Chronic lymphocytic leukemia is characterized by the clonal proliferation and accumulation of small, mature-appearing CD5-positive B lymphocytes in the blood, bone marrow, and secondary lymphoid tissues. A CLL diagnosis is established by the presence of more than 5x109/L peripheral lymphocytes co-expressing CD5, CD19, and CD23, and weakly expressing CD20, CD79b, and surface immunoglobulin. Small lymphocytic lymphoma represents a clinical variant of CLL and is similarly managed.
Chronic lymphocytic leukemia (CLL) is characterized by the clonal proliferation and accumulation of small, mature-appearing CD5-positive B lymphocytes in the blood, bone marrow, and secondary lymphoid tissues.1A CLL diagnosis is established by the presence of more than 5x109/L peripheral lymphocytes co-expressing CD5, CD19, and CD23, and weakly expressing CD20, CD79b, and surface immunoglobulin.2Small lymphocytic lymphoma (SLL) represents a clinical variant of CLL and is similarly managed.3
CLL is the most common adult leukemia in Western countries. Its incidence increases with age; its prevalence and mortality in Western countries will continue to rise. Improved diagnostic methods and frequent blood testing has also led to increasing identification of early-stage CLL among younger patients.2,4Approximately 10% to 15% of patients with CLL are younger than 55 years.2,4
Recent years have seen major advances in diagnostic approaches in CLL.1With the development of novel treatment approaches, the significance of prognostic markers is shifting.
Epidemiology and Risk Factors
The incidence of CLL varies between geographic locations and is lower in Eastern Asian populations.1With an age-adjusted incidence of approximately 4 per 100,000 inhabitants in Europe and the United States, CLL is the most common adult leukemia in Western countries.2In the United States, CLL accounts for approximately one-third of all annual new leukemia diagnoses.5,6According to estimates based on the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database, CLL is most frequent in white populations in the United States, followed by African Americans.1,7Rates are lower among Hispanic Americans, Indigenous Americans, and individuals of Asian or Pacific Island descent.1,7
The risk for CLL increases with age.6More than 70% of patients are older than 65 years at diagnosis, the median age at diagnosis is 72 years, and the incidence rate increases to >30:100,000/year at an age of more than 80 years.2Men are at an approximately 2-fold higher risk for developing CLL than women (male:female ratio of 1.9).5Genetic contributions to CLL susceptibility have also been established.8,9
Evolving Methods of CLL Diagnosis
Many patients with CLL are asymptomatic, and diagnosis follows the detection of lymphocytosis in a routine complete blood count (CBC), ie, above the normal adult upper limit of approximately 3500 cells per μL, typically ≥10,000 cells per μL.1Disease symptoms may include fatigue, involuntary weight loss, excessive night sweats, abdominal fullness with early satiety, increased frequency of infections, symptoms of an autoimmune cytopenia, enlarged lymph nodes, hepatomegaly, and splenomegaly.1
Essential components of the CLL diagnosis include blood immunophenotyping by flow cytometry and fluorescence in situ hybridization (FISH), lymph node biopsy, and absolute B monoclonal B lymphocyte counts.3The initial workup should include a physical exam with palpation of node-bearing areas, determination of liver and spleen size, performance status, CBC, differential blood counts, platelets, and a metabolic panel.3Immunophenotyping by flow cytometry is required to establish CLL diagnosis based on cell identity, clonality, and quantity.2,3Flow cytometric analysis for these markers is therefore used to establish a differential diagnosis from other B-cell lymphoproliferative disorders such as marginal zone lymphoma, lymphoplasmacytic lymphoma, and mantle cell lymphoma (MCL), all of which express B-cell surface antigens, but usually do not express CD23 and have negative or low CD43 expression.2,3MCL cells express CD5 but also exhibit enhanced expression of the gene encoding cyclin D1 (CCND1) due to the (11;14) translocation (t[11;14]), which is absent from CLL cells.1As such, FISH analysis for t(11;14) can help to distinguish MCL from CLL.
More than 80% of patients with previously untreated CLL have cytogenetic abnormalities, most commonly a deletion in chromosome 13q14.3 (del[13q]; 55%), followed by del(11q) (18%), trisomy 12 (16%), del(17p) (7%), and del(6q) (6%).10Recommended analyses include interphase cytogenetic analysis with FISH. for the detection of the del(17p), which affects p53 expression, and if negative, molecular genetics is recommended for the detection of aTP53mutation.2,3
Molecular genetic analysis should also include mutational status of the immunoglobulin heavy chain variable region gene (IGHV). Additional analyses considered informative for prognosis and treatment selection are stimulated metaphase analyses to identify complex karyotypes, extended FISH for additional cytogenetic abnormalities, and polymerase chain reaction or sequencing for mutations inNOTCH1,SF3B1,TP53, orMYD88.2,3
Two clinical staging systems, the Rai and Binet systems, are used in the United States and Europe, respectively, to group patients with CLL into broad prognostic groups.11,12Both systems combine the presence of specific physical parameters, such as lymph node involvement, enlarged spleen and/or liver and blood parameters, to determine tumor burden.
