Paroxysmal nocturnal hemoglobinuria

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Last updated on 2024-09-03:3 regimens on this page
6 variants on this page
=All lines of therapy=
==Danicopan & Eculizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Lee et al. 2023 (ALPHA)	2020-12-16 to 2022-08-29	Phase 3 (E-RT-esc)	1a. Eculizumab1b. Ravulizumab	Higher change in hemoglobin concentration from baseline to week 12 (primary endpoint)
====Immunosuppressive therapy====
*Danicopan (Voydeya) 150 mg PO three times per day
*Eculizumab (Soliris) at current stable dose
Up to 2-year course
====Dose and schedule modifications====
*Danicopan could be increased to 200 mg PO three times per day; see paper for details
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT04469465
==Danicopan & Ravulizumab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Lee et al. 2023 (ALPHA)	2020-12-16 to 2022-08-29	Phase 3 (E-RT-esc)	1a. Eculizumab1b. Ravulizumab	Higher change in hemoglobin concentration from baseline to week 12 (primary endpoint)
====Immunosuppressive therapy====
*Danicopan (Voydeya) 150 mg PO three times per day
*Ravulizumab (Ultomiris) at current stable dose
Up to 2-year course
====Dose and schedule modifications====
*Danicopan could be increased to 200 mg PO three times per day; see paper for details
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT04469465
==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 	Better stabilization of Hgb levels and QoL (co-primary endpoint)
Lee et al. 2018 (CHAMPION 301) 	Not reported 	Phase 3 (C) 	Ravulizumab	Non-inferior efficacy
Kulasekararaj et al. 2018 (CHAMPION 302)	Not reported 	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)	Not reported 	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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00130000
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC content property of 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.
#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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC 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. link to original article EuroPMC 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. link to original article EuroPMC
#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 EuroPMC NCT04469465
==Iptacopan monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Risitano et al. 2021 (CLNP023X2201) 	2018-05-31 to 2019-04-09 	Non-randomized, 10 patients	 	
Peffault de Latour et al. 2024 (APPLY-PNH) 	2021-01-25 to not reported	Phase 3 (E-RT-switch-ooc) 	1a. Eculizumab1b. Ravulizumab	Higher increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion (co-primary endpoint)Higher rate of hemoglobin level of at least 12 g per deciliter without red-cell transfusion (co-primary endpoint)
Peffault de Latour et al. 2024 (APPOINT-PNH)	2021-07-19 to not reported	Non-randomized phase 3 (RT)	 	
====Immunosuppressive therapy====
*Iptacopan (Fabhalta) 200 mg PO twice per day
Continued indefinitely
===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. link to original article EuroPMC NCT03439839
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT04558918
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT04820530
==Ravulizumab monotherapy==
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lee et al. 2018 (CHAMPION 301) 	Not reported 	Phase 3 (E-RT-switch-ic)	Eculizumab	Non-inferior efficacy
Kulasekararaj et al. 2018 (CHAMPION 302)	Not reported 	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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC 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. link to original article EuroPMC NCT04469465
Category:Paroxysmal nocturnal hemoglobinuria regimens
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Category:Hemolytic process