Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 13-30: Chronic Lymphocytic Leukemia + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Most patients are asymptomatic at presentation B-cell lymphocytosis with CD19 expression > 5000/mcL Mature morphologic appearance of lymphocytes Coexpression of CD19, CD5 +++ General Considerations ++ A clonal malignancy of B lymphocytes The course is usually indolent, with slowly progressive accumulation of long-lived small lymphocytes that are immunoincompetent Results in immunosuppression, bone marrow failure, and organ infiltration with lymphocytes Immunodeficiency also related to inadequate antibody production by abnormal B cells In severe disease, may cause damage by direct tissue infiltration Prognostically useful staging system (Rai system) Stage 0, lymphocytosis only Stage I, lymphocytosis plus lymphadenopathy Stage II, organomegaly (spleen, liver) Stage III, anemia Stage IV, thrombocytopenia +++ Demographics ++ Chronic lymphocytic leukemia (CLL) occurs mainly in older patients 90% of cases occur in persons over age 50 Median age at presentation is 70 + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Incidentally discovered lymphocytosis in many patients Fatigue Diffuse lymphadenopathy in 80% Hepatomegaly or splenomegaly in 50% +++ Differential Diagnosis ++ Atypical lymphocytosis due to bacterial or viral infection or pertussis Lymphoma in its leukemic stage, especially mantle cell lymphoma Hairy cell leukemia Waldenström macroglobulinemia Monoclonal B-cell lymphocytosis (MBL) characterized by < 5000/mcL B-cells is considered a precursor to B-CLL + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ White blood cell count is usually > 20,000/mcL (20 × 109/L) and may be markedly elevated to several hundred thousand Differential: usually 75–98% of circulating cells are lymphocytes Hematocrit and platelet count usually normal at presentation On peripheral smear, lymphocytes are usually morphologically indistinguishable from normal small lymphocytes Larger and more immature cells are found in prolymphocytic leukemia (PLL) CLL is diagnosed by coexpression of B-lymphocyte lineage marker CD19 with T-lymphocyte marker CD5 CLL is distinguished from mantle cell lymphoma by Expression of CD23 Low expression of surface immunoglobulin and CD20 Absence of overexpression of cyclin D1 High expression of CD38 or ZAP-70 is correlated with more aggressive course Fluorescence in-situ hybridization (FISH) assesses genomic changes Hypogammaglobulinemia is found in half of CLL patients, becomes more common with advanced disease Serum protein electrophoresis: IgM paraprotein may be present +++ Diagnostic Procedures ++ Bone marrow is variably infiltrated with small lymphocytes Lymph node biopsy shows same pathologic changes as in diffuse small lymphocyte lymphoma + Treatment Download Section PDF Listen +++ +++ Medications ++ Most patients with early stage disease do not require treatment for months or years Initial treatment options include Ibrutinib or venetoclax in combination with anti-CD20 antibody therapy Choice between these agents is based on toxicity as well as preference Ibrutinib A Bruton tyrosine kinase inhibitor targeting B-cell receptor signaling Dose: 420 mg orally daily Can be associated with Hypertension Cardiac arrhythmias Rash Increased infections Use caution when using this agent with Warfarin because of a potential for serious bleeding CYP3A inhibitor or inducers Venetoclax A bcl2 inhibitor resulting in apoptosis Some patients may require hospitalization for initial therapy Dosage: 20 mg orally daily on week 1, then 50 mg orally daily on week 2, then 100 mg orally daily on week 3, etc, slowly titrated up to 400 mg daily Usually given for a shorter course of therapy Can be combined with a monoclonal CD20 antibody, usually obinutuzumab, which can result in infusion reactions Is associated with tumor lysis syndrome and neutropenia Chlorambucil Another treatment option for older adults Dosage: 0.6–1 mg/kg orally every 4 weeks in combination with obinutuzumab For patients with relapsed or refractory disease, Both venetoclax and ibrutinib or acalabrutinib demonstrate significant activity Another option includes idelalisib or duvelisib Idelalisib dosage: 150 mg orally twice a day Duvelisib dosage: 25 mg orally twice a day These PI3k inhibitors are associated with following risks Colitis Liver injury Fatal infectious complications +++ Therapeutic Procedures ++ Indications for treatment (chemotherapy, splenectomy, transplantation, etc) include Progressive fatigue Symptomatic lymphadenopathy Anemia or thrombocytopenia (symptomatic and progressive stage II disease or stage III/IV disease) Allogeneic transplantation is potentially curative, but used only if CLL cannot be controlled by other currently available therapies Nonmyeloablative allogeneic transplant can result in > 40% long-term disease control in CLL at the risk of moderate toxicity + Outcome Download Section PDF Listen +++ +++ Follow-Up ++ Patients undergoing therapy with a nucleoside analog (fludarabine, pentostatin) should receive anti-infective prophylaxis for Pneumocystis jirovecii pneumonia, herpes viruses, and invasive fungal infections until there is evidence of T-cell recovery +++ Complications ++ Autoimmune hemolytic anemia or autoimmune thrombocytopenia may require treatment with rituximab, prednisone, or splenectomy +++ Prognosis ++ Patients with stage 0 or stage I disease have median survival of 10–15 years Patients with stage III or stage IV disease have a 2-year survival of > 90% Biologic markers (eg, gene mutation status, ZAP-70 expression, and cytogenetic abnormalities) are useful in predicting outcomes of subsets of CLL patients Prolymphocytic leukemia, a variant of CLL, often pursues a more aggressive course FISH provides important prognostic information Deletion of chromosome 17p (TP53) confers the worst prognosis Deletion of 11q (ATM) confers an inferior prognosis to the average genotype Isolated deletion of 13q has a more favorable outcome +++ When to Refer ++ All patients with CLL should be referred to a hematologist/oncologist +++ When to Admit ++ Hospitalization is rarely needed + References Download Section PDF Listen +++ + +Aitken MJL et al. Emerging treatment options for patients with p53-pathway-deficient CLL. Ther Adv Hematol. 2019 Dec 5;10:2040620719891356. [PubMed: 31839919] + +Burger JA et al. Evolution of CLL treatment—from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018 Aug;15(8):510–27. [PubMed: 29777163] + +Cuneo A et al. Management of adverse events associated with idelalisib treatment in chronic lymphocytic leukemia and follicular lymphoma: a multidisciplinary position paper. Hematol Oncol. 2019 Feb;37(1):3–14. [PubMed: 30187496] + +Eichhorst B et al. Relapsed disease and aspects of undetectable MRD and treatment discontinuation. Hematology Am Soc Hematol Educ Program. 2019 Dec 6;2019(1):482–9. [PubMed: 31808867] + +von Keudell G et al. The role of PI3K inhibition in lymphoid malignancies. Curr Hematol Malig Rep. 2019 Oct;14(5):405–13. [PubMed: 31359259]