Treatment of older patients with chronic lymphocytic Tait Shanafelt

CHRONIC LYMPHOCYTIC LEUKEMIA: A NEW TREATMENT ERA IS BORN
Treatment of older patients with chronic lymphocytic
leukemia: key questions and current answers
Tait Shanafelt1
1Mayo
Clinic, Rochester, MN
Despite the advanced age at onset, chronic lymphocytic leukemia (CLL) shortens the life expectancy of the majority of newly
diagnosed patients. The management of elderly patients with CLL is more complex than that of younger patients due to the
greater frequency of comorbidities and functional impairment as well as reduced organ function. Many of the recent
advances in the care of CLL patients (prognostication, more intense combination therapy regimens) are of unclear relevance
for elderly patients. This review addresses 5 key questions in the management of elderly patients with CLL: (1) why is
classifying the “fitness” of CLL patients necessary; (2) what criteria should be used to classify patient fitness; (3) when
should elderly patients be treated; (4) how should therapy be selected for elderly patients; and (5) which therapy is best (for
this patient)?
Introduction
The last 2 decades have been a time of tremendous progress in
the care of patients with chronic lymphocytic leukemia (CLL).
Most patients are diagnosed with early-stage disease before
developing symptoms after they are incidentally found to have
lymphocytosis. Insights into the molecular biology and genetics
of the leukemic CLL B cell have not only led to a better
understanding of disease biology,1-3 but have also enhanced the
accuracy of prognostication4,5 and identified potential new
therapeutic targets.6 The development of chemoimmunotherapy
(CIT) combining purine nucleoside analogs with the anti-CD20
monoclonal antibody rituximab has improved response rates,
progression-free survival (PFS), and overall survival (OS).7,8
With such CIT approaches, a high proportion of patients achieve
a minimal residual disease–negative disease state, a depth of
remission rarely achieved with historical treatments.9,10
Unfortunately, these advances do not benefit all patients uniformly. CLL is a disease of the elderly, with a median age of
onset of ⬃ 70 years. According to the Surveillance Epidemiology and End Results (SEER) registry, ⬃ 75% of patients are
more than 65 years of age at the time of diagnosis. Despite the
advanced age at onset, CLL shortens the life expectancy of the
majority of newly diagnosed patients,11-13 with survival relative
to the age-matched population reduced for those ⬍ age 75 at
diagnosis, including those with Rai stage 0 disease.13 Although
studies suggest that there has been an improvement in survival
for CLL patients ⬍ age 70 at diagnosis over the past several
decades, no improvement has been observed for older patients.11,12
Because most patients have early-stage disease at diagnosis and are
observed for several years before starting treatment, the median age
at the time therapy is initiated is closer to 75 years. Elderly patients
have been underrepresented in previous clinical trials, which has
resulted in uncertainty regarding the optimal treatment approaches
for these individuals.14 Although select elderly individuals may be
able to tolerate aggressive treatment approaches,8 standard fludarabine, cyclophosphamide, rituximab (FCR) CIT cannot be tolerated
by the majority of CLL patients who have comorbid health
conditions and begin treatment after the age of 70.15 Despite
158
advanced age, efficacious treatment is needed for these individuals
because a majority of patients beginning treatment for CLL will die
as a direct result of the disease or its complications.16
This review addresses 5 key questions in the management of elderly
patients with CLL: (1) why is classifying the “fitness” of CLL
patients necessary; (2) what criteria should be used to classify
patient fitness; (3) when should elderly patients be treated; (4) how
should therapy be selected for elderly patients; and (5) which
therapy is best (for this patient)?
Why is classifying the “fitness” of CLL patients
necessary?
There are several purposes for classifying fitness level in patients
with CLL. The first is to accurately categorize the patient’s life
expectancy unrelated to CLL (eg, due to other health problems).
