Difference between revisions of "Paroxysmal nocturnal hemoglobinuria"

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[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
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{{#lst:Section editor transclusions|heme}}
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{{#lst:Editorial board transclusions|heme}}
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''Are you looking for a regimen, but can't find it here? For placebo or observational studies in this condition, please visit [[Paroxysmal nocturnal hemoglobinuria - null regimens|this page]]. If you still can't find it, please let us know so we can add it!'' <br>
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*''We have moved [[How I Treat]] articles to a dedicated page.''
 
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=Guidelines=
 
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=="How I Treat"==
 
−
 
−
*'''2021:''' Brodsky [https://doi.org/10.1182/blood.2019003812 How I treat paroxysmal nocturnal hemoglobinuria]
 
−
 
 
=All lines of therapy=
 
=All lines of therapy=
 
==Eculizumab monotherapy {{#subobject:1 |Regimen=1}}==
 
==Eculizumab monotherapy {{#subobject:1 |Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, 12-week course {{#subobject:4bb05f |Variant=1}}===
 
===Regimen variant #1, 12-week course {{#subobject:4bb05f |Variant=1}}===
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{| class="wikitable" style="width: 40%; text-align:center;"  
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{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
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!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
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!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
 
|[https://doi.org/10.1056/NEJMoa031688 Hillmen et al. 2004]
 
|[https://doi.org/10.1056/NEJMoa031688 Hillmen et al. 2004]
−
| style="background-color:#ffffbe" |Pilot, <20 pts
+
|2002-05 to 2002-12
 +
| style="background-color:#ffffbe" |Pilot, fewer than 20 pts
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunosuppressive therapy====
 
====Immunosuppressive therapy====
−
 
 
*[[Eculizumab (Soliris)]] as follows:
 
*[[Eculizumab (Soliris)]] as follows:
−
**Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22
+
**Cycles 1 to 4: 600 mg IV over 25 to 45 minutes once on day 1
−
**Cycles 2 & 3: 900 mg IV over 25 to 45 minutes once per day on days 1 & 15
+
**Cycles 5 to 8: 900 mg IV over 25 to 45 minutes once on day 1
−
 
+
'''7-day cycle for 4 cycles, then 14-day cycle for 4 cycles
−
'''28-day cycle for 3 cycles'''
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</div></div><br>
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, 6-month course {{#subobject:1 |Variant=1}}===
 
===Regimen variant #2, 6-month course {{#subobject:1 |Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 20%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Dates of enrollment
−
! style="width: 25%" |Comparator
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
 
|[https://doi.org/10.1056/NEJMoa061648 Hillmen et al. 2006 (TRIUMPH)]
 
|[https://doi.org/10.1056/NEJMoa061648 Hillmen et al. 2006 (TRIUMPH)]
 +
|2004-10 to 2005-06
 
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
|[[#Placebo|Placebo]]
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|[[Paroxysmal_nocturnal_hemoglobinuria_-_null_regimens#Placebo|Placebo]]
−
| style="background-color:#1a9850" |Superior stabilization of Hgb levels and QoL
+
| style="background-color:#1a9850" |Superior stabilization of Hgb levels and QoL (co-primary endpoint)
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ Lee et al. 2018 (ALXN1210-PNH-301)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ Lee et al. 2018 (CHAMPION 301)]
 +
|NR
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
 
|[[#Ravulizumab_monotherapy|Ravulizumab]]
 
|[[#Ravulizumab_monotherapy|Ravulizumab]]
 
| style="background-color:#eeee01" |Non-inferior efficacy
 
| style="background-color:#eeee01" |Non-inferior efficacy
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ Kulasekararaj et al. 2018 (ALXN1210-PNH-302)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ Kulasekararaj et al. 2018 (CHAMPION 302)]
 +
|NR
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
 
|[[#Ravulizumab_monotherapy|Ravulizumab]]
 
|[[#Ravulizumab_monotherapy|Ravulizumab]]
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|-
 
|-
 
|}
 
|}
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<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunosuppressive therapy====
 
====Immunosuppressive therapy====
−
 
 
*[[Eculizumab (Soliris)]] as follows:
 
*[[Eculizumab (Soliris)]] as follows:
−
**Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22
+
**Cycles 1 to 4: 600 mg IV over 25 to 45 minutes once on day 1
−
**Cycles 2 to 12: 900 mg IV over 25 to 45 minutes once on day 1
+
**Cycles 5 to 15: 900 mg IV over 25 to 45 minutes once on day 1
−
 
