The prognostic significance of cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL)

Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
British Journal of Haematology (Impact Factor: 4.71). 06/2008; 141(5):615-21. DOI: 10.1111/j.1365-2141.2008.07086.x
Source: PubMed


The development of cytopenia in chronic lymphocytic leukaemia (CLL) patients can predict poor prognosis. All CLL patients seen in the Division of Hematology at Mayo Clinic Rochester from 1 January 1995 to 31 December 2004 (n = 1750) were evaluated for cytopenia, aetiology of cytopenia and clinical outcome. Cytopenia occurred in 423 (24.2%) patients and was attributable to CLL in 303 (17.3%) cases, with 228 (75%) of these having bone marrow (BM) failure and 75 (25%) having autoimmune disease (AID). Survival from onset of cytopenia was significantly better for patients with AID (median 9.1 years) compared to patients with BM failure (median 4.4 years, P < 0.001). Patients with AID diagnosed within 1 year of the diagnosis of CLL (n = 35) had similar survival from diagnosis compared to patients without CLL-related cytopenia (median 9.3 vs. 9.7 years, P = 0.881). Although cytopenia caused by BM failure predicted a poorer prognosis in CLL, cytopenia caused by AID was not an adverse prognostic factor. These findings suggest that patients with cytopenia due to AID cannot be meaningfully classified by the current clinical staging systems. Revisions of the National Cancer Institute Working Group 96 criteria should consider the aetiology of cytopenia in staging CLL patients.

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    • "A study of 1750 CLL patients seen over a period of 10 years at Mayo clinic9 found that 24% of patients had cytopenias. The most common causes of cytopenias were marrow failure (54%), autoimmunity (18%), non CLL related cytopenias (11%), long term complications of treatment (4%) and splenomegaly (3%). "
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    ABSTRACT: CLL has been defined as presence of more than 5000 small mature appearing monoclonal B lymphocytes with a specific immunophenotype in peripheral blood. It is a well-known fact that CLL is associated with autoimmune cytopenias. CLL cells are CD5+ B lymphocytes, and usually are not the “guilty” cells which produce autoantibodies. T cell defect is another characteristic of CLL and the total number of T cells is increased, and there is inversion of the CD4/CD8 ratio. Autoimmune hemolytic anemia (AIHA) is the most common autoimmune complication of CLL and has been reported in 10–25% of CLL patients. However, the stage-adjusted estimated rate of AIHA in CLL is about 5%. Conversely, CLL is three times more common in patients who present with AIHA. Direct agglutinin test (DAT) is positive in 7–14% of CLL patients but AIHA may also occur in DAT negative patients. Autoimmune thrombocytopenia (AIT) is the second most common complication of CLL and has been reported in 2–3% of patients. DAT is positive in AIT but presence of antiplatelet antibodies is neither diagnostic nor reliable. Autoimmune neutropenia (AIN) and pure red cell aplasia (PRCA) are very rare complications of CLL and like other autoimmune complications of CLL may occur at any clinical stage. It is believed that most case reports of AIN and PRCA in CLL actually belong to large granular lymphocytic leukemia (LGL). Non-hematologic autoimmune complications of CLL including cold agglutinin disease (CAD), paraneoplastic pemphigus (PNP), acquired angioedema, and anti-myelin associated globulin are rare. Before starting any treatment, clinicians should distinguish between autoimmune cytopenias and massive bone marrow infiltration since autoimmune complications of CLL are not necessarily equal to advanced disease with poor prognosis. According to IWCLL guideline, steroids are the mainstay of treatment of simple autoimmunity. Intravenous immunoglobulin (IVIg), cyclosporine, and rituximab are used in complex, steroid refractory cases. Monotherapy with purine analogues and alkylating agents should be avoided as they may increase CLL associated autoimmune complications.
    Full-text · Article · Nov 2013 · Mediterranean Journal of Hematology and Infectious Diseases
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    • "W leczeniu PRCA, podobnie jak AIHA, proponuje się kortykoidy, leki immunosupresyjne i rytuksymab ewentualnie w skojarzeniu z cyklofosfamidem i deksametazonem . Nie ma natomiast jednoznacznie ustalonego sposobu postępowania w IN [31] [46] [47] [50]. "
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    ABSTRACT: Profound disturbances of different elements of the immune system in chronic lymphocytic leukemia (CLL) lead to impaired elimination of allogeneic antigens, like pathogenic microorganisms, and deficient tolerance of self-antigens, which is responsible for autoimmunological disorders. Susceptibility to infections in CLL patients is due to disease-related immunodeficiency, mainly hypogammaglobulinemia, and aggravated by myelo- and immunosuppressive properties of currently used antileukemic drugs, especially alkylating agents and purine analogues. Severe infections occur in the majority of CLL patients, they may be life-threatening and shortening the patients’ survival. They affect most frequently the respiratory system, and are caused mainly by Gram-positive and Gram-negative bacteria and common viruses like Herpes and Varicella-Zoster. In some patients, especially those treated with purine analogues, opportunistic infections can occur. There are no generally admitted guidelines for the prophylaxis of infections. Vaccinations against influenza and encapsulated bacteria, intravenous immunoglobulins and prophylaxis with cotrimoxazol and antiviral drugs for selected patients under purine analogues or alemtuzumab have been proposed. Autoimmune hemolytic anemia (AIHA) due to the production of anti-erythrocyte autoantibodies is the most common autoimmunological complication of CLL, especially in patients with positive direct antiglobulin test (DAT). It can be also triggered by alkylating agents and purine analogues. The treatment of AIHA includes corticosteroids, rituximab, immunosuppressive agents and splenectomy. Autoimmune thrombocytopenia, pure red cell aplasia, autoimmune neutropenia and non-hematological autoimmune manifestations can also occur.
    Preview · Article · Jul 2013 · Acta haematologica Polonica
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    • "An increased risk to develop autoimmune cytopenia has been observed in patients displaying various adverse clinical or biological prognostic features, such as advanced stage,4,9,16,19 older age,8,12,16 high white cell count,8,14,17 short lymphocyte doubling time,10,16 increased beta-2-microglobulin levels,10,12,17 CD3810,17 and ZAP-70 positivity,9,14 unmutated IGVH genes and stereotyped BCRs20–22 band poor risk cytogenetics.9,22 "
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    ABSTRACT: Autoimmune cytopenias are a frequent complication in CLL, occurring in approximately 5–10% of the patients. The most common manifestation is autoimmune haemolytic anaemia, followed by immune thrombocytopenia and only rarely pure red blood cell aplasia or autoimmune granulocytopenia. Initial treatment is as for the idiopathic autoimmune cytopenias, with most patients responding to conventional corticosteroid therapy. Patients, who do not respond to conventional therapy after 4–6 weeks, should be considered for alternative immunosuppression, monoclonal antibody therapy or splenectomy. While randomized trials demonstrating the benefit of rituximab in CLL-related autoimmune diseases are still lacking, there are considerable data in the literature that provide evidence for its effectiveness. The monoclonal antibody alemtuzumab also displays considerable activity against both the malignant disease and the autoimmune complication in patients with CLL, although at the expense of greater toxicity. A number of new monoclonal antibodies, such as ofatumumab, GA-101, lumiliximab, TRU-016, epratuzumab, and galiximab, are currently investigated in CLL and their activity in CLL-related autoimmune cytopenias should be evaluated in future studies.
    Full-text · Article · Apr 2013 · Mediterranean Journal of Hematology and Infectious Diseases
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