The impact of chemoimmunotherapy on primary cold agglutinin disease and Waldenström macroglobulinemia-associated cold agglutinin syndrome.

BACKGROUND: Cold agglutinin-associated hemolysis (CAH) occurs in diverse clinical contexts, such as primary cold agglutinin disease (pCAD) and Waldenström macroglobulinemia-associated cold agglutinin syndrome (WM-CAS). The differentiation of these entities is often challenging, particularly in MYD88 L265P-negative cases. Since studies that examined the effects of chemoimmunotherapy (CIT) frequently predated routine molecular testing, it remains unclear whether disease classification impacts treatment response and durability. PURPOSES: This study aimed to evaluate the clinicopathological features, responses to CIT, long-term outcomes, and adverse events (AE), such as thrombotic events, among patients with CAH (pCAD and WM-CAS) and WM without CAS (WM-only). METHODS: We retrospectively analyzed patients with pCAD, WM-CAS, and WM without CAS (WM-only) treated at a single center between April 2010 and November 2025. Diagnoses followed the revised fifth edition of the WHO Classification of Hematolymphoid Tumors. Clinicopathological features and outcomes were compared. Treatment responses were assessed using CAD-specific criteria based on hemoglobin and hemolysis markers. Exploratory pooled analyses combining pCAD and WM-CAS as the CAH group were also performed. Time to next treatment (TTNT) and overall survival (OS) were analyzed using Kaplan-Meier methods. RESULTS: Ten patients had CAH (5 pCAD, 5 WM-CAS) and 29 had WM-only. In exploratory pooled comparisons, CAH cases showed higher lactate dehydrogenase and total bilirubin levels, whereas WM-only cases had higher serum IgM levels and greater bone marrow involvement. Rituximab-based CIT predominated as the first-line therapy for both pCAD and WM-CAS. Overall response rates were 100% in pCAD and 80% in WM-CAS. TTNT did not significantly differ between pCAD and WM-CAS, although this comparison was limited by the very small sample size. Elevated FDP levels were more frequent in CAH, while no overt thrombotic events or grade ≥3 infections were observed. CONCLUSION: In this small retrospective cohort, hematologic responses were observed after rituximab-based CIT in patients with both pCAD and WM-CAS. When hemolysis is the dominant clinical issue and strict disease classification is difficult, fixed-duration rituximab-based CIT should be further investigated. These hypothesis-generating findings warrant validation in larger studies.