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Emerging Management Strategies for
Chronic
Lymphocytic
Leukemia
IN HIGH-RISK PATIENTS
Sponsored by the
This activity is supported by
educational grants from
GlaxoSmithKline, Genentech
and Genzyme
Emerging Management Strategies for
Chronic Lymphocytic Leukemia
IN HIGH-RISK PATIENTS
Faculty
Thomas J. Kipps, MD, PhD is the Evelyn and Edwin
Tasch Chair in Cancer Research, a UCSD Professor of
Medicine, and the Deputy Director of Research at the
Moores UCSD Cancer Center in La
Jolla, California. He received his
PhD in Immunology and MD from
Harvard University and completed
his residency and fellowship training
in Internal Medicine, Hematology,
and Genetics at Stanford University.
Prior to serving in his current positions, Dr. Kipps was
Head of Hematology and Oncology, Associate Director of
the Gene Therapy Program, Director of the Translational
Research Program, and Director of the Immunology
Department at UCSD.
Dr. Kipps has a national and international reputation
for his work in cancer research, immunology, and gene
therapy. He is the author of more than 200 publications
and is the PI on several peer-reviewed grants, including
an award from NCI/NIH to fund the Chronic Lymphocytic
Leukemia Consortium (CRC). The CRC involves
collaboration with 8 other Cancer Centers around the
nation. Dr. Kipps has over 20 years experience in
combining research and clinical care responsibilities.
Kanti R. Rai, MD is Chief, Division of Hematology-
Oncology at the Long Island Jewish Medical Center in
New Hyde Park, New York, and the Joel Finkelstein
Cancer Foundation Professor of
Medicine at the Albert Einstein College
of Medicine in the Bronx, New York.
In 1955, he received his MB, BS from
SMS Medical College, University of
Rajasthan, Jaipur, India, after which
he did his residency in pediatrics at
Lincoln Hospital of the City of New York, Bronx, New
York. Dr. Rai then became Chief Resident in Pediatrics
at the North Shore Hospital, in Manhasset, New York in
1958. He followed his residency as a Fellow in Nuclear
Medicine and Hematology at the Long Island Jewish
Hospital in 1959, and then became Research Associate in
Hematology at Brookhaven National Laboratory Medical
Research Center in Upton, New York.
Before assuming his current position, Dr. Rai served
as Chief, Division of Experimental Medicine, Institute
of Nuclear Medicine, New Delhi, India, and then as
Associate Scientist at Brookhaven National Laboratory.
He has also served as Associate Professor of Medicine
(1972-80) and Professor of Medicine (1980-1989) at
the School of Medicine, State University of New York at
Stony Brook, as well as Joel Finkelstein Cancer Foundation
Professor of Medicine (1989-2004), Albert Einstein
College of Medicine. He has been Chief at the Division
of Hematology-Oncology at Long Island Jewish Medical
Center since 1981. Dr. Rai is Certified by the American
Board of Pediatrics.
Dr. Rai has received numerous awards, among which are
the Eastern Leukemia Society Scholar, National Leukemia
Association Scholar, Helena Rubenstein Foundation
Leukemia Research Award, Joel Finkelstein Cancer
Foundation Man of the Year Award, and the Peter Jay
Sharp Foundation Award for CLL Research. He has
served as Co-chair on the Medical Advisory Board of the
Lauri Strauss Leukemia Foundation, and he is a Founding
Member and Co-chair of the International Workshop
on CLL, as well as a member of the NCI-sponsored
Working Group on CLL.
Dr. Rai’s major interests focus on hematological
malignancies, prognostic markers and improved therapy
for CLL.
Lead Nurse Planner
Carol Marietta, NP
Nurse Practitioner
Rancho Mirage, California
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Emerging Management Strategies for
Chronic Lymphocytic Leukemia
IN HIGH-RISK PATIENTS
Intended Audience
This activity was developed for hematologists, oncologists, NPs, RNs, and other
health care professionals working with patients with CLL.
Statement of Need
A number of new therapies have become available and new combination regimens
have been studied for the treatment of CLL in the past few years, yet standard
first- and second-line treatments have yet to be established. Community
hematologists/oncologists are challenged to keep abreast of the latest clinical
study data and expert recommendations on these new treatments or emerging
combination regimens. There are also new tools available for testing for prognostic
markers, and recommendations about which treatment regimens should be used
based on individual patient risk profiles.
Learning Objectives
Upon completion of this activity, participants should be able to:
■
Utilize appropriate tests and biomarkers to
quickly and accurately diagnose, stage, and do
risk assessment for patients with CLL
■
Design optimal treatment protocols for individual patients
■
Provide appropriate supportive care for patients
■
Incorporate data from clinical trials to guide
adoption of new treatment options when available
and appropriate
Nursing Learning Objectives
Upon completion of this activity, participants should be able to:
■
Incorporate new data into their work to enhance
their care of patients and families
This activity will address professional practice gaps in knowledge.
