A very good article on CLL and autoimmunity from the Barcelona group has appeared in Haematologica. The article is available on open access, so I will just summarize the main points it makes.
1] Most recent papers have put the incidence of autoimmune hemolytic anemia in CLL at between 4.3 and 9.8% whereas the incidence of ITP, pure red cell aplasia and autoimmune neutropenia is much less - perhaps 2% for ITP and < 1% for the other two. There is no evidence linking CLL with acquired hemophilia or acquired von Willebrand's disease.
2] Although lymphomas generally are more common in patients with non-hemic autoimmunity, any association with CLL is confused because CLL may exist for many years before it is diagnosed. Case control studies suggest that non-hemic autoimmunity is no commoner in CLL than in the general population.
3] The risk of developing CLL in patients with AIHA is not clear. It is possible that many of the reported cases might have had occult CLL when the AIHA was diagnosed. One of my own patients was diagnosed with CLL and AIHA, but after treatment of the AIHA the CLL disappeared and did not reappear for another 5 years. MBL is more common in patients with de novo AIHA than in controls.
4] The biological reason for the explanation for increased AIHA in CLL is not clear. Stories about autoreactive surface Ig and B1a cells seem wide of the mark since the autoimmune antibodies are polyclonal not monoclonal. The Barker hypothesis seems to be the most convincing explanation. CLL cells are very poor antigen presenting cells except for the red cell Rh antigen. An alternative red cell antigen, B3, seems also to be processed by CLL cells which provoke a T cell response.
5] Autoimmunity is associated with advanced stage, older age, unmutated IGHV status, ZAP-70 positivity, and increased beta-2M levels.
6] Treatment can trigger AIHA. Although both purine analogs and alkylating agents do this equally frequently, the anemia after fludarabine may be more severe and life threatening. Multiply treated patients are more vulnerable. Adding cyclophosphamide and/or rituximab to fludarabine seems to lessen the risk and indeed this may be how patients with AIHA need to be treated. It is generally accepted that patients with a positive Coombs teat (DAT) should not be treated with single agent fludarabine.
7] In patients who definitely need to be treated a positive DAT is a poor prognostic feature. However, anemia or thrombocytopenia that is immune mediated does not carry the same poor prognostic emphasis as it does when caused by bone marrow infiltration. Such patients should not be staged as Binet C or Rai III of IV until the autoimmunity has been treated.
8] Diagnosis of autoimmunity requires a high degree of suspicion. For AIHA, DAT, LDH, bilirubin, haptoglobins, and reticulocyte count should be performed. There need to be some caveats, however. Bilirubin levels are often only high at the start of the hemolysis as the liver rapidly conjugates the fat soluble bilirubin and excretes it. If there is heavy marrow infiltration the reticulocyte count may be normal. LDH rises in advanced CLL without hemolysis. Sometimes the DAT is negative. I find the haptoglobin level the most reliable test. For ITP there is no similar test to the DAT. To rule out the possibility of hypersplenism or marrow infiltration as a cause of thrombocytopenia, bone marrow biopsy will likely be necessary. It may be considered likely to be immune mediated if the platelet count falls suddenly by more than 50 in the absence of splenomegaly or chemotherapy and with plenty of megakaryocytes in the bone marrow.
7] It is possible that the immunoglobulin produced by the CLL may cause an autoimmune disease. Candidates for such conditions include cold hemaggluinin disease, paraneoplastic pmphigus, polyneuropathy and nephrotic syndrome. Acquired angioedema is more likely to be associated with SMZL than CLL and it is doubtful whether any cases associated with CLL have in fact been reported.