The association of autoimmune disease and CLL is well known but misunderstood. There is no general tendency for patients with CLL to develop autoimmune disease. The only autoimmune conditions seen in CLL with any frequency are autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). A few other rare conditions occur in CLL more commonly than would be expected, but the common autoimmune diseases, such as rheumatoid arthritis,

Table 27.2 Paraneoplastic complications of CLL

Autoimmune Antibody produced by tumor Cold agglutination syndrome Acquired angioedema

Some cases of glomerulonephritis or nephrotic syndrome

Antibody produced by residual lymphoid tissue Autoimmune hemolytic anemia Immune thrombocytopenia Immune neutropenia Pure red cell aplasia Paraneoplastic pemphigus Some cases of glomerulonephritis or nephrotic syndrome

Nonimmune Hypercalcemia

Severe reactions to insect bites

Obscure and uncertain Bell's palsy Peripheral neuritis Parkinson's disease RS3PE

thyroid disease, pernicious anemia, and systemic lupus erythematosus (SLE) are no commoner in CLL than in age-matched controls.65

Autoimmune hemolytic anemia

Using the technique of differential agglutination, Berlin was the first to show shortened red cell survival in nine patients with CLL.66 Later, Wasserman et al.67 found hemolytic anemia in 9 of 58 consecutive patients with CLL, with 5 out of 7 testing positive in the direct antiglobulin test. Following this, a series of studies suggested that AIHA occurs at some time in the course of CLL in 10-26% of cases.68

AIHA is commoner in CLL than in the general population. The reported prevalence varies from 1.8 to 35%.69'70 The disparity is because prevalence is closely related to stage and progression. In stable stage A disease, Hamblin et al.65 found a prevalence of 2.9%, compared to 10.5% in stage B and C disease and 18.2% in progressive stage A disease.

From a different point of view, CLL is the commonest known cause. In a large series of patients with AIHA, Engelfriet et al.71 found that 14% were associated with CLL, compared to 7% for SLE, the next most common cause. However, in about half the cases of AIHA no cause is found. AIHA occurs about eight times more commonly in CLL than in other forms of non-Hodgkin's lymphoma, and about two and a half times more commonly than in Hodgkin's disease.

Immune thrombocytopenia

Minot and Buckman72 reported that half their patients with CLL had thrombocytopenia at presentation. Once an immune cause for thrombocytopenia had been recognized, Harrington and Arimura73 reported seven cases of ITP occurring in CLL. Ebbe et al.74 reported five more cases and suggested that the prevalence of ITP in CLL was 2%, and this was confirmed by Hamblin et al.65 and Duhrsen et al.75 However, the numbers were small in all three series and the reliability of the diagnoses suspect. The diagnosis of ITP in CLL depends on the presence of isolated thrombocy-topenia, and normal or increased bone marrow megakaryocytes with an excess of early forms. More sophisticated, though not entirely reliable, tests are increased mean platelet volume and platelet distribution width, and detection of platelet antibodies in the serum or on the platelet membrane.

The diagnosis of ITP is difficult. Bone marrows heavily infiltrated with CLL cells make megakaryocytic numbers difficult to assess. Tests for platelet antibodies are still unsatisfactory. Increased levels of platelet-associated IgG was found in 30% of thrombocytopenic patients with CLL and 10% of nonthrombocytopenic patients.76 Even higher rates were found in non-Hodgkin's lymphomas. This test is known to have a high false-positive rate. The diagnosis is often made by exclusion and confirmed by response to therapy. About one-third of patients with ITP secondary to CLL also have a positive direct antiglobulin test (Evans' syndrome), a much higher rate than for primary ITP.77

Autoimmune neutropenia

When a CLL patient becomes neutropenic, it is usually because of marrow infiltration or treatment. Early reports of immune neutropenia in CLL78 probably referred to the well-recognized syndrome of large granular lymphocytic (LGL) leukemia with neutropenia.79 A study from Crete80 reported higher numbers of CD3+, CD8+, and CD57+ cells in neutropenic patients with CLL and demonstrated that CD8+ cells from neu-tropenic patients exerted a greater suppressive effect on colony-forming unit-granulocyte-macrophage colony growth than that of similar cells from nonneutropenic patients. More recently, it has been suggested that the secretion of high levels of Fas ligand is the cause of the neutropenia that is sometimes seen in B CLL.81 Antineutrophil antibodies seem to be involved only rarely, if at all.