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Emerging Management Strategies for
Chronic Lymphocytic Leukemia
IN HIGH-RISK PATIENTS
Accreditation and Certification
The Annenberg Center for Health Sciences at Eisenhower is
accredited by the Accreditation Council for Continuing Medical
Education to provide continuing medical education for physicians.
The Annenberg Center designates this educational activity for
a maximum of 1 AMA PRA Category 1 Credit . Physicians
should only claim credit commensurate with the extent of their
participation in the activity.
Annenberg Center for Health Sciences is accredited as a
provider of continuing nursing education by the American
Nurses Credentialing Center’s Commission on Accreditation.
The faculty for this activity have disclosed that there
will be discussion about the use of products for non-FDA
approved indications.
Additional content planners: In accordance with the
Accreditation Council for Continuing Medical Education
Standards, parallel documents from other accrediting bodies,
and Annenberg Center policy, the following disclosures
have been made:
The following have no significant relationship to disclose:
Joel Legunn (Medical Writer)
Carol Marietta, NP (Lead Nurse Planner)
A maximum of 1 contact hour may be earned for successful
completion of this activity.
All staff at the Annenberg Center for Health Sciences at
Eisenhower have nothing to disclose.
There is no charge for this activity. Statements of Credit may
be printed online.
The ideas and opinions presented in this educational activity
are those of the faculty and do not necessarily reflect the
views of the Annenberg Center and/or its agents. As in all
educational activities, we encourage practitioners to use their
own judgment in treating and addressing the needs of each
individual patient, taking into account that patient’s unique
clinical situation. The Annenberg Center disclaims all liability
and cannot be held responsible for any problems that may
arise from participating in this activity or following treatment
recommendations presented.
Disclosure
It is the policy of the Annenberg Center to ensure fair balance,
independence, objectivity, and scientific rigor in all programming.
All faculty and planners participating in sponsored programs
are expected to identify and reference off-label product use and
disclose any relationship with those supporting the activity or
any others with products or services available within the scope
of the topic being discussed in the educational presentation.
In accordance with the Accreditation Council for Continuing
Medical Education Standards, parallel documents from other
accrediting bodies, and Annenberg Center policy, the following
disclosures have been made:
Thomas J. Kipps, MD
Research Support
Consultant
Speakers Bureau
Biogen-Idec; Celgene Corporation;
Cephalon, Inc.; Memgen, LLC;
sanofi-aventis
Igenica, Inc.
Educational Concepts; PER;
University of Utah
This activity is supported by educational grants from
GlaxoSmithKline, Genentech and Genzyme.
This activity is an enduring material and consists of a web
activity. Successful completion is achieved by reading and
viewing the material, reflecting on its implications in your
practice, and completing the assessment component.
The estimated time to complete the activity is 1 hour.
This activity was originally released in March 2010 and is
eligible for credit through February 28, 2011.
Kanti R. Rai, MD
Consultant
Biogen Idec; Cephalon, Inc.;
Genentech; GlaxoSmithKline
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Emerging Management Strategies for
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IN HIGH-RISK PATIENTS
Introduction
The clinical course of patients with chronic lymphocytic
leukemia (CLL) is heterogeneous. Whereas some patients
require treatment relatively soon after diagnosis, others
may enjoy a relatively indolent course, free of symptoms,
and not require therapy for many years. Because studies
in the 1990s found that early treatment may actually
compromise patient survival, and because there are no
studies that show early treatment can provide a survival
benefit, it is currently recommended to withhold
therapy until the patient develops progressive and/or
symptomatic disease.1
In recent years, an impressive number of prognostic
markers have been identified that can stratify patients
into subgroups that have different prognoses. Some of
these markers can help assess the relative risk for disease
progression independent of clinical stage.
At the same time, there has been progress in the
treatment of CLL that is providing for an improved
survival benefit. Recent years have witnessed the
use of newer drugs, monoclonal antibodies, and
monoclonal antibody/drug combinations (so called
“chemoimmunotherapy”) that have provided for
TABLE 1
improved response rates and longer progression-free
survival times after treatment. Even in the face of these
advances, however, there are still no standard protocols
for first-line CLL therapy. This discussion highlights
risk categories most often encountered in clinical
practice, the prognostic markers used for risk stratification,
and the approaches to applying both prognostic markers
and new therapeutic options to achieve optimal patient
outcomes in each risk category.
Prognostic Markers –
The Key to Risk Stratifications
Based on a better understanding of the biology of CLL,
we can better stratify patients into different prognostic
subgroups. It is possible to identify features of CLL
cells (Table 1) that are associated with the tendency for
progressive disease that requires treatment relatively soon
after diagnosis. Among these are the mutation status of
the expressed immunoglobulin variable region (heavy
chain) genes (IgHV genes), or expression of the 70-kD
zeta-chain-associated protein kinase (ZAP-70), or CD38.
