Somatic mutations and clonal expansions in paroxysmal nocturnal hemoglobinuria

Hosokawa, Kohei; Nakao, Shinji

doi:10.1053/j.seminhematol.2022.08.004

Cited by 6 publications

(7 citation statements)

References 78 publications

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“…Regarding the association with the underlying myeloproliferative syndrome, we did not evaluate the clonal relationship between PIG-A and CALR mutated hematopoietic stem cells. Heterogeneous mutational patterns have been described for PNH and bone marrow failures, with PIGA mutation possibly coexisting, preceding, or following the myeloid gene lesions ( 11 ). Notably, no progression of the myeloid neoplasm has been observed during anti-complement therapy so far.…”

Section: Discussionmentioning

confidence: 99%

Case report: Transfusion independence and abolition of extravascular hemolysis in a PNH patient treated with pegcetacoplan

et al. 2022

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More than half of patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with complement fraction C5 inhibitors experience residual anemia and hemolysis. This is partly due to the persistent activation of the complement cascade upstream C5, resulting in C3 deposition on PNH erythrocytes and extravascular hemolysis in the reticuloendothelial system. Pegcetacoplan is the first proximal C3 inhibitor to be approved for PNH basing on favorable efficacy and safety data in both naïve and eculizumab treated PNH. Here we report the first Italian patient treated with pegcetacoplan in a named patient program. The patient suffered from hemolytic PNH associated with CALR+ myeloproliferative neoplasm and was heavily transfusion dependent despite eculizumab therapy. Treatment with pegcetacoplan induced a dramatic improvement in Hb, along with normalization of unconjugated bilirubin and reticulocytes, as markers of extravascular hemolysis. Sequential laboratory workup showed the disappearance of C3 deposition on erythrocytes by direct anti-globulin test, the increase of PNH clone on erythrocytes, and a peculiar right shift of the ektacytometry curve. The drug was well tolerated, and the patient reported a significant improvement in his quality of life. Overall, pegcetacoplan appears a safe and effective option “ready to use” in the clinic for patients with PNH and suboptimal response to anti-C5 agents.

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Section: Discussionmentioning

confidence: 99%

Case report: Transfusion independence and abolition of extravascular hemolysis in a PNH patient treated with pegcetacoplan

et al. 2022

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“…Phosphatidylinositol glycan, class A (PIG-A in humans, Pig-a in other mammals) is a highly conserved, X-linked gene that, because of its single-copy status in males and X chromosome inactivation in females, is the most common mutation underlying paroxysmal nocturnal hemoglobinuria (PNH). 6 The gene product is one of many that participate in the early steps of glycosylphosphatidylinositol (GPI) anchor biosynthesis 7 leading to loss of GPI-anchored cell surface proteins such as CD59, CD55, and CD24 on the surface of reticulocytes (RETs) and mature RBCs, and of other markers on various cell types. Clonal expansion of RBCs in humans that lack CD59, an inhibitor of the complement membrane attack complex, and CD55 (complement decay-accelerating factor), render RBCs susceptible to complement mediated hemolysis, as seen in PNH.…”

Section: Introductionmentioning

confidence: 99%

“…Clonal expansion of RBCs in humans that lack CD59, an inhibitor of the complement membrane attack complex, and CD55 (complement decay-accelerating factor), render RBCs susceptible to complement mediated hemolysis, as seen in PNH. 6 The unique properties of the Pig a gene allowed the development of a standardized rodent in vivo mutagenesis assay, 8 and mutation in the PIG A gene is proposed as a direct measure of environmental mutagenesis in humans. 9 The Pig-a mutagenesis assay is outlined in Organization for Economic Cooperation and Development (OECD) test guideline (TG) no.…”

Section: Introductionmentioning

confidence: 99%

In vivo genotoxicity assessment of N‐(‐9 acridinyl)‐b‐alanine hydrochloride (S‐300) using a validated Pig‐a mutagenesis assay