 
 
====Supportive therapy====
 
====Supportive therapy====
−
 
 
*Patients received Neisseria meningitidis meningococcal vaccination
 
*Patients received Neisseria meningitidis meningococcal vaccination
−
 
+
'''7-day cycle for 4 cycles, then 14-day cycle for 11 cycles'''
−
'''28-day cycle for 1 cycle, then 14-day cycle for 11 cycles'''
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
 
===Regimen variant #3, 12-month course {{#subobject:2 |Variant=1}}===
 
===Regimen variant #3, 12-month course {{#subobject:2 |Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
 
|[http://www.bloodjournal.org/content/111/4/1840.long Brodsky et al. 2007 (SHEPHERD)]
 
|[http://www.bloodjournal.org/content/111/4/1840.long Brodsky et al. 2007 (SHEPHERD)]
 +
|NR
 
| style="background-color:#91cf61" |Phase 2 (RT)
 
| style="background-color:#91cf61" |Phase 2 (RT)
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunosuppressive therapy====
 
====Immunosuppressive therapy====
−
 
 
*[[Eculizumab (Soliris)]] as follows:
 
*[[Eculizumab (Soliris)]] as follows:
−
**Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22
+
**Cycles 1 to 4: 600 mg IV over 25 to 45 minutes once on day 1
−
**Cycles 2 to 25: 900 mg IV over 25 to 45 minutes once on day 1
+
**Cycles 5 to 28: 900 mg IV over 25 to 45 minutes once on day 1
−
 
+
'''7-day cycle for 4 cycles, then 14-day cycle for 24 cycles'''
−
'''28-day cycle for 1 cycle, then 14-day cycle for 24 cycles'''
+
</div></div><br>
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #4, indefinite {{#subobject:3 |Variant=1}}===
 
===Regimen variant #4, indefinite {{#subobject:3 |Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
 
|[http://www.bloodjournal.org/content/117/25/6786.long Kelly et al. 2011]
 
|[http://www.bloodjournal.org/content/117/25/6786.long Kelly et al. 2011]
 +
|2002-05 to 2010-07
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunosuppressive therapy====
 
====Immunosuppressive therapy====
−
 
 
*[[Eculizumab (Soliris)]] as follows:
 
*[[Eculizumab (Soliris)]] as follows:
−
**Cycle 1: 600 mg IV over at least 30 minutes once per day on days 1, 8, 15, 22
+
**Cycles 1 to 4: 600 mg IV over at least 30 minutes once on day 1
−
**Cycle 2 onwards: 900 mg IV over at least 30 minutes once on day 1
+
**Cycle 5 onwards: 900 mg IV over at least 30 minutes once on day 1
−
***Patients with return of PNH symptoms, such as red or black urine, abdominal discomfort, or increased LDH before the next dose of eculizumab received higher doses: [[Eculizumab (Soliris)]] 1200 mg IV once on day 1
 
−
 
 
 
====Supportive therapy====
 
====Supportive therapy====
−
 
 
*Meningitis prophylaxis: ''Neisseria meningitidis'' meningococcal vaccination
 
*Meningitis prophylaxis: ''Neisseria meningitidis'' meningococcal vaccination
 
*[[Penicillin V]] 500 mg PO twice per day
 
*[[Penicillin V]] 500 mg PO twice per day
 
**Patients with penicillin allergies instead received: [[Erythromycin]] 500 mg PO twice per day
 
**Patients with penicillin allergies instead received: [[Erythromycin]] 500 mg PO twice per day
−
 
+
'''7-day cycle for 4 cycles, then 14-day cycles'''
−
'''28-day cycle for 1 cycle, then 14-day cycles'''
+
</div>
 +
<div class="toccolours" style="background-color:#fff2ae">
 +
====Dose and schedule modifications====
 +
*Patients with return of PNH symptoms, such as red or black urine, abdominal discomfort, or increased LDH before the next dose of eculizumab received higher doses: [[Eculizumab (Soliris)]] 1200 mg IV once on day 1
 +
</div></div>
  