In addition, there are many other markers that are
associated with more aggressive disease, such as high level
expression of thymidine kinase or lipoprotein lipase.
Prognostic Markers for CLL2
MARKER
LOW RISK
HIGH RISK
Thymidine-kinase
Low or normal
High
Soluble CD23 levels
Low or normal
High
Beta-2 microglobulin
Low or normal
High
IgV(H) mutational status
Mutated
Unmutated
Lactate dehydrogenase
Low or normal
High
CD38 expression
<20% -30%
>20% -30%
ZAP-70 expression
<20% -30%
>20% -30%
Lymphocytic doubling time
>12 months
≤12 months
Serum markers
FISH cytogenetics (see Table 2)
Adapted with permission from Yee KWL, O’Brien SM, Chronic Lymphocytic Leukemia Diagnosis and Treatment. Mayo Clin Proc 2006;81:1105-1129.
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Emerging Management Strategies for
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Using one or a combination of these prognostic markers,
we can now stratify patients into subgroups that have
significantly different risks for disease progression. For
example, patients with leukemia cells that express ZAP-70
and/or that use unmutated IgHV gene will have, on
average, a greater tendency for early disease progression
requiring treatment than patients with CLL cells that do
not express ZAP-70, or that use mutated IgHV. More
recently, the former subgroup of patients also has been
noted to have a shorter progression-free survival after
successful treatment with chemoimmunotherapy than
that latter subgroup.
with a relatively good prognosis. Less common is the
finding of an extra copy of chromosome 12 (trisomy 12),
which is associated with atypical cell morphology, higher
leukemia-cell expression levels of CD20, and a strong
tendency for relatively rapid disease progression. Other
common abnormalities include deletions in the long arm
of chromosome 11 at 11q22.3, or deletions in the short
arm of chromosome 17 at 17p13.1. Each of these
chromosomal abnormalities, particularly deletions at
17p13.1, is associated with a poorer response to certain
types of treatment, particularly those that require active
P53 to function.
Nevertheless, the expression of these prognostic markers
has not been shown to influence the response to treatment.
For example, the relatively complete response rates to
various treatment regimens appear to be the same in both
subsets of patients.
The gene located at 17P13.1 encodes TP53, an important
transcription factor that is activated by a number of
alkylating agents and purine analogs. This activation
induces a range of changes in genes that are involved in
regulating growth arrest, and in genes that encode proteins
that may initiate apoptosis. Therefore, the absence or
deletion of the TP53 gene typically causes the leukemic
cells to be less responsive to these chemotherapeutic
agents, and to demonstrate chemo-resistance.
In contrast, there are certain recurrent genetic changes
identified in CLL cells that are associated with differences
in response to standard therapies and/or survival. These
genetic changes can be identified in blood or marrow CLL
cells through standard cytogenetics or via Fluorescence In
Situ Hybridization (FISH), and are thought to occur during
the development or evolution of the disease (Table 2).
The most common genetic lesion is deletion of a segment
in the long arm of chromosome 13 at 13q14, which, if
found to be the sole genetic abnormality, is associated
TABLE 2
The exact cause of the genetic lesion at 11q22.3 is still
uncertain. There is active investigation of regulatory RNAs
or micro RNAs that map to this region and that might
account for the relative resistance to certain types of drug
therapy. Several clinical trials have demonstrated that
patients with del 11q have a lower response to single-agent
Fluorescence In Situ Hybridization (FISH) Tests for CLL3-5
CYTOGENETIC ABERRATION/LOCUS
PARAMETER DETECTED
IMPLICATION
11q22.3
Deletions of the ATM gene
Found in 11%-18% of cases.
Marked by lymphadenopathy and poor survival.
12cen
Gain of chromosome 12
Found in 16%-25% of cases. Unresolved pathogenic
outcome, but has been shown to be a negative
prognostic factor with median survival approx 5 yrs.
13q14.3
Deletions of the RB1 region
Found in 36%-64% of cases. Good prognosis as
sole abnormality. Disease-free interval and overall
survival is better than cases with normal karyotype
because of slow disease progression.
17p13.1
Deletions of the TP53 gene
Found in 7%-8% of cases that are resistant to
chemotherapy and have a short survival.
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Emerging Management Strategies for
Chronic Lymphocytic Leukemia
IN HIGH-RISK PATIENTS
fludarabine therapy, or to the combination of fludarabine
and rituximab, than do patients who do not have either
this or the 17p deletion abnormality. However, these
patients appear to have a response equivalent to that of
patients without del 11q, if treated with chemotherapy
regimens that include fludarabine and an alkylating
agent, such as cyclophosphamide.
CASE 1
2.
a. be placed on wait-and-watch status
b. have treatment started immediately
Correct Answer: (b)
This patient is in need of therapy. He has symptomatic disease and evidence for compromised
marrow function. Left untreated he probably
would develop worsening cytopenia and increasingly symptomatic disease. Studies have shown
that patients with high-risk stage disease benefit
from therapy.
