Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Chronic Lymphocytic Leukemia
Over the past several years, major advances have been realized in terms of improved understanding of the pathophysiology and therapeutic options for chronic lymphocytic leukemia (CLL). The plethora of information about CLL has increased dramatically and made management of what was a relatively straightforward disease quite complex but more rewarding. This chapter provides a reference source focused on critical issues in routine clinical management of CLL.
Epidemiology
CLL is one of the most prevalent types of leukemia in the Western Hemisphere. Surveillance, Epidemiology, and End Results (SEER) estimates for 2021 indicate that approximately 21,250 patients (13,040 men and 8210 women) would be diagnosed in the United States and that 4320 patients would die from CLL. The median age at diagnosis for CLL was 70 years in 2020, and incidence increases proportionately by decade of life as shown in Fig. 76.1 . This figure illustrates that CLL is a very uncommon diagnosis before 45 years of age and infrequent (33% of total patients diagnosed) in patients before 65 years of age. The age-adjusted incidence rate was 5 per 100,000 men and women per year; 0.6% of men and women born from 2015 to 2017 are expected to be diagnosed with CLL during their lifetime. The estimated time of survival after diagnosis at 5 years is 86.1%, which explains the estimated prevalence of 186,422 in 2017. Similar to other types of leukemia, the risk of dying from disease-specific causes increases proportionately with increasing age. Another analysis of the SEER database, comparing outcome of elderly patients with CLL with age- and sex-matched healthy control participants, demonstrated that CLL has the greatest impact on survival in the most elderly group of patients. However, recent therapeutic advances continue to result in significant improvement in outcomes across all age groups.
CLL is more common in men than women. Women diagnosed with CLL have 5- and 10-year overall survival (OS) rates that exceed those of men. CLL is most common in whites and decreases in frequency in a descending order among blacks, Hispanics, Native Americans and Native Alaskans, and Asians and Pacific Islanders. While adverse outcome based upon race has been reported, this has not been uniformly confirmed in other studies. The rarity of CLL among Asians and Pacific Islanders persists even in immigrants from these areas who have migrated to the Western Hemisphere. This implicates a possible genetic predisposition to the development of CLL. The relationship of environmental factors such as exposure to benzene, radon, and other chemicals to the development of CLL is suggestive but not clearly established. However, CLL is recognized as a service-connected illness among Vietnam War veterans who were exposed to Agent Orange. Occupational or environmental exposure to radiation does not clearly appear to predispose patients to a higher risk of developing CLL. For example, although the frequency of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) were increased among survivors of the atomic bomb at Hiroshima, an increase in CLL was not appreciated as reported by the Life Span Study (LSS) of survivors of that event. This could be secondary to a baseline low incidence of CLL in patients with Asian heritage. However, recent reports of Chernobyl disaster survivors and the international nuclear workers (INWORKS) study suggest an increased incidence of CLL along with a shorter survival. In addition, the International Lymphoma Epidemiology Consortium non-Hodgkin lymphoma Subtypes Project (InterLymph Study) identified multiple factors that were associated with the presence of CLL, including (1) family history of a first-degree relative with hematologic malignancy including lymphomas, leukemias, and myeloma; (2) a history of working or living on a farm; (3) hairdressers; and (4) a history of hepatitis C infection. Protective factors included a history of allergies, blood transfusions, sun exposure, and smoking.
Familial Chronic Lymphocytic Leukemia
Up to 10% of CLL patients have a first- or second-degree relative with CLL, making CLL one of the most common types of malignancy with familial predisposition. The higher frequency of monoclonal B-cell lymphocytosis (MBL) reported in these families provides further evidence of inheritance in a subset of patients. However, unlike other types of familial cancers, it is very uncommon for CLL patients to have large pedigrees with many affected distant relatives throughout an extensive family tree. Rather, the more common finding is for most patients to have one or two first- or second-degree relatives with this diagnosis. Large, case-control studies concluded that the risk ratio (RR) for first-degree relatives of CLL probands to also have CLL was higher than that for most other cancers. Although the average RR for all cancers in a U.S. study was approximately 2.1, CLL showed an RR of 5.0, the fourth highest of all cancers. Relatives of patients with CLL also appear to have a higher frequency of other lymphoproliferative disorders and autoimmune diseases. Unlike a variety of other cancers that have known predisposing genes, identification of divergent genes in CLL has been generally unsuccessful. Multiple association studies have identified numerous putative genes, polymorphisms, and genetic factors including death-associated protein kinase (DAPK) and LEU7 (CD57), IRF4, BAK, CD38, CD5, tumor necrosis factor (TNF)-α, and others, but weak evidence for linkage and conclusive studies demonstrating strong mechanistic contribution to pathogenesis are lacking. The role of anticipation in identifying other family members has been reported by several groups; patients with such a family history are generally diagnosed a median of 10 years earlier than other patients. However, other clinical features of CLL at diagnosis do not appear to be different. Thus, patients with familial CLL do not appear to be genetically or clinically different from individuals with sporadic CLL.
