CLL biology: Historical perspective

CLL is a monoclonal CD5⁺ B-cell lymphoproliferative disorder derived from antigen-experienced B lymphocytes that differ in their level of immunoglobulin heavy chain variable region (IGHV) gene mutations.¹ Table 1 summarizes some of the important differences between the way CLL is defined now and in the past. The pace of research in CLL received a major boost over the past decade with the finding of chromosomal abnormalities and genetic mutations that contribute to the heterogeneity of the clinical presentation and help predict the disease course. Equally important has been the discovery of the role of the microenvironment and of the signaling factors that are necessary to CLL pathogenesis.^2–5 This greater understanding has led to the development of agents that specifically target dysregulated pathways that allow the proliferation and survival of the malignant clone. The recent introduction of therapies with excellent clinical activity in patients previously refractory to chemotherapy is changing the natural history of the disease with long-term survival expectations substantially improved. Despite these rapid advances, the majority of CLL patients who initially achieve a remission eventually relapse. Presently, research is focused on elucidating mechanisms of resistance to the novel targeted agents.

Monoclonal B-cell lymphocytosis and familial CLL

The absence of cytopenias, lymphadenopathy, organomegaly, or disease-related symptoms (B symptoms) in the presence of fewer than 5 × 10⁹ clonal B lymphocytes/L in the peripheral blood is defined as “monoclonal B-lymphocytosis” (MBL).¹³ Rawstron and colleagues¹⁴ found MBL among 13.5% of normal first-degree relatives of people known to have CLL. That incidence is much higher than the 3.5% that Rawstron and colleagues discovered among adults with normal blood counts without a first-degree relative with CLL.¹⁵ Furthermore, there is an increased incidence of CLL or related disorders among the family members of people known to have CLL.^{17, 16} Further research is needed to elucidate a putative CLL predisposition gene or a possible CLL carrier state. Similar to Kyle’s MGUS data in multiple myeloma,¹⁸ the rate of progression to CLL that requires treatment is 1.1% per year.¹⁹

Absolute lymphocytosis in blood

By IWCLL criteria, the presence of at least 5 × 10⁹ B clonal lymphocytes per liter (5000/μL) with the phenotypes CD19+, CD20+, CD23+, and CD5+ is required to diagnose CLL, as lymphocytosis may occur with infections or in other neoplastic conditions (e.g., leukemic phase of lymphomas, hairy cell leukemia (HCL), PLL—Figure 2, and large granular cell leukemia).

Radiologic findings

Radiologic examinations are neither required nor recommended as part of an evaluation at the time of initial diagnosis or during routine follow-up. Computed tomography (CT) scans or chest films will often reveal adenopathy not detected on examination, but these findings do not change the clinical Rai or Binet stage. Unless there is a specific clinical question brought up by a new symptom or complaint, we recommend not doing these procedures. The American Society of Hematology embarked on the “Choosing Wisely” campaign to advocate clinical staging and blood monitoring in asymptomatic patients with early-stage CLL rather than performing CT scans. In the setting of a therapeutic research protocol, imaging may be obtained for specific protocol-related purposes.

Laboratory abnormalities

Although the absolute blood lymphocyte threshold for diagnosing CLL was placed at 5 × 10⁹/L, most patients present with considerably higher counts, occasionally even in the hundred-thousand range. Upon examination of a peripheral blood smear, mature-appearing small lymphocytes may be preponderant in the population of leukocytes, ranging from 50% to as much as 100%.

In addition to an increased ratio of mature-appearing lymphocytes in the smears of aspirated marrows, three patterns of infiltration by lymphocytes are recognized in trephine biopsy specimens of the bone marrow ( Figure 3): nodular, interstitial, and diffuse. It has been observed that patients with diffuse infiltration tend to have advanced disease and worse outlook. For prognostic purposes, nodular and interstitial patterns, which are associated with less-advanced disease and better prognosis, are grouped together and termed “nondiffuse.”^24–26

Asymptomatic anemia and thrombocytopenia may be observed at the time of initial diagnosis, but usually these are of a relatively mild degree. A direct antiglobulin (Coombs) test may be positive in ∼25% of cases, but overt autoimmune hemolytic anemia occurs less frequently. In the absence of a reliable test to demonstrate antiplatelet antibodies, autoimmune thrombocytopenia is most often diagnosed on the basis of the presence of adequate numbers of megakaryocytes in the bone marrow with abnormally low platelet counts.

