chronic lymphocytic leukemia (CLL)

Introduction

Chronic lymphocytic leukemia & small lymphocytic lymphoma are the same disease, the first predominates in peripheral blood, the second predominates in lymph nodes.

Classification

International Workshop Classification#

• Stage A
• no anemia or thrombocytopenia
• < 3 areas of lymphoid enlargement* [A(0), A(I), or A(II)]
• Stage B
• no anemia or thrombocytopenia
• 3 or more areas of lymphoid enlargement* [B(I), B(II)]
• Stage C
  • anemia (hemoglobin < 10 g/dL) &/or thrombocytopenia, regardless of lymphoid involvement

# diagnosis requires absolute lymphocytosis of > 5000/uL

* spleen, liver, lymph nodes (axillary, inguinal, cervical)

Rai classification:

• Stage 0: peripheral & bone marrow lymphocytosis*
• Stage 1: lymphocytosis & lymphadenopathy
• Stage 2: lymphocytosis & splenomegaly
• Stage 3: lymphocytosis & anemia (hemoglobin < 11 g/dL)
• Stage 4: lymphocytosis & thrombocytopenia

* peripheral lymphocytosis > 15,000/uL bone marrow lymphocytosis > 40%

Epidemiology

• most common form of leukemia in patients > 60 years
• accounts for 30% of all leukemias
• 90% of patients are > 50 years of age
  • median age of diagnosis in 70 years
• more common in men than women
• rare in Asia
• B-cell form NOT associated with exposure to radiation, drugs or chemicals

Pathology

• majority of patients have clonal proliferation of B-cells
• neoplastic lymphocytes express high levels of bcl-2 rendering them resistant to apoptosis
• thrombocytopenia is IgG-mediated
• > 40% lymphocytosis on bone marrow biopsy
• aberrant expression of CD5 (T-cell marker)

Genetics

• trisomy 12 is the most common chromosomal abnormality
  • generally associated with an indolent course
• abnormalities in chromosomes 13 & 14 may also be seen
• chromosomal deletions:
  • 17p deletion associated with poor prognosis
  • 11q deletion associated with better prognosis
  • 17p13 deletion associated with p53 deletion (median survival 3 years)
• defects in ARL11 may be a cause of susceptibility to chronic lymphocytic leukemia
• chromosomal translocation t(X;11)(q21;q23) involving ARHGAP20 with BRWD3 associated with B-cell CLL
• defects in ZAP70 (median survival 3 years)
• other implicated genes TBRG1, CLLU1, ARHGAP27, TRIM13 (possibly)

Clinical manifestations

• many cases asymptomatic on presentation
  • diagnosis incidental identified by lymphocytosis
• lymphadenopathy
  • painless
  • most common reason for presentation
  • may wax & wane
• hepatosplenomegaly, generally painless
• weight loss, fatigue may be noted
• fever with Richter's syndrome
• slowly progressive
• B symptoms (fever, night sweats, weight loss), massive lymphadenopathy & hepatosplenomegaly associated with transformation
• manifestations of an acquired immunodeficiency in a small precentage of patients
  • infections
  • hemolytic anemia, immune thrombocytopenia, pure red cell aplasia (see Laboratory)
  • excessive reaction to insect bites

Diagnostic criteria

• CLL is diagnosed by an absolute increase in mature lymphocytes of > 5000/uL for 3 months & demonstrating clonality of peripheral blood B-lymphocytes by flow cytometry

Laboratory

• complete blood count (CBC) with differential
  • absolute lymphocytosis of > 5000/uL
  • thrombocytopenia (<5%)
  • anemia
• peripheral smear
  • small mature-appearing lymphocytes
  • smudge cells often present
• direct antiglobulin test (positive in 10-30%)
  • associated with poor response to treatment & poor prognosis
• serum albumin & total protein shows hypogammaglobulinemia (50%)
  • IgG in serum
• flow cytometry:
  • B-lymphocyte phenotype: CD19+, CD20+, CD23+, CD5+*
  • blood ZAP70 positive patients have higher rates of clonal evolution
  • next test after peripheral smear
• serum beta-2 microglobulin > 3.5 mg/L associated with poor prognosis (median survival 13 months)
• Ig heavy chain gene rearrangement for clonality & prognosis
• bone marrow biopsy
  • not required for diagnosis
  • useful to distinguish CLL marrow infiltration from ITP
• see ARUP consult

