New disease perspectives and goals of therapy in CLL

New disease perspectives
and goals of therapy in CLL
Introduction 3
CLL overview 4
Patient population 4
Predisposing factors 4
Biology and pathophysiology 5
Clinical presentation 7
Clinical diagnosis and staging 7
Treatment initiation 9
Prognostic markers 10
Chromosomal aberrations 11
IgVH gene mutation status 12
Zeta-chain–associated protein kinase 70 (ZAP-70) 13
CD38 expression 13
Prognostic markers in current practice 13
Evolving treatment expectations 15
Evaluating outcomes 16
Minimal residual disease (MRD) 16
Considering the patient 18
Managing older patients 18
Conclusions 19
The understanding and management of patients with chronic lymphocytic leukemia (CLL) have evolved
significantly over the past several decades. Clinical management strategies for CLL have expanded beyond
palliation to improvements in long-term outcomes.
Prior to 1980, the opportunity to impact the course of the disease was limited because of the narrow
spectrum of therapeutic options and the inability to adequately assess genetic, molecular, and prognostic
features.1 Advances in the knowledge of CLL biology, new treatment and supportive care strategies, and
improved diagnostic and prognostic analyses have led to new treatment goals and a change in outlook for
patients with the disease.2
The following sections review patient characteristics, the pathophysiology of CLL, guidelines for diagnosis
and staging, treatment options, and important goals of therapy. Additional topics of discussion include new
molecular markers that are being evaluated as potential prognostic indicators.
This monograph will also explore recent advances in the understanding of CLL biology and how this
progress has led to an evolution in treatment goals and management of the disease.
CLL overview
CLL is the most common leukemia in adults in Western countries and represents approximately 25% to
30% of all adult leukemias.3,4 In the United States, an estimated 15,000 new patients were diagnosed
with CLL in 2008, while the prevalence was approximately 95,000 that same year.5
Patient population
CLL is considered to be mainly a disease of the elderly, accounting for 40% of all leukemias in patients
over the age of 65.6 The median age of diagnosis in the United States is 72 years. Approximately 8.9%
of cases are diagnosed between ages 45 and 54, and incidence rapidly increases at age 65.5 Because the
CLL patient population is often elderly, the majority of patients typically have a number of comorbidities,
such as diabetes and heart disease, that may limit treatment options.7,8
Patients with CLL vary in ethnicity, age, and gender. Geographic and ethnic differences are particularly
important. In Asian countries, CLL represents only 5% of all leukemias.3 In the United States, the
incidence is highest in Caucasian individuals, followed by African Americans and Hispanics. Asian or
Pacific Islander Americans and Native Americans (including Alaskans) have the lowest incidence of the
Men are approximately twice as likely to be diagnosed with CLL as women, and most men present with
later-stage disease. Conversely, women with CLL are more likely to present with early-stage disease and
have a better prognosis than men, regardless of stage and age.11,12
Predisposing factors
Unlike other leukemias, there is no firm evidence linking environmental or occupational exposure with the
incidence of CLL except for exposure to Agent Orange.11,13,14 However, recent research has demonstrated
an increased risk in first-degree relatives of patients with CLL. Therefore, a family history of CLL or other
lymphoproliferative disorder may also be a CLL risk factor.3,15
Biology and pathophysiology
CLL is characterized as an abnormal proliferation of malignant B lymphocytes.9 CLL was once thought to
be a homogeneous disease, in which mature B cells accumulated largely due to a lack of normal cell death.
Recently, however, CLL has been established as a heterogeneous disease of remarkable diversity. Differences
in cell morphology, immunophenotype, cytogenetics, and molecular characteristics have been identified.
This heterogeneity translates into varying clinical courses and responses to treatment.16 Figure 1 provides a
historical overview of some of the changes in how CLL biology is viewed.
Lymphocytosis is a hallmark of CLL.11 Malignant lymphocytes characteristically appear small and mature,
although large atypical cells, cleaved cells, or prolymphocytic cells are also observed.3,17 In CLL, malignant,
long-lived lymphocytes accumulate in the blood, bone marrow, spleen, and lymph nodes.4,11 The phenotype of
CLL distinguishes it from other B-cell malignancies by the presence of B-cell markers (CD19, CD20, CD23,
and CD43) along with CD5, an antigen normally found on T cells. Typically, CLL cells also express surface
immunoglobulin (slg), CD79b, CD20, and CD22 at low density.4,11 The phenotypic features of CLL are not only
used for initial diagnosis, but they also play a role in the assessment of minimal residual disease (MRD), an
important prognostic parameter defined as <1 CLL cell in 10,000 leukocytes.17
CLL is often diagnosed as an indolent disease, with a progressive accumulation of malignant lymphocytes. It
has a heterogeneous clinical course, ranging from one that does not require immediate treatment to a rapidly
progressive disease that requires aggressive management.18,19 Patients with advanced stage often present with
anemia, neutropenia, and thrombocytopenia.3 In approximately 2% to 6% of patients, the disease undergoes
a transformation to large cell lymphoma, which is referred to as Richter’s transformation. Prognosis after
transformation is poor, with a median survival of approximately 6 months.3
The range of CLL clinical presentations, combined with the often prolonged indolent course, creates unique
challenges in diagnosis and staging. Historically, many patients were not diagnosed with CLL until they
became symptomatic; today, there is greater early recognition of this disease due to improvements in patient
care and routine laboratory analysis of peripheral blood.1,20
Figure 1. Comparison of historical and current views of CLL biology21
Historical view
Current view
CLL is a clinically heterogeneous disease with
a homogeneous cellular origin.
