Key Clinical Summary

• Cold agglutinin disease (CAD), warm autoimmune hemolytic anemia (wAIHA), and refractory immune thrombocytopenia (ITP) require nuanced diagnostic evaluation and phenotype-based therapeutic selection.
• Complement-targeted and B-cell–directed therapies are reshaping management, with agents such as sutimlimab, rituximab combinations, and emerging BTK inhibitors showing promise across immune cytopenias.
• Refractory ITP reflects heterogeneous immune dysregulation; updated definitions and new pathway-targeted strategies (eg, mTOR, PI3K, JAK inhibition) support more individualized treatment algorithms.

At the 67th ASH Annual Meeting and Exposition, experts presented rapidly evolving evidence in CAD, wAIHA, and refractory ITP. The session highlighted shifting diagnostic paradigms, expanded understanding of immune pathophysiology, and emerging targeted therapies poised to influence clinical pathways and payer decision-making.

Session Highlights

Advances in Cold Agglutinin Disease

Sigbjorn Berentsen, MD, Haugesund Hospital, Haugesund, Norway, detailed CAD as a distinct B-cell neoplasm characterized by monoclonal IgMκ production with complement-mediated hemolysis. He emphasized distinguishing CAD from cold agglutinin syndrome. Diagnostic challenges include interpreting DAT patterns and optimizing cold agglutinin titers.

Therapeutically, B-cell–directed options, such as rituximab plus bendamustine, deliver high response rates (objective response rate [ORR] 78%; complete response [CR] 53%) with prolonged remissions but notable toxicity. Sutimlimab, a C1s inhibitor, demonstrated rapid hemoglobin improvement and fatigue reduction, though it does not alleviate cold-induced circulatory symptoms and it requires continuous dosing. Berentsen also reviewed novel agents under investigation, including BTK inhibitors (rilzabrutinib, zanubrutinib derivatives), C3 inhibitors, and bispecific antibodies aimed at refractory disease.

Advances in Warm Autoimmune Hemolytic Anemia

Wilma Barcellini, MD, IRCCS Ca’ Granda, Milan, described wAIHA as a heterogeneous, often severe immunoglobulin G (IgG)-mediated disease, with complement involvement in one-third of cases. Complications such as infection, thrombosis, acute kidney injury, and multiorgan failure necessitate careful diagnostic assessment, including peripheral smear evaluation and exclusion of secondary autoimmune or malignant conditions.

First-line steroids remain standard but have high relapse rates and significant toxicity. Rituximab improves long-term response durability and is recommended early in severe or recurrent disease. Barcellini highlighted investigational strategies including BTK inhibitors, PI3K inhibitors, anti-CD19 biologics, BAFF/APRIL inhibitors, and selective complement inhibitors, which are important given the unmet need for targeted therapy in complement-driven wAIHA.

Advances in Refractory Immune Thrombocytopenia

Sandhya Panch, MD, MPH, Fred Hutch Cancer Center at University of Washington Medical Center, reviewed evolving definitions of refractory ITP, underscoring inadequate platelet responses after multiple therapies and increased morbidity. She described multifactorial mechanisms—antibody-mediated destruction, T-cell–driven cytotoxicity, complement activation, and impaired megakaryopoiesis—highlighting emerging roles for multi-omic profiling.

Management emphasizes identifying secondary causes, optimizing sequencing of thrombopoietin receptor (TPO-R) agonists, rituximab, fostamatinib, and using immunosuppressants (eg, sirolimus, mycophenolate mofetil) in select phenotypes. A case example illustrated the importance of genetic testing, where PI3K-pathway mutations guided effective use of leniolisib.

According to Dr Berentsen, therapy must be tailored to clinical phenotype, distinguishing hemolysis-dominant disease from circulatory symptom-dominant phenotypes in CAD. He also stressed avoiding extended bendamustine cycles due to toxicity and diminishing benefit.

Dr Barcellini emphasized the need for early recognition of complement activity and warned that splenectomy carries reduced efficacy and substantial long-term risk. She noted excitement for BTK inhibitors and BAFF/APRIL-directed therapies as potential future standards.

Dr Panch highlighted that refractory ITP is often misclassified, with up to 50% revealing alternate diagnoses, underscoring the need for multidisciplinary evaluation and adoption of biomarker-informed pathway-based treatment.

Implications for Practice

These data underscore a movement toward precision hematology, where immune cytopenia management integrates phenotype, complement activity, and molecular drivers. Clinical pathways may need revision to incorporate complement inhibitors, BTK inhibitors, BAFF/APRIL blockade, and genomic testing for refractory ITP.

Conclusion

Immune cytopenias remain complex, but rapid therapeutic innovation is reshaping management. Ongoing trials of targeted agents and biomarker-driven strategies promise more durable and individualized care approaches for CAD, wAIHA, and refractory ITP.

Reference

Panch S, Berentsen S, Barcellini W. Immune cytopenias: addressing challenges and advancing treatments. Presented at: ASH 2025; December 6-9; Orlando, FL.