Impact of Clonal Size and High Disease Activity on Clinical Outcomes of Paroxysmal Nocturnal Hemoglobinuria: A Multicenter Registry

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder that can lead to outcomes such as thrombosis, cardiovascular diseases, renal disfunction (both acute kidney injury [AKI] and chronic kidney disease [CKD]), and death (1,2). Complement inhibitors (CIs) are currently the standard of treatment, but there is no uniform consensus on whom to treat due to the rarity of the disease. The updated analysis of the International PNH Registry (2) suggests using CIs in patients with high disease activity (HDA), while the consensus of the Canadian PNH Network recommends using CIs in patients with HDA plus clonality >10% (2,3). Our aim is to determine whether HDA and clone size influence clinical outcomes in PNH in order to support either treatment recommendation.

Methods

This retrospective study was conducted at 4 centers in Mexico and included patients diagnosed with PNH by flow cytometry (FLAER+CD14/CD24). Characteristics at diagnosis such as symptoms, lactate dehydrogenase (LDH), thrombosis, cardiovascular events, clonality, and HDA (LDH ≥1.5 times the upper normal limit [UNL] plus PNH symptoms, hemoglobin ≤10g/dl, renal function impairment, or thrombosis) were collected. A descriptive analysis was performed, and a univariate logistic regression model was used to determine the impact of clone size and HAD on clinical outcomes.

Results

Information was collected from 136 patients diagnosed with PNH between 1988 and 2023, with 51.5% (n=70) being women, and a median age of 47 years (IQR;34-57). The classic PNH variant was most frequent, with 69.9% (n=95). The median follow-up was 65.99 months (IQR 14.1-106.5), with a median overall survival of 119 months (CI95% 91.6-183), and 68 patients (50.0%) deceased at the time of analysis.

History of thrombosis was found in 19 patients (14%) and in 5 (3.7%) at diagnosis. Cardiovascular events (transient ischemic attack, myocardial infarction, unstable angina, and/or non-traumatic gangrene) occurred in 11 (8.08%). AKI was found in 22 (16.2%) at diagnosis and developed in 25 (18.4%) later. By last follow-up, 28 patients (20.6%) had CKD, 14 of them being on renal replacement therapy.

LDH ≥1.5 times the UNL was found in 91 patients (66.9%) and 84 (61.8%) met the definition of HDA. An increase in LDH ≥1.5 times the UNL increased the probability of having hemoglobinuria (OR 11.5, CI95% 4.13-31.8, p<0.001), but not other symptoms.

HDA increased the risk of thrombosis (OR 3.84, CI95% 1.06-13.9, p=0.03), cardiovascular disease (OR 14.5, CI95% 0.83-253, p=0.010), AKI (OR 7.81, CI95% 1.74-35.0, p=0.002), and CKD (OR 4.80, CI95%:1.56-14.8, p=0.003). Clonality ≥50% was found in 66.9%. Clone size was not associated with the development of thrombosis (OR 1.28, CI95% 0.46-3.57, p=0.632), AKI (OR 1.34, CI95% 0.51-3.49, p=0.55), CKD (OR 1.63, CI95% 0.63-4.18, p=0.307), or cardiovascular events (OR 2.02, CI95% 0.41-9.96, p=0.377).

Discussion and Conclusions

In the studied population, HDA was associated with severe outcomes such as thrombosis, AKI, CKD, and cardiovascular disease, while clone size was not associated with either of these outcomes. This suggests that the presence of HDA in PNH may justify the initiation of CI treatment regardless of clone size.

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