CLL is a clinically heterogeneous disease
originating from B lymphocytes that may differ
in activation, maturity, or cellular subgroup.
CLL is a disease derived from naive B lymphocytes.
CLL is a disease derived from antigen-experienced
B lymphocytes that differ in the level of
immunoglobulin variable (v) gene mutations.
Leukemic-cell accumulation occurs because of an
inherent apoptotic defect involving the entire mass
of leukemic cells.
Investigators believe leukemic cell accumulation
occurs because of survival signals from the
external environment.
CLL is a disease of lymphocyte accumulation.
CLL is a disease of lymphocyte accumulation with
a higher associated level of proliferation than was
previously recognized.
Prognostic markers identify patients at various risk
levels (low, intermediate, or high in the Rai staging
categories, and A, B, or C in the Binet categories)
with an acknowledged heterogeneity in clinical
outcomes among patients in the low- and
intermediate-risk categories.
New molecular biomarkers are used in both
diagnosis and prognosis to better assess patients.
Adapted from Chiorazzi N et al. N Engl J Med. 2005;352:804-815.
Clinical presentation
CLL is classified based on cell morphology, immunohistochemistry, and flow cytometry. The FrenchAmerican-British classification system classifies CLL disease in the bone marrow into several groups,
referred to as diffuse, nodular, interstitial, or a combination of these groupings, based on the percentage of
abnormal cells.3,11,22 This classification system is further described in Table 1.
Table 1. Laboratory findings in CLL impacting classification11
The French-American-British classification
Typical CLL
>90% of cells are small
11%–54% of cells are prolymphocytes
Atypical CLL
Heterogeneous morphology; <10% prolymphocytes
Marrow involvement
Diffuse involvement
Usually advanced disease; worse prognosis
Nodular, interstitial, or combination
(nondiffuse involvement)
Associated with less advanced disease; better outcomes
Clinical diagnosis and staging
Today, approximately 40% of patients with CLL are diagnosed in the earlier stages of the disease and
are often asymptomatic. Many of these patients have a long symptom-free period. The remaining 60% of
patients present with a range of symptoms of which the most common are fatigue, enlarged lymph nodes,
and weight loss. However, patients may also present with lymphadenopathy or splenomegaly. Patients with
CLL have compromised immune systems and are susceptible to recurrent bacterial and viral infections.3
Figure 2. IWCLL* update of the NCI-WG criteria for diagnosing CLL17,23
Update of the NCI-WG criteria for CLL diagnosis
• A peripheral blood B-lymphocyte count of at least 5109/L, with up to 55% of the cells being prolymphocytes
• The lymphocytes should be monoclonal B lymphocytes expressing B-cell surface antigens (CD19, CD20, CD23)
with light chain restriction and the T-cell antigen CD5
• Each clone of leukemia cells is restricted to expression of either kappa or lambda immunoglobulin light chains
• Variations of the intensity of expression of these markers may exist and do not prevent inclusion of a patient in
CLL clinical trials
*International Workshop on CLL.