 
===References===
 
===References===
−
 
+
#Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004 Feb 5;350(6):552-9. [https://doi.org/10.1056/NEJMoa031688 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14762182/ PubMed]
−
#Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004 Feb 5;350(6):552-9. [https://doi.org/10.1056/NEJMoa031688 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14762182 PubMed]
+
##'''Update:''' Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, Mojcik CF, Rother RP. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005 Oct 1;106(7):2559-65. Epub 2005 Jun 28. [http://www.bloodjournal.org/content/106/7/2559.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/15985537/ PubMed]
−
##'''Update:''' Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, Mojcik CF, Rother RP. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005 Oct 1;106(7):2559-65. Epub 2005 Jun 28. [http://www.bloodjournal.org/content/106/7/2559.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/15985537 PubMed]
+
#'''TRIUMPH:''' Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233-43. [https://doi.org/10.1056/NEJMoa061648 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16990386/ PubMed] [https://clinicaltrials.gov/study/NCT00112983 NCT00112983]
−
#'''TRIUMPH:''' Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233-43. [https://doi.org/10.1056/NEJMoa061648 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16990386 PubMed] NCT00112983
+
##'''Update:''' Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8. Epub 2007 Aug 16. [http://www.bloodjournal.org/content/110/12/4123.long link to original article]  [https://pubmed.ncbi.nlm.nih.gov/17702897/ PubMed]
−
##'''Update:''' Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8. Epub 2007 Aug 16. [http://www.bloodjournal.org/content/110/12/4123.long link to original article]  [https://pubmed.ncbi.nlm.nih.gov/17702897 PubMed]
+
#'''SHEPHERD:''' Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008 Feb 15;111(4):1840-7. Epub 2007 Nov 30. [http://www.bloodjournal.org/content/111/4/1840.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18055865/ PubMed] [https://clinicaltrials.gov/study/NCT00130000 NCT00130000]
−
#'''SHEPHERD:''' Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008 Feb 15;111(4):1840-7. Epub 2007 Nov 30. [http://www.bloodjournal.org/content/111/4/1840.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18055865 PubMed]  
+
##'''Update:''' Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H, Szer J, Browne P, Maciejewski JP, Schubert J, Urbano-Ispizua A, de Castro C, Socié G, Brodsky RA. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013 Jul;162(1):62-73. Epub 2013 Apr 25. [https://doi.org/10.1111/bjh.12347 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744747/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23617322/ PubMed]
−
##'''Update:''' Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H, Szer J, Browne P, Maciejewski JP, Schubert J, Urbano-Ispizua A, de Castro C, Socié G, Brodsky RA. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013 Jul;162(1):62-73. Epub 2013 Apr 25. [https://doi.org/10.1111/bjh.12347 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744747/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23617322 PubMed]
+
#Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011 Jun 23;117(25):6786-92. Epub 2011 Apr 1. [http://www.bloodjournal.org/content/117/25/6786.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21460245/ PubMed] content property of [http://hemonc.org HemOnc.org]
−
#Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011 Jun 23;117(25):6786-92. Epub 2011 Apr 1. [http://www.bloodjournal.org/content/117/25/6786.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21460245 PubMed] content property of [http://hemonc.org HemOnc.org]
 
 
##'''Update: Abstract:''' Anita Hill; Richard J Kelly; Austin G Kulasekararaj; Shreyans A Gandhi; Lindsay D Mitchell; Modupe Elebute; Stephen John Richards; Matthew Cullen; Louise M Arnold; Joanna Large; Alexandra Wood; Gemma L Brooksbank; Tracy Downing; Claire McKinley; Dena Cohen; Walter M Gregory; Judith C. W. Marsh; Ghulam J. Mufti; Peter Hillmen. Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Report of All 153 Patients Treated in the UK. 2012 ASH Annual Meeting abstract 3472. [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/3472?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=3472&searchid=1&FIRSTINDEX=0&volume=120&issue=21&resourcetype=HWCIT link to abstract]
 
