CLL Chronic Lymphocytic Leukemia Pathophysiology Chronic lymphocytic leukemia (CLL) is diagnosed in approximately 7% of new Non-Hodgkin’s Lymphoma (NHL) cases1. The signs and symptoms of CLL often go unnoticed until disease progression, and include lethargy, night sweats, decreased appetite, infection prone status, swollen lymph nodes, hepatomegaly and splenomegaly. Anemia, leukopenia, and thrombocytopenia are signs of advanced CLL2. The leukemic cells in CLL are often dispersed among larger or atypical cells that accumulate as the disease progresses1. Immunophenotyping is necessary for the for the diagnosis and prognostic evaluation of CLL, whereas immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are methods used to evaluate chromosomal changes.1,3 The surface proteins evaluated by flow cytometry include CD3, CD5, CD10, CD20, CD23 and cyclin D1 (the later used to rule out a diagnosis of mantle cell lymphoma MLL). The FISH test evaluates for abnormal chromosomes and genes (located on chromosomes 11, 12, 13, and 17).Relapsed CLL is defined as a patient who has previously achieved complete response or partial response, but after a period of 6 or more months, demonstrates evidence of disease progression.7 Refractory CLL is defined as treatment failure (stable disease, nonresponse, progressive disease, or death from any cause) within 6 months to the last antileukemic therapy. 7 Targeted therapies are important in this patient cohort as advances in treatments provide more efficient methods of treating refractory/relapsed CLL. The goal of treatment for this cohort of patients echoes those for patients receiving an initial diagnosis: to slow the growth of CLL cells, to prolong remission, improve patient quality of life, and survival, and to manage symptoms2.3. Table 1. Prognostic Factors for CLL1 Table 2. Response Criteria for CLL1 Table 3. Differential Diagnosis CLL vs SLL1 References and Additional Reading: NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. Version 5.2018. March 26, 2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf American Cancer Society. Signs and Symptoms of Chronic Lymphocytic Leukemia. Available at: https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/detection-diagnosis-staging/signs-symptoms.html Leukemia & Lymphoma Society. Chronic Lymphocytic Leukemia. Revised 2014. Available at: https://www.lls.org/sites/default/files/file_assets/cll.pdf Shi Y, Li X, Lai Y, Jia L. CD21 and CD23 expression differences in small B-cell lymphomas: comparative analysis in follicular dendritic cells and tumor cells. Int J Clin Exp Pathol. 2016;9(8):8395-8405. Guo A, Lu P, Galanina N, et al. Heightened BTK-dependent cell proliferation in unmuted chronic lymphocytic leukemia confers increased sensitivity to ibrutinib. Oncotarget. 2015 Vol 7, No 4. Hampel PJ, King RL, Hanson CA, et al. Liver biopsy in Patients with Chronic Lymphocytic Leukemia: Indications and Pathological Findings. Blood. 2016 128:5592 Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456. doi:10.1182/blood-2007-06-093906.