Efficacy, Safety and Molecular Response Predictors of Fostamatinib in Warm Autoimmune Hemolytic Anemia (wAIHA) and/or Evans Syndrome (ES): A Multicenter Analysis
Authors: Ruiz Lopez Jorge N , Shao Lipei , Jiang Debbie , Bailey S. Lawrence , Bikkani Thejaswi , Moore Donald C , Murakhovskaya Irina , Piatek Caroline , Pineda-Roman Mauricio , Ping Jin , Poston Jacqueline N , Stolla Moritz , Stroncek David F. , Hudson Krystalyn E. , Panch Sandya R. 
Published: December 2024

Background:
wAIHA is a rare, serious blood disorder due to macrophage-mediated phagocytosis of autoantibody opsonized red blood cells (RBC) at body temperature. wAIHA may occur alone or alongside immune thrombocytopenia (ITP) (termed ES). Currently, there are no US-FDA approved therapies for wAIHA or ES. Fostamatinib (fosta) is a spleen tyrosine kinase inhibitor of macrophage-mediated RBC/platelet destruction that is currently approved for chronic ITP. In a recent randomized placebo-controlled trial, 35% of patients with wAIHA achieved a durable response with fosta. In this real-world multicenter retrospective analysis, we evaluated the safety and efficacy of fosta in wAIHA/ES, as well as immune profiles in a subset of responders (R) and non-responders (NR).
Methods:
This is a retrospective study conducted at 6 tertiary referral centers in the US that included patients with wAIHA or ES treated with fosta after inadequate response to &gt;1 prior therapies. Patient demographics, clinical characteristics, and laboratory results obtained 3 months before and up to 6 months after fosta initiation were collected. The main study outcomes were efficacy and safety of fosta, with response defined as hemoglobin (Hgb) &gt;10g/dL or an increase of &gt;2g/dL from baseline on 2 consecutive visits, and durable response as a Hgb &gt;10g/dL at 6 months. Changes in steroid dose, concomitant therapies, RBC transfusions (txn), hospitalizations, systolic (SBP) and diastolic (DBP) blood pressure, and adverse events (AEs) were evaluated pre- and post-fosta. In a subset of patients also enrolled in a single-center autoimmune cytopenia registry and repository study, we compared inborn errors of immunity (IEI)-associated mutations (574 genes), transcriptomics (Nanostring), and cytokine profiles (Bio-rad) between R and NR.
Results:
Of 22 patients, 13 (59%) had wAIHA and 9 (41%) had ES. The mean age at diagnosis was 51 years; 36% were male, 68% White and 32% of Hispanic ethnicity. 32% had concomitant autoimmune disease (e.g. thyroid disease, R, APLS, SLE) and 32% had a family history of autoimmune disease. 9% had a history of venous thrombosis. Patients received a median of 3 treatments before fosta (excluding splenectomy). All 22 had prior corticosteroid treatment, and 21/22 received rituximab. 9 (41%) received mycophenolate mofetil, which was used concurrently with fosta in 6/9. Other treatments included IVIG, azathioprine, cyclophosphamide, cyclosporine, danazol, and tacrolimus. 4 (18%) had splenectomy.
14/22 (64%) (9/13 wAIHA, 5/9 ES) responded to fosta (mean time to response: 3 weeks), including 3/4 with prior splenectomy. 9/14 responded at a dose of 100mg BID and 5/14 at 150mg BID. A durable response was achieved in 10/22 (46%, 6/13 wAIHA, 4/9 ES). Prednisone was tapered to &lt;20mg daily in 16/22 (73%). 10 (45%) required txn before and 4 (18%) after fosta initiation. Both R and NR had 3 (median) prior treatments. Though not statistically significant, more Hispanics were R (6/14) compared to NR (1/8) (p=0.19). Response did not differ by splenectomy status or ES vs. wAIHA.
AEs occurred in 23% (9% GI symptoms, 9% HTN, and 5% severe neutropenia [ANC≤500/µL]). Dose reductions or discontinuation were documented in 2 patients (1 neutropenia, 1 HTN). A mean increase in DBP of 5mmHg (P=0.03) was observed. The average monthly ED visits pre- and post-fosta (1 and 0.6 respectively) and hospitalizations (0.8 and 0.6 respectively) were not statistically significant.
In a subset of patients, NGS identified a mean of 4 variants/patient in genes associated with IEI, with no difference by response status. Of 15 patients, bone marrow NGS identified variants of uncertain significance in 2 R and 2 NR. Transcriptomics showed upregulated TCR, NF-kB and downregulated JAK-STAT pathways in R compared to NR (p&lt;0.05). Cytokine analysis revealed significantly higher macrophage migration inhibitory factor (MIF) levels in R vs NR (p&lt;0.01).
Conclusions:
In this real-world multicenter retrospective study of fosta in wAIHA/ES, we observed a 64% response rate, 46% durable response, 73% steroid sparing effects, and &gt;50% reduction in RBC txn. 23% had AEs resulting in dose-reduction or discontinuation in 2 patients (9%). No significant differences were observed in demographic or clinical characteristics between R and NR, yet there was a trend toward higher response among Hispanics. Higher MIF levels may be predictive of response.