Expert consensus on the management of pharmacodynamic breakthrough-hemolysis in treated paroxysmal nocturnal hemoglobinuria

ABSTRACT

Introduction:

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, non-malignant hematologic disease characterized by complement-mediated hemolysis (with or without hemoglobinuria), fatigue, increased susceptibility to thrombosis, and bone marrow dysfunction. The development of complement inhibitors has transformed outcomes for patients with PNH, but patients may still experience pharmacodynamic breakthrough hemolysis (BTH), which can be caused by exposure to a complement amplifying condition (CAC), such as vaccination, infection, or surgery.

Materials and methods:

A 13-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on how to classify pharmacodynamic BTH in patients with complement-inhibitor treated PNH. Physicians reviewed literature, rated the appropriateness of over 400 scenarios, and discussed the ratings at an in-person meeting.

Results:

After the meeting, the panel agreed on 77% of scenarios. Here, we present the group’s agreed-upon recommendations on how to manage BTH caused by a CAC, as well as provide a severity classification system for BTH and strategies to mitigate risk of BTH in special circumstances (e.g. vaccination, planned or unplanned surgery, and pregnancy).

Discussion:

In general, as severity of BTH increased, experts agreed more interventions to manage the BTH were appropriate. These recommendations are based on clinical experience and opinion. Without clear data from randomized trials to guide the management of BTH, expert opinion can be useful to support patient care.

KEYWORDS:

• (Need 8): Consensus
• Aplastic anemia
• Bone marrow failure
• Coagulation disorders
• Complement inhibitors
• Hemolysis
• Paroxysmal nocturnal hemoglobinuria
• Red cell disorders

Authorship contributions

All authors have met ICMJE authorship criteria.

Disclosure statement

All authors completed ICMJE forms. All authors declare the following: support for the present manuscript (e.g. funding, provision of study materials, medical writing, article processing charges, etc.): Novartis.

The authors declare the additional following potential conflicts of interest:

DD: Grants or contracts from any entity: K36 Therapeutics. Consulting fees: Alexion/Astra Zeneca, Bristol Myers Squibb, Janssen, Novartis, Apellis, Sanofi, Takeda, Argenx, Legend Biotech. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Alexion, Sanofi. Support for attending meetings and/or travel: Novartis. Participation on a Data Safety Monitoring Board or Advisory Board: Sorrento Therapeutics.

CMD: Consulting fees: Alexion Pharmaceuticals, Apellis Pharmaceuticals, Omeros, Bristol Myers Squibb, Genentech. Consulting fees: Biocryst. Support for attending meetings and/or travel: Novartis. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Alexion Pharmaceuticals, Apellis Pharmaceuticals, Omeros, Bristol Myers Squibb, Genentech. Support for attending meetings and/or travel: Novartis. Participation on a Data Safety Monitoring Board or Advisory Board: Regeneron. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: AA-MDS Foundation Medical Board of Directors.

JLK: Consulting fees: Apellis, Alexion, GSK 2023 Myelofibrosis Community Physician Strategic Council. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Alexion, Apellis, Amgen, Jazz, CTI, BMS, Abbvie, DSMC: Georgetown/John Theurer Cancer Center joint DSMC. Support for attending meetings and/or travel: Novartis.

AGK: Consulting fees: Novartis, Alexion/AstraZeneca, Amgen, Roche, Pfizer, SOBI, Regeneron, Arrowhead, Silence Therapeutics. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SOBI, Alexion/AstraZeneca, Amgen, Roche, Novartis, Celgene/BMS, Janssen. Support for attending meetings and/or travel: Novartis, SOBI, Alexion/Astrazeneca, Amgen, Roche, Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: GERON corporation, Regeneron, Novartis.

JPM: Consulting fees: Novartis. Support for attending meetings and/or travel: Novartis.

BPM: Consulting fees: Apellis. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Apellis. Support for attending meetings and/or travel: Novartis.

JPP: All support for the present manuscript (e.g. funding, provision of study materials, medical writing, article processing charges, etc.): Blueprint. Consulting fees: Apellis/SOBI, Alexion, Amgen, Astra Zeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Deciphera, Grünenthal, F Hoffmann-La Roche Ltd, MSD, Novartis, Pfizer. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Apellis/SOBI, Alexion, Amgen, Biologix, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Gilead, F Hoffmann-La Roche Ltd, MSD, Novartis, Pfizer, Swixx Biopharma. Support for attending meetings and/or travel: Novartis. Participation on a Data Safety Monitoring Board or Advisory Board: Apellis/SOBI, Alexion, Blueprint Medicines, Amgen, Gilead, F Hoffmann-La Roche Ltd, MSD, Novartis, Sanofi. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: DGHO.