Pathobiology
The complexity of the biology of CLL has become increasingly apparent, as the knowledge of the basic science of this disease has expanded. Despite these advances, many questions remain unsolved, including (1) the cell of origin from which CLL is derived; (2) the existence of a CLL stem cell as occurs in other leukemias; (3) the biological etiology of the divergent natural histories of immunoglobulin heavy chain variable region (IGHV)-mutated versus unmutated CLL; and (4) the existence and identification of infectious or other naturally occurring antigens that might drive the B-cell clone in this disease. Nonetheless, significant advances in our understanding of the roles of cytogenetics, immunology, and other relevant biological markers in predicting the natural history of disease progression and response to therapy in CLL make an understanding of the basic biology of CLL increasingly relevant and important to clinicians caring for CLL patients.
For many years, CLL was believed to represent a single disease that had a varied natural history. Basic research focused on understanding (1) the normal cell of origin from which CLL is derived; (2) the function of the B-cell receptor (BCR) in CLL; (3) the maturational point in B-cell development at which CLL occurs; (4) the relevance and contribution of a self- or acquired antigen to driving the disease; and (5) the role of the microenvironment in disease development and progression (see Chapter 81 ). All of these observations are important scientific areas of active, ongoing study, and readers are referred to several recent definitive reviews and Chapter 81 for further information on the basic biology of CLL. The biology and genetics covered within this chapter focus predominately on areas relevant to clinicians who care for patients with CLL.
B-Cell Receptor Pathway and Its Role in Pathogenesis
Modulation of the BCR plays an integral part in the development and maturation of B cells. Its constitutive activation through antigen dependent or independent signaling provides an important survival signal for the propagation of CLL B cells. Signal transduction occurs through a variety of kinases including LYN, PI3K, SYK, and Bruton tyrosine kinase (BTK) with resultant phosphorylation of PLC-γ2 and induction of downstream second messengers that further modulate cell survival regulators. These kinases have been effectively targeted and result in abrogation of the survival signal and B-cell apoptosis. Combinations of these inhibitors with existing and novel therapeutic agents have already changed the natural history of the disease.
X-linked agammaglobulinemia is a disease characterized by a severe immunodeficiency state that results from deficient BTK (see Chapter 52 ). Characterization of this defect and its resultant impact on causing severe impairment in B-cell development and humoral immunity has been critical to our understanding of CLL disease biology. Activating mutations of BTK have not been identified in CLL or other cancers but CLL B cells tend to have higher levels of BTK that can be induced through the BCR signaling pathway. The enzyme BTK is at an essential node for survival of CLL cells as deletion of this gene prevents development of CLL in mouse models and pharmacologic inhibition results has similar phenotype. Indeed, ibrutinib was the first-in-class irreversible, covalent, BTK inhibitor that efficiently targets BTK resulting in significant abrogation of downstream survival signaling transduced through this pathway and inhibition of cell survival and proliferation. Multiple other BTK inhibitors have also shown similar results. These include both reversible and non-covalent BTK inhibitors. Similarly, both SYK and PI3K can be induced by activation of BCR pathway. The PI3-kinase isoform delta inhibitors, idelalisib and duvelisib, and syk inhibitors have been shown to antagonize these survival signals and result in clinically meaningful disease responses.