Pure red cell aplasia

Although well recognized in CLL,82 pure red cell apla-sia (PRCA) is also a frequent complication of LGL leukemia; indeed, this is probably its commonest cause.83 Nevertheless, Chikkappa et al.84 recognized PRCA in 23 cases of B CLL, and subsequently it has been reported on at least five occasions.77 From their own cases, Chikkappa et al.84 estimated the prevalence at 6%, but this seems an exaggeration. In our series, about 1% of our 800 unselected patients with CLL have developed PRCA. The recent spate of cases of PRCA following treatment with erythropoietin has provided an easy assay for determining the autoimmune nature of PRCA.85

Other types of autoimmune disease

The idea that CLL was regularly associated with all types of autoimmune disease was reinforced by reviews by Miller86 and Dameshek.87 However, in an elderly population, autoantibodies are recognized quite commonly. Hamblin et al.65 found that 21.5% of a control population of individuals over 60 years of age had tissue-specific autoantibodies detected by immunofluorescence. In an age-matched series of 195 patients with CLL, the prevalence of autoantibodies was exactly the same. Duhrsen et al.75 confirmed this. However, there are three conditions that should be looked at more closely.

Nephrotic syndrome and glomerulonephritis Nephrotic syndrome occurs more commonly in CLL than would be expected by chance. In 1974, Dathan et al.88 reported two patients with CLL who developed nephrotic syndrome caused by an immune complex glomerulonephritis. Almost immediately, Cameron and Ogg89 reported another three cases, but subsequent letters to the same journal were rejected because there were so many. This complication is therefore much commoner than the 50 cases, mostly in the form of single case reports, uncovered by a PubMed search. Either membranous glomerulonephritis or membra-noproliferative glomerulonephritis may be seen on renal histology. There have been two reports of anti-neutrophil cytoplasmic antibodies, one of which followed treatment with fludarabine.9091

Acquired angioedema As with hereditary angioedema, the acquired form is characterized by recurrent bouts of angioedema and abdominal pain. It is caused by a deficiency of the inhibitor of the first component of complement (C1-INH). It differs from the hereditary form in that there is no family history, and the onset is not until the fifth decade of life. Type I is associated with lymphoproliferative diseases, including CLL, and type II with autoantibodies. The normal C1-INH molecule has a molecular weight (MW) of 105 kd, with a binding site for the serine protease C1s. The autoantibodies recognize two synthetic peptides (peptides 2 and 3) that span the reactive site of the molecule.

A study of six cases of acquired angioedema (AAE) demonstrated that the autoantibodies were monoclonal whether or not they were associated with a lympho-proliferative disease92; and the distinction may well be an artificial one, depending on how hard a lymphoproliferative disease is to find. In both types of AAE, a nonfunctional C1-INH molecule of MW 95 kd is found in the serum. The mechanism of action of the antibody is to cause or allow the cleavage of the C1-INH molecule, rendering it inactive.93

Blistering skin diseases The first report of a patient with CLL and a pemphigoidlike skin disease was by Oppenheim in 1910,94 although the two patients reported by Sachs in 192 1 95 had a more secure diagnosis of CLL. In 1974, Cuni et al. described a single case of bullous pemphigoid, established by the presence of antibasement membrane antibody.96 In their review of the literature, they discovered 16 other cases of CLL with either bullous or vesicular skin lesions. Goodnough and Muir97 reported the next case 6 years later, but in the same year Laskaris et al.98 reported two cases of CLL associated with oral pemphigus.