An Older Patient With High-Risk Features
MR is a 70-year-old man with CLL diagnosed 3 years ago.
He had been doing well until about 4 months ago when
he began experiencing progressive fatigue, night sweats,
and abdominal fullness with early satiety after eating. He
otherwise maintains an excellent performance status of
0/5 by the ECOG criteria and lacks significant medical
co-morbidities. On exam he is noted to have significant
palpable cervical lymphadenopathy and a spleen palpable
7 cm below the left costal margin. His white blood cell
count (WBC) was noted to be 125,000 with 97% well
differentiated lymphocytes, which was significantly
increased from that of his WBC of 13,000 noted at
diagnosis. His hemoglobin was 10.1 gm% and his platelet
count 98,000. His leukemia cells were noted to express
high levels of ZAP-70 and to use unmutated IgHV.
Cytogenetic analyses demonstrated the cells to have
deletions at 11q22.3.
Interactive Questions (circle your answer before reading
the correct answer below.)
This patient should:
3.
High risk patients without significant
symptoms should:
a. be placed under observation
b. given a therapeutic regimen that
will stop progression
c. treated with the goal of achieving
a complete response
Correct Answer: (c)
Even if prognostic markers are favorable, symptomatic high-risk patients should be placed on a
therapeutic regimen with the goal of a complete,
or maximally achievable response.
4.
A preferred therapy for this patient would be:
a. Fludarabine + cyclophosphamide + rituximab
1.
This patient is:
a. high risk
b. low risk
(FCR)
b. Fludarabine + rituximab (FR)
c. Bendamustine-rituximab
Correct Answer (a)
The patient is at high risk (Stage IV), as the
patient’s platelet count is below 100,000. He also
has anemia, most likely reflecting disease-related
marrow suppression. In addition, his prognostic
markers are unfavorable—unmutated IgV(H) gene,
and ZAP-70 positive—and he is symptomatic.
Correct Answer: (a)
In view of his adverse leukemia-cell cytogenetics,
namely the deletion at 11q, he should be considered for combination chemoimmunotherapy
(Table 3 on next page). Clinical studies comparing
the outcome of treatment with fludarabine versus
fludarabine and cyclophosphosphamide have
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Emerging Management Strategies for
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IN HIGH-RISK PATIENTS
demonstrated the combination of the purine
analog with an alkylating agent to yield higher
complete response rates and longer progression
free survival times after therapy than treatment
with fludarabine alone.6-8
TABLE 3
Therapeutic Regimens Used in CLL
DRUG CLASS
Chemotheraphy
Purine analogs
The difference in outcome is particularly apparent for
patients with CLL cells that have the 11q deletion. A
retrospective review of patient outcomes,9 and prospective
randomized phase III clinical studies10 have demonstrated
that the addition of rituximab to the combination of
fludarabine and cyclophosphamide significantly improves
response rates, progression-free survival after treatment,
and overall survival relative to response achieved from
treatment with the combination of fludarabine and
cyclophosphamide alone.
It is important to bear in mind that many of the clinical
CLL treatment trials described in the literature usually
involve patients of a younger median age than the typical
CLL patient. The median ages of the patients in many
studies are typically in the 50s, whereas the median age at
diagnosis for all patients with CLL is closer to 70. However,
age can be a factor in the expected tolerance to treatment.
Older patients generally have a limited myeloid reserve.
A rule of thumb is that marrow cellularity is generally
100 minus a patient’s age, reflecting the age-related
decline in marrow function. Because elderly patients have
less myeloid reserve than younger patients, they might
have a lower tolerance to myelosuppressive therapy.
In addition, elderly patients often have one or more
co-morbidities, such as impaired renal function, cardiovascular disease, or diabetes. Renal function needs to be
considered because a number of therapeutic agents used
in the treatment of CLL undergo renal clearance. Thus,
dosage reductions should be implemented in patients with
renal impairment to avoid toxicity. Patients with cardiovascular disease may not tolerate anemia, and patients with
diabetes have an increased risk for infection that is
independent of the CLL-related decline in immune function.
Thus, older patients’ profiles, with regard to often
compromising co-morbidities and age-related decline,
need to be included as an additional factor when stratifying
the patients into different prognostic groups.
