Difference between revisions of "Aplastic anemia"
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− | + | <div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px"> | |
− | + | [[#top|Back to Top]] | |
− | + | </div> | |
+ | {{#lst:Editorial board transclusions|heme}} | ||
{| class="wikitable" style="float:right; margin-right: 5px;" | {| class="wikitable" style="float:right; margin-right: 5px;" | ||
|- | |- | ||
− | |<div style="background-color: # | + | |<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div> |
− | <div style="background-color: # | + | <div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div> |
|} | |} | ||
{{TOC limit|limit=3}} | {{TOC limit|limit=3}} | ||
+ | =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.''' | ||
+ | ==[https://b-s-h.org.uk/ BSH]== | ||
+ | *'''2024:''' Kulasekararaj et al. [https://doi.org/10.1111/bjh.19236 Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline] [https://pubmed.ncbi.nlm.nih.gov/38247114/ PubMed] | ||
+ | * '''2017:''' Samarasinghe et al. [https://doi.org/10.1111/bjh.15066 Paediatric amendment to adult BSH Guidelines for aplastic anaemia] [https://pubmed.ncbi.nlm.nih.gov/29285764/ PubMed] | ||
=Initial therapy= | =Initial therapy= | ||
− | |||
==ATG (Horse) & Cyclosporine {{#subobject:ab0800|Regimen=1}}== | ==ATG (Horse) & Cyclosporine {{#subobject:ab0800|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #1 {{#subobject:7302a2|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | + | !style="width: 20%"|Study | |
− | + | !style="width: 20%"|Dates of enrollment | |
− | ===Regimen {{#subobject:7302a2|Variant=1}}=== | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | {| | + | !style="width: 20%"|Comparator |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | |[[Levels_of_Evidence#Evidence| | ||
− | | | ||
− | |||
− | |||
− | |||
− | |[[ | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2010-08-304071 Tichelli et al. 2011 (SAA-G-CSF)] |
− | |style="background-color:# | + | |2002-01 to 2008-07 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
|[[Aplastic_anemia#ATG_.28Horse.29.2C_Cyclosporine.2C_G-CSF|ATG (Horse), Cyclosporine, G-CSF]] | |[[Aplastic_anemia#ATG_.28Horse.29.2C_Cyclosporine.2C_G-CSF|ATG (Horse), Cyclosporine, G-CSF]] | ||
+ | |style="background-color:#ffffbf"|Did not meet co-primary endpoints of EFS/OS | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649367/ Scheinberg et al. 2009 (NHLBI 03-H-0193)] |
− | |style="background-color:# | + | |2003-06 to 2005-11 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
|[[Aplastic_anemia#ATG_.28Horse.29.2C_Cyclosporine.2C_Sirolimus|ATG (Horse), Cyclosporine, Sirolimus]] | |[[Aplastic_anemia#ATG_.28Horse.29.2C_Cyclosporine.2C_Sirolimus|ATG (Horse), Cyclosporine, Sirolimus]] | ||
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of hematologic RR | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721503/ Scheinberg et al. 2011 (NHLBI 06-H-0034)] |
− | + | |2005-12 to 2010-07 | |
− | + | |style="background-color:#1a9851"|Phase 3 (C) | |
− | |- | ||
− | |||
− | |style="background-color:# | ||
|[[Aplastic_anemia#ATG_.28Rabbit.29_.26_Cyclosporine|ATG (Rabbit) & Cyclosporine]] | |[[Aplastic_anemia#ATG_.28Rabbit.29_.26_Cyclosporine|ATG (Rabbit) & Cyclosporine]] | ||
+ | |style="background-color:#1a9850"|Superior OS | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
+ | ====Immunosuppressive therapy==== | ||
*[[Antithymocyte globulin, horse ATG (Atgam)]] 40 mg/kg IV once per day on days 1 to 4 | *[[Antithymocyte globulin, horse ATG (Atgam)]] 40 mg/kg IV once per day on days 1 to 4 | ||
− | *Cyclosporine A (type not specified) | + | *[[Cyclosporine|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:'' | |
− | *[[Pentamidine (Nebupent)]] (dose not specified) once per month | + | *[[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 | *[[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)''' | |
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2 {{#subobject:c8f7e9|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1182/blood-2006-11-050526 Teramura et al. 2007] | ||
+ | |1996-06 to 2000-06 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[Aplastic_anemia#ATG_.28Horse.29.2C_Cyclosporine.2C_G-CSF|ATG (Horse), Cyclosporine, G-CSF]] | ||
+ | |style="background-color:#fc8d59"|Seems to have inferior hematologic response rate at 6 months | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Immunosuppressive therapy==== | ||
+ | *[[Antithymocyte globulin, horse ATG (Atgam)|Horse ATG (Lymphoglobuline; Merieux, Lyon, France)]] 15 mg/kg IV over 12 hours once per day on days 1 to 5 | ||
+ | *[[Cyclosporine|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''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
+ | ====Dose and schedule modifications==== | ||
