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C H A P T E R 77

CHRONIC LYMPHOCYTIC LEUKEMIA

Farrukh T. Awan and John C. Byrd

Over the past several decades, major advances have been realized in reported large International Lymphoma Epidemiology Consortium
terms of improved understanding of the pathophysiology and thera- non-Hodgkin lymphoma Subtypes Project (InterLymph Study),
peutic options for chronic lymphocytic leukemia (CLL). The plethora identified multiple factors that were associated with the presence of
of information about CLL has increased dramatically and made CLL; including 1) family history of a first degree relative with
management of what was a relatively straightforward disease quite hematologic malignancy including lymphomas, leukemias, and
complex but more rewarding. The authors herein provide a reference myeloma; 2) a history of working or living on a farm; 3) hairdressers,
source focused on critical issues in routine clinical management and 4) a history of hepatitis C infection. Protective factors included
of CLL. a history of allergies, blood transfusions, sun exposure, and smoking.

EPIDEMIOLOGY FAMILIAL CHRONIC LYMPHOCYTIC LEUKEMIA

CLL is one of the most common types of leukemia in the Western Up to 10% of CLL patients have a first- or second-degree relative
Hemisphere. Surveillance, Epidemiology, and End Results (program with CLL, making CLL one of the most common types of malignancy
and database) (SEER) estimates for 2015 indicate that approximately with familial predisposition. Newer studies identifying an even higher
14,620 patients (9940 men and 4678 women) were diagnosed in the frequency of monoclonal B-cell lymphocytosis (MBL) in these fami-
United States and that 4650 patients died from CLL. The median lies provides further evidence of inheritance in a subset of patients.
age at diagnosis for CLL was 71 years from 2008–2012, according Unlike other types of familial cancer, it is very uncommon for CLL
to the SEER database. The incidence of CLL increases proportion- patients to have large pedigrees with many affected distant relatives
ately by decade, as shown in Fig. 77.1. This figure illustrates that CLL throughout an extensive family tree. Rather, the more common
is a very uncommon diagnosis before 45 years of age and infrequent finding is for most patients to have one or two first- or second-degree
(30% of total patients diagnosed) in patients before 65 years of age. relatives with this diagnosis. Large case-control studies concluded that
The age-adjusted incidence rate was 4.5 per 100,000 men and women the risk ratio (RR) for first-degree relatives of CLL probands to also
per year; 0.6% of men and women born from 2010–2012 are have CLL was higher than that for most other cancers. Although the
expected to be diagnosed with CLL during their lifetime. The esti- average RR for all cancers in a U.S. study was approximately 2.1,
mated survival after diagnosis at 5 years is 81.7%, which explains the CLL showed an RR of 5.0, the fourth highest of all cancers. Relatives
estimated prevalence of 126,299 patients currently living with CLL of patients with CLL also appear to have a higher frequency of other
in the United States. Similar to other types of leukemia, the risk of lymphoproliferative disorders and autoimmune diseases. Unlike a
dying from disease-specific causes increases proportionately with variety of other cancers that have known predisposing genes, identi-
increasing age. Another analysis of the SEER database comparing fication of divergent genes in CLL has been generally unsuccessful.
outcome of elderly patients with CLL with age- and sex-matched Multiple association studies have identified numerous putative genes,
healthy control participants demonstrated that CLL has the greatest polymorphisms and genetic factors including death-associated protein
impact on survival in the most elderly group of patients. However, kinase (DAPK) and LEU7 (CD57), IRF4, BAK, CD38, CD5,
even for patients diagnosed with CLL before the age of 50 years, TNF-α and others, but weak evidence for linkage and conclusive
Montserrat and colleagues demonstrated that the median expected studies demonstrating a strong mechanistic contribution to patho-
life span is only 12.3 years compared with 31.2 years in age-matched genesis are lacking. The role of anticipation in identifying other
control participants. Thus, CLL is a significant health problem affect- family members has been reported by several groups; patients with
ing all ages of patients with this disease. such a family history are generally diagnosed a median of 10 years
CLL is more common in men than women. Women diagnosed earlier than other patients. However, other clinical features of CLL
with CLL have 5- and 10-year overall survival (OS) rates that exceed at diagnosis do not appear to be different. Thus, patients with familial
those of men. CLL is most common in whites and decreases in fre- CLL do not appear to be genetically or clinically different from
quency in a descending order among Blacks, Hispanics, American individuals with sporadic CLL.
Indians and Native Alaskans, and Asians and Pacific Islanders,
respectively. While adverse outcome based upon race has been
reported, this has not been uniformly confirmed in other studies. The PATHOBIOLOGY
rarity of CLL among Asians and Pacific Islanders persists even in
immigrants from these areas who have migrated to the Western The complexity of the biology of CLL has become increasingly appar-
Hemisphere. This implicates a possible genetic predisposition to the ent, as insight into these processes has expanded. Despite these
development of CLL. The relationship of environmental factors such advances, many questions remain unsolved, including (1) the cell of
as exposure to benzene and other chemicals to the development of origin from which CLL is derived, (2) the existence of a CLL stem
CLL is not clearly defined. However, CLL is recognized as a service- cell as occurs in other leukemias, (3) the biologic etiology of the
connected illness among Vietnam War veterans who were exposed to divergent natural histories of immunoglobulin heavy chain variable
Agent Orange. Occupational or environmental exposure to radiation regions (IGHV)-mutated versus unmutated CLL, and (4) the exis-
does not appear to predispose patients to a higher risk of developing tence and identification of infectious or other naturally occurring
CLL. For example, although the frequency of acute myeloid leukemia antigens that may drive the appearance of B-cell clone. Nonetheless,
(AML), chronic myeloid leukemia (CML), and acute lymphoblastic significant advances in our understanding of the roles of cytogenetics,
leukemia (ALL) were increased among survivors of the atomic bomb immunology, and other relevant biologic markers in predicting the
at Hiroshima, an increase in CLL was not appreciated. The recently natural history, disease progression and response to therapy in CLL

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