Fludarabine (Fludara®)
Pentostatin (Nipent®)
2-chlorodeoxyadenosine
Alkylating agents
Cyclophosphamide (Cytoxan®)
Chlorambucil (Leukeran®)
Bendamustine (Treanda®)
Biologic Immunotherapies
Rituximab (Rituxan®)
Alemtuzumab (Campath®)
Investigational Agents
Ofatumumab
Lenalidomide (Revlimid®)
Flavopiridol
Combination Therapies
Fludarabine-cyclophosphamide-rituximab (FCR)
Fludarabine-rituximab (FR)
Fludarabine-cyclophosphamide (FC)
Pentostatin-cyclophosphamide-rituximab (PCR)
Oxaliplatin-fludarabine-cytarabine-rituximab (OFAR)
To reduce the myelotoxicity of the treatment regimens,
investigators at the University of Pittsburgh developed what
they called an “FCR light” regimen, which calls for using
a reduced dose of fludarabine and cyclophosphamide,
but an increased dose of rituximab.11 These investigators
also gave patients rituximab maintenance therapy every
6 months after completing the 6 courses of therapy, in a
fashion similar to how patients are treated with follicular
lymphoma. Because this regimen included rituximab
maintenance therapy, it is difficult to assess progression
free survival after treatment. Nevertheless, the reported
complete response and overall response rates were on
a par with those of the conventional FCR regimen,
making this regimen a potential option for elderly patients
with del 11q.
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Emerging Management Strategies for
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IN HIGH-RISK PATIENTS
Another treatment regimen that is well tolerated in
patients with limited myeloid reserve is that involving
use of high-dose methylprednisolone and rituximab, the
so-called HDMP+R regimen. Excellent response rates of
good duration were observed for patients treated with
HDMP+R without inducing significant myelotoxicity.12, 13
Alemtuzumab
There are newer immune therapies being developed to
address the treatment difficulties encountered with highrisk patients. One of these is alemtuzumab (Campath®), a
monoclonal antibody that appears to have activity in the
treatment of patients who have CLL cells with del(17p).14
In a phase II study involving 93 CLL patients who had
failed treatment with fludarabine, treatment with alemtuzumab resulted in a 50% reduction in disease burden in
33% of the patients and a complete response in 2%.15
Responses to therapy lasted about 7 months on average.
These results were similar to those of 2 smaller studies
conducted previously, demonstrating an overall response
rate of over 30% in patients previously treated with
chemotherapy.16, 17 However, all 3 studies were single-arm
trials lacking controls and making it difficult to fully assess
efficacy and safety. Nevertheless, these results prompted
the FDA to provide accelerated approval in 2001.
The FDA mandated a phase 3 clinical trial, CAMC307,
in which approximately 300 CLL patients were
randomized to receive therapy with either chlorambucil
or alemtuzumab.18 Because there was a nearly 30 percent
greater (83% vs 55%) overall response rate among
patients treated with alemtuzumab versus chlorambucil
(p< 0.0001), and a 12-fold increase (24% vs 2%) in
complete response rates in patients receiving alemtuzumab
(p< 0.0001), the FDA approved the use of alemtuzumab
for the initial treatment of patients with CLL in
September 2007.
Although alemtuzumab is highly effective in clearing
blood and marrow leukemic cells, it appears to be less
effective in clearing cells in the large lymph nodes.19 The
probability of achieving a complete response to treatment
with alemtuzumab decreases in patients with large lymph
nodes. Treatment of patients with lymph nodes less than
2 cm in diameter apparently can provide for complete
response rates of up to 50%. However, the probability
of achieving a complete response to treatment with
alemtuzumab apparently falls to less than 20% in patients
with lymph nodes between 2 and 5 cm, and to virtually
0% in patients with lymph nodes greater than 5 cm in
diameter. As such, alemtuzumab may be best suited for
patients who lack bulky lymphadenopathy or who have
resolution of bulky adenopathy following treatment with
other agents. For patients without bulky adenopathy,
treatment with alemtuzumab may be the most effective
therapy for eradicating minimal residual disease in the
marrow after therapy.
A challenging toxicity that results from use of
alemtuzumab is immune suppression. The anti-CD52
antibody is cytotoxic for both T cells and B cells, and
typically causes significant lymphopenia. Patients treated
with alemtuzumab experience immune suppression that
enhances their risk for opportunistic infection. As such,
there is a need to implement anti-microbial prophylaxis
and to monitor the patient for signs or symptoms of
de novo infections, as well as reactivation of latent virus
infection, such as those caused by cytomegalovirus (CMV).
Surprisingly, the incidence of opportunistic infections
was similar in patients within the two arms of the
CAM307 trial who were treated with either alemtuzumab
or chlorambucil, with the exception of reactivation of
CMV.18 Therefore, careful monitoring for CMV is
needed in patients treated with alemtuzumab.
Reactivation of CMV can be difficult to diagnose as
alemtuzumab-treated patients may fail to produce
detectable levels of antibodies against CMV. As such,
monitoring for CMV using sensitive measures such
as polymerase chain reaction (PCR) is necessary.