IGHV Mutational Status
Two seminal manuscripts in 1999 demonstrated that the IGHV gene had undergone somatic mutation, indicating that CLL arose after this point in B-cell maturation, in 60% of patients at diagnosis. Detailed epigenetic studies examining the methylation changes occurring in normal B cells during development have subsequently suggested that immunoglobulin mutational analysis may indicate simply where in normal B-cell development transformation occurred. In an attempt to identify surrogate genes associated with IGHV-unmutated disease, ZAP-70 overexpression was identified. The majority of IGHV-unmutated CLL cells have ZAP-70 expression and demonstrate evidence of syk activation and other essential BCR downstream activation signals after ligation of surface IgM (sIgM) that is related to overexpression of this protein. In contrast, virtually all IGHV-mutated patients lack significant ZAP-70 expression and do not signal after ligation by sIgM, but can often weakly signal through other alternative BCRs. Thus, although gene expression profiling demonstrates all CLL cells to be most closely related to memory B cells, IGHV-unmutated and -mutated CLL cells differ significantly with respect to their ability to transduce intracellular signals after sIgM ligation. A common repertoire of mutational changes among CLL patients has also been documented that differs significantly from that found in the normal adult B-cell repertoire. These studies have prompted the hypothesis that CLL may represent an antigen-driven disease. IGLV3–21-expressing B cells have recently been described in a subset of patients to acquire a single point mutation (R110) that triggers autonomous BCR signaling and which subsequently identifies a subpopulation of CLL patients with a poor outcome. A multitude of mechanisms of BCR activation are indeed present in CLL. Targeting BCR signaling based on this has already resulted in the development of several therapeutic agents directed against signaling pathways downstream of the BCR.
Defective Apoptosis
Since its initial description and early characterization, CLL has been considered a disease of slow accumulation of tumor cells caused by disrupted or defective apoptosis. Multiple studies have demonstrated that CLL cells overexpress several antiapoptotic proteins, including bcl-2, mcl-1, bak, and X-linked inactivator of apoptosis protein (XIAP), and have diminished expression of compensatory proapoptotic proteins such as bax. Overexpression of bcl-2 and mcl-1 and an increase of the ratio of these proteins to bax have correlated not only with disrupted apoptosis but also shortened OS and poor response to therapy. Studies have demonstrated that CLL cells have constitutive activation of several anti-apoptotic transcription factors, including nuclear factor kappa-B (NFκB), nuclear factor of activated T cells (NFAT), and signal transducer and activator of transcription 3 (STAT3). Each of these transcription factors can influence one or more of the antiapoptotic proteins that promote survival in vivo. The source of activation of these different transcription factors is not completely defined but may be partly attributable to autocrine and paracrine networks involving B-cell activation factor (BAFF), a proliferation inducing ligand (APRIL) vascular endothelial growth factor (VEGF), interleukin-4 (IL-4), and CD40 among others. CLL cells are also maintained through contact with stromal cells (bone marrow [BM] and dendritic) and nurse like cells through a complex interface of adhesion molecules and stromal survival factors such as stromal cell–derived factor-1 (SDF-1). The importance of the in vivo environment to CLL survival is supported by the increase in apoptosis when CLL cells are cultured in vitro. Moreover, targeting the overexpressed anti-apoptotic protein like bcl-2 with a specific bcl-2 inhibitor venetoclax has already led to excellent clinical efficacy.
Genetic Abnormalities
Detailed study of the genetics of CLL is hindered by the inability to effectively induce proliferation of tumor cells for standard metaphase cytogenetic analysis and the poor response of CLL cells to B-cell mitogens (see Chapter 57 ). Nonetheless, several cytogenetic studies identified a variety of deletions, including del(11q22.3), del(17p13.1), del(13q14), and del(6q21-q23), as well as trisomy 12, as common abnormalities in CLL. The frequency of these abnormalities has been further refined by using fluorescence in situ hybridization (FISH), which does not require isolation of dividing cells. These studies have demonstrated that del(13q14) is by far the most common cytogenetic abnormality in CLL followed by trisomy 12, del(11q22.3), del(17p13.1), and del(6q22.3). Stimulation studies with CpG oligonucleotides plus IL-4 or CD40 confirmed the prevalence of these abnormalities and identified unbalanced translocations not generally observed with traditional metaphase cytogenetics. The prognostic implications of these unbalanced translocations appear to be significant. Similarly, complexity of karyotype appears to be a driving poor prognostic factor in CLL. Interestingly, balanced translocations, which are more frequently observed in ALL and AML, are generally not observed in CLL.
The presence of recurrent deletions in CLL suggests the possibility of unique tumor suppressor genes in these different regions. This was confirmed by the discovery of miR15 and miR16, two noncoding microRNAs, in the deleted region of 13q14. Noncoding RNAs range in size from 21 to 25 nucleotides and represent a class of gene products whose function is to silence genes through binding to the 3′-untranslated region of specific genes to inhibit translation. It was later shown that miR16 regulates expression of bcl-2, which is overexpressed in CLL and other B-cell lymphoproliferative disorders. Multiple studies have associated specific miR expression with rapid disease progression, fludarabine resistance, poor prognosis, and modulation of BCR pathway and bcl-2 signaling. In addition, miR34a has been directly related to the adverse outcome associated with p53 dysfunction.
