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In paroxysmal nocturnal hemoglobinuria (PNH), acquired somatic mutations in the PIG-A gene give rise to clonal populations of red blood cells unable to express proteins linked to the membrane by a glycosylphosphatidylinositol anchor. These proteins include the complement inhibitors CD55 and CD59, and this explains the hypersensitivity to complement of red cells in PNH patients, manifested by intravascular hemolysis. The factors that determine to what extent mutant clones expand have not yet been pinpointed; it has been suggested that existing PNH clones may have a conditional growth advantage depending on some factor (e.g., autoimmune) present in the marrow environment of PNH patients. Using flow cytometric analysis of granulocytes, we now have identified cells that have the PNH phenotype, at an average frequency of 22 per million (range 10-51 per million) in nine normal individuals. These rare cells were collected by flow sorting, and exons 2 and 6 of the PIG-A gene were amplified by nested PCR. We found PIG-A mutations in six cases: four missense, one frameshift, and one nonsense mutation. PNH red blood cells also were identified at a frequency of eight per million. Thus, small clones with PIG-A mutations exist commonly in normal individuals, showing clearly that PIG-A gene mutations are not sufficient for the development of PNH. Because PIG-A encodes an enzyme essential for the expression of a host of surface proteins, the PIG-A gene provides a highly sensitive system for the study of somatic mutations in hematopoietic cells.

The International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry (NCT01374360) was initiated to optimize patient management by collecting data regarding disease burden, progression, and clinical outcomes. Herein, we report updated baseline demographics, clinical characteristics, disease burden data, and observed trends regarding clone size in the largest cohort of Registry patients. Patients with available data as of July 2017 were stratified by glycosylphosphatidylinositol (GPI)-deficient granulocyte clone size (< 10%, ≥ 10%–< 50%, and ≥ 50%). All patients were untreated with eculizumab at baseline, defined as date of eculizumab initiation or date of Registry enrollment (if never treated with eculizumab). Outcomes assessed in the current analysis included proportions of patients with high disease activity (HDA), history of major adverse vascular events (MAVEs; including thrombotic events [TEs]), bone marrow failure (BMF), red blood cell (RBC) transfusions, and PNH-related symptoms. A total of 4439 patients were included, of whom 2701 (60.8%) had available GPI-deficient granulocyte clone size data. Among these, median clone size was 31.8% (1002 had < 10%; 526 had ≥ 10%–< 50%; 1173 had ≥ 50%). There were high proportions of patients with HDA (51.6%), history of MAVEs (18.8%), BMF (62.6%), RBC transfusion (61.3%), and impaired renal function (42.8%). All measures except RBC transfusion history significantly correlated with GPI-deficient granulocyte clone size. A large proportion of patients with GPI-deficient granulocyte clone size < 10% had hemolysis (9.7%), MAVEs (10.2%), HDA (9.1%), and/or PNH-related symptoms. Although larger GPI-deficient granulocyte clone sizes were associated with higher disease burden, a substantial proportion of patients with smaller clone sizes had history of MAVEs/TEs.

Background Large clonal populations of cells bearing PIG - A mutations are the sine qua non of PNH, but the PIG - A mutation itself is insufficient for clonal expansion. The association between PNH and aplastic anemia supports the immune escape model, but not all PNH patients demonstrate a history of aplasia; therefore, second genetic hits driving clonal expansion have been postulated. Based on the previous identification of JAK2 mutations in patients with a myeloproliferative/PNH overlap syndrome, we considered TET2 as a candidate gene in which mutations might be contributing to clonal expansion. Methods Here we sequenced the TET2 and JAK2 genes in 19 patients with large PNH clones. Results We found one patient with a novel somatic nonsense mutation in TET2 in multiple hematopoietic lineages, which was detectable upon repeat testing. This patient has had severe thromboses and has relatively higher peripheral blood counts compared with the other patients—but does not have other features of a myeloproliferative neoplasm. Conclusions We conclude that mutations in TET2 may contribute to clonal expansion in exceptional cases of PNH.