+ | *Cyclosporine dose adjusted to keep trough blood level of 150 to 250 ng/ml | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3 {{#subobject:d94e34|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1182/blood.V93.7.2191 Marsh et al. 1999] | ||
+ | |1993-04 to 1997-03 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
+ | |[[Aplastic_anemia#Cyclosporine_monotherapy|Cyclosporine]] | ||
+ | |style="background-color:#91cf60"|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.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Immunosuppressive therapy==== | ||
+ | *[[Antithymocyte globulin, horse ATG (Atgam)|Horse ATG (Lymphoglobuline; Merieux, Lyon, France)]] 15 mg/kg IV once per day on days 1 to 5 | ||
+ | *[[Cyclosporine|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)''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
+ | ====Dose and schedule modifications==== | ||
+ | *Cyclosporine dose adjusted to keep trough blood level of 75 to 200 ng/ml | ||
+ | </div></div> | ||
===References=== | ===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. [ | + | # 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. [https://doi.org/10.1182/blood.V93.7.2191 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10090926/ 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. [ | + | # 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. [https://doi.org/10.1182/blood-2006-11-050526 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17526862/ PubMed] |
− | # 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. [ | + | # '''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. [https://doi.org/10.3324/haematol.13829 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649367/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19181786/ PubMed] [https://clinicaltrials.gov/study/NCT00061360 NCT00061360] |
− | # 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. 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. [ | + | # '''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. [https://doi.org/10.1182/blood-2010-08-304071 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21233311/ PubMed] [https://clinicaltrials.gov/study/NCT01163942 NCT01163942] |
− | # 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. [ | + | ## '''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. [https://doi.org/10.3324/haematol.2019.222562 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193468/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31582549/ 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. [https://doi.org/10.1056/NEJMoa1103975 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721503/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21812672/ PubMed] [https://clinicaltrials.gov/study/NCT00260689 NCT00260689] | ||
==ATG (Horse), Cyclosporine, Eltrombopag {{#subobject:66c8b3|Regimen=1}}== | ==ATG (Horse), Cyclosporine, Eltrombopag {{#subobject:66c8b3|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen variant #1, with pediatric dosing {{#subobject:488f07|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548296/ Townsley et al. 2017 (NHLBI 12-H-0150)] | ||
+ | |NR | ||
+ | |style="background-color:#91cf61"|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 [[#ATG_.28Horse.29_.26_Cyclosporine|NHLBI 06-H-0034]].'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Immunosuppressive therapy==== | ||
+ | *[[Antithymocyte globulin, horse ATG (Atgam)]] 40 mg/kg IV once per day on days 1 to 4 | ||
+ | *[[Cyclosporine|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''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
− | ===Regimen {{#subobject: | + | ====Dose and schedule modifications==== |
− | {| | + | *[[Cyclosporine|Cyclosporine A]] dose adjusted to keep trough blood level of 200 to 400 ng/ml |
− | | | + | </div></div><br> |
− | |[[Levels_of_Evidence#Evidence| | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | |||
+ | ===Regimen variant #2 {{#subobject:48ghc7|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1056/nejmoa2109965 Peffault de Latour et al. 2022 (RACE)] |
− | | | + | |2015-2019 |
− | style="background:# | + | | style="background-color:#1a9851" |Phase 3 (E-esc) |
− | + | |[[#ATG_.28Horse.29_.26_Cyclosporine|ATG (horse) & Cyclosporine]] | |
− | + | | style="background-color:#1a9850" |Superior CHR at 3 months (primary endpoint) | |
− | |||
− | |||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
− | + | ====Immunosuppressive therapy==== | |
− | |||
*[[Antithymocyte globulin, horse ATG (Atgam)]] 40 mg/kg IV once per day on days 1 to 4 | *[[Antithymocyte globulin, horse ATG (Atgam)]] 40 mg/kg IV once per day on days 1 to 4 | ||
− | *Cyclosporine | + | *[[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 | |
− | *[[Eltrombopag (Promacta)]] | + | '''24-month course''' |
