Chronic Lymphocytic Leukemia

Adam J. Olszewski, M.D.

Basic Information

Definition

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by proliferation and accumulation of mature-appearing neoplastic B-cells.

Synonyms

ICD-10-CM CODES
C91.10	Chronic lymphocytic leukemia of B-cell type not having achieved remission
C91.11	Chronic lymphocytic leukemia of B-cell type in remission
C91.12	Chronic lymphocytic leukemia of B-cell type in relapse

Epidemiology & Demographics

•

Most frequent form of leukemia in Western countries (20,110 new cases and 4660 deaths annually in the U.S.). Incidence rate is 4.7 per 100,000 person-years, increasing to 17 cases per 100,000 at age 65. It is more common in patients with a family history of CLL or other lymphoid malignancy.
•

Generally occurs in older patients: median age at diagnosis in the U.S. is 70 years.
•

Male/female ratio of 2:1.
•

CLL accounts for 1% of all cancers and 11% of all hematologic neoplasms.
•

May be preceded by monoclonal B-cell lymphocytosis—a premalignant, asymptomatic condition with less than 5000 /mm³ CLL-like cells circulating in the blood

Physical Findings & Clinical Presentation

•

At presentation most patients are asymptomatic. Many cases are diagnosed on the basis of incidentally discovered lymphocytosis.
•

Symptoms include fatigue, recurrent infections (pneumonia, herpes zoster), enlarging lymph nodes.
•

B symptoms (fever, weight loss, and drenching night sweats) in 10% of patients at initial presentation.
•

Small diffuse lymphadenopathy and splenomegaly are typical findings on clinical examination, but they are absent in a majority of patients at diagnosis.
•

A minority of CLL patients (∼1%-10%) may develop autoimmune hemolytic anemia or immune thrombocytopenia at diagnosis or during the course of the disease.
•

At a rate of 1% per year, CLL patients may experience a transformation of their disease into an aggressive lymphoma (Richter’s transformation), characterized by a rapidly growing nodal mass, elevated LDH, and constitutional symptoms.

Etiology

Remains largely unknown. Accumulation of genetic defects causing resistance to apoptosis and chronic stimulation of the B-cell receptor by autoantigens or undefined microorganisms have been implicated.

Diagnosis

•

The diagnosis of CLL requires presence of >5000/mm³ clonal B-cells, for >3 months, with a characteristic immunophenotype on flow cytometry, which is essential for diagnosis
•

CLL cells are typically positive for CD5, CD19, CD23 and weakly positive for CD20, while they are negative for CD10, Cyclin D1, and CD103. In some cases, molecular studies for CLL-specific chromosomal alterations (deletion of chromosome 13q, 11q, 17p or trisomy 12) may be helpful.

•

Table 1 describes the evaluation of CLL patients at diagnosis.

TABLE1 Evaluation of Chronic Lymphocytic Leukemia (CLL) Patients at DiagnosisAdapted from Hoffmann R et al: Hematology: basic principles and practice, ed 6, Philadelphia, 2013, Elsevier.

History

B-symptom and fatigue assessment
Infectious history assessment
Occupational assessment for chemical exposure
Familial history of CLL and lymphoproliferative disorders
Preventive interventions for infections and secondary cancers

Physical Exam with attention to lymph nodes, spleen, liver, and Waldeyer’s ring

Laboratory Assessment—Essential

Complete blood count with differential
Morphology assessment of lymphocytes
Kidney and liver function tests, lactate dehydrogenase
Flow cytometry assessment to confirm immunophenotype of CLL
FISH analysis for del 17, del 11q, del 13, and trisomy 12
Hepatitis B screening prior to immunochemotherapy

Selected Tests Under Certain Circumstances

IGVH mutational analysis, CD38 or ZAP-70 expression
TP53 mutation status
Serum immunoglobulins
Serum beta-2-microglobulin levels
Direct antiglobulin test (direct Coombs test), reticulocyte count if anemia present
CT scan of chest, abdomen, and pelvis if there is a clinical concern for symptomatic adenopathy, or prior to chemotherapy
PET scan and/or biopsy if large nodal mass with suspected Richter’s transformation present
Bone marrow aspirate and biopsy if unexplained cytopenias present
Familial counseling if first-degree relative with CLL

Teaching

Varicella zoster identification instruction
Skin cancer identification
Disease education (Leukemia and Lymphoma Society, CLL Topics, ACOR)