##'''Update: Abstract:''' Anita Hill; Richard J Kelly; Austin G Kulasekararaj; Shreyans A Gandhi; Lindsay D Mitchell; Modupe Elebute; Stephen John Richards; Matthew Cullen; Louise M Arnold; Joanna Large; Alexandra Wood; Gemma L Brooksbank; Tracy Downing; Claire McKinley; Dena Cohen; Walter M Gregory; Judith C. W. Marsh; Ghulam J. Mufti; Peter Hillmen. Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Report of All 153 Patients Treated in the UK. 2012 ASH Annual Meeting abstract 3472. [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/3472?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=3472&searchid=1&FIRSTINDEX=0&volume=120&issue=21&resourcetype=HWCIT link to abstract]
−
#'''Retrospective:''' Kelly RJ, Höchsmann B, Szer J, Kulasekararaj A, de Guibert S, Röth A, Weitz IC, Armstrong E, Risitano AM, Patriquin CJ, Terriou L, Muus P, Hill A, Turner MP, Schrezenmeier H, Peffault de Latour R. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2015 Sep 10;373(11):1032-1039. [https://doi.org/10.1056/NEJMoa1502950 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26352814 PubMed]
+
#'''Retrospective:''' Kelly RJ, Höchsmann B, Szer J, Kulasekararaj A, de Guibert S, Röth A, Weitz IC, Armstrong E, Risitano AM, Patriquin CJ, Terriou L, Muus P, Hill A, Turner MP, Schrezenmeier H, Peffault de Latour R. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2015 Sep 10;373(11):1032-1039. [https://doi.org/10.1056/NEJMoa1502950 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26352814/ PubMed]
−
#'''ALXN1210-PNH-301:''' Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/530.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30510080 PubMed] NCT02946463
+
#'''CHAMPION 301:''' Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/530.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30510080/ PubMed] [https://clinicaltrials.gov/study/NCT02946463 NCT02946463]
−
#'''ALXN1210-PNH-302:''' Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/540.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30510079 PubMed] NCT03056040
+
#'''CHAMPION 302:''' Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/540.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30510079/ PubMed] [https://clinicaltrials.gov/study/NCT03056040 NCT03056040]
−
#'''PEGASUS:''' Hillmen P, Szer J, Weitz I, Röth A, Höchsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro C, Nishimori H, Tan L, Hamdani M, Deschatelets P, Francois C, Grossi F, Ajayi T, Risitano A, de la Tour RP. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2021 Mar 18;384(11):1028-1037. [https://doi.org/10.1056/nejmoa2029073 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33730455/ PubMed] NCT03500549
+
#'''PEGASUS:''' Hillmen P, Szer J, Weitz I, Röth A, Höchsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro C, Nishimori H, Tan L, Hamdani M, Deschatelets P, Francois C, Grossi F, Ajayi T, Risitano A, de la Tour RP. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2021 Mar 18;384(11):1028-1037. [https://doi.org/10.1056/nejmoa2029073 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33730455/ PubMed] [https://clinicaltrials.gov/study/NCT03500549 NCT03500549]
 
##'''Update:''' de Latour RP, Szer J, Weitz IC, Röth A, Höchsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro CM, Nishimori H, Ajayi T, Al-Adhami M, Deschatelets P, Francois C, Grossi F, Risitano AM, Hillmen P. Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial. Lancet Haematol. 2022 Sep;9(9):e648-e659. [https://doi.org/10.1016/s2352-3026(22)00210-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36055332/ PubMed]
 
##'''Update:''' de Latour RP, Szer J, Weitz IC, Röth A, Höchsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro CM, Nishimori H, Ajayi T, Al-Adhami M, Deschatelets P, Francois C, Grossi F, Risitano AM, Hillmen P. Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial. Lancet Haematol. 2022 Sep;9(9):e648-e659. [https://doi.org/10.1016/s2352-3026(22)00210-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36055332/ PubMed]
 +
#'''ALPHA:''' Lee JW, Griffin M, Kim JS, Lee Lee LW, Piatek C, Nishimura JI, Carrillo Infante C, Jain D, Liu P, Filippov G, Sicre de Fontbrune F, Risitano A, Kulasekararaj AG; ALXN2040-PNH-301 Investigators. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023 Dec;10(12):e955-e965. [https://doi.org/10.1016/s2352-3026(23)00315-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38030318/ PubMed] [https://clinicaltrials.gov/study/NCT04469465 NCT04469465]
  
 
==Iptacopan monotherapy {{#subobject:aa617d |Regimen=1}}==
 
==Iptacopan monotherapy {{#subobject:aa617d |Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:5f179e |Variant=1}}===
 
===Regimen {{#subobject:5f179e |Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 33%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1016/S2352-3026(21)00028-4 Risitano et al. 2021]
+
|[https://doi.org/10.1016/S2352-3026(21)00028-4 Risitano et al. 2021 (CLNP023X2201)]
 +
|2018-05-31 to 2019-04-09
 
| style="background-color:#91cf61" |Non-randomized, 10 patients  
 
| style="background-color:#91cf61" |Non-randomized, 10 patients  
 
|-
 
|-
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunosuppressive therapy====
 
