Background Cold autoimmune haemolytic anemia (AIHA) is a rare hematological disorder which comprehends Cold Agglutinin Disease (CAD), a clinical condition characterized by an indolent and asymptomatic B-cell expansion along with chronic hemolysis; and Cold Agglutinin Syndrome (CAS), which is caused by an autoimmune disorder, a viral infection or a malignant lymphoma.

Methods. A total of 487 reports of cold agglutinin tests were performed in the immunohematology laboratory from 2020 to 2024 in a single-center university hospital, identifying 138 subjects as a possible case of cold or mixed AIHA sustained mainly by cold antibodies based on the results of direct (DAT), indirect antiglobulin and cold agglutinin (CA) test. The data was analyzed statistically with Odds ratio for categorical variables, while Kaplan-Meier was used to evaluate treatment response.

Results. Out of 138 subjects, only 75 (54%) patients were referenced to a hematology consult and treat symptomatic patients with hemolytic anemia in an appropriate manner. Median age of 75 patients with cold antibodies was 63 years (range 19-89) without gender prevalence, but interestingly 0 blood type was present in nearly half of the available patients. Ten patients (13%) had mixed AIHA with both IgM and IgG antibodies, while median titer levels was 256 in 64 patients with CA, while DAT was positive with median IgM 2+ and C3d 3+ levels in 51 patients respectively.

Diagnosis of CAD was confirmed in 26 patients (35%) based on the presence of indolent lymphoproliferative disorder in the bone marrow using histological and/or flow cytometry evaluation. Median hemoglobin (Hb) level at diagnosis was 8.3 g/dL, with moderate anemia (Hb<10 g/dL) in 42 patients.

Rituximab was associated with the longest response duration (median, 24 months) and the lowest proportion of patients needing further treatment (55% in second line, in third line).

There was a statistically significant correlation between the diagnosis of CAD and both IgM titer level ≥ 2+ (p=0.0002) and moderate anemia (p=0.03), respectively.

After a median follow-up of 7.5 months, 35 patients were treated for cold AIHA. One third of the patients was treated successfully with corticosteroids alone, while the rest received rituximab, mainly in the second treatment line due to admission in non-hematogical wards, and in some cases accompanied by immunosuppressants, with an 85% rate of response. The prognostic impact on response rates of corticosteroids (p=0.0004) and rituximab (p=0.001) was confirmed using Kaplan-Meier analysis. Patients older than 65 years, on the other hand, were at greater risk of relapse (p=0.03).

Conclusions. The presence of cold autoantibodies alone should lead to detailed analysis, as many cases are caused by the presence of asymptomatic lymphoproliferative disorder, prompting us to connect immunologists and hematologists, suggesting the need of a multispecialistic dedicated team for the correct management of AIHA. Furthermore, only the presence of clinically significant anemia with confirmed hemolysis represents a treatment indication, and first line choice should be rituximab, even for those patients with mild symptoms.

Disclosures

No relevant conflicts of interest to declare.

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2024
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