Eculizumab in Pregnant Patients with Paroxysmal Nocturnal Hemoglobinuria

Kelly, Richard; Höchsmann, Britta; Szer, Jeff; Kulasekararaj, Austin; Guibert, Sophie de; Röth, Alexander; Weitz, Ilene C.; Armstrong, Elina; Risitano, Antonio M.; Patriquin, Christopher J.; Terriou, Louis; Muus, Petra; Hill, Anita; Turner, Michelle; Schrezenmeier, Hubert; Latour, Régis Peffault de

doi:10.1056/nejmoa1502950

Cited by 205 publications

(265 citation statements)

References 25 publications

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“…While in general terms eculizumab efficiently inhibits TP activation in PNH and aHUS patients, in clinical situations with strong complement activation, residual TP activity may exist even with surplus amounts of eculizumab. 55 A case of eculizumab-refectory hemolysis 56 indicated that the prevention of intravascular hemolysis due to erythrocyte alloantibodies may be inefficient. Our in vitro data show that eculizumab reduces hemolysis levels after alloantibody challenge but that the level of benefit depends on how forcefully the alloantibody activates complement, thus depending on the alloantibody titer and subtype as well as prevalence of its epitope.…”

Section: Discussionmentioning

confidence: 99%

Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation

Harder

Kuhn

Schrezenmeier

et al. 2017

Blood

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115

124

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• Strong complement activation overrides the terminal pathway inhibition by the anti-C5 antibody eculizumab.• The more powerful complement is activated, the less effective is terminal pathway inhibition by diverse anti-C5 agents.Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5, indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin, we determined conditions ex vivo in which C5 inhibition is incomplete. The degree of such residual lytic activity depended on the strength of the complement activator and the resulting surface density of the complement activation product C3b, which autoamplifies via the alternative pathway (AP) amplification loop. We show that at high C3b densities required for binding and activation of C5, both inhibitors reduce but do not abolish this interaction. The decrease of C5 binding to C3b clusters in the presence of C5 inhibitors correlated with the levels of residual hemolysis. However, by employing different C5 inhibitors simultaneously, residual hemolytic activity could be abolished. The importance of AP-produced C3b clusters for C5 activation in the presence of eculizumab was corroborated by the finding that residual hemolysis after forceful activation of the classical pathway could be reduced by blocking the AP. By providing insights into C5 activation and inhibition, our study delivers the rationale for the clinically observed phenomenon of residual terminal pathway activity under eculizumab treatment with important implications for anti-C5 therapy in general. (Blood. 2017;129(8):970-980)

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Section: Discussionmentioning

confidence: 99%

Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation

Harder

Kuhn

Schrezenmeier

et al. 2017

Blood

Self Cite

115

124

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“…In the era of eculizumab, this high prevalence of complement mutations in pregnancyassociated HUS provides the biologic rationale for complement inhibition. Increasing data in both paroxysmal nocturnal hemoglobinuria (83) and aHUS (84) suggests that eculizumab is safe during pregnancy.…”

Section: Secondary Tmas Pregnancy-associated Tmamentioning

confidence: 99%

Thrombotic Microangiopathy and the Kidney

Brocklebank

Wood

Kavanagh

2017

CJASN

261

288

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Thrombotic microangiopathy can manifest in a diverse range of diseases and is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ injury, including AKI. It can be associated with significant morbidity and mortality, but a systematic approach to investigation and prompt initiation of supportive management and, in some cases, effective specific treatment can result in good outcomes. This review considers the classification, pathology, epidemiology, characteristics, and pathogenesis of the thrombotic microangiopathies, and outlines a pragmatic approach to diagnosis and management.

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“…Eculizumab appears to be safe for use in pregnancy, but whether it improves fetalmaternal outcomes is speculative because prospective, randomized studies that address this issue are lacking. 35 Reasons for eculizumab failure. The recommended maintenance dose of eculizumab is fixed (900 mg every 2 weeks 6 2 days) rather than being based on weight or body surface area.…”

Section: How I Treat Pnh Based On Disease Classificationmentioning

confidence: 99%

Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria

Parker

2016

Hematology

123

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Once suspected, the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) is straightforward when flow cytometric analysis of the peripheral blood reveals a population of glycosyl phosphatidylinositol anchor protein-deficient cells. But PNH is clinically heterogeneous, with some patients having a disease process characterized by florid intravascular, complement-mediated hemolysis, whereas in others, bone marrow failure dominates the clinical picture with modest or even no evidence of hemolysis observed. The clinical heterogeneity is due to the close, though incompletely understood, relationship between PNH and immune-mediated bone marrow failure, and that PNH is an acquired, nonmalignant clonal disease of the hematopoietic stem cells. Bone marrow failure complicates management of PNH because compromised erythropoiesis contributes, to a greater or lesser degree, to the anemia; in addition, the extent to which the mutant stem cell clone expands in an individual patient determines the magnitude of the hemolytic component of the disease. An understanding of the unique pathobiology of PNH in relationship both to complement physiology and immune-mediated bone marrow failure provides the basis for a systematic approach to management.

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Eculizumab in Pregnant Patients with Paroxysmal Nocturnal Hemoglobinuria

Abstract: Eculizumab provided benefit for women with PNH during pregnancy, as evidenced by a high rate of fetal survival and a low rate of maternal complications. (ClinicalTrials.gov number, NCT01374360.).

Cited by 205 publications

References 25 publications

Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation

Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation

Thrombotic Microangiopathy and the Kidney

Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria

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