The Spectrum Of Cold Agglutinin Disease At The Era Of Rituximab: A Retrospective Study On 48 Patients

To better describe the baseline characteristics, the management and the outcome of patients diagnosed with cold agglutinin disease (CAD) in the “real life”, a retrospective multicentre study was performed.

All patients diagnosed with CAD in one of the 3 participating university centers in Paris area over a 20-year period were included. The diagnosis of CAD was based on features of active hemolysis (with or without anemia) with a positive direct antiglobulin test (C₃ ± IgG pattern) and the presence of cold agglutinins in the serum at a significant titer (>1/32), in the absence of any other cause of inherited or acquired hemolytic anemia. All patients’ characteristics were collected and retrospectively analyzed by the same investigator (ML) using a standardized study form.

Forty eight patients (64.5 % of females, median age at diagnosis = 65.5 years [range: 30-93 years]) were included. The main symptom or biological abnormality leading to the diagnosis was: unexplained anemia (31%), acrocyanosis (25%), unusual fatigue (20%), hemoglobinuria (10%), neuropathy (8%), jaundice (8%), venous thrombosis (4%) or persistent lymphocytosis (4%). Of note, the diagnosis was incidental in 15% of the cases. The median hemoglobin (Hb) level at diagnosis was 9.3 g/dl [4-16.2 g/dl] and the titer of cold agglutinins varied from 1/32 to 1/64,000 with no obvious correlation with disease activity. Thirty-eight patients (77%) had a monoclonal IgM detected in the serum (kappa light chain in 92% of the cases). At time of diagnosis, a bone marrow aspirate (n= 19) or biopsy (n=11) was performed in 62.5% of the cases, an immunophenotyping of B-cell lymphocytes in the peripheral blood and/or in the bone marrow in 32 patients (66%), and a diagnostic imaging of chest and abdomen in 75% of the cases. Based on these tests, an underlying lymphoproliferative disorder (beyond the sole presence of monoclonal IgM) was found concomitantly in only 40% of the cases: unclassified clonal B cell- lymphoproliferative disorder (21%), chronic lymphocytic leukemia (11%), Waldenström macroglobulinemia (6%), and B-cell prolymphocytic leukemia (2%). The diagnosis of CAD was made after the diagnosis of lymphoma (1 follicular lymphoma and 1 case of marginal zone lymphoma) in 2 cases and before the onset of a diffuse large B-cell lymphoma in 1 case. After a median follow-up of 5 years [0.6-25 years], 12 patients (25%) did not require any other measures than folic acid supplementation and cold avoidance. At least one transfusion of packed-red blood cells (PRBCs) was required in 23 patients (48%), with a median of 10.5 PRBCs [2-40]. Thirty patients (62.5%) were given at least one treatment-line including rituximab (RTX, n=19), corticosteroids(n=14), alkylating agents (n=5), RTX + chemotherapy (n=7) or others (danazol: n=3, azathioprine: n=1, or intravenous immunoglobulin: n=3) The main treatment indication was an active haemolytic anemia (73%), marked cold-induced circulatory manifestations (7%) including 2 cases of cutaneous necrosis or both (13%), or tumor progression (7%). Of note, 15 patients (31%) were treated at least transiently with an erythropoietic-stimulating agent (ESA), mainly darbepoietin alpha, at various doses (ranging from 80µg to 300 µg/week) with a clear benefit observed in at least 8/15 cases (53%). In 5 patients, the use of ESA as a single agent was helpful to overcome one or several hemolytic episodes without the need of transfusion. Four patients (8%) have died during the follow-up period: CLL progression with sepsis (n = 1), myelodysplatic syndrome and sepsis (n =1), unknown cause in 2 elderly patients).

The initial workup and the management was highly heterogeneous and the observed rate of underlying lymphoproliferative disease was lower then previously reported in the literature. Whereas CAD has a relatively good long-term prognosis, a transfusion was required in almost 50% of the cases during follow-up and up to 65% of the patients received at least one treatment-line. The use of ESA off-label seems promising must needs to be better assessed prospectively. In the last decade, the use of rituximab alone or in combination with chemotherapy has emerged but its indications are still far from being consensual. There is definitely a need for international guidelines in order to harmonize the initial workup and treatment’s indications in patients with CAD.

No relevant conflicts of interest to declare.