====Immunosuppressive therapy====
−
*[[Iptacopan (LNP023)]] 200 mg twice daily orally  
+
*[[Iptacopan (Fabhalta)]] 200 mg twice per day orally  
−
 
+
'''Continued indefinitely'''
−
*[[Eculizumab (Soliris)]] as prior or concurrent therapy
+
</div></div>
−
 
 
−
===References===
 
−
#Risitano AM, Röth A, Soret J, Frieri C, de Fontbrune FS, Marano L, Alashkar F, Benajiba L, Marotta S, Rozenberg I, Milojevic J, End P, Nidamarthy PK, Junge G, Peffault de Latour R. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021 May;8(5):e344-e354. Epub 2021 Mar 23. [https://doi.org/10.1016/S2352-3026(21)00028-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33765419/ PubMed]
 
−
 
 
−
==Placebo==
 
−
 
 
−
 
 
−
===Regimen===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
! style="width: 25%" |Study
 
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
−
! style="width: 25%" |Comparator
 
−
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1056/NEJMoa061648 Hillmen et al. 2006 (TRIUMPH)]
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Eculizumab_monotherapy|Eculizumab]]
 
−
| style="background-color:#d73027" |Inferior stabilization of Hgb levels and QoL
 
−
|-
 
−
|}
 
−
''No active treatment. Used as a comparator arm in one or more trials; for reference purposes, only.''
 
−
 
 
 
===References===
 
===References===
−
 
+
#'''CLNP023X2201:''' Risitano AM, Röth A, Soret J, Frieri C, de Fontbrune FS, Marano L, Alashkar F, Benajiba L, Marotta S, Rozenberg I, Milojevic J, End P, Nidamarthy PK, Junge G, Peffault de Latour R. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021 May;8(5):e344-e354. Epub 2021 Mar 23. [https://doi.org/10.1016/S2352-3026(21)00028-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33765419/ PubMed] [https://clinicaltrials.gov/study/NCT03439839 NCT03439839]
−
#'''TRIUMPH:''' Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233-43. [https://doi.org/10.1056/NEJMoa061648 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16990386 PubMed] NCT00112983
+
#'''APPLY-PNH:''' Peffault de Latour R, Röth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Wong Lee Lee L, Yap ES, Sicre de Fontbrune F, Marano L, Alashkar F, Gandhi S, Trikha R, Yang C, Liu H, Kelly RJ, Höchsmann B, Kerloeguen C, Banerjee P, Levitch R, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, Risitano AM. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar 14;390(11):994-1008. [https://doi.org/10.1056/nejmoa2308695 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38477987/ PubMed] [https://clinicaltrials.gov/study/NCT04558918 NCT04558918]
−
##'''Update:''' Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8. Epub 2007 Aug 16. [http://www.bloodjournal.org/content/110/12/4123.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17702897 PubMed]
+
#'''APPOINT-PNH:''' Peffault de Latour R, Röth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Wong Lee Lee L, Yap ES, Sicre de Fontbrune F, Marano L, Alashkar F, Gandhi S, Trikha R, Yang C, Liu H, Kelly RJ, Höchsmann B, Kerloeguen C, Banerjee P, Levitch R, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, Risitano AM. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar 14;390(11):994-1008. [https://doi.org/10.1056/nejmoa2308695 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38477987/ PubMed] [https://clinicaltrials.gov/study/NCT04820530 NCT04820530]
  
 
==Ravulizumab monotherapy {{#subobject:abd213 |Regimen=1}}==
 
==Ravulizumab monotherapy {{#subobject:abd213 |Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#c8a2c8">
−
===Regimen {{#subobject:ba93ab |Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
! style="width: 25%" |Study
+
!style="width: 20%"|Study
−
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Dates of enrollment
−
! style="width: 25%" |Comparator
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
! style="width: 25%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ Lee et al. 2018 (ALXN1210-PNH-301)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ Lee et al. 2018 (CHAMPION 301)]
 +
|NR
 
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 
|[[#Eculizumab_monotherapy|Eculizumab]]
 
|[[#Eculizumab_monotherapy|Eculizumab]]
 
| style="background-color:#eeee01" |Non-inferior efficacy
 
| style="background-color:#eeee01" |Non-inferior efficacy
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ Kulasekararaj et al. 2018 (ALXN1210-PNH-302)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ Kulasekararaj et al. 2018 (CHAMPION 302)]
 +
|NR
 
