How I treat paroxysmal nocturnal hemoglobinuria

Brodsky, Robert A.

doi:10.1182/blood.2019003812

Cited by 97 publications

(121 citation statements)

References 49 publications

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“…Genome editing by CRISPR was enabled through the transduction of HepG2-HBV cells with lentivirus expressing Cas9, and a clonal cell line was selected that maintained stable, high-level Cas9 expression over several passages (Cas9 HepG2-HBV; Figure S1A). The efficiency of genome editing was evaluated using a fluorescent-labeled aerolysin (FLAER) assay that measures disruption of the cellular enzyme phosphatidylinositol glycan complementation class A (PIG-A) in the glycosylphosphatidylinositol (GPI)-anchor protein biosynthesis pathway (Brodsky, 2009;Estoppey et al, 2017). Using this method, Cas9 editing efficiency at 21 days was determined to be >90% (Figure S1B), and results were confirmed by next-generation sequencing (NGS) across the PIG-A gene locus (Figure S1C).…”

Section: A Genome-wide Crispr Screen To Identify Host Factors Required For Hbv Transcriptionmentioning

confidence: 99%

A Genome-wide CRISPR Screen Identifies ZCCHC14 as a Host Factor Required for Hepatitis B Surface Antigen Production

et al. 2019

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Section: A Genome-wide Crispr Screen To Identify Host Factors Required For Hbv Transcriptionmentioning

confidence: 99%

A Genome-wide CRISPR Screen Identifies ZCCHC14 as a Host Factor Required for Hepatitis B Surface Antigen Production

et al. 2019

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“…HCT was first performed in a patient with PNH in 1971 and remains the only curative therapy [17,18]. Current indications for HCT include life-threatening cytopenias, severe hemolysis or thrombosis refractory to eculizumab, and/or the concomitant presence of another marrow disorder, such as aplastic anemia (AA), MDS, or AML [18,19]. Both myeloablative conditioning (including busulfan-, treosulfan-, and 8 Gy total body irradiation [TBI]-based regimens) and reduced-intensity conditioning (including cyclophosphamide with or without antithymocyte globulin [ATG] and fludarabine with 6 Gy TBIbased regimens) have been successfully used for HCT in patients with PNH [20À25].…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria in the Age of Eculizumab

Cooper

Farah

Stevenson

et al. 2019

Biology of Blood and Marrow Transplantation

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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic cell disease characterized by the destruction of hematopoietic cells through activation of the complement system with manifestations that can be lifethreatening including hemolysis, thrombosis, and marrow failure. Allogeneic hematopoietic cell transplantation (HCT) remains the sole cure for PNH, but eculizumab, a terminal complement inhibitor of C5, has been used to prevent complement-mediated hemolysis in patients with PNH since its approval by the Food and Drug Administration in 2007. We examined outcomes of HCT in patients with PNH to evaluate the effects of disease subtype, conditioning intensity, and eculizumab use either pre-HCT or post-HCT. Fifty-five patients with a diagnosis of PNH underwent at least 1 HCT, with 4 patients requiring a second HCT for graft failure. The median age at the time of first HCT was 30.0 years (range, 4.2 to 66.9 years). Seventeen patients (30.9%) had classical PNH, and the remaining 38 patients had PNH associated with another marrow disorder (aplastic anemia in 26 of the 38). Indications for HCT included pancytopenia in 47.3% of the patients, myeloid malignancy (myelodysplastic syndrome, myeloproliferative neoplasm, or acute myelogenous leukemia) in 21.8%, recurrent hemolysis in 20.0%, and thrombosis in 10.9%. Of the 55 first HCTs, 26 were performed with myeloablative conditioning, 27 were performed with reduced-intensity conditioning, and 2 sets of identical twins underwent HCT without any conditioning. Donor types included HLA-matched related in 38.2%, HLA-matched unrelated in 34.5%, single HLA-allele mismatched unrelated in 16.4%, umbilical cord blood in 5.5%, syngeneic in 3.6%, and HLA-haploidentical in 1.8%. The median duration of follow-up in surviving patients was 6.1 years (range, 2.1 to 46.1 years) after first HCT. The median time to neutrophil and platelet engraftment was 17 days and 19 days, respectively; all but 2 patients (96.3%) had sustained engraftment. Overall survival was 70% at 5 years. Neither the choice of conditioning intensity nor PNH subtype affected survival. Nineteen patients died during follow-up, including 12 patients before day +365. Six patients received treatment with eculizumab before HCT, and 2 were treated after HCT. All patients treated with eculizumab were alive at a median follow-up of 2.3 years (range, .2 to 6.9 years). Both patients treated with eculizumab after HCT had minimal to no acute GVHD (aGVHD), with grade I skin aGVHD in 1 patient and no aGVHD in the other patient, and no chronic GVHD at 2.1 and 4.1 years post-HCT, respectively. With the approval of eculizumab, the indications for HCT include persistent hemolysis, persistent thrombosis, and associated marrow failure. Administration of eculizumab before and after HCT warrants further study, particularly considering our observation of minimal to no GVHD in 2 patients who received eculizumab after HCT.