VP: Consulting fees: Novartis. Support for attending meetings and/or travel: Novartis.

Participation on a Data Safety Monitoring Board or Advisory Board: Novartis.

AR: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Alexion, Amgen, Apellis, Novartis, Roche, Sanofi, Sobi. Support for attending meetings and/or travel: Novartis, Sobi, Alexion. Participation on a Data Safety Monitoring Board or Advisory Board: Alexion, Amgen, Apellis, Novartis, Roche, Sanofi, Sobi, Samsung.

JS: Grants or contracts from any entity: Alexion, CTI, BMS, Protagonist, Astra Zeneca, Apellis, AbbVie. Consulting fees: Alexion- Astra Zeneca, BMS, Apellis, CTI, GSK, Novartis, Incyte, Sanofi, Sobi, Blueprint. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: OncLive, PER, Alexion, Apellis, Incyte, Sanofi, Novartis. Support for attending meetings and/or travel: Novartis, Alexion. Participation on a Data Safety Monitoring Board or Advisory Board: NS-BIO, Apellis. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: ASH executive committee, MJH board member. Stock or stock options: AbbVie, Baxter.

LT: Consulting fees: SOBI, Alexion AZ, Novartis, Roche. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SOBI, Alexion, Novartis. Payment for expert testimony: Roche. Support for attending meetings and/or travel: Novartis, Alexion AZ.

ICW: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Alexion Pharmaceuticals. Participation on a Data Safety Monitoring Board or Advisory Board: AAV Duchene. Support for attending meetings and/or travel: Novartis.

IY: Support for attending meetings and/or travel: Novartis. IY is an employee of PHAR, which was paid by Novartis to conduct the research described in the manuscript. PHAR also discloses financial relationships with the following entities outside of the submitted work: Akcea, Amgen, BioMarin Pharmaceuticals, Bristol-Myers Squibb, Celgene, Dompe, Eisai, Genentech, Gilead, Greenwich Biosciences, Ionis, Jazz, Nobelpharma, Pfizer, Recordati, Regeneron. Sanofi US Services, Takeda Pharmaceuticals U.S.A.

SNG: Support for attending meetings and/or travel: Novartis. SNG is an employee of PHAR, which was paid by Novartis to conduct the research described in the manuscript. PHAR also discloses financial relationships with the following entities outside of the submitted work: Akcea, Amgen, BioMarin Pharmaceuticals, Bristol-Myers Squibb, Celgene, Dompe, Eisai, Genentech, Gilead, Greenwich Biosciences, Ionis, Jazz, Nobelpharma, Pfizer, Recordati, Regeneron. Sanofi US Services, Takeda Pharmaceuticals U.S.A.

MSB: Support for attending meetings and/or travel: Novartis. MSB is an employee of PHAR, which was paid by Novartis to conduct the research described in the manuscript. PHAR also discloses financial relationships with the following entities outside of the submitted work: Akcea, Amgen, BioMarin Pharmaceuticals, Bristol-Myers Squibb, Celgene, Dompe, Eisai, Genentech, Gilead, Greenwich Biosciences, Ionis, Jazz, Nobelpharma, Pfizer, Recordati, Regeneron. Sanofi US Services, Takeda Pharmaceuticals U.S.A.

DOB: DOB is an employee of PHAR, which was paid by Novartis to conduct the research described in the manuscript. PHAR also discloses financial relationships with the following entities outside of the submitted work: Akcea, Amgen, BioMarin Pharmaceuticals, Bristol-Myers Squibb, Celgene, Dompe, Eisai, Genentech, Gilead, Greenwich Biosciences, Ionis, Jazz, Nobelpharma, Pfizer, Recordati, Regeneron. Sanofi US Services, Takeda Pharmaceuticals U.S.A.

DJK: Grants or contracts from any entity: Alnylam, Biocryst, Novartis, Rigel, Sanofi (Principia), Takeda (Bioverativ), UCB. Royalties or licenses: Uptodate. Consulting fees: AIRx, Alexion (Syntimmune), Alnylam, Alpine, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, Cellularity, Cellphire, Chugai, CRICO, Daiichi Sankyo, Dianthus, Electra Therapeutics, Fuji, Hemopure, Hengrui, Immunovant, Incyte, Inmagenebio, Kezar, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Nuvig, Pfizer, Platelet Biogenesis, Platelet Disorder Support Association, Protagonist, Rigel, Sanofi (Bioveratif), Sanofi (Principia), Sanofi (Genzyme), Sobi (Dova), Takeda, UCB, Up-To-Date, Zafgen. Support for attending meetings and/or travel: Novartis. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Platelet Disorder Support Association. Stock or stock options: Rubius.

Additional information

Funding

This work was supported by Novartis Pharmaceutical Corporation.