This multicenter, phase II, open label study will enroll patients with chronic cold agglutinin disorder. A single course of Bortezomib will be given at the dose of 1,3 mg/sqm iv on days 1, 4, 8, 11.

Based on its activity in MM, single agent Bortezomib was tested in phase II trials in lymphoplasmacytic lymphoma, the disorder most frequently associated with CAD, and achieved 40-80% responses. These striking clinical responses indicate that proteasome activity is critical for the survival of immunoglobulin-secreting cells. The resolution of transfusion requirement in two patients with refractory CAD associated with IgMk monoclonal gammopathy has been reported after treatment with a short course of Bortezomib. It may be interesting to test the efficacy of Bortezomib in a larger series of patients with refractory CAD, idiopathic or associated with an otherwise asymptomatic B cell clonal disorder, and to evaluate the duration of clinical benefit.

Inclusion Criteria:

• Patients with chronic cold agglutinin disorder requiring or with a hemoglobin concentration below 10g/L determined at least monthly during the two months before entering the trial;
• Failure of at least one previous treatment attempt;
• Hemoglobin level assessment;
• Presence of serum cold agglutinin (CA). If an overnight incubation is used for CA detection, a titer at 4°C of 64 or higher is required;
• Written informed consent.

Exclusion Criteria:

• Presence of a concomitant lymphoproliferative disorder requiring specific treatment for reasons other than cold agglutinin related hemolytic anemia;
• Preexisting peripheral neuropathy;
• Known hypersensitivity to Bortezomib;
• Non-cooperative behaviour or non-compliance;
• Psychiatric diseases or conditions that might impair the ability to give informed consent;
• Patients who are pregnant (women of childbearing potential must have a negative serum pregnancy test). Post-menopausal women must be amenorrhoic for at least 24 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.