Hypogammaglobulinemia may be present at the time of initial diagnosis, but it becomes clinically significant only later in the course of the disease. All three immunoglobulin classes (IgG, IgA, and IgM) are usually decreased, although in some patients only one or two classes may be reduced. Concurrent hypogammaglobulinemia and neutropenia result in increased vulnerability of CLL patients to severe bacterial, viral, and opportunistic infections. As a large proportion of cells are B lymphocytes, the normal lymphocyte T : B ratio (2 : 1) is altered. As patients are not immunocompetent, they should avoid inoculation of any live vaccines (varicella, measles, Bacille Calmette-Guérin, etc.). In this immunocompromised population, replication of the virus after administration can be enhanced and live vaccines can actually induce active infection.^{27, 28}

No abnormalities in blood chemistry are characteristic of CLL, but increased levels of serum lactate dehydrogenase, uric acid, hepatic enzymes [alanine aminotransferase (ALT) or aspartate aminotransferase (AST)], and (rarely) calcium may be observed. Pseudohyperkalemia can occur occasionally in patients with extreme leukocytosis.

Method of Rai and colleagues

The Rai system is based on the concept that in CLL, a gradual and progressive increase in the tumor burden of leukemic lymphocytes occurs, resulting in sequential clinical manifestations of the disease. The abnormalities start in the blood followed by the lymph nodes, spleen, and liver; to eventually compromise the bone marrow function. The earliest stage is blood lymphocytosis (clinical stage 0). The later stages (anemia and thrombocytopenia—excluding AIHA and ITP) are explained by progressively increasing bone marrow infiltration by CLL cells.

At the time of initial diagnosis of CLL, approximately 25% of patients are in the earliest clinical stage (stage 0), ∼25% are in the advanced stages (stages III and IV), with the remaining 50% in the stage I or II categories. Table 4 shows the stage distributions from various series, revealing a consistent pattern. The median survival times from the time of diagnosis in the Rai series were 150 months for stage 0, 101 months for stage I, 71 months for stage II, 19 months for stage III, and 19 months for stage IV.³⁴ Although Rai and colleagues noted in their 1975 paper that only three (and not five) distinct actuarial survival patterns emerged from the data (stage 0, stages I and II combined, and stages III and IV combined), they recommended that the five-stage system be maintained to investigate prospectively whether biologic and clinical differences would emerge between stages I and II and between stages III and IV. In 1987, the Rai staging system was modified to consist of three groups: low (Rai stage 0), intermediate (Rai stages I and II combined), and high (Rai stages III and IV combined) risk categories.³⁹ The modified Rai staging system was used for risk stratifying patients in the landmark study of chlorambucil against fludarabine in the front-line therapy of CLL conducted in the 1990s that established the superiority of fludarabine.⁴⁰ Fludarabine and purine analogs are now part of the combination regimens for frontline therapy in fit patients with no major comorbidities.^{41, 42}

^a The hemoglobin level for stage III in Medical Research Council of Great Britain Chronic Lymphocytic Leukemia Trial I was <110 g/L.

Method of Binet and colleagues

Binet’s method classifies all patients with anemia (defined as hemoglobin below 100 g/L) and/or thrombocytopenia (platelets less than 100 × 10⁹/L), or both, as stage C.³⁸ All of the remaining (non-C) patients are divided into two groups, depending on the presence of fewer than three (stage A) or three or more (stage B) sites of palpable enlargement of lymphoid organs. This staging takes into consideration five sites: cervical, axillary, and inguinal lymph nodes (whether unilateral or bilateral, each area is counted as one), and the spleen and liver. This system has been found to be of great value in dividing patients into three types of survival curves, with A, B, and C corresponding, respectively, to Rai’s low-, intermediate-, and high-risk groups.