Recurring Mutations in Chronic Lymphocytic Leukemia
Until the advent of whole-exon and whole-genomic sequencing, CLL was not typically associated with recurring mutations early in the pathogenesis of the disease. Probably best characterized are p53 mutations, which occur in approximately 10% of patients at diagnosis, often in conjunction with deletion of the alternative allele (at 17p13.1 loci) that is associated with rapid disease progression and poor survival. With treatment and subsequent relapse, the frequency of p53 mutations continues to increase proportionately and is most common in patients with Richter transformation. Thus, p53 mutations are considered by most to be a secondary abnormality in CLL associated with progression. Nonetheless, p53 mutations or deletions have significant impact on consideration of treatment of CLL, and conventional chemoimmunotherapy-based approaches have no role in the treatment of patients with this abnormality. Other recurring mutations in CLL, including SF3B1, NOTCH1, MYD88, XPO1, and ERK1 and more than 100 other mutations have been described with varying physiologic significance. A summary of important genetic abnormalities and their impact is provided in Table 76.1 .
Table 76.1
Summary of Important Prognostic Markers and Their Role in Disease Biology
| Prognostic Markers | Frequency (%) | Putative Role in Disease Biology |
|---|---|---|
| Del17p/loss of TP53 | ∼7–10 | Loss of p53 protein and decreased levels of miR34a results in cell cycle dysfunction. Predicts for poor response to treatment and worse survival |
| Del11q | ∼18–20 | Results in ATM gene deletion in the majority of patients and subsequently a lack of repair of double-stranded DNA breaks. Predicts for shorter time to treatment failure and survival. Impact may be overcome with the use of alkylator based chemoimmunotherapy |
| Trisomy 12 | ∼16–20 | Impact may be through a gene dosage effect especially of genes encoding CDK4 and MDM2. Predicts for intermediate risk disease |
| Del13q | ∼55–60 | Results in the loss of miR-15a and miR16-1 along with DLEU7 that results in loss of tumor suppressor activity. Generally associated with favorable outcomes including response to chemoimmunotherapy and survival |
| NOTCH1 mutation | ∼10 | Constitutive activation of NOTCH1 results in increased cell survival and resistance to apoptosis and predicts for inferior response to rituximab and shorter treatment-free interval |
| SF3B1 mutation | ∼9–18 | Mutually exclusive with NOTCH1 mutations. May cause abnormal transcription and splicing events. Associated with rapid disease progression |
| BIRC3 mutation | ∼5 | Associated with unmutated IGHV, a shorter treatment free interval, and del11q. Mutually exclusive with TP53 mutations |
| MYD88 mutation | ∼3–13 | Important adapter of the IL-1 and toll-like receptor pathway. Gain-of-function mutations result in increased cytokine production and activation of the NF-κB pathway. Associated with improved survival |
MYD88 , myeloid differentiation primary response 88; SF3B1 , NA splicing factor 3B, subunit 1.
Immune and Micro-Environmental Features
The importance of progressive immune suppression with progression of CLL has become appreciated in both human CLL and murine models of this disease. The absolute number of T cells and natural killer (NK) cells in CLL patients at diagnosis has been shown to predict OS. In particular, expansion of suppressive T-regulatory cells has been documented as patients approach the time of requiring therapy. The immunosuppressive effects observed in CLL lie predominately with the CLL clone as demonstrated in human and mouse models of CLL. Similarly, the importance of microenvironmental compartments of CLL such as lymph nodes and BM, where stromal cells provide proliferative signals as well as survival signals to protect from apoptosis, are recognized. Derived from this work are biomarkers of measurable chemokines responsible for T-cell recruitment to the microenvironment. Given the link of these stimuli to BCR signaling, inhibitory molecules directed at kinases involved in this interaction have resulted in significant clinical advances.