The International Workshop on CLL (IWCLL) update of the National Cancer Institute-sponsored Working
Group (NCI-WG) has outlined specific criteria for diagnosing CLL, as detailed in Figure 2. A number of
other B-cell malignancies cause increased circulating lymphocytes and thus need to be considered in the
differential diagnosis. Advances in flow cytometry have allowed immunophenotyping to become a routine
diagnostic tool used to differentiate CLL from other diseases, such as mantle cell and marginal zone
leukemia/lymphoma, or other leukemias/lymphomas that may resemble CLL.3,17,24
Table 2. Rai and Binet staging systems for classification of CLL18,19,25
Median survival
Rai staging system
(low risk)
Lymphocytosis only
11.5 years
(intermediate risk)
Lymphocytosis and lymphadenopathy
11.0 years
(intermediate risk)
Lymphocytosis in blood and marrow
with splenomegaly and/or hepatomegaly
(with or without lymphadenopathy)
7.8 years
(high risk)
Lymphocytosis and anemia (hemoglobin
<11 g/dL or hematocrit <33%)
5.3 years
(high risk)
Lymphocytosis and thrombocytopenia
(platelet count <100,000/mm3)
7.0 years
Enlargement of <3 lymphoid areas
(cervical, axillary, inguinal, spleen, liver);
no anemia or thrombocytopenia
11.5 years
Enlargement of ≥3 lymphoid areas
8.6 years
Anemia (hemoglobin <10 g/dL
or thrombocytopenia
platelet count <100,000/mm3), or both
7.0 years
Binet staging
Table 2 summarizes the major staging systems used for the classification of CLL: the original Rai staging
system, the modified Rai staging system, and the Binet staging system.18,19,25 The original Rai system,
published in 1975, consists of stages 0 through IV. It is based on the presence of lymphocytosis,
lymphadenopathy, organomegaly, and cytopenias.19 This staging system was later modified from a
5-tier to a 3-tier system that categorizes patients as having a low, intermediate, or high risk for disease
progression.17,25 The Binet system is also a 3-tier system, with categories A through C. It is based on a
retrospective analysis of disease burden that correlates lymphocyte count and the degree of bone marrow
infiltration with disease progression.18
Both the Rai and Binet staging systems give a general indication of prognosis. These staging systems are
static, do not take patient variability into consideration, and do not predict which patients will progress
or require therapy. Moreover, survival within each stage may vary significantly, particularly in patients
with Rai stage 0 and Binet stage A.11 In these groups, a significant percentage of patients have indolent
CLL, whereas others have more aggressive disease that may require earlier intervention.3,16,26 The median
survival of patients with Rai stage 0 disease is more than 12 years, and patients with Rai stages I and II
have median survival rates of approximately 5 to 10 years.19
Treatment initiation
Criteria exist to guide oncologists in determining when to initiate treatment in patients with CLL. The updated
IWCLL NCI-WG criteria on CLL focus on Rai and/or Binet stage when determining when to treat patients.
According to the criteria, “newly diagnosed patients with asymptomatic early-stage disease (Rai 0, Binet
A) should be monitored without therapy [watch-and-wait approach] unless they have evidence of disease
progression. . . . [P]atients [with] intermediate ([Rai] stages I and II) and high risk [disease] ([Rai] stages III
and IV) according to the modified Rai classification or at Binet stage B and C usually benefit from the initiation
of treatment. . . .” Thus, treatment according to the NCI-WG criteria depends heavily on disease stage.
However, even some later-stage patients, such as those with Rai stage III or IV or Binet stage C disease, can
also be followed without therapy until they become symptomatic or their disease progresses.17
The National Comprehensive Cancer Network (NCCN) provides more detailed guidance for treatment based
not only on stage, but also on symptomatology. NCCN guidelines suggest first classifying patients based on
the Rai staging system, then further classifying Rai low-risk and Rai intermediate-risk patients according
to a list of conditions that influence treatment, including whether the patient has autoimmune cytopenia,
recurrent infections, common B symptoms, threatened end-organ function, cytopenias, bulky disease, steady
progression, or histologic progression, as described in Figure 3.27
Figure 3. NCCN CLL indications for treatment27
NCCN CLL indications
• Significant disease-related symptoms:
— Fatigue
— Night sweats
— Weight loss
— Fever without infection
• Threatened end-organ function
• Bulky disease (spleen >6 cm beneath costal margin, lymph nodes >10 cm)
• Lymphocyte doubling time ≤6 months*
• Progressive anemia
• Platelet count <100,000 cells/mm3
• Eligible for clinical trial†
*Absolute lymphocyte count alone is not an indication for treatment.
Given incurability with conventional therapy, consider a clinical trial as first line of treatment.
Adapted from National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology:
Non-Hodgkin’s Lymphomas. V.2.2009.
Prognostic markers
The Rai and Binet staging systems are simple and reliable prognostic tools that form the basis of the decision
to treat most patients.11 However, there is considerable variation in outcome with each stage. Therefore,
additional factors are more commonly being considered in predicting individual patient prognosis and
stratifying patient risks.
The World Health Organization (WHO) publications and NCI-WG criteria suggest a number of disease activity
markers, such as b2-microglobulin, CD23, rapid lymphocyte doubling time, and serum thymidine kinase,
for use in predicting patient outcomes.4,17 In addition, recent advances have identified additional biologic
markers, such as IgVH mutational status, chromosomal aberrations, and expression of zeta-chain–associated
protein kinase 70 (ZAP-70) and CD38, that complement the conventional prognostic factors previously
described.17 These additional biomarkers may be used in conjunction with staging to potentially predict
outcome or level of tumor burden, as described in Table 3.17
Table 3. Markers that identify poor prognosis in CLL4,11
Routinely available markers
Advanced Rai or Binet stage
Atypical morphology
Peripheral lymphocyte doubling time <12 months
Serum markers: elevated thymidine kinase and sCD23
Immunophenotyping: dim surface IgM/IgD, CD20+, CD22+, CD5+, CD19+, CD79a+, CD23+, CD43+
High β2-microglobulin level
Diffuse marrow histology
Poor response to chemotherapy
Investigational markers
Lack of IgVH gene mutation
Expression of ZAP-70 protein
FISH studies showing trisomy 12q, del 11q, del 17p, del 6q
sCD23=soluble CD23; FISH=fluorescence in situ hybridization.