Differential Diagnosis

•

Few acute infections with lymphocytosis (mononucleosis, pertussis)
•

Other lymphoproliferative disorders that involve blood (can be distinguished using flow cytometry): follicular lymphoma, mantle cell lymphoma, splenic marginal zone lymphoma, prolymphocytic leukemia, adult T-cell lymphoma/leukemia, hairy cell leukemia.
•

Acute lymphocytic leukemia can be differentiated by presence of lymphoblasts rather than mature lymphocytes
•

Persistent polyclonal B-cell lymphocytosis: a rare, benign condition affecting (predominantly female) middle-aged smokers

Laboratory Tests

•

Complete blood count demonstrates lymphocytosis with mature lymphocytes and characteristic “smudge cells” on the peripheral smear (Fig. 1); anemia and thrombocytopenia may be present in more advanced cases.

FIG.1

Chronic lymphocytic leukemia.

Peripheral blood smear (A–E) typically shows mature lymphocytes slightly larger than the red cells a with small amount of cytoplasm and smudge cells (A). Bone marrow biopsy (F, G) shows hypercellularity with infiltration by the leukemic cells.
•

Bone marrow examination is not indicated in most cases, except when differentiation between autoimmune cytopenias and marrow infiltration by CLL is difficult.
•

Hypogammaglobulinemia and elevated lactate dehydrogenase may be present at the time of diagnosis.

•

Cytogenetic evaluation (using fluorescent in-situ hybridization, FISH) is essential for prognostic assessment and optimal treatment selection (Table 2).

TABLE2 Prognosis of Patients With CLL at the Time of Diagnosis, Stratified by Cytogenetic Risk Group

Cytogenetic alteration	Risk group	Percent of patients (some may overlap)	Median time to first chemotherapy	Median survival
Deletion 13q	Favorable	40%-60%	8 yr	11 yr
None	Intermediate	<20%	4 yr	9 yr
Trisomy 12	Intermediate	15%-30%	3 yr	9 yr
Deletion 11q	High	15%-20%	1 yr	7 yr
Deletion 17p	Ultra-high	∼10%	<1 yr	3 yr

•

Other prognostic markers include: mutational status of the immunoglobulin heavy chain variable region (IGHV, unmutated gene with >98% homology indicates poor prognosis), presence of CD38 or ZAP-70 (also associated with poor prognosis). Additional mutation analysis is gaining importance for identifying patients with worse prognosis (mutations in TP53, NOTCH1, SF3B1, and BIRC3 genes).

Staging

Staging reflects the clinical burden of disease and aids assessment of prognosis and treatment decision making. The historical staging systems by Rai and Binet remain in clinical use. They use only physical examination and the CBC (i.e., no scans). The modified Rai system distinguishes three risk groups:

•

Low risk (lymphocytosis alone, or Stage 0)
•

Intermediate risk (presence of lymphadenopathy, hepatomegaly or splenomegaly, formerly Stage I/II)
•

High risk (presence of anemia with hemoglobin <11 g/dL, or thrombocytopenia with platelet count <100,000/mm³, formerly stage III/IV).

The Binet system divides CLL into three stages:

•

Stage A: involvement of <3 nodal areas (counting separately cervical, axillary, or inguinal lymph nodes, spleen, and liver).
•

Stage B: three or more areas involved.
•

Stage C: presence of anemia (hemoglobin <10 g/dl) or thrombocytopenia (<100,000/mm³), independent of the areas involved.

Prognosis in CLL can be determined using the CLL-International Prognostic Index (CLL-IPI), which includes five factors: 17p/TP53 status, IGVH mutational status, serum beta-2-microglobulin, Rai/Binet stage (0/A vs. I-IV/B-C), and age >65 years. Overall 5-year survival varies from 93% for the low-risk group to 23% for the very high-risk group.

Imaging Studies

Imaging studies (CT or PET/CT scans) are not necessary for asymptomatic patients at diagnosis. They are obtained in case of clinical concerns for bulky internal adenopathy, Richter’s transformation, or prior to starting chemotherapy.

Treatment

•

At present, there is no standard curative therapy for CLL, so treatment is only instituted for progressive or symptomatic disease with a goal of symptom relief and prolongation of life.
•

“Watchful waiting” (i.e., observation without therapy) is the optimal strategy for all early-stage, asymptomatic patients outside of clinical trials because early chemotherapy provides no survival or quality-of-life benefit.
•

Immunochemotherapy is the standard of care for patients with symptoms related to disease, bulky adenopathy, rapidly increasing lymphocyte count, or progressive cytopenias (except for autoimmune cytopenias, which can be treated without chemotherapy).