− | + | </div></div> | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | # '''Abstract:''' Townsley et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia Accelerates Count Recovery and Increases Response Rates. ASH 2015 Annual Meeting LBA-2 [https:// | + | <!-- # '''Abstract:''' Townsley et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia Accelerates Count Recovery and Increases Response Rates. ASH 2015 Annual Meeting LBA-2 --> |
+ | # '''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. [https://doi.org/10.1056/NEJMoa1613878 link to original article] '''contains partial protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548296/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28423296/ PubMed] [https://clinicaltrials.gov/study/NCT01623167 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. [https://doi.org/10.1056/nejmoa2109965 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34986284/ PubMed] [https://clinicaltrials.gov/study/NCT02099747 NCT02099747] | ||
− | ==ATG (Horse), Cyclosporine, | + | ==ATG (Horse), Cyclosporine, Methylprednisolone {{#subobject:77c8b3|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:477f07|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1056/NEJM199105093241901 Frickhofen et al. 1991] | ||
+ | |1986-05 to 1989-06 | ||
+ | | style="background-color:#1a9851" |Phase 3 (E-esc) | ||
+ | |[[#ATG_.26_Methylprednisolone_888|ATG & Methylprednisolone]] | ||
+ | | style="background-color:#91cf60" |Seems to have superior ORR | ||
|- | |- | ||
− | |||
|} | |} | ||
+ | ''Note: See paper for details about duration and tapering of cyclosporine.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====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/m<sup>2</sup> 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''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
+ | ====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 | ||
+ | </div></div> | ||
+ | ===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. [https://doi.org/10.1056/NEJM199105093241901 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2017225/ PubMed] | ||
+ | ==ATG (Horse), Cyclosporine, G-CSF {{#subobject:d0ab72|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:6dfca3|Variant=1}}=== | ===Regimen {{#subobject:6dfca3|Variant=1}}=== | ||
− | {| | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | | | + | !style="width: 20%"|Study |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|Dates of enrollment |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2006-11-050526 Teramura et al. 2007] |
− | |style="background-color:# | + | |1996-06 to 2000-06 |
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
|[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | |[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | ||
+ | |style="background-color:#91cf60"|Seems to have superior hematologic response rate at 6 months | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2010-08-304071 Tichelli et al. 2011 (SAA-G-CSF)] |
− | |style="background-color:# | + | |2002-01 to 2008-07 |
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
|[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | |[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | ||
+ | |style="background-color:#ffffbf"|Did not meet co-primary endpoints of EFS/OS | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
+ | ====Immunosuppressive therapy==== | ||
+ | *[[Antithymocyte globulin, horse ATG (Atgam)|Horse ATG (Lymphoglobuline; Merieux, Lyon, France)]] 15 mg/kg IV over 12 hours once per day on days 1 to 5 | ||
+ | *[[Cyclosporine|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/m<sup>2</sup> IV once every other day | ||
+ | ***Days 29 to 84: 400 mcg/m<sup>2</sup> 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''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
+ | ====Dose and schedule modifications==== | ||
+ | *Cyclosporine dose adjusted to keep trough blood level of 150 to 250 ng/ml | ||
+ | </div></div> | ||
===References=== | ===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. [ | + | # 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. [https://doi.org/10.1182/blood-2006-11-050526 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17526862/ PubMed] |
− | # 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. 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. [ | + | # '''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. [https://doi.org/10.1182/blood-2010-08-304071 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21233311/ PubMed] [https://clinicaltrials.gov/study/NCT01163942 NCT01163942] |
− | |||
==ATG (Horse), Cyclosporine, Sirolimus {{#subobject:623c6e|Regimen=1}}== | ==ATG (Horse), Cyclosporine, Sirolimus {{#subobject:623c6e|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:84d40c|Variant=1}}=== | ===Regimen {{#subobject:84d40c|Variant=1}}=== | ||