Chromosomal aberrations
No single genetic mutation or abnormality responsible for CLL development has been identified. Rather,
the disease is characterized by a variety of chromosomal abnormalities. These may be detected in 40% to
50% of patients using chromosome banding and in approximately 80% of patients using fluorescence in
situ hybridization (FISH) analysis.3 The most common genetic aberration identified by FISH in untreated
CLL patients is the 13q deletion, which is found in 55% of patients.28 The next most common aberrations
are 11q deletion, trisomy 12q, and 17p deletion, found in 18%, 16%, and 7% of patients, respectively.28
Genetic aberrations are important predictors of disease outcome; specifically, deletions of 17p and 11q
have been associated with poor survival.28 In a study of 325 patients with CLL, chromosomal deletion at
17p predicted aggressive disease, with patients surviving an average of less than 3 years. Patients with the
11q deletion also had a poor overall prognosis, with a median survival of less than 7 years. Patients with a
13q deletion had a median survival of 11 years and, therefore, more favorable outcomes.28 The impact of
genetic abnormalities on overall survival (OS) of CLL patients is shown in Figure 4.
Figure 4. Prognostic implication of chromosomal abnormalities28
Prognostic implication of chromosomal abnormalities
Estimated survival probability
13q– single
13q– single
Overall survival (months)
Adapted from Döhner H et al. N Engl J Med. 2000;343:1910-1916.
IgVH gene mutation status
It has been suggested that there are 2 types of CLL, characterized by the presence or absence of a
mutated immunoglobulin variable region (IgVH), which follow distinct clinical courses. These are depicted
in Figure 5.
CLL patients can be divided into 2 prognostic groups based on mutation status.29,30 The IgVH mutated
group has an approximate survival of 25 years, while the IgVH unmutated group has a more aggressive
clinical course and an approximate survival of 10 years.30 Patients with IgVH gene mutations are also
more likely to have a 13q deletion and a good prognosis, whereas those without IgVH gene mutations more
frequently have trisomy 12q and a poorer prognosis.31,32
Although there is an established correlation between IgVH mutation status and prognosis, assays to detect
mutation status are not broadly available.33-36 Thus, other laboratory tests are used as surrogate markers but
are still under investigation.33,34
Figure 5. Schematic of selected biologic differences between IgVH unmutated CLL B-cell clones and IgVH
mutated CLL B-cell clones37
Schematic of selected biological differences between IgVH unmutated
and mutated CLL B-cell clones
Median survival 8 to 10 years
Median survival 25 years
Low CD38
High CD38
Unmutated lgVH
p53 defects
Mutated lgVH
Low ZAP-70
High ZAP-70
FISH (ie, 17p–; 11q–)
FISH (ie, 13q–)
Adapted from Shanafelt TD et al. Blood. 2004;103:1202-1210. Blood: journal of the American Society of
Hematology Copyright 2004 by AMERICAN SOCIETY OF HEMATOLOGY (ASH). Reproduced with permission of
AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Internet posting via Copyright Clearance Center.