Acute General Rx

•

The initial chemotherapy is chosen depending on the patient’s age, comorbidities, and CLL cytogenetics (Fig. 2).

FIG.2

Treatment approach in chronic lymphocytic leukemia.

Courtesy of ADAM J. OLSZEWSKI, M.D.
•

The combination of fludarabine, cyclophosphamide, and rituximab is considered the most active immunochemotherapy regimen; it results in complete remission in 72% of patients, while about 30% remain in remission after 12 years of follow-up. It is considered a standard of care for fit patients younger than 65 years and without TP53 abnormalities.
•

For older patients, several treatment options are supported by randomized controlled trials: combinations of rituximab with bendamustine, chlorambucil with obinutuzumab or ofatumumab, or oral ibrutinib as a single agent. The choice largely depends on the patient’s baseline comorbidities and personal preferences. With these regimens, a majority (>80%) of patients achieve at least a partial remission, with median progression-free survival of about 2 to 4 years.
•

CLL with deletion 17p or TP53 mutation does not respond well to standard immunochemotherapy, and alternative agents (B-cell receptor complex inhibitors ibrutinib or idelalisib, anti-CD52 monoclonal antibody alemtuzumab) are recommended. Venetoclax, an oral selective BCL-2 inhibitor, has been FDA-approved for treatment of CLL in patients with 17p deletion who have received at least one prior therapy.
•
Recurrent CLL is often characterized by acquired deletion or mutation of the TP53 gene and can also be treated with a variety of salvage regimens:
1. –
  
  B-cell receptor signaling inhibitors: ibrutinib and idelalisib. These oral agents are characterized by high rate of durable responses, occasional persistent lymphocytosis, and extremely high cost of therapy, which is usually long-term.
2. –
  
  Venetoclax, an oral BCL2 inhibitor, is characterized by a high response rate (79%) and risk of tumor lysis.
3. –
  
  Anti-CD20 monoclonal antibodies: ofatumumab, obinutuzumab, rituximab, alone or in combination with chemotherapy: purine analogues (fludarabine, pentostatin); alkylating agents (bendamustine, cyclophosphamide, CHOP-like combinations)
4. –
  
  Alemtuzumab (anti-CD52 monoclonal antibody)
5. –
  
  High-dose methylprednisolone
6. –
  
  Lenalidomide (an oral immunomodulatory drug)
7. –
  
  Palliative radiation therapy to bulky lymph nodes or spleen.
•

Allogeneic bone marrow transplantation can be used for younger patients with recurrent, refractory, or ultra-high cytogenetic risk disease, but is associated with high rates of transplant-related mortality

Chronic Rx

Treatment of systemic complications:

•

Tumor lysis syndrome may occur during initial or subsequent chemotherapy but is extremely unlikely without chemotherapy in CLL, even with high lymphocyte counts.
•

CLL patients are at increased risk of solid tumors and should adhere to age-appropriate screening modalities; skin cancers, including melanoma, are particularly common.
•

Hypogammaglobulinemia is frequent in CLL and may cause recurrent infections, particularly pneumonias. Immunoglobulin supplementation (250 mg/kg IV every 4 wk) may prevent infections but has no effect on the course of CLL.
•

Patients after chemoimmunotherapy are at risk for, and often ultimately succumb to, opportunistic infections. Herpes zoster and Pneumocystis jiroveci prophylaxis is used during and after some chemoimmunotherapy regimens.
•

Novel targeted agents are associated with specific adverse effects. Ibrutinib may cause atrial fibrillation, chronic diarrhea, and hemorrhage and must be held before surgical procedures. Idelalisib may cause severe hepatitis and pneumonitis.
•

Autoimmune hemolytic anemia, thrombocytopenia, and (rare) neutropenia may be treated with steroids, immunoglobulin, or immune suppression without cytotoxic chemotherapy
•

CLL is a contraindication to administration of live vaccines (varicella zoster, mumps/measles/rubella, yellow fever, intranasal influenza). Patients should adhere to the recommended schedule of immunization against Pneumococcus and influenza.

Disposition

Most patients die due to infectious complications of therapy for refractory disease after several lines of treatment. Histologic transformation to an aggressive lymphoma is also associated with high mortality. Palliative treatment should be offered to patients who are no longer benefiting from aggressive therapy to avoid pervasive and futile treatment with distressing complications.

Ferri – Chronic Lymphocytic Leukemia