Mutational landscape and its clinical significance in paroxysmal nocturnal hemoglobinuria.
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ABSTRACT:
SUBMITTER: Chen F
PROVIDER: S-EPMC7966366 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
Publications
Mutational landscape and its clinical significance in paroxysmal nocturnal hemoglobinuria.
Chen Fangfei F Hu Shimin S Ruan Jing J Chen Miao M Han Bing B
Blood cancer journal 20210316 3
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Project description:Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, rare, life-threatening hematopoietic stem cell disorder that causes stem cell-derived cells to be vulnerable to complement-mediated lysis and manifests as hemolytic anemia, thrombosis, and peripheral blood cytopenias. C5 inhibitors, eculizumab, and ravulizumab, are recognized as the current standard of care for PNH treatment in countries where they are available. Crovalimab (PiaSky®), which is approved for the treatment of PNH, is a novel anti-C5 inhibitor with an every-4-weeks, low-volume, subcutaneous maintenance dosing regimen with the possibility for self-administration. Data from three phase III studies highlight the overall favorable benefit-risk profile of crovalimab, showing that crovalimab has promising potential to address the unmet medical and socioeconomic challenges in the PNH treatment landscape.
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Project description:Paroxysmal nocturnal hemoglobinuria (PNH) is a rare bone marrow failure disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias. The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. GPI anchor protein deficiency is almost always due to somatic mutations in phosphatidylinositol glycan class A (PIGA), a gene involved in the first step of GPI anchor biosynthesis; however, alternative mutations that cause PNH have recently been discovered. In addition, hypomorphic germ-line PIGA mutations that do not cause PNH have been shown to be responsible for a condition known as multiple congenital anomalies-hypotonia-seizures syndrome 2. Eculizumab, a first-in-class monoclonal antibody that inhibits terminal complement, is the treatment of choice for patients with severe manifestations of PNH. Bone marrow transplantation remains the only cure for PNH but should be reserved for patients with suboptimal response to eculizumab.
| S-EPMC4215311 | biostudies-literature
Project description:Pregnancies in paroxysmal nocturnal hemoglobinuria (PNH) are associated with increased morbidity and mortality. Retrospective studies suggest that outcome has improved with the advent of the complement inhibitor eculizumab. To substantiate this assumption we analyzed the data from patients treated in our department since 2009. All patients were included in the International PNH registry and followed prospectively. We identified 16 pregnancies in 9 patients with classical PNH, and two pregnancies in two patients with aplastic anemia (AA)-PNH. In classical PNH, 13 pregnancies were supported by eculizumab. Breakthrough hemolysis occurred in six pregnancies, necessitating an increase in the biweekly eculizumab dose from 900 mg to 1,200-1,800 mg. Red blood cell transfusions were given in six and platelet transfusions in two pregnancies. A Budd-Chiari syndrome and cholecystitis complicated the course of two pregnancies. Four of 13 pregnancies supported by eculizumab ended in spontaneous abortion or stillbirth, and one was prematurely terminated because of fetal trisomy 21. None of the three pregnancies not supported by eculizumab had a successful outcome. Half the deliveries were preterm. None of the patients died, and, in all but one patient, the post-partum period was uneventful. Both pregnancies in patients with AA-PNH took a favorable course. Our results confirm low maternal mortality and frequent breakthrough hemolysis in pregnant PNH patients receiving eculizumab. Fetal mortality and the rate of preterm delivery were higher than reported previously, possibly related to the use of registry data that are likely to reduce the risk of publication and recall biases.
| S-EPMC7546795 | biostudies-literature
Project description:In this large single-centre study, we report high prevalence (25%) of, small (<10%) and very small (<1%), paroxysmal nocturnal hemoglobinuria (PNH) clones by high-sensitive cytometry among 3085 patients tested. Given PNH association with bone marrow failures, we analyzed 869 myelodysplastic syndromes (MDS) and 531 aplastic anemia (AA) within the cohort. PNH clones were more frequent and larger in AA vs. MDS (p = 0.04). PNH clone, irrespective of size, was a good predictor of response to immunosuppressive therapy (IST) and to stem cell transplant (HSCT) (in MDS: 84% if PNH+ vs. 44.7% if PNH-, p = 0.01 for IST, and 71% if PNH+ vs. 56.6% if PNH- for HSCT; in AA: 78 vs. 50% for IST, p < 0.0001, and 97 vs. 77%, p = 0.01 for HSCT). PNH positivity had a favorable impact on disease progression (0.6% vs. 4.9% IPSS-progression in MDS, p < 0.005; and 2.1 vs. 6.9% progression to MDS in AA, p = 0.01), leukemic evolution (6.8 vs. 12.7%, p = 0.01 in MDS), and overall survival [73% (95% CI 68-77) vs. 51% (48-54), p < 0.0001], with a relative HR for mortality of 2.37 (95% CI 1.8-3.1; p < 0.0001) in PNH negative cases, both in univariate and multivariable analysis. Our data suggest systematic PNH testing in AA/MDS, as it might allow better prediction/prognostication and consequent clinical/laboratory follow-up timing.