Conceivably, patients who are seropositive for CMV
infection prior to treatment with alemtuzumab might
benefit from preemptive therapy with valgancyclovir
similar to that administered to solid organ transplant
recipients.20
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Emerging Management Strategies for
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CASE 2
An Asymptomatic Older Patient
CZ, an 80-year-old white woman has been referred by her
hematologist-oncologist for a second opinion regarding
management decisions/options. She was diagnosed with
CLL about 5 years earlier and, since she has been symptom
free, she has been on “wait-and-watch” for these past
5 years. She was in clinical stage 0 at diagnosis. About a
year prior to this consultation the lymph nodes had
become clinically palpable, but they have all remained
small in size. Her hemogram has been monitored at 3to 6-month intervals in the past, showing normal platelets
and hemoglobin/hematocrit. However, her white blood
cell count and absolute lymphocyte count (ALC), which
were 28,000 and 20,000 respectively at the time of initial
diagnosis, had increased steadily thereafter. At 1 year, the
ALC was 30,000, at 3 years it was 38,000 and now, 5 years
later, it is 50,000. The patient has no symptoms and leads
an active life for an 80-year-old. The markers show typical
phenotype of CLL that uses a mutated IgV(H) gene and
is ZAP-70 negative.
Correct Answer: (a)
Wait-and-watch is the preferred protocol. Studies
have shown that patients given early treatment do
not have an increased life expectancy compared
with those who are placed under observation.
Notably, those patients given early treatment were
at higher risk of developing second malignancies.
3.
a. be placed under observation
b. given a therapeutic regimen that will
stop progression
c. treated with the goal of achieving a
complete response
Correct Answer: (c)
Even if prognostic markers are favorable,
symptomatic low-risk patients should be placed
on a therapeutic regimen with the goal of a
complete, or maximally achievable response.
Interactive Questions (circle your answer before reading
the correct answer below.)
1.
This patient is:
a. high risk
b. low risk
Correct Answer (b)
The patient is at low risk (Stage 1). Although
the patient has some lymph node enlargement,
the nodes remain small in size. Platelets and
hemoglobin are normal. In addition, her prognostic
markers are favorable—mutated IgV(H) gene, and
ZAP-70 negative—and she is asymptomatic. Her
lymphocytosis, however, has increased.
2.
This patient should:
a. be placed on wait-and-watch status
b. have treatment started immediately
Low-risk patients with significant symptoms
should:
4.
If this low-risk patient was symptomatic, the
preferred therapy should be:
a. FCR
b. FR
c. Bendamustine-rituximab
Correct Answer (b):
FR is preferred in view of the advanced age
of the patient.
Low-risk CLL patients are those who are in clinical
stages zero, 1, or 2, (Table 4 on next page) and can be
either asymptomatic or symptomatic. If these patients
present with mutated IgV(H) gene status, then the
prognosis is more favorable, and a watch-and-wait
protocol can be followed. Moreover, if these patients
also have other good prognostic markers such as negative
(ZAP-70), or a del 13q as the sole aberration evident
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Emerging Management Strategies for
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Staging of Chronic Lymphocytic Leukemia21.
TABLE 4
Rai
Lymphocytosis
Lymph Node
Enlargement
Spleen/Liver
Enlargement
Hemoglobin < 11 g/dL
Platelet < 100 x 109/L
Survival (years)
0
Yes
No
No
No
No
>13
I
Yes
Yes
No
No
No
8
II
Yes
±
±
No
No
5
III
Yes
±
±
Yes
No
2
IV
Yes
±
±
±
Yes
1
This research was originally published in Hematology. Kay N, Hamblin TJ, Jelinek DF, et al. Chronic Lymphocytic Leukemia. Hematology. 2002:193-213.
© American Society of Hematology
from a FISH panel, then the clinician should feel
confident in placing these patients under an observationonly status. Unfortunately, to date, there are no clinical
trials that clearly define observation as the standard of
care for these patients versus some effective treatment.
In a French study conducted several years ago,
asymptomatic CLL patients were randomized to treatment
with chlorambucil or wait-and-watch.22 It was found that
there was no difference in overall life expectancy whether
the patients were in the treatment or observation arm.
Of note is that in the early treatment group there was a
higher incidence of second malignancies, such as epithelial
cancers. As a result, most clinicians do not favor early
treatment in low-risk patients with favorable prognostic
markers. A trial is currently in progress (CALGB) that is
randomizing asymptomatic, low-risk CLL patients with
poor prognostic markers to either early treatment with
FR, or observation only. The results will be available in a
few years, and until then, the recommended approach is
to keep these patients under observation only.
In an asymptomatic patient with unfavorable prognostic
markers, such as unmutated IgV(H) gene, positive ZAP-70,
positive CD 38 co-expression on leukemic cells, del 11q,
12 trisomy, or del(17p), the disease is likely to progress
sooner, which mandates treatment intervention.
Low-risk CLL patients with symptoms are another matter.