The confusion over pemphigus and pemphigoid was resolved when Anhalt et al.99 described paraneoplastic pemphigus. The clinical features are of painful erosions of the oropharynx, and vermilion borders of the lips that are resistant to conventional treatment. There is severe pseudomembranous conjunctivitis. There are several types of itchy cutaneous lesions including confluent erythema with skin denudation, and papules on the trunk and extremities forming target lesions, with central blistering. Anhalt reported that patients with this condition had often been previously misdiag-nosed as pemphigus vulgaris or erythema multiforme. Histologically, he observed three elements: suprabasilar intraepithelial acantholysis, necrosis of individual keratinocytes, and vacuolar interface change. Immunofluorescence studies revealed the presence in the serum of antibodies that reacted with the intracel-lular spaces, such as is seen in pemphigus vulgaris or foliaceus. However, direct immunofluorescence studies of the skin also demonstrated complement deposition along the basement membrane typical of bullous pem-phigoid.

Investigation of patients' sera showed immunopre-cipitation of a complex of four polypeptides from ker-atinocyte extracts with MWs of 250, 230, 210, and 190 kd, respectively. Subsequently, several groups confirmed this pattern of autoantibodies,100-102 but two groups also found an antibody against a 130-kd component.103104 These antigenic components have subsequently been identified. The 130-kd glycoprotein is characteristically involved in pemphigus vulgaris. It has been cloned and sequenced105 and termed desmoglein 3. It belongs to the cadherin family of cell adhesion molecules. Antibodies to the 230-kd polypeptide are characteristically found in the sera of patients with bullous pemphigoid. The protein is known as BPAG2,100 is intracellular, and localizes to the hemidesmosomal plaque. The 250-kd protein is desmoplakin I,100 the 210-kd protein is envoplakin,106 and the 190-kd protein is periplakin.107

Although it is rare, paraneoplastic pemphigus is a discrete autoimmune blistering skin disease with characteristic clinical features, a pathognomonic pattern of antibody specificity, and an association with lymphoid tumors. It may occur in an array of lymphoid tumors, and especially in Castleman's disease, but about 30% of cases occur in CLL.108

Mechanisms of autoimmunity in CLL Secretion of autoantibody by tumor cells Perhaps the simplest explanation for autoimmune disease in CLL would be that the autoantibodies were the product of the tumor. Using a sensitive immunoblotting technique, Beaume et al.109 found monoclonal immunoglobulin in the sera of 80% of CLL patients. However, the light-chain type was the same as that of the surface immunoglobulin in only half the cases. In CLL, serum monoclonal immunoglobulins cannot be assumed to have been produced by the tumor.

There is some evidence that CLL lymphocytes may be induced to produce autoantibodies. When stimulated with phorbol ester cells, 12 of 14 patients with CLL secreted IgM that reacted with a variety of autoantigens.110 Similar polyreactive antibodies have been described by Sthoeger et al.111 The antibodies were of the same light-chain types as the surface Ig of the CLL cells, and therefore not the product of contaminating normal B cells. These findings give weight to the hypothesis that CLL is derived from a B cell of separate lineage akin to the Ly-1 (CD5) B cell of mice, although this hypothesis is in increasing disrepute.68

Sthoeger et al.112 reported two cases of CLL with AIHA where immunoglobulin eluted from direct antiglobulin positive red cells reacted with anti-K, but not anti-X antibodies. In addition, the CLL cells produced in culture a monoclonal IgM that reacted with red cells, though more strongly at 4oC than at 37oC. Most agree that the antibody in AIHA is polyclonal and the product of the residual lymphoid tissue, and not of the tumor cells. A study by Sikora et al.113 demonstrated that the monoclonal Ig rescued from CLL cells was not responsible for a concurrent warm antibody AIHA.