| S-EPMC8550969 | biostudies-literature
Project description:Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder characterized by hemolysis and a high risk of thrombosis, that is due to a deficiency in several cell surface proteins that prevent complement activation. Its origin has been traced to a somatic mutation in the PIG-A gene within hematopoietic stem cells (HSC). However, to date the question of how this mutant clone expands in size to contribute significantly to hematopoiesis remains under debate. One hypothesis posits the existence of a selective advantage of PIG-A mutated cells due to an immune mediated attack on normal HSC, but the evidence supporting this hypothesis is inconclusive. An alternative (and simpler) explanation attributes clonal expansion to neutral drift, in which case selection neither favours nor inhibits expansion of PIG-A mutated HSC. Here we examine the implications of the neutral drift model by numerically evolving a Markov chain for the probabilities of all possible outcomes, and investigate the possible occurrence and evolution, within this framework, of multiple independently arising clones within the HSC pool. Predictions of the model agree well with the known incidence of the disease and average age at diagnosis. Notwithstanding the slight difference in clonal expansion rates between our results and those reported in the literature, our model results lead to a relative stability of clone size when averaging multiple cases, in accord with what has been observed in human trials. The probability of a patient harbouring a second clone in the HSC pool was found to be extremely low ([Formula: see text]). Thus our results suggest that in clinical cases of PNH where two independent clones of mutant cells are observed, only one of those is likely to have originated in the HSC pool.
| S-EPMC6023248 | biostudies-literature
Project description:Clinical and hematological parameters in six cases of paroxysmal nocturnal hemoglobinuria (PNH) are presented. The mean delay in diagnosis after onset of symptoms was 3.7 years. Initial diagnoses considered were: (a) hematuria; (b) iron-deficiency; hemolytic; megaloblastic or refractory anemia and (c) myelodysplastic syndrome. Clinical features included; reddish urine (5/6), unexplained abdominal pain (4/6) and pallor (6/6). Laboratory investigations showed anemia (6/6), leucopenia (3/6), thrombocytopenia (3/6), unconjugated hyperbilirubinemia at some stage (6/6), and bone marrow erythroid hyperplasia (6/6). Complications encountered were (a) gall stones needing cholecystectomy, hemosiderosis and proximal tubular acidosis in 1 case, (b) disseminated tuberculosis in 1 case and (c) abortion with congestive cardiac failure in one. PNH may present with atypical features and tests for hemosiderinuria, sucrose lysis test and HAM's test are required to establish the diagnosis.
| S-EPMC5529684 | biostudies-literature
Project description:Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a consequence of somatic mutations in the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene. Clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure. Treatment of PNH mainly relies on the use of complement-targeted therapy (C5 inhibitors), with the newest agents being explored against other factors involved in the complement cascade to alleviate unresolved intravascular hemolysis and extravascular hemolysis. This review summarizes the biology and current treatment strategies for PNH with the aim of reaching a general audience with an interest in hematologic disorders.
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| S-EPMC8672449 | biostudies-literature
Project description:Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder associated with an acquired deficiency in glycophosphatidylinositol-anchor biosynthesis that renders erythrocytes susceptible to complement attack. Intravascular hemolysis via the membrane attack complex is a clinical hallmark of the disease, and C5 blockade is currently the only approved treatment for PNH. However, residual anemia is an emerging observation for many PNH patients receiving anti-C5 treatment. A range of complement-targeted therapeutic approaches, encompassing surface-directed inhibition of C3 convertases, blockade of membrane attack complex assembly or C3 interception using peptidic inhibitors, has yielded promising results and offers leverage for even more effective treatment of PNH. This article discusses recent advances in this rapidly evolving field, integrating critical perspectives from preclinical PNH models and diverse complement modulation strategies with genetic insights and therapy response profiles. It also evaluates the relative efficacy, limitations and benefits afforded by C3 or C5 inhibition in the context of PNH therapeutics.
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