Zeta-chain–associated protein kinase 70 (ZAP-70)
ZAP-70 is a member of the Syk-ZAP-70 protein kinase family. This kinase is normally expressed in
T and natural killer (NK) cells, and it plays a role in initiating T-cell signaling and in signaling through
the B-cell receptor of CLL cells.34,38 Recent research exploring ZAP-70 as a potential surrogate marker
for IgVH gene mutation status has indicated that ZAP-70 overexpression is correlated with an unmutated
IgVH and is predictive of poorer outcomes in CLL.33,34,38,39 ZAP-70 expression may be measured by flow
cytometry, Western blotting, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), and
immunohistochemistry.38,39 Currently, assays examining ZAP-70 expression are inconsistent, with no clear
guidelines for use. In addition, the correlation between ZAP-70 and outcomes, and its subsequent use as a
marker for treatment decisions, remains subject to ongoing debate.17
In an investigation evaluating ZAP-70 expression as a surrogate for IgVH mutation status, ZAP-70
expression correctly identified 91% of patients with unmutated IgVH genes, and no patient with mutated
IgVH genes overexpressed ZAP-70.38 Overall, there is a strong correlation between ZAP-70 expression and
IgVH mutation; however, because ZAP-70 expression has been found to remain unchanged over time, some
oncologists believe it to have independent prognostic value.34,38,40
CD38 expression
CD38 expression on CLL cells has been correlated with IgVH mutations.29 Because CD38 cell-surface
expression can be easily detected by flow cytometry, CD38 expression has been suggested as a
surrogate marker for determining IgVH mutation status in CLL.29 However, studies have not supported
the role of CD38 as the desired surrogate. This work has indicated that the relationship between CD38
expression and IgVH mutation is not absolute and may be discordant in approximately 30% of cases.34,41
Furthermore, CD38 expression may also fluctuate in patients, with karyotype evolution occurring in 15%
to 40% of patients.32 CD38 expression and IgVH mutation status are considered independent prognostic
indicators.34,41 In addition, CD38 correlation with outcomes and subsequent use as a marker for treatment
remains subject to ongoing debate.17,35
ZAP-70 and CD38 expression may ultimately provide complementary prognostic information; however,
neither CD38 nor ZAP-70 assays are widely used outside of clinical trials.17,34
Prognostic markers in current practice
The recent IWCLL updated the NCI-WG criteria for diagnosis and treatment of patients with CLL to include
standard prognostic indicators and possibly a CLL-relevant FISH panel in general practice (Table 4). Although
still under debate, the current NCI-WG criteria further recommend that some of the newer molecular
biomarkers, such as CD38, IgVH mutation status, and ZAP-70, as mentioned previously, be included in
clinical trials.17
Prospective CLL studies that include the newly identified biomarkers will continue to refine the understanding
of the clinical behavior and biology of this disease, and will be pivotal in the future refinement of new treatment
strategies. Once these assays are perfected and incorporated into clinical practice, they are likely to guide
patient management decisions.35
Chromosomal abnormalities, IgVH mutation status, and ZAP-70 and CD38 expression may ultimately be
combined with more established prognostic indicators, such as lymphocyte doubling time, to predict the
clinical course of patients.16 In addition, consideration of response to therapy and the eradication of MRD
may be used to help predict patient outcomes.42 These indicators may guide patient stratification into lowand high-risk populations, optimizing the clinician’s ability to individualize treatment strategies to achieve
greater clinical goals.17
Table 4. IWCLL update of the NCI-WG recommendations for pretreatment evaluations of patients with CLL17
Diagnostic test
General practice*
Clinical trial
Complete blood count and differntial count
Immunophenotyping of lymphocytes
History and physical, performance status
Complete blood count and differential
Marrow aspirate and biopsy
Serum chemistry, serum immunoglobulin, direct antiglobulin test
Chest radiograph
Infectious disease status
Cytogenetics (FISH) for del 13q, del 11q, del 17p, trisomy 12q,
del 6q in the peripheral blood lymphocytes
IgVH mutation status, ZAP-70, and CD38
CT scan of chest, abdomen, and pelvis
MRI, lymphangiogram, gallium scan, PET scans
Abdominal ultrasound
Tests to establish diagnosis
Assessment before treatment
Additional tests before treatment
NGI=not generally indicated.
*The use of accepted options for a patient with CLL who is not enrolled in a clinical trial. Adapted from Hallek M et al.
Blood. 2008;111:5446-5456.
Evolving treatment expectations
In the past 10 years, the CLL therapeutic landscape has dramatically evolved, as shown in Figure 6.
Treatment options expanded from the use of alkylating agent monotherapy in the 1960s and 1970s to the
introduction of purine analogs, and moved to combination therapy in the 1980s and 1990s. In the current
decade, treatment strategies have expanded to include immunotherapy.3,43
Figure 6. CLL treatment overview by decade44
CLL treatment overview by decade
Alkylating agents
and alkylators
Adapted from Kay NE. Blood. 2006;107:848. Blood: journal of the American Society of Hematology Copyright 2004 by
in the format Internet posting via Copyright Clearance Center.
The expansion of the therapeutic landscape has shifted CLL treatment expectations to include both
palliative care and symptom management as well as therapy with more response-driven intent. Recent
treatment strategies have focused on achieving higher and better quality response rates and longer
progression-free survival (PFS).45-49 As advances in CLL clinical research have continued to progress into
the new millennium, treatment goals have included achieving longer survival as well as improved quality
and duration of complete remission, with the hope of achieving MRD negativity.50 As shown in Figure 7,
oncologists have begun to expect CLL therapy to result in improvements in outcomes—beyond response
rates and into PFS and MRD negativity. As research continues to refine the treatment goals for patients
with CLL, the progress in CLL achieved over the past 3 decades is likely to continue.
Figure 7. CLL treatment expectations by decade51,52
Goals of treatment for CLL have evolved over time
Palliation, higher CR, FFP
response rates
PFS, MRD-negative CR
FFP=freedom from progression.