On the other hand, in cold agglutination syndrome, most cases seem to be caused by a monoclonal IgM. The molecular basis for this reaction is now understood. A rat monoclonal antibody, 9G4, raised against the surface IgM of a B-cell lymphoma recognized a shared idiotypic determinant on all anti-I or anti-i cold agglutinins.114 B cells from patients with cold agglutination syndrome were immortalized with EBV. The 9G4-positive lines were investigated for the use of immunoglobulin VH genes and found exclusively to use the V434 gene.115'116 This specificity was retained whether the VH gene was in germline configuration or showed evidence of somatic mutation. The detailed biochemistry of both the reaction with red cells and with the 9G4 monoclonal has been elucidated.117

However, cold agglutination syndrome is rare in CLL. CLL cells do not usually secrete enough immunoglobu-lin for it to be detected by conventional methods. Thus although 6 of 78 patients with persistent cold agglutinins had CLL,118 the definition then in use for CLL would not have excluded diseases like splenic marginal zone lymphoma, which has a greater propensity for secreting large amounts of monoclonal immunoglobulin. The same is true of the single case report from Feizi et al.119 and the single case of CLL with cold agglutination syndrome reported by Hamblin et al.65 which, in retrospect, had a spillover lymphoma. A more recent case was also CD5 nega-tive,112 an almost certain indication that this also was a different type of lymphoma. In this case, the heavy-chain gene used by the surface immunoglobulin was DP54 and not V4 34, an indication that the cold agglu-tinin was not the product of the tumor. In the last 5 years, we have seen a single patient with long-standing cold agglutination syndrome who developed definite CLL during his last illness. Both his anti-I antibody and the surface immunoglobulin used the VH434 gene; the same is true for the case reported recently by Ruzickova et al.120

As far as other autoimmune syndromes are concerned, there is little evidence that the autoantibodies are the product of the CLL cell. It is believed that CLL-associated angioedema,92 and possibly CLL-associated glomerulonephritis,121 may be caused in this way. On the other hand, a recent publication suggests that the anti-230-kd autoantibody associated with paraneo-plastic pemphigus is not synthesized by CLL cells.122

Autoimmunity triggered by treatment Although the suggestion that autoimmunity might be triggered by treatment in CLL was made nearly 40 years ago,123 there were few corroborating reports124-126 until the association with fludarabine was realized. The first report of two cases appeared as a letter,127 though in only one of the cases was the association with treatment secure. A contrary view was reported by investigators from the MD Anderson Cancer Center, who argued that the cases represented the natural prevalence of AIHA in CLL.128 Five out of 112 patients treated with fludarabine developed hemolysis after between 1 and 6 courses of therapy, and a further four patients with preexisting AIHA deteriorated after fludarabine treatment, though four further patients with preexisting AIHA received fludarabine safely.

Two years later, Myint et al.129 reported that of 52 heavily pretreated patients, 12 developed AIHA after between 2 and 6 courses of fludarabine. Since then, many reports involving well over 100 patients have confirmed the association. The frequency of hemolysis depends on how much previous treatment the patient has received. Only about 2% of patients treated for the first time develop AIHA, compared with about 5% of patients who have received some previous treatment, and over 20% of heavily pretreated patients.

Among 1203 patients studied at University "La Sapienza" in Rome,130 52 cases of AIHA were observed (4.3%). In 19 patients, the AIHA was present at the time of diagnosis of the CLL, and a further 20 developed AIHA while still untreated. Ten developed AIHA while on therapy, seven on low-dose chlorambucil (1.8% of those so treated) and three on fludarabine (2.5% of those so treated). Current thinking is that AIHA triggered by treatment has been underreported in the past, and is probably as common after chloram-bucil treatment as after fludarabine, but after fludara-bine it is more severe and difficult to treat. Early suggestions are that the risk is less with the fludarabine/ cyclophosphamide combination.

Autoimmune thrombocytopenia may also be triggered by fludarabine. Montillo et al.131 first reported relapse of CLL-associated ITP after exposure to fludarabine. Over 30 cases of fludarabine-related ITP have now been reported.68 Only one possible case of immune neutropenia132 and three cases of PRCA have been reported.68 Paraneoplastic pemphigus has been reported in five cases.68 There have been two cases of postflu-darabine glomerulonephritis.68

The other purine analogs, cladribine and pentostatin, are also capable of triggering autoimmune complica-tions.68 As the best known toxicity of the purine analogs is their profound T-cell suppression, it is interesting to note that treatment with Campath-1H can also trigger autoimmunity in CLL.68 Interestingly, paraneoplastic pemphigus may also be triggered by radiotherapy.68

From these observations some general conclusions can be drawn. Most cases of postfludarabine autoim-munity have occurred in heavily pretreated patients. Usually, patients have previously received an alkylat-ing agent. The complication is severe and often difficult to treat. In many cases it has been fatal. If control is achieved, then reexposure to any of the purine analogs retriggers the complication. Even alkylating agents may retrigger it. The recurrence is likely to be even more virulent. Although commonest in CLL, autoimmunity may also be induced in other low-grade lymphoproliferative diseases.