Clinical Manifestations
At diagnosis, CLL most often does not have clinical manifestations associated with the disease. For early-stage CLL patients, the diagnosis is often identified as part of routine blood tests for evaluation of an unrelated problem such as infection, kidney stone, or preoperative assessment in which an elevated leukocyte count is noted with increased numbers of mature lymphocytes observed on the blood smear. For a much smaller subset of patients with CLL, presentation of disease occurs as a consequence of fatigue, weight loss, early satiety (from spleen enlargement), petechiae (from low platelets), or new palpable lymph nodes. Patients with symptomatic CLL at diagnosis represent only 15% of those seen, due to the more indolent nature of this disease at diagnosis. With additional follow-up, the majority of CLL patients will eventually manifest symptoms of the disease that ultimately lead to the need for treatment. The most common symptoms of progression include increasing fatigue (as a consequence of anemia and cytokines from disease), increasing lymph node and spleen size, worsening hematologic parameters (anemia and thrombocytopenia), and rarely infiltration of other organs (kidney, lung, pleural space, skin) that necessitates initiation of treatment to palliate symptoms. Unusual symptoms generally not associated with CLL progression are night sweats, fevers, and weight loss. These are generally suggestive of Richter transformation.
Separate from direct CLL progression, the disease is also immunosuppressive, and with more advanced disease, an increase in infections is generally observed. This represents a major morbidity of CLL and is a leading contribution to mortality associated with this disease. Other manifestations of immune suppression, including higher rate of secondary malignancies and autoimmune complications, are also increased in CLL (see box on Initial Evaluation of Young Patients With Chronic Lymphocytic Leukemia ).
Diagnosis and Laboratory Manifestations
The diagnosis of CLL, as defined by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria, requires an absolute malignant B-cell lymphocyte count of greater than 5000/μL that co-express CD5 and CD23 on peripheral blood immunophenotyping. Morphologically, the lymphocytes must appear mature with fewer than 55% prolymphocytes ( Fig. 76.2A–E ). The BM aspirate smear if done should show greater than 30% of all nucleated cells to be lymphoid, or the BM core biopsy must show lymphoid infiltrates consistent with CLL (see Fig. 76.2F and G ). The overall cellularity must be normocellular or hypercellular. Immunophenotyping must reveal a predominant B-cell monoclonal population coexpressing the B-cell markers CD19, CD20, and CD23 and the T-cell antigen CD5 in the absence of other pan-T-cell markers (see later section). In some cases a hypocellular marrow can be present as an artifact of marrow aspiration.
Patients may present with tumor cells immunophenotypically consistent with CLL but have predominately lymph node disease or organomegaly, without a peripheral B-cell lymphocyte count of 5000/μL despite BM involvement. These patients are considered to have small lymphocytic lymphoma (SLL) and both entities share similar immunophenotypic features, genetic findings, natural history, and complications. The clinical management of SLL patients should be similar to CLL with respect to diagnostic testing and treatment.
Initial Evaluation of Young Patients With Chronic Lymphocytic Leukemia
Only 10% of patients diagnosed with CLL are younger than 50 years of age, and these patients often present a diagnostic and therapeutic dilemma to hematologists initially evaluating them. The great majority of patients diagnosed before the age of 50 years will have early-stage CLL with a slightly higher incidence of a prior first-generation relative with this disease. Additionally, these patients are generally of a higher economic status or have chronic fatigue or medical illnesses for which they have been undergoing routine blood testing, leading to diagnosis of CLL. When the diagnosis of CLL is made, these younger patients have a more challenging time understanding how the disease will impact them. For patients with no symptoms referable to CLL, we generally discuss complications of the disease during the first visit and have a detailed discussion regarding assessment of genetic risk factors predisposing to early disease progression, including select interphase chromosomal abnormalities [del(17p13.1) and del(11q22.3)] and IGHV mutational status (unmutated). During this time, it is important to counsel patients that identification of high-risk genomic features can actually increase anxiety because no treatment intervention is indicated in the absence of symptoms, regardless of genomic profile, outside of a clinical trial. In our experience, the great majority of patients desire this testing. We provide considerable discussion about the excellent outcomes with novel agents and the limited role of chemotherapy for the management of this disease. Despite the potential benefit of allogeneic SCT in younger patients with CLL and possibility of a curative option, we generally avoid mention of this option and do not pursue consultation or tissue typing of patients or siblings. More recent advances with chimeric antigen receptor T-cell (CAR-T) therapy are occasionally mentioned. During the second visit 4 to 6 weeks later, we review the results of these prognostic factors and answer additional questions that have arisen, and reiterate the rationale behind active surveillance and the lack of improvement in OS with early intervention. Since “watchful waiting” is a difficult concept to grasp by a patient who has recently been diagnosed with a malignancy, we use “active surveillance” as a preferred term for our management approach. Ultimately, the majority of patients have low-risk disease, and knowing this allows patients to take partial control of their disease and move on with their lives. Serial assessment of the psychological well-being of patients with CLL during this first year is incredibly important. At no place during the evaluation do we refer to CLL as being a good or favorable leukemia. In our experience, the most common reason for dissatisfaction toward the initial hematology evaluation is lack of explanation of the disease process or the minimization of CLL as a “good leukemia to have.”