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 
|[[#Eculizumab_monotherapy|Eculizumab]]
 
|[[#Eculizumab_monotherapy|Eculizumab]]
Line 190: Line 179:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Induction {{#subobject:ba93ab |Variant=1}}===
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunosuppressive therapy====
 +
*[[Ravulizumab (Ultomiris)]] by the following weight-based criteria:
 +
**40 up to 60 kg: 2400 mg IV once on day 1
 +
**60 up to 100 kg: 2700 mg IV once on day 1
 +
**100 kg or more: 3000 mg IV once on day 1
 +
'''14-day course'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Maintenance {{#subobject:ba93ab |Variant=1}}===
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunosuppressive therapy====
 
====Immunosuppressive therapy====
−
 
+
*[[Ravulizumab (Ultomiris)]] by the following weight-based criteria:
−
*[[Ravulizumab (Ultomiris)]]
+
**40 up to 60 kg: 3000 mg IV once on day 1
−
 
+
**60 up to 100 kg: 3300 mg IV once on day 1
−
'''6-month course'''
+
**100 kg or more: 3600 mg IV once on day 1
 +
'''8-week cycle for up to 13 cycles (2 years)'''
 +
</div></div></div>
 
===References===
 
===References===
−
 
+
#'''CHAMPION 301:''' Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/530.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30510080/ PubMed] [https://clinicaltrials.gov/study/NCT02946463 NCT02946463]
−
#'''ALXN1210-PNH-301:''' Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/530.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367644/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30510080 PubMed] NCT02946463
+
#'''CHAMPION 302:''' Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/540.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30510079/ PubMed] [https://clinicaltrials.gov/study/NCT03056040 NCT03056040]
−
#'''ALXN1210-PNH-302:''' Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. [http://www.bloodjournal.org/content/133/6/540.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30510079 PubMed] NCT03056040
+
#'''ALPHA:''' Lee JW, Griffin M, Kim JS, Lee Lee LW, Piatek C, Nishimura JI, Carrillo Infante C, Jain D, Liu P, Filippov G, Sicre de Fontbrune F, Risitano A, Kulasekararaj AG; ALXN2040-PNH-301 Investigators. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023 Dec;10(12):e955-e965. [https://doi.org/10.1016/s2352-3026(23)00315-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38030318/ PubMed] [https://clinicaltrials.gov/study/NCT04469465 NCT04469465]
−
 
 
−
=Investigational agents=
 
−
''These are drugs under study with at least some promising results for this disease.''
 
−
*[[Pegcetacoplan (APL2)]]
 
−
*[[Danicopan (ACH-4471)]]
 
  
 
[[Category:Paroxysmal nocturnal hemoglobinuria regimens]]
 
[[Category:Paroxysmal nocturnal hemoglobinuria regimens]]

Revision as of 23:45, 15 May 2024

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Section editor
Tillman Benjamin-2.jpg
 Benjamin Tillman, MD
Vanderbilt University
Nashville, TN, USA
LinkedIn

Are you looking for a regimen, but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!

  • We have moved How I Treat articles to a dedicated page.
3 regimens on this page
6 variants on this page


All lines of therapy

Eculizumab monotherapy

Regimen variant #1, 12-week course

Study Dates of enrollment Evidence
Hillmen et al. 2004 2002-05 to 2002-12 Pilot, fewer than 20 pts

Immunosuppressive therapy

  • Eculizumab (Soliris) as follows:
    • Cycles 1 to 4: 600 mg IV over 25 to 45 minutes once on day 1
    • Cycles 5 to 8: 900 mg IV over 25 to 45 minutes once on day 1

7-day cycle for 4 cycles, then 14-day cycle for 4 cycles


Regimen variant #2, 6-month course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hillmen et al. 2006 (TRIUMPH) 2004-10 to 2005-06 Phase 3 (E-RT-esc) Placebo Superior stabilization of Hgb levels and QoL (co-primary endpoint)
Lee et al. 2018 (CHAMPION 301) NR Phase 3 (C) Ravulizumab Non-inferior efficacy
Kulasekararaj et al. 2018 (CHAMPION 302) NR Phase 3 (C) Ravulizumab Non-inferior efficacy

Immunosuppressive therapy

  • Eculizumab (Soliris) as follows:
    • Cycles 1 to 4: 600 mg IV over 25 to 45 minutes once on day 1
    • Cycles 5 to 15: 900 mg IV over 25 to 45 minutes once on day 1