Evaluating outcomes
The NCI-WG recently updated the standard CLL response criteria (shown in Table 5). This update confirms
the use of conventional biomarkers, defines new prognostic and predictive markers, and diagnostic
parameters, and accommodates new treatment goals and options.17 Until recently, response to therapy,
or overall response rate (ORR), in CLL was determined using the 1996 NCI-WG response criteria defining
complete remission, partial response (PR), stable disease (SD), and progressive disease (PD).17,23 However,
most current clinical trials have also included more sensitive evaluation techniques that have since become
available.17 These newer publications include reports on complete molecular remission as well as the
standard designations of overall response (OR), complete response (CR), and PR.17
The incorporation of MRD testing allows oncologists to more closely examine the quality of response
to therapy. Improvements in PFS have been observed in patients who achieve CR, and even greater
improvements for those achieving MRD negativity.24,42 This has prompted reevaluation of treatment
paradigms to include more vigilant monitoring of the depth of CR through MRD analysis.42
Minimal residual disease (MRD)
Today, MRD negativity is emerging as an important treatment assessment. Despite the growing consensus
regarding the importance of MRD negativity and its possible correlation with long-term treatment outcomes,
MRD assessment is not widely used.3 MRD negativity is the eradication of disease to undetectable levels,
defined as <1 CLL cell in 10,000 leukocytes.17 Because MRD assessment leads to a more accurate
prognosis, it has been added to the NCI-WG criteria for clinical trials as a goal of therapy.17
Patients who achieve MRD negativity after therapy usually have a better prognosis than those with lowerquality responses to therapy.53,54 In clinical studies, it has been reported that CLL patients achieving
MRD-negative status generally had longer disease-free periods and better OS than MRD-positive patients.
These findings stress the importance of eradicating disease at the molecular level.53,54 MRD negativity may,
therefore, become a decisive indicator of treatment success.42
Table 5. 2008 revision of the NCI-WG criteria for response in CLL17
Treatment goals in CLL
Complete response (CR)
At ≥2 months posttherapy:
• Absence of lymphadenopathy >1.5 cm, hepatomegaly, splenomegaly,
and constitutional symptoms
• Normalization of CBC (neutrophils >1,500/µL, platelets >100,000/µL,
hemoglobin >11 g/dL)
• Lymphocytes <4,000/µL
• Additional assessments in clinical trials:
- Minimal residual disease (MRD) <1 CLL cell per 10,000 leukocytes
- Bone marrow biopsy shows normal cellularity, lymphocytes <30%
Partial response (PR)
At ≥2 months posttherapy:
• A decrease in the number of blood lymphocytes by ≥50% from the value
before therapy
• Reduction in lymphadenopathy (by CT scans in clinical trials or by palpation
in clinical practice) as defined by
- Decrease in lymph node size by ≥50%
- No increase in any lymph node, and no new enlarged node(s) detected
• Normalization of CBC (neutrophils >1,500/µL or 50% improvement over
baseline; platelets >100,00/µL or 50% improvement over baseline;
hemoglobin >11 g/dL or ≥50% over baseline)
Stable disease (SD)
No CR or PR, no progressive disease
Progressive disease (PD)
At least 1 of the following:
• Lymphadenopathy (≥50% increase)
• ≥50% increase in hepatomegaly or splenomegaly
• Transformation to a more aggresive histology (Richter’s transformation)
• Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia)
attributable to CLL
Progressive-free survival (PFS)
The time from study entry until objective disease progression or death
Treatment failure
Includes the following responses:
• Stable disease
• Nonresponse
• Progressive disease
• Death from any cause
Patient achieved CR or PR but at ≥6 months shows evidence of
disease progression
Treatment failure or disease progression within 6 months of the last
antileukemic therapy
Minimal residual disease (MRD)
For patients who have achieved a CR, eradication of disease cells as
determined by flow cytometry or PCR (<1 CLL cell per 10,000 leukocytes)
Adapted from Hallek M et al. Blood. 2008;111:5446-5456.
Considering the patient
Fine-tuning treatment and goals of therapy based on the unique characteristics of each patient is an
important consideration in CLL management. Medical fitness, age, and the ability to tolerate aggressive
therapy are critical and interrelated patient characteristics that should all be considered when choosing a
treatment regimen.
Medical fitness is receiving greater attention in CLL treatment planning. Medically fit patients have normal
organ function, no additional health problems or only mild, nondebilitating health problems, and a good
performance status. Conversely, medically unfit patients may present with a worse performance status or
reduced organ function, as well as multiple or severe comorbidities that should be considered in treatment
Age is another critical factor when individualizing treatment goals. However, the effects of aging differ
greatly among individuals, and treatment plans should account for this diversity. Younger patients typically
have good medical fitness with few comorbidities. Conversely, the majority of CLL patients present at an
older age and may have significant comorbidities. However, age does not automatically dictate medical
unfitness. Therefore, regardless of a patient’s age, the patient’s medical history should be considered.
