Paroxysmal nocturnal hemoglobinuria

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Tillman Benjamin-2.jpg
 Benjamin Tillman, MD
Vanderbilt University
Nashville, TN
3 regimens on this page
6 variants on this page


Guidelines

"How I Treat"

All lines of therapy

Eculizumab monotherapy

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Regimen variant #1, 12-week course

Study Evidence
Hillmen et al. 2004 Pilot, <20 pts

Immunosuppressive therapy

  • Eculizumab (Soliris) as follows:
    • Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22
    • Cycles 2 & 3: 900 mg IV over 25 to 45 minutes once per day on days 1 & 15

28-day cycle for 3 cycles

Regimen variant #2, 6-month course

Study Evidence Comparator Comparative Efficacy
Hillmen et al. 2006 (TRIUMPH) Phase III (E-RT-esc) Placebo Superior stabilization of Hgb levels and QoL
Lee et al. 2018 (ALXN1210-PNH-301) Phase III (C) Ravulizumab Non-inferior efficacy
Kulasekararaj et al. 2018 (ALXN1210-PNH-302) Phase III (C) Ravulizumab Non-inferior efficacy

Immunosuppressive therapy

  • Eculizumab (Soliris) as follows:
    • Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22
    • Cycles 2 to 12: 900 mg IV over 25 to 45 minutes once on day 1

Supportive medications

  • Patients received Neisseria meningitidis meningococcal vaccination

28-day cycle for 1 cycle, then 14-day cycle for 11 cycles

Regimen variant #3, 12-month course

Study Evidence
Brodsky et al. 2007 (SHEPHERD) Phase II (RT)

Immunosuppressive therapy

  • Eculizumab (Soliris) as follows:
    • Cycle 1: 600 mg IV over 25 to 45 minutes once per day on days 1, 8, 15, 22
    • Cycles 2 to 25: 900 mg IV over 25 to 45 minutes once on day 1

28-day cycle for 1 cycle, then 14-day cycle for 24 cycles

Regimen variant #4, indefinite

Study Evidence
Kelly et al. 2011 Non-randomized

Immunosuppressive therapy

  • Eculizumab (Soliris) as follows:
    • Cycle 1: 600 mg IV over at least 30 minutes once per day on days 1, 8, 15, 22
    • Cycle 2 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 medications

  • 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

28-day cycle for 1 cycle, then 14-day cycles

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 verified protocol 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 verified protocol PubMed
    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 verified protocol PubMed
    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 verified protocol 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. 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. link to original article link to PMC article contains verified protocol PubMed NCT02946463
  7. 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. 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

Iptacopan monotherapy

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Regimen

Study Evidence
Risitano et al. 2021 Non-randomized, 10 patients

Immunosuppressive therapy

References

  1. 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

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Hillmen et al. 2006 (TRIUMPH) Phase III (C) Eculizumab 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

  1. 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 verified protocol PubMed
    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

Ravulizumab monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Lee et al. 2018 (ALXN1210-PNH-301) Phase III (E-RT-switch-ic) Eculizumab Non-inferior efficacy
Kulasekararaj et al. 2018 (ALXN1210-PNH-302) Phase III (E-RT-switch-ic) Eculizumab Non-inferior efficacy

Immunosuppressive therapy

6-month course

References

  1. 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. link to original article link to PMC article contains verified protocol PubMed NCT02946463
  2. 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. link to original article link to PMC article PubMed NCT03056040

Investigational agents

These are drugs under study with at least some promising results for this disease.

Pegcetacoplan

Danicopan

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