Supportive therapy

  • Patients received Neisseria meningitidis meningococcal vaccination

7-day cycle for 4 cycles, then 14-day cycle for 11 cycles


Regimen variant #3, 12-month course

Study Dates of enrollment Evidence
Brodsky et al. 2007 (SHEPHERD) NR Phase 2 (RT)

Immunosuppressive therapy

  • Eculizumab (Soliris) as follows:
    • Cycles 1 to 4: 600 mg IV over 25 to 45 minutes once on day 1
    • Cycles 5 to 28: 900 mg IV over 25 to 45 minutes once on day 1

7-day cycle for 4 cycles, then 14-day cycle for 24 cycles


Regimen variant #4, indefinite

Study Dates of enrollment Evidence
Kelly et al. 2011 2002-05 to 2010-07 Non-randomized

Immunosuppressive therapy

  • Eculizumab (Soliris) as follows:
    • Cycles 1 to 4: 600 mg IV over at least 30 minutes once on day 1
    • Cycle 5 onwards: 900 mg IV over at least 30 minutes once on day 1

Supportive therapy

  • Meningitis prophylaxis: Neisseria meningitidis meningococcal vaccination
  • Penicillin V 500 mg PO twice per day
    • Patients with penicillin allergies instead received: Erythromycin 500 mg PO twice per day

7-day cycle for 4 cycles, then 14-day cycles

Dose and schedule modifications

  • Patients with return of PNH symptoms, such as red or black urine, abdominal discomfort, or increased LDH before the next dose of eculizumab received higher doses: Eculizumab (Soliris) 1200 mg IV once on day 1

References

  1. Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004 Feb 5;350(6):552-9. link to original article contains dosing details in manuscript PubMed
    1. Update: Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, Mojcik CF, Rother RP. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005 Oct 1;106(7):2559-65. Epub 2005 Jun 28. link to original article PubMed
  2. TRIUMPH: Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233-43. link to original article contains dosing details in manuscript PubMed NCT00112983
    1. Update: Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, Schrezenmeier H, Szer J, Brodsky RA, Hill A, Socié G, Bessler M, Rollins SA, Bell L, Rother RP, Young NS. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8. Epub 2007 Aug 16. link to original article PubMed
  3. SHEPHERD: Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008 Feb 15;111(4):1840-7. Epub 2007 Nov 30. link to original article contains dosing details in manuscript PubMed NCT00130000
    1. Update: Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H, Szer J, Browne P, Maciejewski JP, Schubert J, Urbano-Ispizua A, de Castro C, Socié G, Brodsky RA. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013 Jul;162(1):62-73. Epub 2013 Apr 25. link to original article link to PMC article PubMed
  4. Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011 Jun 23;117(25):6786-92. Epub 2011 Apr 1. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
    1. Update: Abstract: Anita Hill; Richard J Kelly; Austin G Kulasekararaj; Shreyans A Gandhi; Lindsay D Mitchell; Modupe Elebute; Stephen John Richards; Matthew Cullen; Louise M Arnold; Joanna Large; Alexandra Wood; Gemma L Brooksbank; Tracy Downing; Claire McKinley; Dena Cohen; Walter M Gregory; Judith C. W. Marsh; Ghulam J. Mufti; Peter Hillmen. Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Report of All 153 Patients Treated in the UK. 2012 ASH Annual Meeting abstract 3472. link to abstract
  5. Retrospective: Kelly RJ, Höchsmann B, Szer J, Kulasekararaj A, de Guibert S, Röth A, Weitz IC, Armstrong E, Risitano AM, Patriquin CJ, Terriou L, Muus P, Hill A, Turner MP, Schrezenmeier H, Peffault de Latour R. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2015 Sep 10;373(11):1032-1039. link to original article PubMed
  6. CHAMPION 301: Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02946463
  7. CHAMPION 302: Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. link to original article link to PMC article PubMed NCT03056040
  8. PEGASUS: Hillmen P, Szer J, Weitz I, Röth A, Höchsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro C, Nishimori H, Tan L, Hamdani M, Deschatelets P, Francois C, Grossi F, Ajayi T, Risitano A, de la Tour RP. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2021 Mar 18;384(11):1028-1037. link to original article PubMed NCT03500549
    1. Update: de Latour RP, Szer J, Weitz IC, Röth A, Höchsmann B, Panse J, Usuki K, Griffin M, Kiladjian JJ, de Castro CM, Nishimori H, Ajayi T, Al-Adhami M, Deschatelets P, Francois C, Grossi F, Risitano AM, Hillmen P. Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial. Lancet Haematol. 2022 Sep;9(9):e648-e659. link to original article PubMed
  9. ALPHA: Lee JW, Griffin M, Kim JS, Lee Lee LW, Piatek C, Nishimura JI, Carrillo Infante C, Jain D, Liu P, Filippov G, Sicre de Fontbrune F, Risitano A, Kulasekararaj AG; ALXN2040-PNH-301 Investigators. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023 Dec;10(12):e955-e965. link to original article PubMed NCT04469465

