Changes in hemoglobin and clinical outcomes drive improvements in fatigue, quality of life, and physical function in patients with paroxysmal nocturnal hemoglobinuria: post hoc analyses from the phase III PEGASUS study

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, acquired, hematologic, life-threatening disease characterized by thrombosis, impaired bone marrow function, and complement-mediated hemolysis. The PEGASUS phase III clinical trial demonstrated superiority of pegcetacoplan over eculizumab regarding improvements in hemoglobin levels in patients with suboptimal response to prior eculizumab treatment. The objective of this post hoc analysis was to compare the patient-reported outcome (PRO) response rates observed among PEGASUS participants and the relationships between their PRO scores with clinical and hematological parameters. Data from the 16-week randomized, controlled (1:1 to pegcetacoplan or eculizumab) period of the PEGASUS trial included comparisons of weekly PRO measurements taken using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) scales. A clinically meaningful FACIT-F response was defined as an increase from baseline of ≥5 points. Convergent validity was assessed using conventional threshold correlations between FACIT-F, EORTC QLQ-C30, and laboratory parameters. A clinically meaningful improvement in FACIT-F score was seen in 72.2% of pegcetacoplan-treated patients compared to 22.9% of eculizumab-treated patients. At week 16, the FACIT-F total score correlated with hemoglobin levels (r=0.47, p< 0.0001), absolute reticulocyte count (r=-0.37, p<0.01), and indirect bilirubin levels (r=-0.25, p<0.05). Clinically meaningful improvements in pegcetacoplan-treated patients were also observed for multiple EORTC scales. Fatigue and other self-reported outcomes were correlated with clinically meaningful improvements in clinical and hematological parameters. Clinical trial registration: NCT03500549.

Keywords: Bilirubin; EORTC QLQ-C30; FACIT-F; Hemoglobin; Patient-reported outcomes.

Fig. 1

PEGASUS study design. ECU, eculizumab; I/E, inclusion/exclusion; PEG, pegcetacoplan; SC, subcutaneous

Fig. 2

FACIT-F score % responders from baseline to week 16. CID, clinically important difference; ECU, eculizumab; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; ICE, intercurrent events; PEG, pegcetacoplan. ^aMean Hg (g/dl) for ECU (≥3 CID) = −0.20 and PEG (≥3 CID) = 3.10; ^bMean Hg (g/dl) for ECU (≥4 CID) = −0.22 and PEG (≥4 CID) = 3.13; ^cMean Hg (g/dl) for ECU (≥5 CID) = −0.07 and PEG (≥5 CID) = 3.19. An increase of 3–5 points on the FACIT-F is in the range of published estimates of clinically important differences [–28]

Fig. 3

Hemoglobin and FACIT-F scores at week 16. FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue. Green shaded bands represent normal score ranges for hemoglobin values and FACIT-F values

Fig. 4

Patients with improvements in hemoglobin, indirect bilirubin, and ARC showed improvements in FACIT-F scores. ARC, absolute reticulocyte count; FACIT, Functional Assessment of Chronic Illness Therapy – Fatigue

Fig. 5

Patients with improvements in hemoglobin, indirect bilirubin, and ARC showed improvements in EORTC-QLQ-C30 physical functioning and fatigue scores. ARC, Absolute Reticulocyte Count; EORTC, European Organization for the Research and Treatment of Cancer