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“…Furthermore, complement has also been implicated in neurodegenerative disorders, such as Alzheimer's disease (39), multiple sclerosis (40), and Guillain-Barrésyndrome (41). The spectrum of clinical presentations associated with complement dysregulation also includes protein-losing enteropathy (CD55 deficiency) (42) and paroxysmal nocturnal hemoglobinuria (PNH) (CD55+CD59 deficiency) (43).…”

Section: Clinical Relevance Of Complementmentioning

confidence: 99%

Expanding Horizons in Complement Analysis and Quality Control

Frazer‐Abel¹,

Kirschfink²,

Prohászka³

2021

Front. Immunol.

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Complement not only plays a key role in host microbial defense but also modulates the adaptive immune response through modification of T- and B-cell reactivity. Moreover, a normally functioning complement system participates in hematopoiesis, reproduction, lipid metabolism, and tissue regeneration. Because of its powerful inflammatory potential, multiple regulatory proteins are needed to prevent potential tissue damage. In clinical practice, dysregulation and overactivation of the complement system are major causes of a variety of inflammatory and autoimmune diseases ranging from nephropathies, age-related macular degeneration (AMD), and systemic lupus erythematosus (SLE) to graft rejection, sepsis, and multi-organ failure. The clinical importance is reflected by the recent development of multiple drugs targeting complement with a broad spectrum of indications. The recognition of the role of complement in diverse diseases and the advent of complement therapeutics has increased the number of laboratories and suppliers entering the field. This has highlighted the need for reliable complement testing. The relatively rapid expansion in complement testing has presented challenges for a previously niche field. This is exemplified by the issue of cross-reactivity of complement-directed antibodies and by the challenges of the poor stability of many of the complement analytes. The complex nature of complement testing and increasing clinical demand has been met in the last decade by efforts to improve the standardization among laboratories. Initiated by the IUIS/ICS Committee for the Standardization and Quality Assessment in Complement Measurements 14 rounds of external quality assessment since 2010 resulted in improvements in the consistency of testing across participating institutions, while extending the global reach of the efforts to more than 200 laboratories in 30 countries. Worldwide trends of assay availability, usage, and analytical performance are summarized based on the past years’ experiences. Progress in complement analysis has been facilitated by the quality assessment and standardization efforts that now allow complement testing to provide a comprehensive insight into deficiencies and the activation state of the system. This in turn enables clinicians to better define disease severity, evolution, and response to therapy.

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How I treat paroxysmal nocturnal hemoglobinuria

Cited by 97 publications

References 49 publications

A Genome-wide CRISPR Screen Identifies ZCCHC14 as a Host Factor Required for Hepatitis B Surface Antigen Production

A Genome-wide CRISPR Screen Identifies ZCCHC14 as a Host Factor Required for Hepatitis B Surface Antigen Production

Hematopoietic Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria in the Age of Eculizumab

Expanding Horizons in Complement Analysis and Quality Control

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