Chronic lymphocytic leukemia is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. It is the most common adult leukemia in Western populations.
Chronic lymphocytic leukemia (CLL) is reported to have a genetic basis and is known to run in families (familial CLL). The age at diagnosis of the second-generation offspring is nearly 20 years younger as compared to the parent. Moreover, 17% of first-degree family members of patients with CLL had monoclonal B cell lymphocytosis, which is a precursor of CLL.
CLL comprises 25% to 30% of all leukemias in the United States. The disease has a slightly higher incidence in male populations as compared to female populations (1.3:1). However, studies have shown that women can have a more aggressive form of the disease as compared to men. It can affect adults as young as 30 years of age. However, the median age at diagnosis is 70 years. It has a racial predisposition and is most common in whites and least common in Asians. The incidence in African Americans is intermediate between the two.
CLL is a monoclonal expansion of B cells. In all patients, it is preceded by an oligoclonal expansion of B cells termed monoclonal B-cell lymphocytosis. It is said to have a genetic basis, and certain genetic polymorphisms are known to predispose individuals to develop CLL.
Classical smudge cells are seen on peripheral blood smear; these are pathognomic of CLL. On peripheral blood flow cytometry, immunophenotypic analysis of the peripheral circulating lymphocytes can be performed which can help to diagnose CLL. The presence of B-cell antigens such as CD19, weak CD20 and CD23, T-cell antigen CD5 and low levels of surface membrane immunoglobulins which is usually IgM or both IgM and IgD and only one type of light chain suggesting the monoclonality of the lymphocytes. However, in some cases, biclonal CLL, expressing both light chains or different levels of expression of other immunophenotypic antigens, is also seen.
The presentation of CLL can range from asymptomatic to more severe complications due to the disease. Patients may be diagnosed after they are found to have incidental lymphocytosis on a complete blood count (CBC) done for an unrelated condition. Some patients may notice non-tender swelling of lymph nodes, particularly in the cervical region. The swelling comes and goes. Only 5% to 10% of patients present with the B symptoms of fever, weight loss, night sweats, and fatigue.
Some other presenting symptoms include hypersensitivity to insect bites, autoimmune hemolytic anemias, and recurrent infections.
The most common physical examination finding is lymphadenopathy. It could be localized or generalized and is firm, non-tender, and mobile when palpated.
Splenomegaly and hepatomegaly are other signs for which to look.
Skin examination is an important part of physical examination because skin cancers are a relatively frequent complication of CLL. Sometimes CLL cells infiltrate the skin resulting in a condition called leukemia cutis which can manifest as plaques, papules, nodules, among others.
The first step in evaluation is to perform a CBC which demonstrates lymphocytosis. There could be some degree of anemia and thrombocytopenia depending on the stage of the disease.
A CT scan helps in evaluation to see the degree of lymphadenopathy and organ infiltration in the form of spleen and liver sizes.
As per Rai’s staging:
Bone marrow aspiration and biopsy, though not needed for diagnosis often are done as a part of a diagnostic workup or before treatment. These show more than 30% involvement by CLL cells for diagnosis of the disease. Reduction of lymphocytic infiltration to less than 30% on treatment indicates a complete response.
Flow cytometry can be performed on both peripheral blood and bone marrow aspirate to look for the classical immunophenotypic markers of CLL.
Lab studies which are of importance include serum lactate dehydrogenase (LDH) and beta-2 microglobulin (read with creatinine because it can normally be elevated in patients with elevated creatinine) which correlate with disease activity.
Serum immunoglobulins and free-light chains are also measured at baseline to look at immune deficiency and on treatment to look at immune reconstitution especially with the newer generation B-cell receptor signaling drugs.
Given that most patients with CLL are asymptomatic, treatment is not recommended for everyone. The recommendation for treatment depends on severe disease symptoms or rapidly progressing disease. Symptoms such as severe fatigue interfering with daily activities, B-symptoms, recurrent infections, or increased tumor burden are an indication for early treatment. Rapidly progressing disease such as an absolute lymphocyte count doubling time of fewer than 12 months is also an indication for early treatment.
For patients who are not considered for treatment, regular follow-up at 3-month intervals is recommended. At the 12-month mark, depending on the symptoms and pace of disease, a decision whether treatment is needed can be made.
Symptomatic CLL is treated and despite many recent advances, remains to be an incurable disease.
For those patients for whom treatment is considered, a pre-treatment assessment should be done including gather information about age and general health, other features such as Tp53 abnormalities or adverse cytogenetics, relapsed disease, or treatment-naive status. There haven’t been studies comparing different treatment modalities, and an individual approach needs to be considered.
In patients younger than 70 years, fludarabine-based regimens are not recommended due to increased side effects. Single-agent ibrutinib is the most popular treatment in this age bracket. Drugs such as chlorambucil and CD20 antibodies can be added for patients with contraindications to ibrutinib such as bleeding tendencies or atrial fibrillation.
Those with a very aggressive form of the disease, such as patients with 17p deletion, especially in younger patients, HLA-matched donors should be recommended to get bone marrow transplant. Those without a matched donor or older in age can be given a trial of ibrutinib.
It is important to differentiate CLL from other causes of lymphocytosis including other B-cell disorders which can present similarly.
Reactive lymphocytosis: Certain infections can present with lymphocytoses such as pertussis and infectious mononucleosis. However, unlike CLL it is transient and is not monoclonal.
Monoclonal B-cell lymphocytosis (MBL): MBL is a condition which precedes CLL. It is characterized by a lymphocyte count of fewer than five times 10L. All cases of CLL are preceded by MBL, but all cases of MBL might not progress to CLL.
Other B cell disorders: Mantle cell lymphoma, splenic marginal zone lymphoma, follicular lymphoma, hairy cell leukemia. Even though these disorders can mimic CLL clinically, careful look at the immunophenotypic markers, morphology or specific genetic abnormalities such as translocation t(14;18) for follicular lymphoma, can lead us to the diagnosis.