This information can then be used for patient counseling and to
help define the importance of durable disease control when
selecting treatment. An 18-month remission in a symptomatic
CLL patient is acceptable for an individual with a life expectancy
of 24 months due to other health problems, whereas it would be
considered inadequate for an individual with a 10-year life
expectancy unrelated to CLL.
Physicians often underestimate the life expectancy of older adults.
For example, the life expectancy of the average 70-year-old man in
the United States according to the actuarial calculations of the
United States Social Security Office is ⬃ 15 years.17 The life
expectancy for the average 80-year-old man is ⬃ 8 years (Table
1).17 These data illustrate the limitations of using chronologic
age alone to estimate survival in patients with CLL.
The second reason to classify fitness is to help determine the
patient’s ability to tolerate aggressive therapy. A 70-year-old
woman with CLL in need of treatment may have an average life
expectancy unrelated to CLL of greater than 15 years. Although this
implies that the goal of treatment should be durable remission and
prolongation of life, it does not necessarily indicate that she will be
able to tolerate an aggressive therapeutic regimen that has been
developed and tested in younger individuals. Rather than chronologic age, the patient’s comorbid health conditions, organ function
American Society of Hematology
Table 1. Life expectancy in the United States17
Life expectancy, y
Current age, y
65
70
75
80
85
Men
Women
18.9
15.0
11.5
8.5
5.9
20.9
16.7
12.9
9.6
6.8
and the pharmacokinetics (absorption, metabolism, excretion) of the
drugs to be used become key considerations in evaluating the
suitability of a given treatment approach. This principle is well
illustrated by the Cancer and Leukemia Group B (CALGB) 9011
trial, which found that creatinine clearance rather than age was the
primary predictor of higher toxicity with fludarabine-based therapy
in CLL patients.18
The third reason for classification of patient fitness is to allow more
consistent stratification and selection of patients across clinical
trials. Historically, trials have primarily used an exclusionary (rather
than a stratification) approach declaring patients above an age cutoff
or with any decrease in organ function or performance status
ineligible.19 These criteria have excluded those with the characteristics
typical of real-world CLL patients from participating.20 A stratification
approach allows trials to be designed with more liberal eligibility and to
use alternative dosing strategies or different treatments for those
deemed unable to receive aggressive regimens. A consistent approach
to stratification in CLL trials that can also be applied in practice would
help oncologists more readily interpret the relevance of trial results to
the patient they are evaluating and facilitate more rapid translation of
trial results into routine clinical practice.
What criteria should be used to classify patient fitness?
There are currently no standardized criteria by which to define fitness in
CLL patients. Although patients were traditionally classified based on
age alone, it is now well recognized that chronologic age is not a
reliable surrogate for physiologic age or fitness.21 Although organ
function, muscle mass, and endurance show a general decline with age,
there is wide variability at the level of the individual.
Comprehensive geriatric assessment (CGA) of functional status is one
strategy used to assess fitness/frailty more accurately. CGA includes
evaluation of function, coexisting health problems, level of social
support, cognitive ability, nutritional status, and common syndromes
that affect geriatric patients (dementia, delirium, falls, neglect, failure to
thrive, depression, polypharmacy).21,22 Although there is limited information on the use of CGA to predict outcomes in patients with CLL,
standardized scales to perform CGA are available23,24 and these
assessments have been shown to reliably predict the ability of elderly
patients to tolerate chemotherapy in other malignancies.25
The number and severity of comorbid health conditions also provides
important information regarding patient fitness. A Mayo Clinic study of
373 unselected CLL patients found that 89% of newly diagnosed
patients had at least one comorbid condition and 46% had at least one
major comorbidity (eg, coronary artery disease, peripheral vascular
disease, diabetes mellitus, pulmonary disease [COPD], etc).20 An
additional 9% of patients reported having difficulty in performing
activities of daily living independently (eg, eating, bathing, dressing,
walking, toileting). Although the presence of a major comorbidity
affected OS on univariate analysis, it was not a significant predictor on
the multivariate analysis adjusting for CLL-specific characteristics (eg,
stage).20 This finding underscores that CLL-related characteristics are
often the major factor influencing survival even when substantial
comorbidities are present. Although it enrolled only fit older patients
(performance status 0-2, no severe organ disfunction), the presence of 2
or more comorbid health conditions was still associated with shorter
PFS and shorter OS in the German CLL5 trial.16 There are a variety of
methods to assess comorbidity,26 of which the Cumulative Index
Rating Scale (CIRS)27 and the Charlson Comorbidity Index28 are
among the most widely used.
