Fatigue, hemoglobin, and inflammatory markers in warm autoimmune hemolytic anemia: Analysis from a phase 2b trial of rilzabrutinib (LUMINA2)

Abstract

Abstract Background: Warm autoimmune hemolytic anemia (wAIHA) is characterized by complex immune dysregulation along with red blood cell destruction primarily mediated by immunoglobin G autoantibodies, leading to hemolysis and anemia. Fatigue is a debilitating symptom that significantly impacts the quality of life among patients with wAIHA. Rilzabrutinib, a novel, highly selective, Bruton's tyrosine kinase inhibitor acts via multiple immunomodulatory effects. In the phase 2b LUMINA 2 study (NCT05002777), treatment with rilzabrutinib led to durable hemoglobin (Hb) response, decreased inflammation and hemolysis, and reduced fatigue in previously treated patients with primary wAIHA. Objective: This post hoc analysis assessed the effect of rilzabrutinib on Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score, and its association with Hb response in patients with wAIHA enrolled in the phase 2b LUMINA 2 study. Associations between FACIT-F scores, Hb levels, and inflammatory marker levels were also explored. Methods:In this open-label, single-arm, multicenter study, 22 patients with primary or subset of secondary wAIHA were eligible to receive oral rilzabrutinib 400 mg twice daily for 24 weeks (Part A). Patients with ≥2 g/dL increase in Hb level from baseline by Week 24 were considered Hb responders and continued treatment in Core Part B for up to Week 52. Data obtained after 50 weeks of treatment are reported here. Durable Hb response was defined as Hb level ≥10 g/dL with ≥2 g/dL increase from baseline at 3 consecutive scheduled visits between Weeks 24–50. Fatigue was assessed using the FACIT-F scale (13-item questionnaire; 7-day recall). Individual items on the scale were rated on a 5-point Likert scale (0=Very much, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Not at all; total score 0–52; higher scores=less fatigue). FACIT-F response was defined as ≥3-point increase from baseline (clinically meaningful within-patient improvement). The correlation between changes in Hb levels and FACIT-F scores from baseline was assessed using Spearman's rank correlation coefficient. The association of selected inflammatory biomarkers including interleukin-10 (IL-10), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) with FACIT-F scores was also evaluated. Results: This analysis included 22 patients (median age: 65 years; range: 33-87), with 23% aged ≥75 years. Baseline mean (SD) FACIT-F score was 30.0 (11.1). At Week 24, 14 patients were Hb responders, and 8 were Hb non-responders. Hb responders had a mean (SD) FACIT-F score change from baseline (CFB) of 7.8 (9.6; n=14) vs 3.8 (15.0; n=6) for Hb non-responders. FACIT-F response (≥3-point increase from baseline) was achieved by 64.3% (9/14) of Hb responders vs 25% (2/8) of Hb non-responders. The Hb responders continued to Core Part B (n=14) and demonstrated fatigue improvement through Week 50. The mean (SD) CFB was 7.9 (8.4) at Week 50. The patients with durable response (n=12) showed sustained improvement in FACIT-F scores (mean [SD] CFB at Week 24: 8.8 [10.0]; Week 50: 9.3 [8.1]). The proportion of FACIT-F responders among durable Hb responders increased to 71.4% (10/14) by Week 50. Rilzabrutinib treatment led to progressive reduction in the proportion of patients reporting severe fatigue symptoms across all FACIT-F domains from baseline through Week 50. The most notable improvements were observed in core fatigue symptoms, i.e., feeling fatigued and tired. FACIT-F score changes showed moderate correlation with Hb levels at Week 24 (r=0.486; n=20), but at Week 50, the correlation was weaker (r=0.265; n=14). Moderate-to-strong negative correlation was observed between FACIT-F scores and IL-10, IFN-γ, and TNF-α levels at Week 24 (r=−0.65; –0.663, −0.772; n=10), indicating correlation between reduced fatigue and lower levels of inflammatory biomarkers.Conclusions: Rilzabrutinib treatment was associated with clinically meaningful within-patient improvement in fatigue in wAIHA. The improvement was most pronounced in patients with durable Hb response but was also observed in a few non-responders. Weak-to-moderate correlation of FACIT-F scores with Hb levels and moderate-to-strong negative correlation with inflammatory marker levels suggests that mechanisms other than anemia, particularly chronic inflammation, may contribute to fatigue in wAIHA. These findings support rilzabrutinib's potential to address fatigue in wAIHA via multiple immunomodulatory effects.