CHRONIC LYMPHOCYTIC LEUKEMIA
Amanda Pressman, M.D.
July 2005
Background
First described in 1924 by Minot and Isaacs, CLL is the most common adult leukemia in North America
and Western Europe. The epidemiology varies widely with geography (higher rates in Western Europe,
lower in East Asia)
Clinical Presentation
Asymptomatic
Diagnosis made when routine CBC demonstrates significant lymphocytosis (25%)
Lymphadenopathy
Generalized or localized lymphadenopathy is the most common finding (50-80%)
Most commonly affect the cervical, supraclavicular and axillary lymph nodes
Typically appear as firm, discrete, nontender, LAD
Hepatomegaly/Splenomegaly
Likely enlarged secondary to leukemic infiltration, is present in 25-50% at presentation
“B” symptoms
Fatigue, nightsweats, fevers, weight loss are present in 10-20%
Labs
Lymphocytosis in most cases, often with smudge cells
Anemia and thrombocytopenia are common
Autoimmune hemolytic anemia and autoimmune thrombocytopenia may be seen
Often elevated LDH, b-2 microglobulin and rarely elevated uric acid, transaminases, Ca
Radiography
Not required to diagnose CLL
CXR may show hilar or mediastinal lymphadenopathy
CT may show enlarged lymph nodes, hepatosplenomegaly, or provide a baseline
Diagnosis
Lymphocytes
Absolute lymphocyte count >10,000/uL (normal <2,500) and sustained for 1-6 months
Peripheral smear with mature-appearing lymphocytes, 50-100% of leukocytes
If absolute lymphocyte count between 5-10,000, phenotyping must be performed
Phenotyping
Malignant B-CLL has the morphologic appearance of normal, small lymphocytes
Reflective of functional and developmental immaturity of lymphocytes
Very low levels of surface membrane immunoglobulin (SmIg)
Expression of B-cell antigens CD19, CD20, CD24
Expression of T-cell associated antigen CD5
Others: CD23, mouse RBC receptors, common CLL-associated antigen
Bone Marrow
Normo to hypercellular bone marrow with at least 30% lymphocytes
May form nodular, interstitial, or diffuse patterns
Chromosomal Abnormalities
No specific pattern for CLL, but may see trisomy 12, 3, or 6, translocations of (11;14),
(q13;q32), (14:18), and deletions in the long arm of 11, 13 and the short arm of 17
Differential Diagnosis
Infection: EBV, pertussis and toxoplasmosis may cause transient lymphocytosis
Small lymphocytic lymphoma: identical disease to CLL but represents a different stage in which
disease is confined to a lymph node due to differences in adhesion molecules
Mantle cell lymphoma: Have irregular or cleaved lymphocyte nuclei and are SmIg (+)
Lymphoplasmacytic lymphoma: Maturation towards plasma cell, my be PCA1 and CD38 (+)
Hairy cell leukemia: Typical morphologic features, CD5 & CD21(-)/CD25, CD11c, CD 103 (+)
Large granular lymphocytic leukemia: Large mononuclear cells, CD3, CD8, CD57 (+)/CD4 (-)
Beth Israel Deaconess Medical Center Interns’ Report
Mycosis fungoides: cerebriform nuclei and CD4 (+) and CD 8(-)leukemic manifestation of
cutaneous T cell lymphoma
Adult T cell lymphoma/leukemia: clover leaf nucleus and often patients have HTLV-1 Ab
Prolymphocytic leukemia: large, less mature lymphocytes, often presenting with massive
splenomegaly and lymphocytosis >100,000/uL. Normal SmIG, CD5 (-) in the B-cell variant.
Staging/Prognosis
Rai Staging System
Low risk: Stage 0 (lymphocytosis)  median survival 150 months
Intermediate risk: Stages I-II (lymphadenopathy, organomegaly)  71-101 months
High risk: Stages III and IV (anemia, thrombocytopenia)  9-24 months
Binet Staging System
Stage A: Fewer than 3 lymphoid sites involved  <120 months
Stage B: 3 or more lymphoid sites involved  60 months
Stage C: Presence of anemia and/or thrombocytopenia  24 months
Treatment
Indications
Rai stages II or IV and Binet stage C
Symptomatic disease (“B” symptoms, bulky lymphadenopathy)
Worsening lymphocytosis and rapid doubling time (<6 months) or Richter’s transformation
Occasionally for autoimmune hemolytic anemia or thrombocytopenia,
Repeated infections
Options
Alkylating agents: chlorambucil or cyclophosphamide with or without prednisone
Purine analogs: fludarabine, cladribine, pentostatin are currently 2 nd line and are still
undergoing study to become 1st line.
BMT: aimed at cure for young patients, but mortality has been high
Immunotherapy: IFN-a an dIL-2 are being investigated
Monoclonal antibodies: rituximab and others are being investigated
Radiation therapy: palliation of bulky lymphoid tissue
Splenectomy: may be indicated in patients with refractory cytopenia
Response
Complete remission
No symptoms, normal physical, absolute lymphocyte count<4,000/uL,
ANC>1,500/uL, platelets>100,000, hemoglobin >11g/dL, bone marrow
lymphocytosis<30% and no nodules on bone marrow biopsy
Partial remission
Decrease in LAD, spleno/hepatomegaly of at least 50% and ANC >=1,500,
platelets >= 100,000, hemoglobin >= 11, or 50% improvement over previous
reduction in hemoglobin or platelet count
Complications
Infection
Largest contributer to morbidity and mortality in patients with CLL
Immunosuppressed state generally secondary to hypogammaglobulinemia (usually all 3
classes: IgG, IgA and IgM), but also affected by hypersplenism and chemotherapy
Most common infections are bacterial, however patients treated with purine analogs are
at risk of developing opportunistic infections and are at risk for fungal and viral
infections as well as TB, listeria, PCP
In patients with repeated infections, periodic IVIG infusion significantly reduces the
incidence of bacterial infections
Malignancy
Transformations
Richter’s transformation: diffuse large cell lymphoma in CLL patients that presents
with abrupt fever, asymmetric LAD, and causes rapid patient decline
Hodgkin’s, ALL
Second malignancies
Non-melanoma skin cancer, sarcoma, kidney, lung
Beth Israel Deaconess Medical Center Interns’ Report