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Review
. 2023 Jul;102(7):1637-1644.
doi: 10.1007/s00277-023-05269-4. Epub 2023 May 18.

Relationship of paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size to disease burden and risk of major vascular events in untreated patients: results from the International PNH Registry

David Dingli  1 , Jaroslaw P Maciejewski  2 , Loree Larratt  3 , Ronald S Go  4 , Britta Höchsmann  5 , Ke Zu  6 , Philippe Gustovic  7 , Alexander D Kulagin  8
Affiliations
Review

Relationship of paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size to disease burden and risk of major vascular events in untreated patients: results from the International PNH Registry

David Dingli et al. Ann Hematol. 2023 Jul.

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by acquired gene mutations resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins on the surface of blood cells, leading to terminal complement-mediated intravascular hemolysis and increased risk of major adverse vascular events (MAVEs). Using data from the International PNH Registry, this study investigated the relationship between the proportion of GPI-deficient granulocytes at PNH onset and (1) the risk for MAVEs (including thrombotic events [TEs]) and (2) the following parameters at last follow-up: high disease activity (HDA); lactate dehydrogenase (LDH) ratio; fatigue; abdominal pain; and rates of overall MAVEs and TEs. A total of 2813 patients untreated at enrollment were included and stratified by clone size at PNH disease onset (baseline). At last follow-up, higher proportion of GPI-deficient granulocytes (≤ 5% vs. > 30% clone size) at baseline was associated with significantly increased HDA incidence (14% vs. 77%), mean LDH ratio (1.3 vs. 4.7 × upper limit of normal), and rates of MAVEs 1.5 vs. 2.9 per 100 person-years) and TEs (0.9 vs. 2.0 per 100 person-years). Fatigue was evident in 71 to 76% of patients regardless of clone size. Abdominal pain was more frequently reported with clone size > 30%. A larger clone size at baseline appears to indicate a greater disease burden and risk of TEs and MAVEs and may inform decision making among physicians managing PNH patients at risk of experiencing TEs or other MAVEs. ClinicalTrials.gov ID: NCT01374360.

Keywords: Cohort studies; Disease progression; GPI-deficient granulocytes, Risk factors; Paroxysmal nocturnal hemoglobinuria; Thromboembolism.

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Conflict of interest statement

David Dingli has received honoraria and consulting fees from Alexion, AstraZeneca Rare Disease, Apellis, Novartis and Sanofi, and participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion, AstraZeneca Rare Disease. Jaroslaw P. Maciejewski has received consulting fees from Alexion, AstraZeneca Rare Disease; Apellis Pharmaceuticals; and Ra Pharma. He has also received speaker fees from and is a member of the Executive Committee of the International PNH Registry for Alexion, AstraZeneca Rare Disease. Loree Larratt has received honoraria and research support (for the laboratory at the University of Alberta, for ADAMTS13 testing) from Alexion, AstraZeneca Rare Disease. Ronald S. Go participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion, AstraZeneca Rare Disease. Britta Höchsmann has received honoraria, consulting fees, and research support (to University Hospital of Ulm) from Alexion, AstraZeneca Rare Disease, Novartis, Apellis Pharmaceuticals, Sobi, and Roche. Ke Zu was an employee of Alexion, AstraZeneca Rare Disease at the time of the study, and is currently affiliated with Merck & Co., Inc. Philippe Gustovic is an employee and stockholder of Alexion, AstraZeneca Rare Disease. Alexander D. Kulagin has received honoraria and consulting fees from Alexion, AstraZeneca Rare Disease, Novartis, and GENERIUM JSC, and is a member of the Executive Committee of the International PNH Registry for Alexion, AstraZeneca Rare Disease.

Figures

Fig. 1
Fig. 1
Patients with high disease activity at last follow-up stratified by clone size at baseline. High disease activity was defined as LDH ratio ≥ 1.5 × ULN within 6 months before and including baseline and ≥ 1 of the following: history of MAVEs (including TEs) at any time before baseline, anemia (defined as hemoglobin < 10 g/dL) at any time before and including baseline, or history of physician-documented symptoms of abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, or erectile dysfunction at any time before baseline. Baseline was defined as PNH onset (i.e., disease start date) at the earliest reported GPI-deficient clone, date of PNH diagnosis, or PNH symptom. N indicates total number of patients at risk. Data within bars reflect number of patients with high disease activity / total number of patients with nonmissing data. GPI, glycophosphatidylinositol; LDH, lactate dehydrogenase; MAVE, major adverse vascular event; PNH, paroxysmal nocturnal hemoglobinuria; TE, thrombotic event; ULN, upper limit of normal
Fig. 2
Fig. 2
LDH ratio × ULN at last follow-up stratified by clone size at baseline. Baseline was defined as PNH onset (ie, disease start date) at the earliest reported GPI-deficient clone, date of PNH diagnosis, or PNH symptom. Data within bars reflects total number of patients with nonmissing data. GPI, glycophosphatidylinositol; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal hemoglobinuria; ULN, upper limit of normal
Fig. 3
Fig. 3
Rates of MAVEs from baseline to last follow-up stratified by clone size at baseline. A Unadjusted model. B adjusted model. Baseline was defined as PNH onset (i.e., disease start date) at the earliest reported GPI-deficient clone, date of PNH diagnosis, or PNH symptom. MAVEs included TE MAVEs. Data within bars reflect total number of patients with nonmissing data. BMF, bone marrow failure; GPI, glycophosphatidylinositol; LDH, lactate dehydrogenase; MAVE, major adverse vascular event; PNH, paroxysmal nocturnal hemoglobinuria; PY, person-years; TE, thrombotic event
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