Guidelines
Initial therapy
ATG (Horse) & Cyclosporine
Regimen variant #1
Immunosuppressive therapy
- Antithymocyte globulin, horse ATG (Atgam) 40 mg/kg IV once per day on days 1 to 4
- Cyclosporine A (type not specified) as follows:
- Starting dose, 12 and older: 5 mg/kg (route not specified) every 12 hours on day 1
- Starting dose, younger than 12: 7.5 mg/kg (route not specified) every 12 hours on day 1
- Dose adjusted to keep trough blood level of 200 to 400 ng/ml
- 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)
Supportive medications
Regimen variant #2
Immunosuppressive therapy
Supportive medications
- 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
Regimen variant #3
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) as follows:
- Starting dose: 2.5 mg/kg (route not specified) twice per day
- Dose adjusted to keep trough blood level of 75 to 200 ng/ml
- Duration: at least 6 months; if blood cell count continued to increase at 6 months, 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
Supportive medications
- 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)
References
- 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 verified protocol PubMed
- 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 verified protocol PubMed
- 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 verified protocol link to PMC article PubMed
- 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
- 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. 2019 Oct 3. [Epub ahead of print] link to original article PubMed
- 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
ATG (Horse), Cyclosporine, Eltrombopag
Regimen variant #1, with pediatric dosing
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) as follows:
- Starting dose, 12 and older: 5 mg/kg (route not specified) every 12 hours
- Starting dose, younger than 12: 7.5 mg/kg (route not specified) every 12 hours
- Dose adjusted to keep trough blood level of 200 to 400 ng/ml
Supportive medications
- Eltrombopag (Promacta) as follows:
- Patients 2 to 5 years old: 2.5 mg/kg PO once per day
- Patients 6 to 11 years old: 75 mg PO once per day
- Patients 12 and older: 150 mg PO once per day
- East or Southeast Asian participants had a 50% dose reduction
- Pentamidine (Nebupent) (dose not specified) once per month
- Valacyclovir (Valtrex) (dose not specified) once per day
6-month course
Regimen variant #2
Immunosuppressive therapy
Supportive medications
24-month course
References
- 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
- 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 verified protocol PubMed NCT02099747
ATG (Horse), Cyclosporine, Methylprednisolone
Regimen
Immunosuppressive therapy
References
- 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 PubMed
ATG (Horse), Cyclosporine, G-CSF
Regimen
Immunosuppressive therapy
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 medications
- 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
References
- 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 verified protocol PubMed
- 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
ATG (Horse), Cyclosporine, Sirolimus
Regimen
Immunosuppressive therapy
- Antithymocyte globulin, horse ATG (Atgam) 40 mg/kg IV once per day on days 1 to 4
- Cyclosporine A (type not specified) as follows:
- Starting dose, 12 and older: 5 mg/kg (route not specified) every 12 hours on day 1
- Starting dose, younger than 12: 7.5 mg/kg (route not specified) every 12 hours on day 1
- Dose adjusted to keep trough blood level of 200 to 400 ng/ml
- Duration: 6 months
- Sirolimus (Rapamune) as follows:
- Starting dose: 2 mg/day (1 mg/m2/day in children less than 40 kg) on day 1
- Dose adjusted to keep levels between 5 to 15 ng/ml
- Duration: 6 months
Supportive medications
References
- 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 verified protocol link to PMC article PubMed
ATG (Rabbit) & Cyclosporine
Regimen
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) as follows:
- Starting dose, 12 and older: 5 mg/kg (route not specified) every 12 hours
- Starting dose, younger than 12: 7.5 mg/kg (route not specified) every 12 hours
- Dose adjusted to keep trough blood level of 200 to 400 ng/ml
Supportive medications
References
- 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
Cyclosporine monotherapy
Regimen
Immunosuppressive therapy
- Cyclosporine A (type not specified) as follows:
- Starting dose: 2.5 mg/kg (route not specified) twice per day
- Dose adjusted to keep trough blood level of 75 to 200 ng/ml
- Duration: at least 6 months; if blood cell count continued to increase at 6 months, 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
Supportive medications
- 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)
References
- 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
- 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 verified protocol PubMed
Relapsed or refractory
ATG (Rabbit) & Cyclosporine
Regimen
To be completed
Immunosuppressive therapy
References
- 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 PubMed
- 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
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
- 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 verified protocol link to PMC article PubMed
- 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 verified protocol link to PMC article PubMed