OBJECTIVES : Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia. Most individuals with PNH experience debilitating fatigue. Limited evidence characterizes the association between fatigue-scales and hemoglobin, an indicator of anemia and disease activity, across disease states. To examine the extent of the gap, this review aims to identify potential benchmarks for clinically meaningful improvements in patients with and without PNH.

METHODS : MEDLINE, Embase, Cochrane, and PsycINFO database searches were conducted in addition to Google Scholar to identify English publications for patients with and without PNH. Full-texts (no date restriction) and conference abstracts (2017 or later) of clinical trials or observational studies conducted in the US or Western Europe that examined patient-reported fatigue or associations between fatigue-scales and hemoglobin were included. Data (i.e., relationship between improvements in fatigue-scales and clinical outcomes; clinically meaningful fatigue-scale thresholds) were extracted using a standardized form.

RESULTS : Among 161 search results, 16 peer-reviewed publications (4 [25%] PNH and 12 [75%] cancer studies) were included. Four clinical trials conducted in patients with PNH receiving ravulizumab or eculizumab reported that patients achieved and sustained clinically meaningful improvements in fatigue (i.e., ≥3 points). However, these studies did not examine the association between fatigue and hemoglobin. Twelve studies conducted in patients with cancer (anemic; with or without chemotherapy) demonstrated a statistically significant association between increased hemoglobin and improvements in fatigue (p<0.05). Two studies showed the greatest incremental gain (i.e., >3 mm in Linear Analog Scale Assessment) in improvement in fatigue was observed when hemoglobin increased from 11-12 g/dL.

CONCLUSIONS : Substantial evidence in non-PNH literature (i.e., anemia of chronic disease) demonstrates that increased hemoglobin levels are associated with clinically significant improvements in fatigue (e.g., an increase of ≥3 points as measured by Functional Assessment of Chronic Illness Therapy-Fatigue). Future studies establishing this connection should be further validated among patients with PNH.