Chronic Lymphocytic Leukemia (CLL)

· Classified as a B-cell neoplasm by WHO criteria

Epidemiology:

· most common form of leukemia in adults in the western world

· median age of onset is 70 yrs (>80% of cases occur in persons over age 60)

· no clear associated exposure risk factors

· 5 year survival is approx 75%

Clinical presentation:

· >50% of patients are asymptomatic at the time of diagnosis (based on peripheral blood leukocytosis)

· Constitutional symptoms are present in up to 15% of patients, and can include night sweats, weight loss and fatigue (fever less common)

· Most common exam findings include lymphadenopathy, splenomegaly or hepatomegaly

Diagnosis

· By peripheral blood flow cytometry expressing the characteristic B-cell immunophenotype

· BM biopsy no longer required for diagnosis

2 main staging systems: Rai and Binet
Rai is based on the belief that CLL progresses but at varied paces
lymphocytosis->lymphadenopathy->organomegaly-> anemia/thrombocytopenia
   * Stage 0 (lymphocytosis) — 25 percent
   * Stages I to II (lymphadenopathy, organomegaly) — 50 percent
   * Stages III to IV (anemia, thrombocytopenia) — 25 percent

Prognosis

· Certain gene mutations are associated with a poorer prognosis: 17p-, 11q-, IgVH unmutated

· Other risk factors include short doubling time of lymphocyte count, cytologic atypia, increased B2 microglobulin levels

Survival by Rai Stage:
   * Stage 0 — 150 months
   * Stage I — 101 months
   * Stage II — 71 months
   * Stages III and IV — 19 months

Treatment

Criteria for initiating treatment are B symptoms (F, weight loss, night sweats), symptoms due to LN enlargement, hepatosplenomegaly or worsening cytopenias
No treatment other than HSCT has curative potential (not generally offered unless a particularly young patient)
Chemotherapy is generally with purine-based regimens (better than alkylating agents); best response rates have been achieved with FCR (fludarabine, cyclophosphamide and rituximab)
alemtuzumab, a humanized anti-CD52 monoclonal antibody has been shown to induce clinical remission in pts with CLL, but is associated with high rates of infection and neutropenia (see below); approved for use in refractory patients

Complications:

Infections are a common complication in CLL and are the most likely cause of death in these patients:

patients often have hypogammaglobulinemia, which predisposes them to bacterial infections, esp with encapsulated organisms.
Neutropenia is also a common complication due to BM crowding/lymphocytosis
T-cell dysfunction also occurs due to abnormal costimulation by B-cells. Predisposed to viral, fungal, mycobacterial infections etc.
IVIG has been shown to decrease the incidence of infection in patients with recurrent infections, but has not been shown to affect mortality

Chemotherapeutic agents (in addition to disease itself) cause a host of opportunistic infections
Hemolytic anemia occurs in up to 30% of patients
ITP can also occur (distinct from thrombocytopenia due to BM infiltration)
Secondary malignancies are more common in pts with CLL: Kaposi sarcoma, melanoma, head and neck cancer, lung cancers and brain cancer
Malignant transformation can occur, either into a more aggressive prolymphocytic leukemia (PLL) or a large cell lymphoma (Richter’s syndrome). AML or MDS are rare complications

See link below for a review of CLL diagnosis and treatment in Mayo Clinic Proceedings ’06:

http://www.mayoclinicproceedings.com.laneproxy.stanford.edu/content/81/8/1105.long

(Ellen Eaton MD, 10/28/10)

(Victoria Kelly MD, 5/14/11)