Pulmonary involvement and skin involvement are rare complications of plasma cell neoplasms. Here we describe what may be the first reported case of a patient with relapse in both of these sites following autologous peripheral blood stem cell transplantation.

Background PNH is associated with abdominal vein thrombosis, which can cause splenomegaly and hypersplenism. The combination of thrombosis, splenomegaly, and thrombocytopenia (TST) is challenging because anticoagulants are indicated but thrombocytopenia may increase the bleeding risk. Splenectomy could alleviate thrombocytopenia and reduce portal pressure, but it can cause post-operative thromboses and opportunistic infections. We therefore sought to determine whether selective splenic artery embolization (SSAE) is a safe and effective alternative to splenectomy for TST in patients with PNH. Methods Four patients with PNH and TST received successive rounds of SSAE. By targeting distal vessels for occlusion, we aimed to infarct approximately 1/3 of the spleen with each procedure. Results Three of 4 patients had an improvement in their platelet count, and 3 of 3 had major improvement in abdominal pain/discomfort. The one patient whose platelet count did not respond had developed marrow failure, and she did well with an allo-SCT. Post-procedure pain and fever were common and manageable; only one patient developed a loculated pleural effusion requiring drainage. One patient, who had had only a partial response to eculizumab, responded to SSAE not only with an improved platelet count, but also with an increase in hemoglobin level and decreased transfusion requirement. Conclusions These data indicate that SSAE can decrease spleen size and reverse hypersplenism, without exposing the patient to the complications of splenectomy. In addition, SSAE probably reduces the uptake of opsonised red cells in patients who have had a limited response to eculizumab, resulting in an improved quality of life for selected patients.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) on anti‐C5 often experience extravascular hemolysis with anemia. Iptacopan, the first oral proximal complement inhibitor targeting factor B, has shown efficacy and safety in PNH patients. APPULSE‐PNH (NCT05630001), a phase 3b, single‑arm, open‐label trial, enrolled adult patients with PNH and hemoglobin ≥10 g/dL on stable anti‐C5 for ≥6 months. Patients switched to iptacopan monotherapy (200 mg twice daily; 24 weeks). Primary endpoint: mean hemoglobin change from baseline across four visits (Days 126–168). At baseline, 57.7% of patients had elevated absolute reticulocyte counts (ARCs; above ULN = 123 × 109/L) and 50% had C3 deposition on red blood cells (RBCs) >10%, indicative of extravascular hemolysis. There was a statistically significant increase in hemoglobin during the trial; adjusted mean change from baseline (95% CI) was +2.0 g/dL (1.7–2.3) overall, and in patients with baseline hemoglobin <12 g/dL and ≥12 g/dL, +2.4 (2.0–2.7) and +1.4 (1.0–1.8), respectively. Patients maintained transfusion independence, 92.7% with hemoglobin ≥12 g/dL. Adjusted mean change from baseline (95% CI) in lactate dehydrogenase and ARC were −1.3% (−6.6 to 4.3) and −89.2 × 109/L (−95.5 to −82.9), respectively. Mean (SD) proportion of C3d+ PNH RBCs, assessed by flow cytometry, decreased from 11.0% (8.6) to 0.2% (0.7) at Day 168. No patients had breakthrough hemolysis or major adverse vascular events. FACIT‐Fatigue and treatment satisfaction scores improved by Days 84 and 168. Safety showed consistency with previous iptacopan PNH trials. Iptacopan improved hematologic outcomes in PNH patients with hemoglobin ≥10 g/dL on anti‐C5, maintaining control of intravascular hemolysis and resolving extravascular hemolysis.

Geographic limits to Atlantic Alliance handling of non-European crises and conflicts; with particular attention to the strategies of various European NATO members; implications for U.S.-European relations; 12-article symposium.