North,

Ling,

Ricaud

et al. 2024

Transfusion

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BackgroundN‐(‐9 acridinyl)‐b‐alanine hydrochloride (S‐300) is the main byproduct of red blood cell (RBC) amustaline/glutathione(GSH) pathogen reduction, currently undergoing phase III US clinical trials following successful European studies(1–3). Phosphatidylinositol glycan, class A (Pig‐a) X‐linked gene mutagenesis is a validated mammalian in vivo mutation assay for genotoxicity, assessed as clonal loss of glycosylphosphatidylinositol‐linked CD59 cell‐surface molecules on reticulocytes (RETs) and RBCs.MethodsMale Sprague–Dawley rats received continuous infusion of S‐300 up to the maximum feasible dose (240 mg/kg/day—limited by solubility and volume) for 28 days. Positive controls received a known mutagen by oral gavage on Days 1–3. Plasma levels of S‐300 were assessed by HPLC before, during and after infusion. CD59‐negative RBCs and RETs were enumerated in pre‐dose and Day 28 samples, using a flow cytometric method. Outcome was evaluated by predetermined criteria using concurrent and historical controls. Toxicity was assessed by laboratory measures and necropsy.ResultsS‐300 reached maximum, dose‐dependent levels (3–15 μmol/L) within 2–8 h that were sustained for 672 h and undetectable 2 h after infusion. Circulating RET levels indicated a lack of hematopoietic toxicity. Necropsy revealed minimal‐mild observations related to poor S‐300 solubility at high concentrations. Pig‐a assessment met the preset acceptability criteria and revealed no increase in mutant RBCs or RETs.ConclusionsMaximum feasible S‐300 exposure of rats by continuous infusion for 28 days was not genotoxic as assessed by an Organization for Economic Cooperation and Development‐compliant, mammalian, in vivo Pig‐a gene mutation assay that meets the requirements of International Conference on Harmonization (ICH) S2(R1) and FDA guidances on genotoxicity testing.

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“…[3][4][5] PNH results from defective expression of glycosylphosphatidylinositol (GPI)-anchored proteins on the surface of erythrocytes due to mutations in the X-linked phosphatidyl-inositol glycan anchor biosynthesis class A (PIGA) gene and clonal expansion of GPI-deficient haematopoietic cells. 6 In normal erythrocytes, GPI-anchored proteins including CD55 and CD59 regulate the complement pathway, thereby preventing the cell's destruction by the immune system. In PNH, deficiency of GPI-anchored proteins results in uncontrolled complement activation and complement-mediated haemolysis.…”

Section: Introductionmentioning

confidence: 99%

Pegcetacoplan in paroxysmal nocturnal haemoglobinuria: Its use, its clinical effectiveness, and its influence on health‐related quality of life and productivity

Wilson,

Rich,

Hakimi

et al. 2023

European J of Haematology

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ObjectivesTo describe real‐world use/effectiveness of pegcetacoplan (PEG) in paroxysmal nocturnal haemoglobinuria (PNH).MethodsData were drawn from the Adelphi PNH Disease Specific Programme™, a cross‐sectional survey conducted in France, Italy, Germany, Spain and the United States from January to November 2022. Patients had a confirmed PNH diagnosis and received PEG for ≥1 month. Physicians reported patient characteristics, treatment use/satisfaction and their perception of patients' fatigue and health‐related quality of life (HRQoL). Patients reported treatment satisfaction and completed questionnaires assessing fatigue, HRQoL and productivity. Descriptive statistics were reported.ResultsOverall, 14 physicians provided data for 61 patients who had received 1080 mg/dose PEG for 1.3–14.8 months. At data collection compared to PEG initiation: haemoglobin was 2.5 g/dL higher on average; proportion of patients with lactate dehydrogenase (LDH) ≥1.5 × upper limit of normal was reduced by 27.4%; physician‐perceived fatigue was lower and HRQoL better. Physician‐ and patient‐reported treatment satisfaction was high for >90% of patients. Physicians and patients were more satisfied with PEG than previously prescribed C5 complement inhibitors. Mean work impairment and activity impairment in the 7 days prior to data collection were 32.9% and 22.4%, respectively.ConclusionsThese real‐world data support the effectiveness of PEG through positive effects on haemoglobin, LDH, fatigue and HRQoL.

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Somatic mutations and clonal expansions in paroxysmal nocturnal hemoglobinuria

Cited by 6 publications

References 78 publications

Case report: Transfusion independence and abolition of extravascular hemolysis in a PNH patient treated with pegcetacoplan

Case report: Transfusion independence and abolition of extravascular hemolysis in a PNH patient treated with pegcetacoplan

In vivo genotoxicity assessment of N‐(‐9 acridinyl)‐b‐alanine hydrochloride (S‐300) using a validated Pig‐a mutagenesis assay

Pegcetacoplan in paroxysmal nocturnal haemoglobinuria: Its use, its clinical effectiveness, and its influence on health‐related quality of life and productivity

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