The Rai system, originally including 5 groups, has been modified to define low-risk disease (former stage 0) as lymphocytosis with leukemia cells in the blood and/or marrow. Intermediate risk disease (stage I/II) is defined as enlarged nodes in any site, and splenomegaly and/or hepatomegaly (lymph nodes being palpable or not), and high-risk disease (stage II/IV) as lymphocytosis and cytopenia (hemoglobin [Hb] level less than 11 g/dL and/or platelet count of less than 100,000/μL) (TABLE).3,11,12
The Binet staging system relies on determining the number of involved areas, ie, enlarged lymph nodes of greater than 1 cm in diameter or organomegaly, and the presence anemia or thrombocytopenia. Binet stages are low risk (stage A), with less than 3 palpable enlarged sites without cytopenia; intermediate risk (stage B), with 3 or more palpable enlarged sites without cytopenia, and high risk (stage C) in all patients who have Hb of less than 10 g/dL and/or a platelet count of less than 100,000/μL, irrespective of organomegaly.3,11,12
Available survival estimates linked with staging suggest similar survival to age-matched controls for patients with low-risk disease by Rai stage (median, 150 months), shorter survival for patients with intermediate-risk disease (median, 71-101 months), and poor survival for high-risk features (median, 19 months).1,3However, these estimates reflect treatment with chemotherapy or chemoimmunotherapy, and life expectancies are increasing with newer small molecule inhibitor-based therapy.1,3
Newly diagnosed CLL is characterized by a highly variable clinical course. Prognostic factors used for patient stratification include patient factors, clinical features of the disease, and genetic, molecular, and biochemical characteristics of the CLL clone.3
Traditional prognostic factors or clinical features associated with poorer outcome are male sex, age ≥65 years, poor performance status due to medical comorbidities, high serum levels of beta-2 microglobulin (>3.5 mg/L), high absolute lymphocyte count (>50,000 cells/μL), and/or late-stage disease at diagnosis.13-15Elevated serum β2 microglobulin is an independent prognostic indicator for treatment-free interval, response to treatment, and overall survival (OS) in response to first-line chemoimmunotherapy regimens,3,14andif remaining after 6 months of treatment—for inferior progression-free survival (PFS) with ibrutinib (Imbruvica)-based therapies.16
Biological prognostic markers that reflect CLL cell characteristics and are used for risk stratification include cytogenetic abnormalities;IGHVmutational status;TP53mutation; expression of ZAP-70, CD49d (also known as integrin alpha-4), or CD38; and mutations inNOTCH1,SF3B1,BIRC3, andMYD88.3Among these, del(17p) and TP53 mutations are considered pertinent for treatment selection, and multiple other markers are considered of predictive value. Among prognostic surface markers detected by flow cytometry or immunohistochemistry, CD49d is independent ofFISHandIGHV.17Del(17p) andTP53mutations are currently the only disease-based predictive markers that affect treatment selection in CLL. With changing treatment options, the value of other prognostic markers continues to evolve.
Factors Affecting Treatment Selection
In 2008, the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) published revised guidelines for the diagnosis and treatment of CLL.18These revised guidelines acted as an update to the National Cancer Institute sponsored Working Group’s (NCI-WG) 1996 guidelines.19
When assessing the level of response to treatment in patients with CLL, a physical exam and blood and marrow evaluation is required. Unlike response assessment in solid tumors, imaging studies are not necessary.
The characterization of a complete remission, as defined by the iwCLL, requires the absence of clonal lymphocytes in the peripheral blood, no hepatomegaly or splenomegaly, and the absence of constitutional symptoms, all within 3 months of the completion of therapy.18Additionally, polymorphonuclear leukocyte levels should be above 1500/μL, platelets above 100,000/μL, and hemoglobin above 11 g/dL untransfused.20
Other variables affecting treatment selection follow:
Del(17p). The presence of a deletion of chromosome 17p (del[17p]) and mutatedTP53represent the most relevant disease characteristics that guide the choice of therapy in patients with CLL.1Del(17p) causes the loss of 1TP53allele and is associated with mutations in the remainingTP53allele in more than 80% of patients, resulting in loss or dysfunction ofTP53. Both del(17p) and mutatedTP53are associated with poor response to chemotherapy-based regimens, short PFS, and short OS, independent ofIGHVmutation status.21-23Recent trials have demonstrated activity of novel targeted agents in patients with del(17p)/TP53-mutant CLL, who are considered a distinct subgroup who require a specific therapeutic approach.21,24
Del(11q). The del(11q22.3) cytogenetic abnormality is detected in up to 20% of patients with CLL at diagnosis and at a higher frequency in relapsed/refractory CLL. It has been considered an unfavorable cytogenetic alteration associated with extensive lymphadenopathy, disease progression, and shorter median survival (79 months).22The presence of del(11q) predicts poor response to chlorambucil-, fludarabine-, or FCR (fludarabine, chlorambucil, rituximab [Rituxan])-based regimens, with shorter duration of remission and OS compared with other cytogenetic groups.22,25Previous findings have shown that adding an alkylating agent such as cyclophosphamide to fludarabine-based chemoimmunotherapy can improve outcomes.21The presence of del(11q) was not an adverse prognostic factor for PFS in patients who received ibrutinib-based treatment. Additionally, treatment with ibrutinib was associated with superior clinical outcomes versus comparators regardless of del(11q) status.26
IGHV. Mutational status of theIGHVin the CLL clone has been increasingly considered as a parameter when determining treatment choice, whereas del(11q) is no longer considered a marker with relevance for treatment selection in current guidelines by the National Comprehensive Cancer Network.21CLL cells expressing unmutatedIGHVoriginate from B cells that have not undergone somatic hypermutation, which has been associated with a more aggressive disease course and poor outcomes with standard chemotherapy-based regimens.27
New advances in diagnosis and risk stratification may lead to new treatment strategies of CLL. The next article in this publication reviews treatment options for CLL and explores the practical implications of the expanding therapeutic landscape.