For young patients presenting with other chronic medical problems who are asymptomatic from their CLL, we follow the approach outlined above. More commonly, these patients have fatigue, mild anemia, or other symptoms that could be referable to the CLL. Additionally, this group is more commonly overweight or obese. In either setting, it is important to first think like an internist and pursue other causes for symptoms potentially referable to CLL. In particular, an effective weight loss and exercise plan often results in improvement in quality of life and reduction in symptoms of fatigue, along with better control of other medical comorbidities. In some cases methylphenidate can be effective for the management of CLL related fatigue. It is very important to note that younger patients with CLL can often go a decade or more without therapy, and early treatment of this patient group in the absence of symptoms still offers no proven long-term advantage. For this reason, we remain very conservative on starting therapy for young patients with CLL unless they have high-risk disease and are treated on a clinical trial. To date, trials with chemotherapy, chemoimmunotherapy, and BTKi have not demonstrated survival differences with early intervention although follow-up with the later therapies is short.
Monoclonal B-Cell Lymphocytosis
The increase in diagnostic blood testing for other medical conditions and easy availability of immunophenotyping has led to recognition of a precursor condition to CLL called MBL. Patients with MBL have circulating peripheral blood B cells immunophenotypically consistent with CLL but do not have enlarged lymph nodes, a malignant lymphocyte count greater than 5000/μL, cytopenias, organomegaly, extramedullary involvement, or other features of a lymphoproliferative disorder. Immunophenotyping can further classify this entity into three separate categories: (1) CLL-type MBL; (2) Non-CLL type MBL; (3) Atypical CLL-type MBL. Care must be taken to differentiate this entity from circulating disease frequently observed in a variety of non-Hodgkin lymphomas (NHLs).
The frequency of MBL increases with age; 0.3% of patients younger than the age of 40 years have MBL compared with 3.5% to 6.7% of 40- to 60-year-old patients and 5% to 9% of 60- to 90-year-old patients. The frequency of MBL in family members of patients with a first-degree relative with CLL is significantly higher in both young and older patients. Similar to the relationship of monoclonal gammopathy of undetermined significance and multiple myeloma, it appears that only a small proportion of patients with MBL develop overt CLL over time. These are mostly patients with high count MBL, defined as a monoclonal B-cell count of 500 to 5000/μL with a risk of progression to CLL of 1% to 2%/year. However, a similar incidence of 1%/year has also been reported in patients with low count MBL (<500/μL) despite earlier studies suggesting minimal risk of progression. Since the classification of SLL is based on lymphadenopathy evaluated on physical examination, patients with MBL who are found to have lymphadenopathy on CT scans are frequently misclassified as SLL. These patients without palpable lymphadenopathy and only limited adenopathy on imaging have similar risk of progression as patients without lymphadenopathy on imaging with concurrent MBL. We therefore do not recommend the routine use of CT scans in the initial workup or routine follow-up of patients with CLL, SLL, or MBL. Similarly, the degree of BM involvement is not correlated with risk of progression, and while the diagnostic criteria for MBL does not include BM involvement, the presence of BM disease alone does not change the diagnosis from MBL to CLL or SLL.
Patients with MBL are generally evaluated similarly to patients with early-stage CLL with comprehensive prognostic testing and IGHV mutational status and cytogenetic and mutational abnormalities. They also generally have many of the long-term complications of CLL related to immune suppression including a higher frequency of infections and secondary malignancies. We therefore approach the initial counseling of these patients in a similar manner as newly diagnosed CLL patients with respect to interventions (vaccines, dermatologic evaluation, and education) to minimize these complications. We also continue to follow these patients with yearly blood counts and exams.