Weight loss is one such symptom, particularly a 10% loss
in baseline body weight within a period of 6 months
without dieting or other effort to lose weight. Profound
drenching sweats, profound fatigue that interferes with
normal lifestyle, and frequent bacterial infections requiring
antibiotic intervention are also among the constellation
of symptoms to monitor. If a patient in the early stage of
disease presents with one or more of these symptoms,
therapeutic intervention becomes justifiable, regardless
of prognostic marker status. It is necessary to consider,
when initiating treatment for the first time, what the
therapeutic endpoint should be, that is, what is the
objective of treatment? A recent report from the
international workshop on CLL has updated existing
guidelines and criteria for diagnosis, prognosis, and
treatment of CLL.1 There is emerging evidence suggesting
that those patients who achieve a better response are
more likely to have a longer life expectancy and a better
quality of life, in addition to a longer interval before the
next treatment is required. So, whether the patients are
given FR or FCR, for example, the objective should be to
achieve a complete, or maximally achievable remission
without any undue toxicities.
Determining Remission Status
It would be instructive, at this point, to discuss what is
meant by a complete remission. Up until now, the principal
criterion has been the absence of clinical evidence of
disease. Among these are absence of palpable disease,
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Emerging Management Strategies for
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such as palpably enlarged lymph nodes, spleen or liver,
and normalization of blood count. Recently, however,
owing to the success of FR or FCR regimens to achieve
complete remission, attention is being focused on
minimal residual disease (MRD) levels in patients who
have achieved complete remission by clinical criteria.
Investigators are beginning to look for the presence of
residual CLL cells in circulating blood or in the bone
marrow using two- or four-color flow cytometry, or with
PCR to uncover any molecular markers of residual CLL.
These tests would, of course, have to be negative to
consider the remission complete. Whether such negative
molecular marker status is achievable is under investigation.
At present, then, the best level of achievable clinical
remission without undue toxicity is the accepted standard.
CASE 3
Interactive Questions (circle your answer before reading
the correct answer below.)
1.
a. low risk
b. high risk
Correct Answer (b)
This patient has unfavorable prognostic markers—
unmutated IgV(H) gene and positive ZAP 70—
which implies high risk even though the patient
is asymptomatic.
2.
A Younger Patient With High White Cell
Count and Poor Prognostic Markers
MJ, a 53-year-old white male is referred by his internist
because of a high blood white cell count discovered upon
a routine annual check-up. MJ had been watched by his
internist over a period of one year before this referral.
He has no symptoms and maintains an active and busy
professional and social life. The TWBC a year ago was
62,000 with an ALC of 40,000, hemoglobin, hematocrit,
platelets, and neutrophils were all within normal limits.
Six months later, the ALC had increased to 66,000, and
now, at the time of this referral a year after the initial
discovery, the ALC had further increased to 78,000.
There are still no symptoms, and the rest of the blood
counts have remained normal. Upon examination, there
were palpably enlarged small nodes, measuring about
1 to 1.5 cm diameter in the neck, axillae, and groin
bilaterally. Spleen and liver were not clinically palpable.
Flow cytometry of blood lymphocytes showed a phenotype
characteristic of CLL—CD19+, CD20+, CD23+, CD5+,
lambda light chains with sIGM and sIGD positivity.
IgV(H) showed unmutated genes and ZAP-70 was positive.
This patient is:
Should this patient be placed on therapy?
a. yes
b. no
Correct Answer (a)
Because of the clinical stage, and presence of
unfavorable prognostic markers, this high-risk
younger patient will have more to gain by being
placed on an aggressive therapeutic regimen.
Without such aggressive treatment, the patient
has a high probability of developing a more
rapidly progressing disease.
3.
The preferred therapy for this patient should be:
a. FCR
b. Alemtuzumab
c. Bendamustine-rituximab
Correct Answer (a)
FCR is preferred because 1) There is experience
with a large number of patients, 2) The patient is
relatively young and has a good performance
status, 3) Our overall objective is to try to reach a
complete remission. (b) and (c) are also good
options, but our experience is with a lower number
of patients.
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Emerging Management Strategies for
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It should be emphasized that high-risk younger patients
(age 40 to 55 years) have more to gain and less to lose by
receiving a much more aggressive approach to treatment.
For these patients, prognostic markers are critically
important if these patients are being categorized as high
risk because of the clinical stage and the presence of
unfavorable markers, such as an unmutated IgV(H) gene.
The objective of their treatment is twofold: 1) to achieve
a complete clinical response, and 2) once the response has
been achieved, to discuss with the patient the option of
receiving an allogeneic hemopoietic stem cell transplant
(SCT); this would be a human-leukocyte-antigen
(HLA)-matched sibling transplant, or if a sibling is not
available, an unrelated HLA-matched donor transplant.