Thus, a treatment algorithm should not be devised based exclusively on patient age.3,8
Managing older patients
The management of older patients with CLL involves identifying those who may tolerate and benefit from
more aggressive therapy.8 Data are emerging that confirm many patients over 65 are able to tolerate
and benefit from more aggressive therapy.56 However, many oncologists believe that the toxicity of some
therapies is not well tolerated by patients 70 years or older.2
While age has been defined as an important factor in selecting optimal treatment strategies, it should
also be recognized that there is significant heterogeneity in the elderly population with regards to medical
fitness and the risk of disease progression. Thus, a one-size-fits-all approach to the treatment of this
patient population may not be ideal. Devising treatment strategies for elderly patients is also made difficult
by the fact that this population is often underrepresented in clinical trials. In a recent review of available
scientific literature pertaining to elderly CLL patients, Eichhorst et al concluded that medically fit patients
with no or mild comorbidity and normal life expectancy should be treated intensively irrespective of their
chronological age.2
Over the past 3 decades, an increased understanding of the biology of CLL, advances in diagnostic and
prognostic analyses, new treatment strategies, and better supportive care have all led to improved patient
outcomes.1 The conventional view of CLL as a disease treated with palliation has now evolved to focus on
improving long-term patient outcomes.1,57
CLL treatments have expanded from alkylating agents, to combining purine analogs with alkylators, to the
addition of immunotherapy. This increase in treatment options has resulted in a concomitant increase in
complete response rates compared with prior generations of therapy.1 Today, the goals of treatment for
patients with CLL include high-quality responses, including CR with MRD negativity, duration of response,
and PFS.17
Oncologists have begun to refine and tailor treatment strategies for a more individualized approach that
is based on patient characteristics. Ongoing scientific research in this field will continue to contribute to
improved outcomes in CLL over the coming decades.
References: 1. Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood.
2008;111:4916-4921. 2. Eichhorst B, Goede V, Hallek M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50:171-178. 3. Wierda WG,
Keating MJ, O’Brien S. Chronic lymphocytic leukemias. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer Principles & Practice of Oncology. 8th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2008:2278-2292. 4. Müller-Hermelink HK, Montserrat E, Catovsky D, et al. Chronic lymphocytic leukaemia/small lymphocytic lymphoma.
In: Swerdlow SH, Campo E, Harris NL, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research
on Cancer; 2008:180-182. 5. Horner MJ, Ries LAG, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2006.
Accessed May 15, 2009. 6. British Society for Haematology. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol. 2004;125:294-317.
7. Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma.
2008;49:49-56. 8. Extermann M, Overcash J, Lyman GH, et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol. 1998;16:1582-1587.
9. Watson L, Wyld P, Catovsky D. Disease burden of chronic lymphocytic leukaemia within the European Union. Eur J Haematol. 2008;81:253-258. 10. Zent CS, Kyasa MJ,
Evans R, et al. Chronic lymphocytic leukemia incidence is substantially higher than estimated from tumor registry data. Cancer. 2001;92:1325-1330. 11. Johnston JB, Seftel M,
Gibson SB. Chronic lymphocytic leukemia. In: Greer JP, Foerster J, Rodgers GM, et al, eds. Wintrobe’s Clinical Hematology. 12th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2009:2214-2255. 12. Catovsky D, Fooks J, Richards S; for MRC Working Party on Leukaemia in Adults. Prognostic factors in chronic lymphocytic leukaemia: the
importance of age, sex and response to treatment in survival. Br J Haematol. 1989;72:141-149. 13. Dawson G. Chronic lymphocytic leukemia associated with Agent Orange.
J Natl Med Assoc. 2003;95:A21. 14. Chamie K, DeVere White RW, Lee D, et al. Agent Orange exposure, Vietnam War veterans, and the risk of prostate cancer. Cancer.
2008;113:2464-2470. 15. Rawstron AC, Yuille MR, Fuller J, et al. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood.
2002;100:2289-2291. 16. Wierda WG, O’Brien S, Wang X, et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic
leukemia. Blood. 2007;109:4679-4685. 17. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from
the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446-5456. 18. Binet JL,
Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198-206. 19. Rai KR,
Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219-234. 20. CLL Trialists’ Collaborative Group. Chemotherapeutic options in
chronic lymphocytic leukemia: a meta-analysis of the randomized trials. J Natl Cancer Inst. 1999;91:861-868. 21. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic
leukemia. N Engl J Med. 2005;352:804-815. 22. Bennett JM, Catovsky D, Daniel MT, et al; for French-American-British (FAB) Cooperative Group. Proposals for the classification of
chronic (mature) B and T lymphoid leukaemias. J Clin Pathol. 1989;42:567-584. 23. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group
guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87:4990-4997. 24. Rawstron AC, Villamor N, Ritgen M, et al.