Organ function is a third factor in assessing patients’ suitability for
aggressive treatment. It is well recognized that renal function decreases
with age.29,30 Analysis of ⬎ 15 000 adults participating in the National
Health and Nutrition Examination Survey (NHANES) found that 38%
of individuals ⬎ age 70 had an estimated glomerular filtration rate
⬍ 60 mL/min/1.73 m2 as measured using the Modification of Diet in
Renal Disease (MDRD) equation.30 Common methods to estimate
renal function, such as the Cockcroft-Gault method, are heavily
influenced by age and lose precision among elderly patients. For
example, a study of ⬃ 100 000 individuals from Japan found that
⬎ 80% of those ⬎ age 70 had a calculated creatinine clearance ⬍ 60
mL/min/1.73 m2 when estimated by the Cockcroft-Gault method.31 In
the Mayo Clinic series of unselected, newly diagnosed CLL patients,
⬃ 4% had decreased organ function (ie, total bilirubin ⬎ 2 mg/dL or a
serum creatinine ⬎ 1.5 times the upper limit of normal).20
It should be emphasized that functional status (CGA), performance
status, comorbidities, and organ function are related but distinct
dimensions. Measuring only one of these dimensions can lead to an
inaccurate assessment of overall patient fitness.32,33 Although Eastern Cooperative Oncology Group (ECOG) performance status, the
most widely used assessment of patient fitness in oncology practice,
has a moderate correlation with more formal CGA instruments,32 it
is an inadequate measure of function for most older adults.33,34
Although not yet defined, the optimal method to assess fitness for
patients with CLL will likely involve a combination of CGA, comorbidity evaluation, and assessment of organ function (Table 2). Given the
importance of assessing fitness/frailty in the management of CLL
patients, the International Workshop on CLL (IWCLL) recently
Table 2. Selected standardized tools to evaluate various dimensions of patient fitness
CGA and functional assessment
Activity of Daily Living (ADL)
101
Comorbidities
CIRS-G27
Instrument of Activities of Daily Living (AIDL)103,104
Charlson Comorbidity Index28
ECOG performance status106
Adult Comorbidity Evaluation (ACE-27)107
Others26
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Quality of life
European Organization for Research and Treatment
of Cancer (EORTC) QLQ-C30102
Functional assessment of cancer therapy-general
(FACT-G)105
Patient Reported Outcome Measurement
Information System (PROMIS)108
Others109
159
launched an international initiative to bring greater consistency to this
assessment. It is hoped that this effort will identify standard criteria by
which both fit and less fit CLL patients may be selected for trials and
that can be used to stratify patients within a trial to evaluate how fitness
relates to response and toxicity. This effort will also explore how such
criteria may be used to inform therapy selection in routine clinical practice.
Table 3. Supportive care considerations for CLL patients
When should elderly patients be treated?