Iptacopan monotherapy

Regimen

Study Dates of enrollment Evidence
Risitano et al. 2021 (CLNP023X2201) 2018-05-31 to 2019-04-09 Non-randomized, 10 patients

Immunosuppressive therapy

Continued indefinitely

References

  1. CLNP023X2201: Risitano AM, Röth A, Soret J, Frieri C, de Fontbrune FS, Marano L, Alashkar F, Benajiba L, Marotta S, Rozenberg I, Milojevic J, End P, Nidamarthy PK, Junge G, Peffault de Latour R. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021 May;8(5):e344-e354. Epub 2021 Mar 23. link to original article PubMed NCT03439839
  2. APPLY-PNH: Peffault de Latour R, Röth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Wong Lee Lee L, Yap ES, Sicre de Fontbrune F, Marano L, Alashkar F, Gandhi S, Trikha R, Yang C, Liu H, Kelly RJ, Höchsmann B, Kerloeguen C, Banerjee P, Levitch R, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, Risitano AM. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar 14;390(11):994-1008. link to original article PubMed NCT04558918
  3. APPOINT-PNH: Peffault de Latour R, Röth A, Kulasekararaj AG, Han B, Scheinberg P, Maciejewski JP, Ueda Y, de Castro CM, Di Bona E, Fu R, Zhang L, Griffin M, Langemeijer SMC, Panse J, Schrezenmeier H, Barcellini W, Mauad VAQ, Schafhausen P, Tavitian S, Beggiato E, Chew LP, Gaya A, Huang WH, Jang JH, Kitawaki T, Kutlar A, Notaro R, Pullarkat V, Schubert J, Terriou L, Uchiyama M, Wong Lee Lee L, Yap ES, Sicre de Fontbrune F, Marano L, Alashkar F, Gandhi S, Trikha R, Yang C, Liu H, Kelly RJ, Höchsmann B, Kerloeguen C, Banerjee P, Levitch R, Kumar R, Wang Z, Thorburn C, Maitra S, Li S, Verles A, Dahlke M, Risitano AM. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024 Mar 14;390(11):994-1008. link to original article PubMed NCT04820530

Ravulizumab monotherapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2018 (CHAMPION 301) NR Phase 3 (E-RT-switch-ic) Eculizumab Non-inferior efficacy
Kulasekararaj et al. 2018 (CHAMPION 302) NR Phase 3 (E-RT-switch-ic) Eculizumab Non-inferior efficacy

Induction

Immunosuppressive therapy

  • Ravulizumab (Ultomiris) by the following weight-based criteria:
    • 40 up to 60 kg: 2400 mg IV once on day 1
    • 60 up to 100 kg: 2700 mg IV once on day 1
    • 100 kg or more: 3000 mg IV once on day 1

14-day course


Maintenance

Immunosuppressive therapy

  • Ravulizumab (Ultomiris) by the following weight-based criteria:
    • 40 up to 60 kg: 3000 mg IV once on day 1
    • 60 up to 100 kg: 3300 mg IV once on day 1
    • 100 kg or more: 3600 mg IV once on day 1

8-week cycle for up to 13 cycles (2 years)

References

  1. CHAMPION 301: Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. Epub 2018 Dec 3. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02946463
  2. CHAMPION 302: Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. Epub 2018 Dec 3. link to original article link to PMC article PubMed NCT03056040
  3. ALPHA: Lee JW, Griffin M, Kim JS, Lee Lee LW, Piatek C, Nishimura JI, Carrillo Infante C, Jain D, Liu P, Filippov G, Sicre de Fontbrune F, Risitano A, Kulasekararaj AG; ALXN2040-PNH-301 Investigators. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023 Dec;10(12):e955-e965. link to original article PubMed NCT04469465
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