Emili Montserrat's group in Barcelona has just published its experience with autoimmune phenomena in CLL over the past 28 years Blood 2010, 116:4771-6. Among 961 patients with CLL seen in that time, autoimmune cytopenias were confirmed in 70 ((7%). 49 had AIHA, 20 ITP and one had both at presentation though a further three with ITP later developed AIHA. In 3 patients the autoimmune thrombocytopenia preceded the diagnosis of CLL and in a further 19 the diagnosis was simultaneous. In 35 (50%) the autoimmunity occured during or soon (immediately up to 10 months) after therapy (8/204 after fludarabine, 12/231 after chlorambucil).
Autoimmunity was associated with advanced clinical stage, high lymphocyte count and short lymphocyte doubling time. Among more modern prognostic factors, beta-2 M, CD38and ZAP-70 were associated with autoimmunity but too few patients had IGHV mutations or cytogenetics done to make a correlation with these. There were no significant differences between overall survivals of those with and without autoimmune phenomena.
Neither Binet nor Rai staging takes account of the effect of autoimmunity. Thus patients with ITP are automatically assigned to Rai stage 4 or Binet stage C. I have always though this nonsensical and Montserrat agrees with me. He differentiates between Binet stage C (immune) and C (infiltrative). They compared 19 patients with stage C (immune) with 54 patients with stage C (infiltrative) The groups were demographically similar except that the infiltrative group had higher beta-2M levels and more marrow infiltration. There was a major difference in survival between the two groups with the immune patients having an average survival of 7.4 years and the infiltrative patients having an average survival of 3.7 years.
The reason for this difference was the relative response to steroids with immune patients being downstaged to stage A in 84% of cases and the infiltrative patients being downstaged to stage A in only 16% of cases. The ITP cases did slightly better than the AIHA with 100% downstaged compared to 75%. The development of an autoimmune disease during the course of the CLL did not significantly affect prognosis, though for patients with early stage A average survival was 9 years compared to that of stage A patients who did not develop autoimmune phenomena who survived on average for 10 years. Median survival for stage A were 10.2 years, for stage B 5.6 years, stage C immune 7.4 years and stage C infiltrative 3.7 years.
Agreeing with what was found in LRFCLL4 the prevalence of AIHA after chlorambucil and after fludarabine was similar at 5% and 4% respectively.
The same group have also published a systematic review of the subject in Haematologica and I quote extensively from it.
Among the additional points they make are that the monoclonal B cell lymphocytosis (MBL) is markedly more common in patients with supposed idiopathic AIHA or ITP than in matched controls which emphasizes the importance of excluding CLL and other chronic lymphoproliferative diseases in patients with AIHA and ITP.
In the early 1990s we published our concern that treatment with purine analogs (particularly fludarabine) was associated with a higher frequency of autoimmune cytopenia (Myint H et al, Br J Haematol 1995;91:341-4) and several other authors agreed. This was thought to be related to prolonged suppression of CD4+CD25+FOXP3+ regulatory T cells (Tregs) which has been shown to lead to autoimmune disease, and Tregs are highly sensitive to fludarabine. The cases reported were mainly in patients who had been heavily pre-treated with purine analogs. As a result of these observations, there has been agreement that purine analogs should be avoided in
patients with a history of autoimmune cytopenia, particularly if related to purine-analog therapy.
More recent trials in patients treated with first line therapy have suggested that the risk for developing autoimmune cytopenia after purine analog exposure is not greater than with other agents though cases may be more severe. In the UK LRFCLL4 trial no differences were observed in the percentage of patients becoming DAT positive after therapy (14% chlorambucil, 13% fludarabine, and 10% fludarabine plus cyclophosphamide), but the incidence of AIHA was significantly lower in patients treated with fludarabine plus cyclophosphamide (5%) than in those allocated to receive chlorambucil (12%) or fludarabine alone (11%) (p<0.01). This suggests that the addition of cyclophosphamide to fludarabine might have a “protective” effect on the appearance of AIHA. An earlier smaller study from MDACC supports this low incidence of AIHA in patients treated with fludarabine, cyclophosphamide and rituximab. The most recent data come from the German CLL 8 trial of patients with CLL requiring treatment and without clinically apparent autoimmune cytopenia. When treated with fludarabine and cyclophosphamide with or without rituximab, the rate of AIHA was <1%. Taken together these results demonstrate that the risk of AIHA is not higher following regimes in which fludarabine and cyclophosphamide (with or without rituximab) are given together in comparison to the risk seen after older therapies for CLL.
Treatment of patients with CLL and autoimmune cytopenia is largely based on
expert opinion and depends on whether the patient’s CLL requires treatment at the same time. In those patients with immune cytopenia in the context of quiescent CLL, the treatment is the same as idiopathic AIHA initially with corticosteroids, and then in patients who fail to respond or relapse quickly, alternative immunosuppression such as ciclosporine, mycophenylate or azathioprine, or sometimes splenectomy. There are case reports of the use of combinations of rituximab with or without immunosuppression with good effect; alemtuzumab has also been successfully used. Intravenous immunoglobulin can be useful where a rapid response is needed though as a single agent it will not give lasting effects. The new thrombopoietin receptor agonists may be effective in CLL associated ITP as they are in primary ITP. Despite the fact that the problem is destruction rather tha failure to produce blood elements, supportive care should include blood product transfusion as clinically indicated. Folic acid in AIHA and local efforts to control bleeding in ITP may also be required. Failure of autoimmune cytopenia to respond to conventional treatment is considered an indication for anti-CLL therapy.
Given the concerns about therapy-triggered AIHA, there has been recent interest in the most appropriate treatment for patients with active CLL and immune cytopenia or a positive DAT Monotherapy with fludarabine is not appropriate, either in terms of risk of AIHA or efficacy in treatment of CLL. The studiesquoted in this article suggest that treatment with FC with or without rituximab does not provoke an excess of AIHA sompared to previous treatments, and that patients with a previous history of AIHA or a positive DAT might be safely treated with such regimens. Indeed, optimal treatment of CLL may be the most efficient way to treat associated cytopenias. However, patients with active AIHA or ITP are still excluded from clinical trials, and given ongoing concerns about using fludarabine in
this situation, alternative regimens which do not feature fludarabine such as R-CVP and R-CD have also been explored.
ITP in CLL is difficult to diagnose and its incidence may be underestimated. There is no specific test and thrombocytopenia in CLL is more commonly due to splenomegaly and bone marrow failure secondary to infiltration by disease. Thrombocytopenia in a patient with CLL can be considered immune mediated when there is a sudden profound fall in platelets (>50% fall to a platelet count <100 x 109/L) in the absence of splenomegaly, infection or chemotherapy and with plentiful megakaryocytes in the bone marrow. In advanced disease, anemia usually occurs before thrombocytopenia, so isolated thrombocytopenia is more likely to be immune in origin. However, ITP with a gradual rather than sudden decline in platelet count is seen more commonly in adults than classic acute ITP of childhood, and can provide particular diagnostic difficulties. Response of thrombocytopenia to steroids may be the diagnostic test.