Vaccination strategies54
The indications to initiate therapy for elderly patients with CLL are
generally the same as those for younger patients.35 These indications
include cytopenias due to BM failure (hemoglobin ⬍ 11.0 g/dL,
platelets ⬍ 100 ⫻ 109/L), massive/symptomatic lymphadenopathy or
organomegaly, and disease-related constitutional symptoms (disabling
fatigue, unintentional weight loss, drenching night sweats, fevers
unrelated to infectious complications).35 Care should be used when
applying these criteria in elderly patients because they are at higher risk
for having other disease processes that may contribute to fatigue or
weight loss (eg, second cancer, malnutrition, neglect, other organ
dysfunction). Up to 50% of older patients have been found to have
depression,34,36 and patients should be specifically screened for depression and other disorders associated with fatigue (eg, hypothyroid, sleep
apnea, anemia from a cause unrelated to CLL) before attributing fatigue
to CLL. Although a lymphocyte doubling time of less than 6 months is
considered an acceptable indication for treatment,35 treatment on this
basis alone is rarely indicated in the absence of other indications for
therapy. CLL experts appear to have a greater tolerance for delaying
therapy when it is not indicated,37 particularly in elderly patients.13
It is also worth emphasizing several features that are not acceptable
reasons to initiate therapy. The degree of elevation in the absolute
lymphocyte count, regardless of magnitude, is not an acceptable
reason to initiate therapy in the absence of other indications.35 It is
also not necessary to initiate treatment for asymptomatic lymph
node enlargement or slow, progressive lymphadenopathy. Because
treatment increases rather than decreases the risk of infection,
frequent or recurrent infections are also not a reason to initiate
therapy.35 Rather, patients with frequent or recurrent infections
should undergo assessment for hypogammaglobulinemia or other
causes of immunocompromise.38,39
While under observation, older patients should receive aggressive
supportive care measures to minimize disease-related complications.
This includes age-appropriate cancer screening and regular evaluation
for skin cancer specifically.40,41 Given the heightened risk of both
melanoma and nonmelanoma skin cancer, patients should also be
counseled regarding sun protection and avoidance.42 Approximately
50% of adults are vitamin D deficient43-45 and counseling to avoid sun
exposure can exacerbate this problem. Studies from both the United
States and Italy suggest that low vitamin D levels may be associated
with more rapid CLL disease progression and shorter survival,46,47 a
finding that has also been found in other malignancies.48-50 It is
unknown whether screening for vitamin D deficiency and/or vitamin D
replacement reverses this association. Nonetheless, vitamin D assessment in patients at risk can be considered good general care for elderly
patients due to bone health51 as well as to reduce falls52,53 and we
routinely perform vitamin D assessment at the time of diagnosis.46,47
Vaccination strategies should also be employed in CLL patients to
try to reduce infectious complications.38,39 In the United States, the
Center for Disease Control vaccination guidelines (updated in
2012) suggest that all immunocompromised patients, such as
those with leukemia, receive initial pneumococcal vaccination
with the Prevnar 13 vaccine followed 8 weeks later by the
160
Suggestions
Cancer screening
Fatigue
Other considerations
● Whole-body skin examination
annually.41,42
● Age-appropriate screening for breast,
colon, and cervical cancer should be
done.
● Prevnar 13 pneumococcal vaccination
should be given at diagnosis followed 8
weeks later by Pneumovax (23-valent)
vaccine.
● Repeat Pneumovax approximately every
5 years.
● Patients who have previously received
Pneumovax but who have never
received Prevnar 13 should receive a
single dose of Prevnar 13 at least 12
months after last pneumococcal
vaccination.
● Annual influenza vaccination should be
given.
● Avoid live attenuated vaccines including
vaccines for zoster, yellow fever, and
live attenuated typhoid vaccines.
● Fatigue must be carefully evaluated
before attributing to CLL, particularly in
older adults.
● Consider evaluation for depression,
second cancers, hypothyroidism, sleep
apnea, anemia due to causes unrelated
to CLL before attributing fatigue to
CLL.
● Provide education regarding skin
protection and avoidance of sun
exposure to reduce risk of skin cancer.
Consider evaluation of vitamin D levels
because this recommendation
increases risk of vitamin D deficiency.