Laboratory Manifestations
For many years, the diagnosis of CLL was made based on morphologic examination of the peripheral blood smear, which demonstrated mature lymphocytes with an abundance of smudge cells. Despite rigorous morphology, many diseases can mimic CLL in both appearance and clinical presentation, as summarized in Table 76.2 , resulting in incorrect diagnoses. With the advent of new, more effective targeted therapies in CLL and other related diseases listed in Table 76.2 , determining the correct diagnosis is of great importance. Flow cytometry, or immunophenotyping, is now the standard approach to establish the diagnosis of CLL ( Fig. 76.3 , for example). The diagnosis of CLL relies on immunophenotypic confirmation, and flow cytometry should therefore be performed on all CLL patients at diagnosis. CLL cells have a relatively consistent immunophenotype, which differentiates CLL from mantle cell lymphoma, hairy cell leukemia, follicular lymphoma, marginal zone lymphoma, and other indolent B-cell malignancies. Specifically, CLL cells express a variety of B-cell markers, including dim sIg, CD19, dim CD20 and CD23, CD200, as well as the pan-T-cell marker CD5. κ or λ restriction is always present, establishing the presence of a clonal B-cell population, although sIg expression may be so dim that light chain restriction may be difficult to determine. In contrast, the presence of CD10, FMC7, or CD79b (all typically absent on CLL cells) or bright expression of CD11c, CD20, or CD25 (all typically dim on CLL cells) suggests an alternative low-grade B-cell lymphoproliferative malignancy. Expression of CD5 without CD23 suggests mantle cell lymphoma (see Chapter 86 ), and FISH for t(11;14) should be performed to exclude mantle cell lymphoma. Some genetic subsets of CLL are predisposed to variant antigen expression, particularly patients with trisomy 12. Repeating immunophenotyping after the initial diagnosis is not required unless there is a suspicion of transformation to a more aggressive histology or there is a need to assess BM response or antigen expression for an antibody-directed therapeutic agent. Transformation of CLL ( Fig. 76.4A–C ) to either prolymphocytic leukemia (PLL) or large cell lymphoma (Richter transformation) is often associated with immunophenotypic drift, where CD5 is lost and FMC7 expression is acquired. Additionally, expression of CD20 and surface immunoglobulin typically becomes brighter in PLL or Richter transformation. Although the morphologic appearance of prolymphocytes or large lymphoid cells in blood, BM, or lymph nodes is typically adequate to make the diagnosis of transformation, immunophenotyping may be useful in cases when morphologic findings are less clear.
Table 76.2
Diseases That Can Mimic Chronic Lymphocytic Leukemia
|
Patients with CLL often present with no symptoms, with the diagnosis being made as a consequence of asymptomatic enlarged lymph nodes or splenomegaly detected on physical examination or routine blood work done for another cause. Other patients present with symptoms of BM replacement (fatigue, dyspnea, or petechiae secondary to anemia and thrombocytopenia), symptomatic lymphadenopathy or hepatosplenomegaly, autoimmune complications (hemolytic anemia or idiopathic thrombocytopenic purpura), or B symptoms (fevers, night sweats, and weight loss). A small proportion of CLL patients will have pulmonary infiltrates at diagnosis that are representative of CLL involvement in some cases and active infection in others.
In addition to blood and BM lymphocytosis, a few abnormal laboratory findings are commonly observed in CLL. Neutropenia, anemia, and thrombocytopenia can develop as a consequence of BM infiltration or myelosuppressive therapy administered to eliminate the leukemia. A positive direct antibody, or Coombs, test result is observed in approximately 10% to 25% of CLL patients at some time during the course of the disease. Similarly, autoimmune thrombocytopenia or neutropenia may be present, although other causes such as BM replacement or a chemotherapy effect are much more common and should be excluded. Pure red blood cell (RBC) aplasia can sometimes be observed with isolated anemia and absence of RBC precursor cells (see Chapter 33 ). Hypogammaglobulinemia is common in CLL and becomes more frequent and marked as the disease progresses. A monoclonal protein, most commonly IgM, can be present in a subset of CLL. By contrast, hypercalcemia and a markedly elevated lactate dehydrogenase (LDH) level are not common in CLL and suggest progression to Richter transformation. Clearly, a wide spectrum of presentations exists for patients with CLL.
