Chronic Lymphocytic Leukemia (CLL)

Definition, Etiology, PathogenesisTop

Chronic lymphocytic leukemia (CLL) is a neoplasm originating from morphologically mature B cells present in peripheral blood, bone marrow, lymphatic tissue, and other organs. Etiology is unknown. CLL is the most common type of leukemia.

Clinical Features and Natural HistoryTop

The large majority of patients are asymptomatic at diagnosis, as most patients are diagnosed after observing asymptomatic lymphocytosis on complete blood count (CBC).

1. Symptoms: Constitutional symptoms (present in 5%-10% of patients; the first 3 are so-called B symptoms): At least 10% weight loss over the previous 6 months, fever (>38 degrees Celsius) persisting ≥2 weeks (with no infection), drenching night sweating for >2 weeks (with no infection), marked fatigue (≥2 in Eastern Cooperative Oncology Group [ECOG] performance status [available at ecog-acrin.org]), a subjective feeling of abdominal distention and abdominal pain (manifestations of splenomegaly).

2. Signs: Lymphadenopathy; enlargement of the spleen, rarely of the liver or other lymphatic organs (Waldeyer ring, tonsils); very rarely involvement of extralymphatic organs (most frequently skin).

3. Complications: Infections, autoimmune cytopenia (in particular autoimmune hemolytic anemia or immune thrombocytopenia), acquired immunodeficiency states.

4. Natural history: The course of CLL may be predicted on the basis of the Rai staging system (Table 1) or the Binet staging system (Table 2). Other prognostic features include the lymphocyte doubling time; biochemical (including lactate dehydrogenase), cytogenetic, and molecular markers; IGHV mutation status; CD38 and ZAP-70 expression. In <10% of patients, CLL undergoes transformation to a more aggressive lymphoma (Richter syndrome). CLL and small lymphocytic lymphoma fall on a spectrum and may be indistinguishable in some patients.Evidence 1High Quality of Evidence (high confidence that we know true effects of the intervention). Rawstron AC, Bennett FL, O'Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008 Aug 7;359(6):575-83. doi: 10.1056/NEJMoa075290. PubMed PMID: 18687638. Shanafelt TD, Kay NE, Rabe KG, et al. Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol. 2009 Aug 20;27(24):3959-63. doi: 10.1200/JCO.2008.21.2704. PubMed PMID: 19620484; PubMed Central PMCID: PMC2734397.

DiagnosisTop

Diagnostic Tests

1. CBC: Lymphocytosis (>5×109/L) with predominant small, morphologically mature lymphocytes as well as anemia and thrombocytopenia (in patients with advanced disease this is due to the suppression of normal hematopoiesis by a leukemic clone; at every stage of the disease cytopenias may also be autoimmune). Peripheral blood smear may show characteristic “smudge cells.”

2. Immunophenotyping (peripheral blood or bone marrow) is used to establish diagnosis and for prognosis evaluation. It reveals clonality (kappa or lambda light chain restriction) and characteristic coexpression of B-cell antigens (CD19, CD22, CD23) and a T-cell antigen (CD5).

3. Cytogenetic (fluorescent in situ hybridization in peripheral blood) and molecular studies: No single cytogenetic abnormality is typical for CLL. The most frequent abnormalities of prognostic value are del(13q), trisomy 12, del(11q), del(17p), and TP53 mutations; del(17p) and TP53 mutations are associated with poor prognosis.

4. Other laboratory studies: Positive direct antiglobulin test results (Coombs test; in 35% of patients), hypogammaglobulinemia.

Diagnostic Criteria

1. Peripheral blood lymphocytosis ≥5×109/L with a predominant population of morphologically mature small lymphocytes.

2. Clonal nature of the circulating B cells documented by a characteristic immunophenotype observed by flow cytometry.

Differential Diagnosis

Monoclonal B-cell lymphocytosis (this is associated with the presence of a clone of lymphocytes with the phenotype characteristic for CLL, cell counts <5×109/L, and no clinical symptoms or signs; the annual risk of progression to CLL is 1%-2%), prolymphocytic leukemia, hairy cell leukemia, large granular cell leukemia, mantle cell lymphoma, follicular lymphoma, Waldenström macroglobulinemia.

TreatmentTop

1. Indications to start treatment:

1) Significant constitutional symptoms.

2) Significant anemia or thrombocytopenia caused by bone marrow involvement.

3) Massive, progressive, or symptomatic lymphadenopathy, or massive, progressive, or symptomatic spleen enlargement.

4) Very high lymphocyte counts (usually >500×109/L) causing symptoms of leukostasis, or rapidly progressive lymphocytosis (>50% increase over 2 months, or lymphocyte doubling time <6 months in patients with initial lymphocyte counts >30×109/L).

5) Autoimmune cytopenias refractory to initial treatment with glucocorticoids.

In patients who do not require treatment, follow-up visits are recommended every 3 to 12 months (physical examination, CBC).

2. First-line treatment: CLL is a disease of active research interest with rapid advances being made in therapy. Treatment should be provided in expert clinical centers. There may be significant differences in available therapy between centers, jurisdictions, and countries.

1) The choice of first-line treatment is guided by prognostic features of the disease and the patient’s fitness.

a) For patients with del(17p), first-line therapy with a targeted agent (such as ibrutinib, acalabrutinib, or venetoclax) is preferred.

b) For patients without IGHV mutation, first-line therapy with targeted agents (such as ibrutinib, acalabrutinib, or venetoclax) is preferred.

c) For patients with standard-risk disease, either chemoimmunotherapy (ie, fludarabine, cyclophosphamide, and rituximab) or targeted agents can be considered.

2) Chlorambucil in combination with an anti-CD20 antibody (rituximab, obinutuzumab) or ibrutinib, or acalabrutinib, or venetoclax plus obinutuzumab are recommended in elderly patients or patients with comorbidities.

3) In patients with del(17p) or TP53 mutation: Ibrutinib or acalabrutinib, or venetoclax with or without obinutuzumab, or idelalisib plus rituximab.

3. Management of patients with relapse or failure of the first-line treatment: Use an alternate agent not used in the first line. Allogeneic stem cell transplant may be considered in selected cases following failure of several lines or therapy or earlier in patients with high-risk disease.

4. Patients with purine analogue resistance, del(17p), or Richter transformation: Reduced-intensity allogeneic HSCT for transplant-eligible patients. In patients with Richter transformation, multiagent chemotherapy is required (eg, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] as in diffuse large B-cell lymphoma), and autologous HSCT may be preferred.

5. Prevention of infections: Influenza and pneumococcal vaccination. Oral acyclovir (INN aciclovir) 400 to 800 mg bid and trimethoprim/sulfamethoxazole 160 mg/800 mg daily 3 times a week in patients treated with purine analogues and alemtuzumab. In patients with hypogammaglobulinemia (<500 mg/dL) and recurrent respiratory tract infections requiring intravenous antimicrobial therapy and/or hospitalization, consider intravenous immunoglobulin (IVIG).

6. Treatment of autoimmune cytopenia: Glucocorticoids. Second-line treatments include rituximab, IVIG, and immunosuppressive agents. If there is no response, definitive treatment of the underlying CLL is required.

Prognosis in Patients Requiring TreatmentTop

Treatment with purine analogues combined with cyclophosphamide and rituximab results in the highest remission rates and longest progression-free survival rates. The most frequent causes of death are infections, and many older patients die “with” the disease rather than “from” it. In younger patients (who are not expected to die of other disease), 10-year survival is >80%. The risk of developing another malignancy (solid tumors or hematologic diseases) is 2-fold to 7-fold higher than in the general population.

TablesTop