Autoimmune Cytopenias in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL): The Clinical Implications of Earlier Diagnosis and Longer Follow-Up.
Authors: Zent Clive S. , Slager Susan L. , Ding Wei , Giordano Karin F. , Schwager Susan M. , Hoyer James D. , Call Timothy G. , Shanafelt Tait D. , Kay Neil E. 
Published: October 2019

Abstract
Patients with CLL complicated by autoimmune diseases causing cytopenias (AID) are often considered to have clinically advanced disease (Rai stage III - IV, Binet C). With the use of automatic differential counts and flow cytometric immunophenotyping of peripheral blood, CLL is now most often diagnosed in asymptomatic patients with early stage disease. These changes in clinical practice could have an impact on clinical presentation and prognosis of CLL patients with AID. To more fully define AID complicating CLL, we conducted an observational study of a large cohort of CLL patients.
Methods All 1737 patients with chronic B cell lymphoproliferative diseases seen in the Division of Hematology at Mayo Clinic Rochester from January 1, 1995 to December 30, 2004 were included. Lymphoid malignancies were classified using WHO and modified NC-WG 1996 criteria (CLL = 1649, “atypical” CLL = 4, leukemic phase of lymphoma = 9, chronic B cell lymphoproliferative disorders (not otherwise classified) = 75). Autoimmune hemolytic anemia (AIHA) was defined as a Hgb ≤ 10 g/dL with at least one appropriate marker of hemolysis (elevated indirect bilirubin, LDH, or reticulocyte count; or increased bone marrow erythropoiesis without bleeding) and evidence of an autoimmune mechanism (positive DAT, cold agglutinins), or at least 2 markers of hemolysis in absence of evidence of bleeding or hypersplenism. Immune thrombocytopenia (ITP) was defined as a platelet count of ≤100 x 109/L with normal/ increased bone marrow (BM) megakaryocytes or normal/increased absolute reticulocyte count. Pure red blood cell aplasia (PRBCA) was defined as a Hgb ≤ 10 g/dL, reticulocytopenia, and an isolated absence of BM erythrocyte precursors. Autoimmune granulocytopenia (AIG) was defined as sustained neutropenia (< 0.5 x 109/l) in the absence of chemotherapy for at least 8 weeks and with decreased/absent BM granulocyte precursors.
Results Seventy four (4.5%) CLL patients had AID (78% male, median age at diagnosis 67 yr). The diagnosis of AID preceded CLL in 12% and was concomitant with the diagnosis of CLL in 15% of patients. Of the CLL patients with AID, 55% had AIHA, 47% ITP, 10% PRBCA and 4% AIG; 10% had coincident AIHA and ITP (Evans syndrome). Most AIHA (74%) patients presented with symptomatic anemia but 68% of the ITP patients were asymptomatic at diagnosis. Forty one patients (55%) developed AID prior to receiving any treatment for CLL. Only 9 of the 33 patients who developed AID after treatment for CLL had received purine analogues. Eighteen (24%) patients with CLL and AID died; the estimated median survival was 12.4 yr.
Discussion In this CLL population with predominantly early stage disease at diagnosis (> 60% Rai stage 0), AID is clinically distinct from that previously reported in patients with more advanced disease. A higher proportion of patients had ITP which was usually asymptomatic. Most patients with AID had not previously required therapy for CLL. Purine analogue therapy did not appear to be a major cause of AID in this population. Overall survival was considerably more favorable than that previously reported with CLL induced bone marrow failure (Rai stage III-IV, Binet C). We conclude that the earlier diagnosis and subsequently longer follow up of patients with CLL has altered the clinical presentation and prognostic consequences of AID. A more detailed analysis of the correlation between novel prognostic risk factors and the risk of AID in CLL patients is planned.