. 2012 Jul 19;367(3):284. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00922883
   1. Update: Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M, Parikh AR, Broder K, Calvo KR, Wu CO, Young NS, Dunbar CE. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014 Mar 20;123(12):1818-25. Epub 2013 Dec 17. link to original article contains dosing details in manuscript link to PMC article PubMed