Chronic Lymphocytic Leukemia: Symptoms, Diagnosis, and Treatment
Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia (CLL), also known as small lymphocytic lymphoma (SLL) when it primarily involves the lymph nodes, is a chronic lymphoproliferative malignancy characterized by the accumulation of mature B lymphocytes in the bone marrow, lymphoid tissues, and peripheral blood (Figure 1). CLL accounts for approximately 30% of all leukemias and is the most common leukemia in Western countries. It occurs about twice as often in men as in women, with a peak incidence around 70 years of age, making it predominantly a disease of older adults. Although the exact cause remains unknown, first-degree relatives of affected individuals have a several-fold increased risk of developing CLL, suggesting a genetic predisposition.
Clinical Manifestations
In many patients, CLL is diagnosed incidentally during routine blood testing before symptoms develop. As the disease progresses, patients may experience characteristic B symptoms and manifestations related to lymphocyte accumulation or bone marrow failure.
Common symptoms include:
- Fatigue and generalized weakness.
- Unexplained fever.
- Night sweats.
- Unintentional weight loss.
- Generalized itching (pruritus).
- Enlarged, painless peripheral lymph nodes, particularly in the neck, axillae, or groin.
- Pain or fullness beneath the right or left costal margin due to hepatomegaly or splenomegaly.
- Easy bruising or increased bleeding resulting from thrombocytopenia.
- Recurrent infections caused by impaired immune function.
Diagnosis
CLL should be suspected in patients with persistent absolute lymphocytosis and is confirmed by immunophenotyping together with bone marrow examination when indicated.
Diagnostic findings include:
- Complete blood count (CBC): leukocytosis with persistent absolute lymphocytosis (>5 × 10⁹/L). In advanced disease, lymphocyte counts may exceed 300 × 10⁹/L, while anemia and thrombocytopenia may also be present.
- Peripheral blood smear: lymphocytes typically account for more than 70% of circulating white blood cells, and characteristic smudge cells (basket cells), representing disrupted lymphocytes, are commonly observed (Figure 2).
- Biochemical tests: lactate dehydrogenase (LDH) and uric acid levels may be elevated.
- Flow cytometry (immunophenotyping): confirms the diagnosis by demonstrating the characteristic CLL immunophenotype. Leukemic cells typically express CD19, CD20, CD5 (approximately 95% of cases), CD23, and CD79a, while FMC7, CD79b, and Cyclin D1 are usually negative. These markers help distinguish CLL from acute leukemias and other B-cell lymphomas.
- Bone marrow aspiration and biopsy: typically demonstrate lymphocytic infiltration exceeding 30%.
- Cytogenetic testing: provides important prognostic information. Most patients have detectable chromosomal abnormalities. Common findings include:
- Deletion 13q14 – associated with a more favorable prognosis and longer survival.
- Deletion 11q23 – associated with more advanced disease.
- Deletion 17p13 (TP53 deletion) – associated with aggressive disease, resistance to conventional chemotherapy, and poor prognosis (Table 1).
Following confirmation of the diagnosis, the disease is staged using established clinical staging systems, which are essential for determining prognosis and guiding treatment decisions (Tables 2 and 3).