A caveat here is that these transplants should be done with
a nonmyeloablative-conditioning-based treatment. A
number of institutions are conducting prospective clinical
trials with patients who meet these criteria to determine
whether a complete remission and good success with a
marrow transplant will be of benefit.23 There are, in fact,
somewhere under 100 patients who are alive today as a
result of allogeneic SCTs done with nonmyeloablative
conditioning. The reason for emphasizing nonmyeloablative
conditioning is that the success of this particular transplant
method is based on immune modulation rather than on
replacing or seeding an aplastic marrow—that is, one
that has been rendered aplastic by prior preparatory
chemotherapy. As a result of myeloablative conditioning,
there has been an unacceptable mortality rate (40% to
50%), within 100 days of the transplant. In contrast,
the mortality rate has gone down significantly with
nonmyeloablative conditioning. Recently published reports
indicate that with nonmyeloablative conditioning-based
allogeneic transplants, not only is the mortality rate
reduced, but also the morbidity with chronic and acute
graft-versus-host disease has been in an acceptable range,
and there is rapid patient recovery.24, 25 Thus, for high-risk
younger patients, first-line options should be very
aggressive, since these CLL patients have a high probability
of dying because of the disease. A 5-year follow-up study
evaluated for factors that influence the outcomes of
patients undergoing allogeneic transplantation for CLL.26
It was found that younger patients with no concomitant
morbidities, and without bulky disease—such as lymph
nodes >5 cm in diameter—fare much better with allogeneic
SCT than do patients who do not have these characteristics.
Investigational Therapies
There are investigational agents that appear to be effective
in treating elderly high-risk patients. One of these is
lenalidomide (Revlimid®) an immune modulator derived
from thalidomide, which was banned in the 1960s for
causing birth defects in the babies of pregnant women
who were taking it as a sedative. This class of agent
inhibits angiogenesis, a mechanism required by cancer
cells. Lenalidomide does not appear to have cytotoxic
effects against leukemic cells. In two trials of previously
treated CLL patients, however, lenalidomide was shown
to have activity in this disease.27, 28
Another group of novel agents are the BCL2 antagonists,
which are involved in initiating apoptosis. As such,
they may obviate the need for induction of P53, which
ordinarily is required for the induced expression of
pro-apoptotic molecules, such as PUMA, that are responsible for the cytotoxic effects of anti-leukemia drugs,
such as fludarabine.29 The use of agents that can emulate
the effects of such molecules as PUMA might obviate the
need to induce P53 to provide for leukemia-cell apoptosis.
In addition, there are the newer monoclonal antibodies,
such as the humanized anti-CD20 agent ofatumumab,
which has striking activity, but has not been compared
with rituximab.
Refractory or relapse patients have already been treated
with first-line agents, and now require carefully structured
second-line therapeutic regimens. With regard to patients
who have fludarabine-refractory CLL, or who have
Richter’s Syndrome (RS), a group at the MD Anderson
Cancer Center developed a regimen that employs varying
combinations of oxaliplatin, fludarabine, cytarabine, and
rituximab combination therapy (OFAR).30 This regimen
has the advantage of reduced myelotoxicity compared
with standard FC combinations, and has demonstrated
very strong activity in RS patients, as well as activity in
fludarabine-refractory CLL patients. Given the activity
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Emerging Management Strategies for
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of OFAR, particularly in patients with del(17p) and in patients older than
70 years, a larger study of OFAR is currently being pursued by this group.
In high-risk elderly patients with del(17p), alkylating agents and purine
analogs do not have high activity. A retrospective review of the literature
by the MD Anderson group found that there may be some heterogeneity
among these patients who have del(17p) regarding their response patterns
to an FCR regimen.31
A note of caution here is that the presence of del(17p) in CLL cells does
not necessarily indicate that the leukemia cell lacks functional P53.32, 33
Conversely, CLL cells that lack del(17p) can have dysfunctional P53.34 As
such, the association between del(17p) and dysfunctional P53 is not absolute.
Conceivably, the patients with CLL cells that harbored del(17p), and who
have a favorable response to chemoimmunotherapy had CLL cells with
functional P53. This is possibly reflected in a retrospective analysis of the
CLL4 trial patients, which found that the adverse outcome associated with
del(17p) was observed for patients who have more than 20% of their
leukemia cells harboring deletions at 17p.35 A sizable subset of patients,
who had fewer than 20% of their CLL cells with del(17p) as defined by
FISH analysis, had outcomes similar to those of patients who had CLL cells
that did not have any detectable deletions at 17p. As such, patients who are
noted to have fewer than 20% of their CLL cells with del(17p) by FISH
might respond well to more standard chemoimmunotherapy regimens.
Conclusion
The management of CLL has advanced from palliative measures to newer
therapeutic options such as biologic immune modulators, purine analogs
and chemo-immunotherapeutic combinations. At the same time, the
evolution of prognostic markers has provided for a greater degree of certainty
in applying risk-adapted first-line therapy. As a result, the perspective of
first-line treatment has changed to one in which complete remission is now
a clinically realistic goal, with the possibility of increased survival time for
CLL patients.
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