Synthesis: why is CLL complicated by autoimmunity? The cause of the autoimmune complications of CLL is unknown. Although they are a feature of all low-grade B-cell lymphomas, they are worse in CLL, just as the immunodeficiency is worse. Both the immunodeficiency and the autoimmunity are made worse by treatment. They are probably related. Noting the almost AIDS-like, CD4 T-cell suppression that occurs after treatment with fludarabine, Hamblin68 suggested that autoimmunity in CLL is caused by loss of T-cell regulatory control of autoreactive T cells.

In most cases of AIHA, the autoantibody preferentially reacts with components of the Rh antigen. A

recent study has demonstrated that CLL cells act as the most potent antigen presenting cells for purified Rh antigen.133

Treatment of autoimmune complications Acquired angioedema Treatment of AAE has been recently reviewed by Markovic et al.134 They recommend treatment of the CLL as the most important element of the management. The androgens, stanozolol and danazol, have been widely used for both the hereditary and acquired form of the disease and are generally successful. They act by increasing the production of C1 esterase inhibitor by the liver. For those who are unhappy taking androgenic steroids, tranexamic acid (0.5 g three times daily) is as successful in the acquired form as in the in the hereditary form.

Autoimmune hemolytic anemia There are no controlled trials of treatment of AIHA secondary to CLL, and treatment does not differ from AIHA in other circumstances. Prednisolone 1 mg/kg for 10-14 days has been the standard treatment for acute hemolysis for 50 years.135 As most cases occur in progressive CLL, it would be usual to also treat the CLL, with either chlorambucil or fludarabine, but this carries a risk. For patients in whom the AIHA has been triggered by fludarabine, further exposure to purine analogs or even to any other cytotoxic drug may be hazardous. Patients failing to respond to prednisolone, or relapsing when the dose is reduced, are offered azathioprine or cyclophosphamide.

There are few data on the value of splenectomy in this condition. In a series of 113 splenectomies for AIHA, only 4 were for hemolysis secondary to CLL.136 The hazards of splenectomy are well known, and are certainly increased in frail, elderly, immunodeficient patients. Nevertheless, it may be lifesaving.

Among 73 cases of AIHA treated with intravenous immunoglobin (IVIG) detailed in the literature,137 40% responded. Doses of 0.4 g/kg/day for 5 days were effective. Only 18 of the 73 cases also had CLL. Response was transient, lasting only 3-4 weeks, but retreatment was effective.77

Cyclosporine is used in AIHA when other modalities have failed.138 The dose is 5-8 mg/kg/day, tapering to a maintenance dose of about 3 mg/kg/day. We aim to keep the blood level at about 100 ^g/L.

The severity of hemolysis following fludarabine is often extreme, and several reports detail fatalities. Patients who develop these complications are often immunosuppressed and prone to infection. Further immunosuppressive treatment will intensify this risk. Anticipating that the complication will be difficult to control, we move rapidly to secondary treatments. Where steroids have failed, we have found success with IVIG and splenectomy, but many of our patients have required cyclosporine and, because responses are often delayed, we move rapidly to prescribing it.68

A special risk is the retriggering of autoimmunity by reexposure to fludarabine, cladribine, or pentostatin.68 Even chlorambucil may retrigger the complication.68 The current Medical Research Council trial suggests that there is no extra hazard in treating a patient with a positive direct antiglobulin test (DAT), but there is if the patients has preexisting AIHA.