Table 1. Cytogenetic Findings in Chronic Lymphocytic Leukemia
| Cytogenetic Abnormality | Median Survival (months) |
|---|---|
| 17p deletion | 32 |
| 11q deletion | 79 |
| Trisomy 12 | 114 |
| Normal karyotype | 111 |
| 13q deletion | 133 |
Table 2. Rai Staging System
| Stage | Clinical Features |
|---|---|
| Stage 0 | Lymphocytosis in the peripheral blood and bone marrow without lymphadenopathy. |
| Stage I | Stage 0 criteria plus enlarged lymph nodes. |
| Stage II | Stage I criteria plus hepatomegaly and/or splenomegaly. |
| Stage III | Stage 0–II criteria plus anemia (hemoglobin <110 g/L). |
| Stage IV | Stage 0–III criteria plus thrombocytopenia (platelet count <100 × 10⁹/L). |
Table 3. Binet Staging System
| Stage | Clinical Features |
|---|---|
| A | Lymphocytosis in the peripheral blood and bone marrow, hemoglobin >100 g/L, platelet count >100 × 10⁹/L, involvement of up to two lymph node regions. Median survival: >120 months. |
| B | Same hematological criteria as Stage A, but involvement of more than two lymph node regions. Median survival: 84 months. |
| C | Same criteria as Stage A or B, with hemoglobin <100 g/L and/or platelet count <100 × 10⁹/L, regardless of the number of involved lymph node regions. Median survival: 60 months. |
Course of the Disease
Not all patients diagnosed with chronic lymphocytic leukemia (CLL) require immediate treatment. Patients with mild lymphocytosis, minimal lymphadenopathy, and no significant disease-related symptoms are generally managed using a "watch and wait" approach. These patients are typically reviewed by a hematologist every 3–6 months, undergo clinical assessment and repeat blood tests, and are monitored for signs of disease progression. Clinical studies have demonstrated that initiating treatment at an early stage does not improve overall survival.
- Approximately 30% of patients have an indolent, non-progressive disease throughout their lifetime and never require treatment.
- Approximately 30% of patients require treatment soon after diagnosis because of aggressive disease that may be more difficult to manage.
- Approximately 30% of patients do not initially meet treatment criteria, but their disease gradually progresses over time, eventually requiring therapy.
Indications for Initiating Treatment
Treatment should be considered in patients with evidence of disease progression, including:
- Doubling of the lymphocyte count within less than 6 months.
- Worsening anemia.
- Progressive thrombocytopenia.
- Progressive enlargement of lymph nodes.
- Increasing and symptomatic splenomegaly or hepatomegaly.
- Autoimmune complications.
- Richter transformation, in which CLL transforms into an aggressive lymphoma.
Treatment
Chronic lymphocytic leukemia remains an incurable disease, and treatment is aimed at controlling disease progression and improving patient outcomes.
The main treatment goals are to:
- Prolong progression-free survival.
- Improve the patient's overall well-being and quality of life.
- Suppress the proliferation of malignant lymphocytes.
- Prevent and manage infectious and immune-related complications.
Treatment is individualized according to the patient's overall health, age, comorbidities, social circumstances, and genetic prognostic factors. Depending on the indication, patients may receive chemotherapy, monoclonal antibody immunotherapy, or combination immunochemotherapy (Table 4).
Table 4. Medications Used in the Treatment of Chronic Lymphocytic Leukemia
| Chemotherapy | Glucocorticoids | Monoclonal Antibodies | Immunomodulatory Agents | BTK Inhibitors* |
|---|---|---|---|---|
| Chlorambucil | Prednisolone | Rituximab | Lenalidomide | Ibrutinib |
| Fludarabine | Methylprednisolone | Obinutuzumab | CAL-101† | |
| Cyclophosphamide | Dexamethasone | Alemtuzumab | ||
| Doxorubicin | ||||
| Vincristine |
* BTK – Bruton's tyrosine kinase inhibitors.
† CAL-101 is the former developmental name for idelalisib, a PI3K inhibitor.
Treatment
Chlorambucil is an oral chemotherapy agent that is generally well tolerated and is commonly used as monotherapy. Various treatment schedules are available. Treatment usually lasts 6–12 months, with an overall response rate of up to 75%, although complete remission is achieved in only about 15% of patients. It is primarily prescribed for older patients and those with significant comorbidities.
Fludarabine may be administered either as monotherapy or in combination with other agents, orally or intravenously. Treatment responses are observed in up to 70% of patients, with complete remission achieved in up to 40%. Patients treated with fludarabine should receive irradiated blood products for up to 2 years after completing therapy to reduce the risk of transfusion-associated graft-versus-host disease.
Cyclophosphamide, vincristine, and doxorubicin are generally administered as part of combination chemotherapy regimens rather than as single agents.