International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007;21:956-964. 25. Rai KR. A critical
analysis of staging in CLL. In: Gale PR, Rai KR, eds. Chronic Lymphocytic Leukemia: Recent Progress and Future Direction. New York, NY: Alan R. Liss, Inc.; 1987:253-264.
26. French Cooperative Group on Chronic Lymphocytic Leukaemia. Natural history of stage A chronic lymphocytic leukaemia untreated patients. Br J Haematol. 1990;76:45-57.
27. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas.
nhl.pdf. V.2.2009. Accessed May 1, 2009. 28. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med.
2000;343:1910-1916. 29. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.
Blood. 1999;94:1840-1847. 30. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia.
Blood. 1999;94:1848-1854. 31. Kröber A, Seiler T, Benner A, et al. VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic
leukemia. Blood. 2002;100:1410-1416. 32. Oscier DG, Gardiner AC, Mould SJ, et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational
status, and loss or mutation of the p53 gene are independent prognostic factors. Blood. 2002;100:1177-1184. 33. Orchard JA, Ibbotson RE, Davis Z, et al. ZAP-70 expression and
prognosis in chronic lymphocytic leukaemia. Lancet. 2004;363:105-111. 34. Del Principe MI, Del Poeta G, Buccisano F, et al. Clinical significance of ZAP-70 protein expression in
B-cell chronic lymphocytic leukemia. Blood. 2006;108:853-861. 35. Hus I, Podhorecka M, Bojarska-Junak A, et al. The clinical significance of ZAP-70 and CD38 expression in
B-cell chronic lymphocytic leukaemia. Ann Oncol. 2006;17:683-690. 36. Shanafelt TD, Jenkins G, Call TG, et al. Validation of a new prognostic index for patients with chronic
lymphocytic leukemia. Cancer. 2009;115:363-372. 37. Shanafelt TD, Geyer SM, Kay NE. Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for
patients with CLL. Blood. 2004;103:1202-1210. 38. Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in
chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764-1775. 39. Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia
subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2003;101:4944-4951. 40. Rassenti LZ, Huynh L, Toy TL,
et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med.
2004;351:893-901. 41. Hamblin TJ, Orchard JA, Ibbotson RE, et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in
chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood. 2002;99:1023-1029. 42. Rawstron AC, Kennedy B, Evans PAS, et al.
Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize
therapy. Blood. 2001;98:29-35. 43. US Food and Drug Administration Web site. Drugs at FDA: FDA approved drug products.
DrugsatFDA/index.cfm?fuseaction=Search.SearchResults_Browse&StartRow=201&StepSize=100. Accessed March 13, 2009. 44. Kay NE. Treatment and evaluation of CLL:
a complicated affair. Blood. 2006;107:848. 45. International Workshop on Chronic Lymphocytic Leukemia. Chronic lymphocytic leukemia: recommendations for diagnosis,
staging, and response criteria. Ann Intern Med. 1989;110:236-238. 46. Montserrat E, Alcalá A, Parody R, et al. A randomized trial comparing chlorambucil plus prednisone versus
cyclophosphamide, vincristine, and prednisone. Cancer. 1985;56:2369-2375. 47. Leporrier M, Chevret S, Cazin B, et al. Randomized comparison of fludarabine, CAP, and ChOP
in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001;98:2319-2325. 48. Keating MJ, O’Brien S, Kantarjian H, et al. Long-term
follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. Blood. 1993;81:2878-2884. 49. Rai KR, Peterson BL, Appelbaum FR, et al.
Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343:1750-1757. 50. Hillmen P, Skotnicki AB, Robak T, et al.
Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-5623. 51. Montserrat E. Treatment of chronic
lymphocytic leukemia: achieving minimal residual disease–negative status as a goal. J Clin Oncol. 2005;23:2884-2885. 52. Montserrat E. CLL therapy: progress at last!
Blood. 2005;105:2-3. 53. Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy
is associated with prolonged survival. J Clin Oncol. 2005;23:2971-2979. 54. Bosch F, Ferrer A, López-Guillermo A, et al. Fludarabine, cyclophosphamide and mitoxantrone
in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002;119:976-984. 55. Goede V, Hallek M. State-of-the-art treatment of chronic
lymphocytic leukaemia. EJHP Pract. 2008;14:69-71. 56. Fabbri A, Lenoci M, Gozzetti A, et al. Low-dose oral fludarabine plus cyclophosphamide in elderly patients with chronic
lymphoproliferative disorders. Hematol J. 2004;5:472-474. 57. Mentzer SJ, Osteen RT, Starnes HF, et al. Splenic enlargement and hyperfunction as indications for splenectomy
in chronic leukemia. Ann Surg. 1987;205:13-17.
© 2010 Genentech USA, Inc. All rights reserved. GA10000084200 Printed in USA.