− | {| | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | | | + | !style="width: 20%"|Study |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|Dates of enrollment |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649367/ Scheinberg et al. 2009 (NHLBI 03-H-0193)] |
− | |style="background-color:# | + | |2003-06 to 2005-11 |
+ | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | ||
|[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | |[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | ||
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of hematologic RR | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
− | + | ====Immunosuppressive therapy==== | |
+ | *[[Antithymocyte globulin, horse ATG (Atgam)]] 40 mg/kg IV once per day on days 1 to 4 | ||
+ | *[[Cyclosporine|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/m<sup>2</sup>/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''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # 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. [ | + | # '''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. [https://doi.org/10.3324/haematol.13829 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649367/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19181786/ PubMed] [https://clinicaltrials.gov/study/NCT00061360 NCT00061360] |
− | |||
==ATG (Rabbit) & Cyclosporine {{#subobject:e2426d|Regimen=1}}== | ==ATG (Rabbit) & Cyclosporine {{#subobject:e2426d|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
− | |||
===Regimen {{#subobject:131d15|Variant=1}}=== | ===Regimen {{#subobject:131d15|Variant=1}}=== | ||
− | {| | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | | | + | !style="width: 20%"|Study |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|Dates of enrollment |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721503/ Scheinberg et al. 2011 (NHLBI 06-H-0034)] |
− | |style="background-color:# | + | |2005-12 to 2010-07 |
+ | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | ||
|[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | |[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | ||
+ | |style="background-color:#d73027"|Inferior OS (secondary endpoint) | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
+ | ====Immunosuppressive therapy==== | ||
*[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] 3.5 mg/kg IV once per day on days 1 to 5 | *[[Antithymocyte globulin, rabbit ATG (Thymoglobulin)]] 3.5 mg/kg IV once per day on days 1 to 5 | ||
− | *Cyclosporine A (type not specified) | + | *[[Cyclosporine|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 | + | ====Supportive therapy==== |
*[[Pentamidine (Nebupent)]] (dose not specified) once per month | *[[Pentamidine (Nebupent)]] (dose not specified) once per month | ||
*[[Valacyclovir (Valtrex)]] (dose not specified) once per day | *[[Valacyclovir (Valtrex)]] (dose not specified) once per day | ||
− | + | '''One course''' | |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
+ | ====Dose and schedule modifications==== | ||
+ | *Cyclosporine dose adjusted to keep trough blood level of 200 to 400 ng/ml | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # 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. [ | + | # '''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. [https://doi.org/10.1056/NEJMoa1103975 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721503/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21812672/ PubMed] [https://clinicaltrials.gov/study/NCT00260689 NCT00260689] |
− | ==Cyclosporine {{#subobject:754320|Regimen=1}}== | + | ==Cyclosporine monotherapy {{#subobject:754320|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:e076cf|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood.V79.10.2540.2540 Gluckman et al. 1992] |
− | | | + | |1986-01 to 1989-12 |
− | + | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | |
− | + | |[[#ATG_.28Horse.29_.26_Prednisone_888|ATG (Horse) & Prednisone]] | |
− | + | | style="background-color:#ffffbf" |Did not meet primary endpoint of hematologic RR | |
− | | | ||
− | |[[ | ||
− | | | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood.V93.7.2191 Marsh et al. 1999] |
− | |style="background-color:# | + | |1993-04 to 1997-03 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
|[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | |[[Aplastic_anemia#ATG_.28Horse.29_.26_Cyclosporine|ATG (Horse) & Cyclosporine]] | ||
+ | |style="background-color:#fc8d59"|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.'' | |
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
+ | ====Immunosuppressive therapy==== | ||
+ | *[[Cyclosporine|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)''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
+ | ====Dose and schedule modifications==== | ||
+ | *Cyclosporine dose adjusted to keep trough blood level of 75 to 200 ng/ml | ||