Monoclonal antibodies, including rituximab and obinutuzumab (anti-CD20 antibodies) and alemtuzumab (anti-CD52 antibody), are laboratory-produced immune proteins that specifically recognize and destroy malignant lymphocytes expressing the target antigen. Rituximab is routinely combined with chemotherapy. Obinutuzumab is used together with chlorambucil in previously untreated patients with significant comorbidities who are not suitable candidates for fludarabine-based therapy. Alemtuzumab is primarily indicated in patients with 17p deletion or in those with disease that is refractory to standard treatment (Figure 3).
Glucocorticoids are particularly effective in patients with CLL complicated by autoimmune hemolytic anemia or immune thrombocytopenia. In patients without autoimmune complications, they may temporarily control disease activity in approximately 10% of cases. Combination chemotherapy with cyclophosphamide, vincristine, and prednisolone (CVP) produces responses in up to 75% of patients, although complete remissions are uncommon. Currently, the most effective treatment for patients requiring therapy is immunochemotherapy combining rituximab, fludarabine, and cyclophosphamide (FCR), which provides the highest remission rates and significantly prolongs both progression-free and overall survival.
The combination of obinutuzumab and chlorambucil has also been shown to significantly prolong progression-free survival and improve quality of life in patients who are not eligible for fludarabine-based chemotherapy because of comorbidities, as demonstrated in the CLL11 clinical trial.
Bruton's tyrosine kinase (BTK) inhibitors, particularly ibrutinib, are indicated for adult patients with CLL who have received at least one previous line of therapy or as first-line treatment for patients with 17p deletion or TP53 mutation who are not suitable candidates for chemoimmunotherapy.
A small proportion of patients younger than 55 years with rapidly progressive, treatment-resistant CLL and confirmed 17p deletion may be considered for allogeneic hematopoietic stem cell transplantation (allo-HSCT) if a suitable donor is available.
Radiotherapy may be used to reduce symptomatic enlargement of bulky lymph nodes compressing adjacent organs when chemotherapy is ineffective.
Splenectomy may be considered in patients with advanced disease complicated by immune-mediated cytopenias.
Regular follow-up is essential for all patients with CLL, regardless of whether they are receiving treatment. During follow-up visits, patients undergo clinical examination, routine blood tests, lymphocyte count monitoring, and ultrasound assessment of peripheral lymph nodes, spleen, and liver when indicated.
Complications and Recommendations
The most common complications of CLL are infectious complications. Both treated and untreated patients have impaired immune function and are therefore at a substantially higher risk of infections than healthy individuals.
Treatment-related neutropenia is common. Patients with an absolute neutrophil count below 0.5 × 10⁹/L who develop fever should receive urgent inpatient assessment and prompt initiation of antibiotic therapy.
During periods of neutropenia, patients should maintain strict hygiene measures, particularly meticulous oral hygiene, regular antiseptic mouth rinses, and frequent hand washing.
Dietary precautions are also recommended. Patients should consume only thoroughly cooked foods, fresh products, pasteurized dairy products, and carefully washed or peeled fruits and vegetables while avoiding mold-ripened cheeses and other foods that may increase the risk of infection.
Patients are advised to avoid crowded public places, public transportation whenever possible, and close contact with individuals who have viral infections.
Annual influenza vaccination is recommended for all patients with CLL and their household contacts. However, live attenuated vaccines are contraindicated.
Patients who develop symptomatic anemia, after autoimmune hemolytic anemia has been excluded, may require red blood cell transfusions.
Patients with bleeding caused by severe thrombocytopenia, after immune thrombocytopenia has been excluded, may require platelet transfusions.
Patients currently receiving or previously treated with fludarabine should receive irradiated blood components for all transfusions for 2 years following treatment.
Prognosis
The prognosis of patients with chronic lymphocytic leukemia varies considerably and depends on multiple factors, including the patient's overall health, disease stage, molecular and cytogenetic abnormalities, and the presence of comorbid conditions.
Source: Lithuanian Doctor's Journal, No. 2, 2016.