Prognosis
Historically, patients with CLL were staged using either the Rai or Binet system. Both of these discriminate CLL by the sites of disease and degree of cytopenias induced by BM replacement by the leukemia cells. Patients can be categorized into three groups on the basis of these features. According to the modified Rai criteria, patients in the low-risk group (stage 0) have lymphocytosis without any other abnormality; patients in the intermediate-risk group (stages I and II) have, in addition to their lymphocytosis, enlarged lymph nodes, spleen, or liver; and patients in the high-risk group (stages III and IV) have anemia (hemoglobin <11.0 g/dL) or thrombocytopenia (platelets <100 × 10 9 /L). The historical median survival times for the Rai low-, intermediate-, and high-risk groups are similar to those of Binet stages A, B, and C: 12+, 8, and 2 years ( Table 76.3 ). For early-stage patients with CLL (Rai low and intermediate stage and Binet stages A and B), a significant range of time to developing symptoms of CLL exists. The lack of survival advantage with early treatment, the observation that a subset of CLL patients will never require therapy, and the varied natural history of the disease have resulted in the identification of specific biologic or clinical prognostic factors that predict time to progression. Multiple tools have been developed and validated to address this issue, and the CLL-International Prognostic Index (CLL-IPI) score appears to have the most discriminative ability for predicting disease progression and OS in patients with newly diagnosed and previously untreated CLL. This weighted score incorporates five prognostic factors including age, clinical stage, β2-microglobulin, IGHV mutational status, and del17p or TP53 mutation status, with del17p or TP53 mutation status being the most significant variable. This allows separation of patients in low-risk to very high-risk cohorts with respect to survival outcomes, and also provides management suggestions, e.g. active surveillance in patients in the low-risk group. Given the impact of BTKi and other targeted therapies for CLL, the impact of historical staging systems relative to survival for newly diagnosed patients is limited.
Table 76.3
Rai Staging System
Adapted from Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood . 1975;46(2):219–234.
| Rai Stage at Diagnosis | Percent of Patients Never Requiring Chronic Lymphocytic Leukemia Therapy | Expected Survival in Months From Initial Diagnosis |
|---|---|---|
| 0— Lymphocytosis >5 × 10 9 /L only | 59 | 150 |
| 1— Lymph node enlargement | 21 | 101 |
| 2— Spleen or liver enlargement | 23 | 71 |
| 3— Anemia with hemoglobin <11 g/dL | 5 | 19 |
| 4— Thrombocytopenia <100 × 10 12 /L | 0 | 19 |
Although lymphadenopathy is a common clinical feature of CLL and is incorporated into both major clinical staging systems, computed tomography (CT) scans are not commonly used to determine staging or to evaluate response to therapy outside of clinical trials. However, several studies have examined whether the incorporation of CT scans in initial staging or response evaluation may affect the ability to predict disease progression at diagnosis and assessment of clinical response to therapy. Although a few studies have suggested that these may help predict disease progression at diagnosis, studies done serially at the time of treatment and for response show that CT scans generally do not impact assessment of response, progression-free survival (PFS), or OS. Additionally, CT scan identification of new nodal areas did not impact decisions for retreatment. Thus, routine CT scans should not be performed for staging and response evaluation in CLL. Similarly, PET scans appear to be sensitive for Richter transformation, with a high negative predictive value, but specificity is poor. We generally use these studies to identify patients who warrant biopsy for suspected Richter transformation and to localize where to biopsy.
With recent advances in the molecular biology of CLL, some prognostic factors such as BM infiltration pattern, which requires an invasive procedure at diagnosis, have not maintained their usefulness in predicting disease progression. Prognostic features outside of the traditional staging systems outlined above relative to daily practice are summarized in Table 76.4 .
Table 76.4
Evaluation of Chronic Lymphocytic Leukemia Patients at Diagnosis
| History |
|
| Physical Examination |
| Laboratory Assessment |
|
| Selected Tests Under Certain Circumstances |
|
| Teaching |
|
BM , Bone marrow; CBC , complete blood count; CLL , chronic lymphocytic leukemia; CT , computed tomography; DAT , direct antiglobulin test; LDH , lactate dehydrogenase; LFT , liver function test; PET , positron emission tomography.
Thymidine Kinase Activity and β 2 -Microglobulin
Thymidine kinase is an enzyme involved in the salvage pathway of DNA synthesis and correlates with proliferative activity. Elevated thymidine kinase activity (TKA) has been observed to be predictive of early progression in a subgroup of untreated patients with early-stage CLL. β 2 -Microglobulin (β 2 M) is an extracellular protein component of the human leukocyte antigen (HLA) class I complex. β 2 M has been shown to have significant prognostic relevance in lymphoma and multiple myeloma and correlates with disease burden in CLL. Both these variables have been validated as independent predictors of shortened PFS, and shorter survival time for both untreated and previously treated patients. Elevated β 2 M was also observed in patients with high tumor burden and extensive BM infiltration. In addition to disease progression, both β 2 M and TKA have been associated with short duration of remission and inferior survival after treatment with chemoimmunotherapy. In some studies, β 2 M also predicts for shorter remission after targeted therapies as well.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here