Rituximab infusion is rapidly gaining favor for the treatment of autoimmune complications of CLL, especially those occurring after exposure to fludarabine. Zaja et al. reported remarkable responses in cases of AIHA, ITP, cold agglutination syndrome, and axonal degenerating neuropathy.139

Autoimmune thrombocytopenia This complication is so rarely diagnosed that there is next to no guidance in the literature on treatment. It therefore seems wise to follow the Clinical Guidelines of the American Society of Hematology140 for the treatment of idiopathic thrombocytopenic purpura, and to treat the CLL independently as required. Thus, asymptomatic thrombo-cytopenia should only be treated when the platelet count is <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 <30 X 109/L).

Prednisolone is given in the same dose as for AIHA. Patients failing to respond are treated with IVIG 0.4 g/kg/day for 5 days. The response rate is higher than that for AIHA. Splenectomy is also more effective than in AIHA, with response rates of over 70% in patients unresponsive to steroids.141 Other treatments found to be successful in AIHA may also be tried. Unique to autoimmune thrombocytopenia is treatment with vinca alkaloids. Vincristine 1 mg i.v. weekly X 6 is often effective, but vinblastine has also been used. The drugs may be given as boluses or by slow infusion.68

ITP complicating CLL may be severe, causing intractable bleeding. Special measures may need to be taken to control the bleeding, including IVIG followed immediately by platelet transfusion. Alternatively, methylprednisolone 1 g/day i.v. X 3 followed by platelet transfusion may be effective. Tranexamic acid is worth trying, as is recombinant factor VIIa.142

Pure red cell aplasia Treatment for this complication has been reviewed by Diehl and Ketchum.77 On the basis of literature reports of 41 treatments in 33 patients, they recommend instituting treatment to control the CLL, as this will be necessary to achieve long-term remission of the PRCA. At the same time, the PRCA is treated with prednisolone 1 mg/kg/day. If there is no response, then cyclosporine is added. The reticulocyte count should increase within 2-3 weeks, and the hemoglobin normalize in 1-2 months. At this point, the steroid dose can be reduced and stopped. Cyclosporine should be continued for 6-7 months and then gradually withdrawn.

Paraneoplastic pemphigus This syndrome is frequently fatal68; four of the original five patients died, and two patients who developed it following fludara-bine also succumbed. One patient has survived post-fludarabine paraneoplastic pemphigus after having been treated with prednisolone 500 mg/day, cyclophosphamide 100 mg/day for several weeks, together with IVIG 120 mg over the first 3 days. Other patients with a similar syndrome, unrelated to malignancy, have responded to IVIG. Three British patients responded to the combination of high-dose steroids and cyclosporine or cyclophosphamide, although one later died from sepsis.

Rapidly progressive glomerulonephritis Treatment for glomerulonephritis involves intense immunosuppres-sion with high-dose intravenous methylprednisolone and cyclophosphamide.68 Plasma exchange has a role in those cases that present with renal failure requiring dialysis. Aggressive immunosuppression has the added benefit of suppressing the CLL. It is moot whether control of the CLL or control of the autoimmune process is responsible for the beneficial effect of such treatment.


Hypercalcemia is a rare complication of CLL.143 The cause is obscure. Rossi et al.144 have suggested that cases of CLL might have abnormal osteoclast differentiation, leading to increased bone resorption.

Abnormal reactions to insect bites

There has long been a story that patients with CLL respond abnormally to insect bites. Two recent studies have entered the literature.145 146 Histology showed T- and B-cell infiltrates with prominent eosinophil infiltration and eosinophil granule deposition. One patient developed bullous lesions.

Neurologic complications

Hamblin147 reported patients with various neurologic complications, including Bell's palsy, Parkinson's disease, and peripheral neuropathy. It is difficult to know whether such complications are neoplastic, paraneo-plastic, or incidental. Creange et al.148 reported seven cases of inflammatory neuromuscular disorders in which there was clear evidence of infiltration with CLL cells. Bell's palsy is now thought to be a complication of Herpes simplex infections in most cases, and Hamblin147 reported a temporal relationship of Parkinson's disease to severe Herpes zoster infections.

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