Treatment of Autoimmunity in CLL

Treatment of the autoimmune complications of CLL is not guided by good data. In general, the same treatments have been applied as when the disease occurs spontaneously. However, some treatments are less appropriate, and there is also the question of whether and how to treat the CLL itself. The possibility that the immunosuppression caused by the disease or its treatment has triggered the autoimmunity has to be weighed against the prospect that treating the disease will eliminate the complication.

2.5.1. Autoimmune Hemolytic Anemia

There are no controlled trials of treatment for AIHA secondary to CLL. Autoimmune destruction of blood cells in CLL is frequently vigorous, especially when triggered by purine analogs. Some patients have died because of the mistaken belief that, because the immune process will also destroy transfused red cells, transfusion is of no value. On the contrary, the transfusion of red cells is often vital. It is also important to replenish folic acid. The type of specific treatment used is guided by what has been established for idiopathic AIHA.

2.5.1.1. Corticosteroids and Cytotoxic Drugs. Most patients will respond to the standard treatment for acute hemolysis of prednisolone 1 mg/kg for 10-14 d (114), reducing slowly over the next 3 mo. The usual steroid side effects should be looked for, and, especially in immunode-ficient patients, prophylaxis against fungal infections should be given. There are multiple modes of action of steroids including decreased lymphocyte proliferation, decreased interleukin-2 (IL-2) production, decreased T-cell activation and T-helper function, impaired natural killer (NK) function, monocyte maturation and handling of antigen by macrophages, and deficient macrophage chemotaxis (115).

Since most cases occur in progressive CLL, it would be usual to treat the CLL also, either with chlorambucil or fludarabine, but this carries a risk. In patients in which the AIHA has been triggered by fludarabine, further exposure to purine analogs or even to alkylating agents. may be hazardous.

2.5.1.2. Splenectomy. Only four of a series of113 splenectomies for AIHA were for hemolysis secondary to CLL (116). The well-known hazards of splenectomy are certainly increased in frail, elderly, immunodeficient patients. Laparoscopic splenectomy extends the possibility of operation to a less healthy population. Patients with AIHA with IgG alone and no complement components on their red cells respond better (117). Before elective splenectomy, vaccination against pneumococcus is recommended, and some groups also recommend long-term prophylactic penicillin or the equivalent.

2.5.1.3. Intravenous Immunoglobulin. Of 73 cases of AIHA treated with intravenous immunoglobulin in the literature (118), 40% responded to doses of 0.4 g/kg/d for 5 d. Only 18 of the 73 also had CLL. In these, although reduction in the size of lymph nodes and spleen was also noted, response was transient, lasting only 3-4 wk.

2.5.1.4. Cyclosporin. Cyclosporin is used in AIHA when other modalities have failed. Since treatment of AIHA complicating CLL is often unsuccessful, cyclosporin has been used most frequently in this situation (119). The dose is 5-8 mg/kg/d, tapering to a maintenance dose of about 3 mg/kg/d. We aim to keep the blood level at about 100 |g/L. In a series from the M.D. Anderson Cancer Center, 63% of patients with AIHA complicating CLL responded to cyclosporin 300 mg/d with an increase in Hb of more than 3 g/dL (120).

2.5.1.5. Other Treatments. In patients too sick for splenectomy, especially when the spleen is very large, splenic irradiation may be substituted (121). Danazol may have a role in steroid sparing, although its use in CLL is unreported. Plasma exchange has been successful in a few reports of idiopathic AIHA, but there are no reports in cases secondary to CLL (53). Immunoadsorption onto a column containing protein A is sometimes used as an adjunct to plasma exchange. At least one patient has been successfully treated in this way (122). The infusion of vincristine-loaded platelets to inactivate macrophages has been successful in one patient whose

CLL-related AIHA was unresponsive to other modes of treatment (123). Rituximab has produced responses in AIHA caused by both warm (124,125) and cold (126, 127) reacting antibodies. It was very effective in a patient with cold agglutinins associated with a CD20-positive, low-grade non-Hodgkin's lymphoma (128), and it has some activity in CLL (129), but there have so far been no reports of its use in AIHA associated with CLL. Similarly, although there have been no reports of the use of Campath 1H in the treatment of AIHA associated with CLL, it has a beneficial effect in patients with refractory AIHA (130).

2.5.2. Autoimmune Thrombocytopenia

There are no reported clinical trials of therapy in CLL-associated ITP, and it is wise to follow the Clinical Guidelines of the American Society of Hematology (131) for the treatment of ITP and treat the CLL independently as required. These recommend that asymptomatic thrombocytopenia should only be treated when the platelet count is less than 30 x 109/L. Hospitalization should be confined to patients with mucous membrane or other severe bleeding. Conventional-dose oral prednisolone is the treatment of choice for those who need any treatment, (those with severe bleeding or a platelet count less than 30 x 109/L).

Prednisolone should be given in the same dose as for AIHA, and those patients failing to respond should be treated with intravenous immunoglobulin 0.4 g/kg/d for 5 d. A higher response rate than for AIHA, should be expected. Splenectomy is also more effective than in AIHA with response rates of over 70% in patients unresponsive to steroids (132). Other treatments that work in AIHA may also be tried, but of special value in ITP is bolus or slow infusions of vincristine at a dose of 1 mg iv weekly x 6 (133).

ITP complicating CLL may cause intractable bleeding and be a medical emergency. In this circumstance, intravenous immunoglobulin followed immediately by platelet transfusion (134) or methylprednisolone 1 g/d iv x 3 followed by platelet transfusion may be effective. Alternatively, tranexamic acid is worth trying. In refractory cases Campath 1H may be effective (130).

2.5.3. Pure Red Cell Aplasia

On the basis of literature reports of 41 treatments in 33 patients, Diehl and Ketchum (53) recommend instituting treatment to control the CLL since this will be necessary to achieve long-term remission of the PRCA. At the same time the PRCA may be treated with prednisolone 1 mg/ kg/d. If it is unresponsive, then cyclosporin should be added. The reticulocyte count should increase within 2-3 wk and the hemoglobin should normalize in 1-2 mo. At this point the steroid dose can be reduced and stopped. Cyclosporin should be continued for 6-7 mo and then gradually withdrawn. Campath 1H may be effective in unresponsive cases (130).

2.5.4. Management of Post-Fludarabine Autoimmunity

The severity of hemolysis or thrombocytopenia following fludarabine is often extreme, and it may be fatal. It is important not to stint on transfusions of red cells or platelets. Immunosuppression is a hazard in these patients, and further immunosuppressive treatment will intensify the risk of infection. When treatment with steroids fails, most patients should be started on cyclosporin, even though intravenous immunoglobulin and splenectomy may still be tried.

A special risk is the retriggering of autoimmunity by re-exposure to purine analogs and even chlorambucil may retrigger the complication (135). However it is possible to reintroduce fludarabine while the patient is maintained on cyclosporin (120). Whether it is safe to use purine analogs in patients with a positive Coombs' test or evidence of pre-existing AIHA is difficult to answer. Some patients have had an exacerbation of their hemolysis or thrombocytopenia when treated this way, but both fludarabine and cladribine have been used successfully in these circumstances (136,137). Our current advice is to introduce purine analogs under the cover of cyclosporin with careful regard to renal function.

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