Page 1098 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1062 ParT EighT Immunology of Neoplasia

T-cell subsets appear to prevent the development of autoreactive represses the emergence of fludarabine-induced AIHA, but the
B cells. When these are absent (e.g., after treatment with purine latter may also be seen with other chemotherapies (i.e., benda-
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analogues), autoreactive B-cell clones may easily emerge and mustine). Autoimmune phenomena in patients treated with
expand. purine analogues (mostly fludarabine-related) are of a more
severe nature.
Immunological Deficiencies Other rare entities are reported as paraneoplastic autoimmune
Patients with CLL are extremely sensitive to a number of infec- disorders with connective tissue disease manifestations, such
tious agents. A monoclonal Ig peak, usually of the IgM type, is as polymyositis, dermatopolymyositis, and focal myositis or
found in 5% of patients with CLL, and a small amount of a as vasculitis, pemphigus vulgaris, and acquired angioedema.
monoclonal component can be identified in the serum or urine These autoimmune disorders are related to T-cell dysfunc-
of 60% of patients. Hypogammaglobulinemia occurs in at least tion and may be associated with purine analogue treatment.
60% of B-cell CLL cases and may include all three classes (IgG, Paraneoplastic pemphigus also occurs in patients with CLL
IgA, and IgM). The pathogenesis of hypogammaglobulinemia and may be triggered by chemotherapy and radiotherapy.
in B-cell CLL is poorly understood, as this phenomenon is rare Glomerulonephritis and nephrotic syndrome are seldom
in other B-cell malignancies except multiple myeloma. Low reported but, when present, are related to different mecha-
Ig levels correlate with recurrent infections of encapsulated nisms, such as cryoglobulins and antineutrophil cytoplasmic
organisms. In patients who receive intravenous immune globulin antibodies (ANCAs).
(IVIG), there is a decrease in the incidence of major bacterial Therapy of autoimmune phenomena includes high-dose
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infections. steroids and disease control. In patients refractory to or
Infections are a major cause of morbidity and mortality in relapsing after steroid therapy, more aggressive treatment is
patients with CLL. Impaired humoral and cellular immunities, warranted. High-dose Igs offers transient amelioration in some
defects in the complement systems, and variable neutropenia, patients. Splenectomy or splenic irradiation, cytotoxic agents,
depending on marrow infiltrates, all contribute to the high rate or cyclosporine may represent valid rescue approaches. In
of infections. Opportunistic infections are initially uncommon cases where AIHA has been triggered by fludarabine, further
as the result of the relative preservation of cellular immunity exposure is hazardous. Rituximab may be an alternative
early in the disease. Infection risk increases following purine agent for the treatment CLL-associated autoimmune diseases,
analogue therapy because of the side effects of myelosuppression including rare autoimmune phenomena, such as pemphigus
and marked lymphopenia with T-cell depletion. The addition and PRCA.
of rituximab, the anti–B cell marker CD20 antibody, to nucleoside
analogue-based therapy does not appear to increase the risk of Other Malignancies
early or late infections but may increase the rate of neutropenia. Second malignancies (hematological and solid tumors) are not
Active immunization with vaccines is hampered by the patient’s uncommon in CLL. The most common hematological malignancy
inability to generate or retain a long and significant immune is the Richter transformation to diffuse large B-cell lymphoma,
response. which occurs in ≈5% of patients, as well as other high-grade
lymphoproliferative diseases. Dermatological tumors, such as
Autoimmune Phenomena basal cell carcinoma, are the most frequent of the solid tumors
Autoimmune-associated features are common in CLL. These encountered in patients with CLL, and these malignancies are
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manifestations primarily affect hematopoietic cells. For example, more likely to be locally aggressive and metastatic. The patho-
the most common known cause of autoimmune hemolytic anemia genesis of these second cancers is not fully understood, and
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(AIHA) is CLL. Positive result of direct antiglobulin test (direct although disease-related genetic factors (i.e., 17p deletion, notch
Coomb test) has been reported to be as high as in 7–35% of mutation) are a major determinant, it is probably multifactorial
patients with CLL, and AIHA itself occurs in 10–25% of patients and includes Epstein-Barr virus (EBV) infection and BCR
during the course of their disease, twice as often in patients with configuration to respond to multiple autoantigens and immune/
unmutated genes as in those with mutated ones. Autoantibodies inflammatory stimuli present in the microenvironment. 32,43
against red blood cells (RBCs) are warm-reactive polyclonal IgG.
They are not secreted by the malignant clone, but rather by CONCLUSIONS
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normal B cells. Cold agglutinins are rare. AIHA is thought to
arise from the imbalance among lymphocyte subsets, contributed CLL is a common indolent lymphoid neoplasm with a wide
to by therapy, resulting in the emergence of the autoimmune clinical heterogeneity. It is suspected and diagnosed more
clone. It is usually observed in advanced stages of the disease, commonly because of routine blood tests. Diagnosis is made
correlates with a poor prognosis, and has a close relationship with simple immunophenotyping. Cytogenetics and molecular
with the activity of the CLL. After therapy, the autoimmune diagnostic techniques are needed to determine the prognosis.
antibodies may remit in 70% of the treated patients. The complications of CLL appear to be unique to this neoplasm
Idiopathic thrombocytopenic purpura (ITP) is observed in and are part of a failing immune system with T-cell and B-cell
about 2–3% of cases and presents as increased megakaryocytes in dysregulation causing both deficiencies predisposing patients to
bone marrow. It should be distinguished from immune thrombo- recurrent infections and autoimmune diseases. New molecular
cytopenia induced by marrow infiltration, which is very common and protein markers are key to finding novel effective targeted
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in up to 50% of patients at presentation. Two-thirds of patients therapies.
with CLL-associated ITP also have AIHA (Evan syndrome). Pure
red cell aplasia (PRCA) and autoantibodies against neutrophils Please check your eBook at https://expertconsult.inkling.com/
are only rarely observed but are part of the CLL-related autoim- for self-assessment questions. See inside cover for registration
munity repertoire. Interestingly, the addition of cyclophosphamide details.