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Chapter 77 Chronic Lymphocytic Leukemia 1247

CLINICAL MANIFESTATIONS
Initial Evaluation of Young Patients With Chronic Lymphocytic
Leukemia
At diagnosis, most CLL patients do not have clinical manifestations
associated with their disease. For early stage CLL patients, the diag- Only 10% of patients diagnosed with CLL are younger than 50 years
nosis is often identified as part of routine blood tests for evaluation of age, and these patients often present a diagnostic and therapeutic
of an unrelated problem such as an infection, kidney stones, or during dilemma to hematologists initially evaluating them. The great majority
a preoperative assessment in which an elevated leukocyte count is of patients diagnosed before the age of 50 years will have early-stage
noted with increased mature lymphocytes observed. For a much CLL with a slightly higher predisposition to a prior first-generation
smaller subset of patients with CLL, presentation of disease occurs as relative with this disease. In addition, these patients are generally of
a consequence of fatigue, weight loss, early satiety (from spleen a higher economic status or have chronic fatigue or medical illnesses
enlargement), petechiae (from low platelets), or new palpable lymph for which they have been undergoing routine blood testing, leading to
diagnosis of CLL. When the diagnosis of CLL is made, these younger
nodes. Patients with symptomatic CLL at diagnosis represent only patients have a more challenging time understanding how the disease
15% of those seen, corresponding to the more indolent nature of this will impact them. For patients with no symptoms referable to CLL, we
disease at diagnosis. With additional follow-up, the majority of CLL generally discuss complications of the disease during the first visit and
patients will eventually manifest symptoms of the disease that ulti- have a detailed discussion regarding assessment of genetic risk factors
mately lead to the need for treatment. The most common symptoms predisposing to early disease progression, including select interphase
associated with progression include increasing fatigue (as a conse- chromosomal abnormalities (del[17p13.1] and del[11q22.3]) and
quence of anemia and cytokines elaborated by the involved tissues), IGHV mutational status (unmutated). During this time, it is important
increasing lymph node and spleen size, worsening hematologic to counsel patients that identification of high-risk genomic features
parameters (anemia and thrombocytopenia), and rarely infiltration of can actually increase anxiety because no treatment intervention is
indicated in the absence of symptoms, regardless of genomic profile,
other organs (kidney, lung, pleural space, skin) that necessitates initia- outside of a clinical trial. In our experience, the great majority of
tion of treatment to palliate symptoms. Symptoms generally associ- patients desire this testing. Despite the potential benefit of allogeneic
ated with CLL progression are night sweats, fevers, and weight loss. stem cell transplantation in younger patients with CLL, we generally
These are generally suggestive of Richter transformation. mention this only as one treatment option used in this disease and
Separate from direct CLL progression, the disease is also immuno- do not pursue consultation or tissue typing of patients or siblings
suppressive, and with more advanced disease, an increase in infections until patients are truly symptomatic from their disease. We provide
is generally observed. This represents a major morbidity of CLL and considerable discussion about the promising but early data with kinase
is a leading contribution to mortality associated with this disease. inhibitors currently approved and other promising novel molecules
Other manifestations of immune suppression, including higher rate and therapies available in clinical trials. During the second visit 4 to
6 weeks later, we review the results of these prognostic factors and
of secondary malignancies and autoimmune complications. answer additional questions that have arisen. 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.
DIAGNOSIS AND LABORATORY MANIFESTATIONS Serial assessment of the psychologic well-being of patients with CLL
during this first year is incredibly important. At no place during the
The diagnosis of CLL, as defined by the IWCLL 2008 criteria, evaluation do we refer to CLL as being a good or favorable leukemia.
requires an absolute malignant B-cell lymphocyte count of greater In our experience, the most common reason for dissatisfaction toward
than 5000/µL that coexpress CD5 and CD23 on immunophenotyp- the initial hematology evaluation is lack of explanation of the disease
ing. Morphologically, the lymphocytes appear mature with fewer process or the minimization of CLL as a “good leukemia to have.”
For young patients presenting with other chronic medical problems
than 55% prolymphocytes (Fig. 77.2A–E). The BM aspirate smear who are asymptomatic from their CLL, we follow the approach outlined
if done, should show greater than 30% of all nucleated cells to be earlier. More commonly, these patients have fatigue, mild anemia, or
lymphoid, or the BM core biopsy shows lymphoid infiltrates consis- other symptoms that could be attributable to the CLL. In addition, this
tent with CLL (Fig. 77.2F–G). The overall cellularity is normocellular group is more commonly overweight or obese. In either setting, it is
or hypercellular. Immunophenotyping reveals a predominant B-cell important to first think like an internist and pursue other causes for
monoclonal population coexpressing the B-cell markers CD19, symptoms potentially attributable to CLL. In particular, encouragement
CD20, and CD23 and the T-cell antigen CD5 in the absence of other of both weight loss and a fixed exercise plan should be encouraged
pan-T cell markers (see later section). In some cases, a hypocellular for fatigue and often improve quality of life and in other medical
marrow can be present as an artifact of marrow aspiration. comorbidities. In some cases here, methylphenidate can be effective
for the management of CLL related fatigue. It is very important to note
Patients may present with tumor cells immunophenotypically that younger patients with CLL can often go a decade or more without
consistent with CLL but have predominantly lymph node disease therapy and early treatment of this patient group in the absence of
without a peripheral B-cell lymphocyte count of 5000/µL despite symptoms still offers no proven long-term advantage. For this reason,
BM involvement. Although these patients are considered to have our group remains very conservative on starting therapy for young
small lymphocytic lymphoma (SLL) and not true CLL by the patients with CLL unless they have high-risk disease and are treated
National Cancer Institute criteria, the most recent World Health on a clinical trial.
Organization classification considers such SLL patients to have CLL,
given the similar immunophenotypic features, genetic findings,
natural history, and complications of these two diseases. The clinical
management of SLL patients should be similar to CLL with respect have been recognized than in the past with many patients being
to diagnostic testing and treatment. downstaged from early CLL to MBL. Similar to the relationship of
The recent increase in diagnostic blood testing for other B-cell monoclonal gammopathy of undetermined significance and multiple
lymphoid cancers has led to recognition of a clinical precursor to CLL myeloma, it appears that only a small proportion of patients with
called MBL. Patients with MBL have circulating peripheral B cells MBL develop overt CLL over time. Whereas genetic features such as
immunophenotypically consistent with CLL but do not have enlarged IGHV mutational status and cytogenetic abnormalities may predict
lymph nodes, a malignant lymphocyte count greater than 5000/µL, progression of CLL, it is unclear if these tests bear any relevance to
or cytopenias. The frequency of MBL increases with age; 0.3% of predicting MBL progression to CLL. For this reason, we generally do
patients younger than the age of 40 years have MBL compared with not perform these tests in MBL patients. Interestingly, these patients
2.1% of 40- to 60-year-old patients and 5.2% of 60- to 90-year-old have many of the long-term complications of CLL related to immune
patients. The frequency of MBL in family members of patients with suppression including a higher frequency of infections and also sec-
a first-degree relative with CLL is significantly higher in both young ondary malignancies. We therefore approach the initial counseling of
and older patients. With the new IWCLL 2008 definition of CLL these patients similar to newly diagnosed CLL patients with respect
requiring 5000/µL malignant B lymphocytes, more cases of MBL to interventions (vaccines and education) to minimize these