* CD5+ is a T-cell marker

Radiology

• computed tomography (CT):
  • thorax, abdomen, pelvis
  • assess lymph node & visceral involvement
  • not useful for asymptomatic patient

Complications

• increased incidence of solid tumors
  • lung
  • skin (basal cell & squamous cell)
• secondary chemotherapy-induced acute non-lymphocytic leukemia
• transformation into aggressive form of large-cell lymphoma (Richter's syndrome of Richter transformation)
• autoimmune disorders
  • warm autoantibody-mediated hemolytic anemia
  • autoimmune pure red cell aplasia
    • positive direct antibody test (DAT) rules out aplastic anemia*
  • immune thrombocytopenic purpura (ITP)
  • leukocytoclastic vasculitis
• humoral immune dysfunction (hypogammaglobulinemia) with infections due to:
  • Staphylococcus aureus
  • Streptococcus pneumonia
  • Pseudomonas
  • Neisseria meningitidis
  • Haemophilus influenza
  • Klebsiella
  • Pneumocystis
  • cytomegalovirus
  • Candida
  • Herpes simplex
  • Herpes zoster

* given DAT positive in 10-30% of patients with CLL, taken with a 'grain of salt'

Management

• treat fever as infection (Richter's syndrome is exception)
• recurrent infections
  • prophylactic intravenous immune globulin for gamma-globulin levels < 0.3 g/dL
  • raise serum IgG to > 0.6 g/dL
• observe stage 0 or stage A patients
  • do not treat asymptomatic patients with good prognosis regardless of leukocyte count
• criteria for treatment of CLL
  • fever, weight loss, & night sweats
  • symptoms due to lymphadenopathy
  • hepatosplenomegaly
  • worsening cytopenia
  • treat patients with Rai stages III or IV or international workshop stage C
  • patients with poor prognostic features
• ibrutinib for untreated older patients (>=65 years)
  • may be superior to ofatumumab
  • superior to treatment with bendamustine + rituximab
  • ibrutinib + venetoclax may be useful for untreated patients with CLL
  • ibrutinib + rituximib no better than ibrutinib alone
  • may increase risk of infection during first 6 months of treatment
• zanubrutinib (Brukinsa) for untreated older patients (>=65 years)
  • may be superior to bendamustine-rituximab
• acalabrutinib (Calquence) FDA-approved for treatment of CLL
• rituximab-based chemotherapy
  • fludarabine, cyclophosphamide, rituximab yields bestresponse (ibrutinib + rituximib better)
  • pentostatin, cyclophosphamide, rituximab (see PCR regimen)
  • idelalisib in combination with rituximab for treatment failure
  • venetoclax +rituximab may be superior to bendamustine + rituximab
• other chemotherapy regimens
  • chlorambucil with or without prednisone or fludarabine
  • fludarabine is treatment of choice for patients who have relapse after chlorambucil &/or prednisone
  • cladribine
  • alemtuzumab (Campath-1H) treatment of refractory leukemia (B-CLL) {FDA approved 2001}
  • ofatumumab in previously treated CLL
  • obinutuzumab, in combination with chlorambucil, as an option for adults with untreated CLL unable to tolerate full-dose fludarabine-based therapy, only if: bendamustine-based therapy is not suitable (NDG, NICE)
• radiation therapy for localized painful or massive lymph nodes
• splenectomy for persistent cytopenia or symptoms related to splenomegaly
• allogeneic stem cell transplantation is only curative therapy
  • patients < 60 years of age
  • good performance status
  • stage III/IV disease
• thrombocytopenia is treated with glucocorticoids
• restage for aggressive relapse or transformation
• prognosis is dependent on genetic factors
  • course is chronic in 60% of patients
  • median survival time is 5 years from onset of treatment
  • median survival once anemia or thrombocytopenia develops is 18 months
• suitability for elective surgery dependent upon symptoms & performance status
  • asymptomatic patients with good preformance status may proceed to elective surgery

More general terms

• lymphoid leukemia
• chronic leukemia

More specific terms

• B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL)
• prolymphocytic leukemia
• T-cell prolymphocytic leukemia (TPLL)

Additional terms

• apoptosis
• bcl-2 proto-oncogene
• humoral immune dysfunction
• Richter's syndrome; Richter transformation
• small lymphocytic lymphoma

Patient information

chronic lymphocytic leukemia patient information

Database

• OMIM: https://mirror.omim.org/entry/151400