+ | </div></div> | ||
===References=== | ===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. [ | + | # 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. [https://doi.org/10.1182/blood.V79.10.2540.2540 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1586706/ 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. [https://doi.org/10.1182/blood.V93.7.2191 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10090926/ PubMed] | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
+ | =Relapsed or refractory= | ||
+ | ==ATG (Rabbit), Cyclosporine, Methylprednisolone {{#subobject:d140da|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:c687c5|Variant=1}}=== | ===Regimen {{#subobject:c687c5|Variant=1}}=== | ||
− | {| | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | | | + | !style="width: 33%"|Study |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1046/j.1365-2141.1999.01693.x Di Bona et al. 1999] |
− | | | + | |1991-10-01 to 1997-08 |
− | style="background | + | |style="background-color:#91cf61"|Phase 2 |
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1111/j.1365-2141.2006.06098.x Scheinberg et al. 2006] |
− | | | + | |2000-01 to 2005-05 |
− | style="background | + | | style="background-color:#ffffbe" |Retrospective |
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
− | + | ====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|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''' | ||
+ | </div></div> | ||
===References=== | ===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. 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 | + | # 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]. [https://doi.org/10.1046/j.1365-2141.1999.01693.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10583220/ 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. [ | + | # '''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. [https://doi.org/10.1111/j.1365-2141.2006.06098.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/16704436/ PubMed] |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
+ | ==Eltrombopag monotherapy {{#subobject:6a217b|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:ca8fc4|Variant=1}}=== | ===Regimen {{#subobject:ca8fc4|Variant=1}}=== | ||
− | {| | + | {| class="wikitable sortable" style="width: 80%; text-align:center;" |
− | | | + | !style="width: 25%"|Study |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 25%"|Dates of enrollment |
+ | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422737/ Olnes et al. 2012 (NHLBI 09-H-0154)] |
− | | | + | |2009-2011 |
− | style="background | + | |style="background-color:#91cf61"|Phase 2 |
− | + | |RR: 44% | |
− | |||
− | |||
− | |||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
− | *[[Eltrombopag (Promacta)]] 50 mg PO once per day, increased by 25 mg every 2 weeks until platelet count > | + | ====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 10<sup>9</sup>/L or maximum of 150 mg per day | |
+ | '''Continued indefinitely''' | ||
+ | </div></div> | ||
===References=== | ===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. [ | + | # '''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. [https://doi.org/10.1056/NEJMoa1200931 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422737/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22762314/ PubMed] [https://clinicaltrials.gov/study/NCT00922883 NCT00922883] |
− | ## '''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. [ | + | ## '''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. [https://doi.org/10.1182/blood-2013-10-534743 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962161/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24345753/ PubMed] |
+ | [[Category:Aplastic anemia regimens]] | ||
+ | [[Category:Disease-specific pages]] | ||
+ | [[Category:Bone marrow failure syndromes]] | ||
+ | [[Category:Cytopenias]] |
Latest revision as of 12:50, 29 June 2024
Section editor | |
---|---|
Benjamin Tillman, MD Vanderbilt University Nashville, TN, USA |
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 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
- 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
- Filgrastim (Neupogen) as follows:
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
- 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
- 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
- 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
- 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
- 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 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
- 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
- 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
- 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
- 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