● Smoking cessation should be advised
given apparent increased risk of
smoking-related cancers in CLL
patients.110,111
pneumococcal 23 vaccine.54 The pneumococcal 23 vaccine
should then be repeated at 5-year intervals. Adult patients who
have previously had the pneumococcal 23 vaccine should receive
the Prevnar 13 vaccination at least once during their lifetime
(administer 12 months after the most recent pneumococcal 23
vaccine).54 Although annual influenza vaccination is also recommended, live attenuated vaccines, including Zostavax, are contraindicated in patients with CLL (Table 3).
Although the genetic and biologic characteristics of CLL B cells
have been found to predict outcome in younger CLL patients, there
is limited information on the utility of these molecular biomarkers
for predicting outcome in older CLL patients.55,56 The Mayo Clinic
evaluated the utility of prognostic testing based on age at diagnosis
in a cohort of ⬃ 2500 CLL patients, including 748 patients age
65-74 and 433 patients age ⱖ 75.13 After adjusting for disease stage,
IGHV, ZAP-70, and CD38 remained powerful predictors of time to
first treatment in patients of all ages, including those age ⱖ 75. In
contrast, prognostic testing had minimal to no value for predicting
OS among patients age ⱖ 75 after adjusting for stage.13 These
findings suggest that these molecular biomarkers remain relevant to
the biology and natural history of CLL in elderly patients, but that
American Society of Hematology
Figure 1. Determining the goals of treatment for older patients with CLL.
competing causes of death may decrease their direct relevance for
predicting OS with increasing age.
How to select therapy for older patients
In younger patients without comorbidities, genetic characteristics of the
clonal B cells (del[17p13], TP53 gene mutations, del[11q23]) are the
primary factor influencing therapy selection. Deep remission (even
minimal residual disease–negative remission) is the goal of treatment57
and the treatment strategies offering the best PFS and OS should be
prioritized. Based on a series of phase 3 trials,8,58-64 most patients (with
exception of those having TP53 defects) should receive an FCR8 or
FCR-like65,66 treatment regimen. The German CLL Study Group
(GCLLSG) CLL10 trial will determine whether bendamustine and
rituximab (BR)67 is an acceptable alternative in these patients. Inclusion
of an alkylating agent appears to be important for patients with deletion
11q23.68 Although associated with PFS, this cytogenetic defect does
not appear to effect OS when these patients are treated with FCR-like
platforms.69 As outlined in the accompanying chapter in this publication by Gribben and Riches,70 suitable young patients with del(17p13)
in need of treatment should be debulked and proceed to reduced
intensity allogeneic stem cell transplantation.71,72
As discussed, the selection of therapy in older patients is more
complex because they are more likely to have coexistent health
conditions that affect organ function and the ability to tolerate
treatment. Establishing the goals of treatment is the first step in
therapy selection (Figure 1). Patient characteristics (rather than the
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characteristics of the treatment regimen) determine the goals of
therapy. The combination of performance status, comorbidity
assessment, CGA (such as independence with activities of daily
living), and organ function (primarily creatinine clearance) are more
important factors than age in determining treatment goals.
In patients with a long life expectancy unrelated to CLL and good
functional status, deep remission remains an appropriate goal
regardless of age. For those with short life expectancy due to other
health conditions, palliation is appropriate. Most older patients with
CLL fall somewhere in between and require that clinicians balance a
variety of considerations when selecting therapy. It must also be kept in
mind that, with the exception of allogeneic stem cell transplantation,
the current treatments for CLL are noncurative. Although achieving the
longest remission duration possible is an appropriate strategy in
younger patients, intermediate durations of remission (eg, 3-4 years)
with salvage therapy at relapse may be more appropriate for some
elderly patients if this approach offers less toxicity and better quality of
life. Selecting a too aggressive approach that requires extensive dose
reduction or results in discontinuation of treatment may be less
beneficial than choosing a better tolerated treatment that allows
administration of a full course of therapy.15,73
Which therapy is best (for this patient)?
The fact that a majority of CLL patients have comorbid conditions
and greater than half have at least one major comorbidity underscores that therapy selection must be individualized. There is
161
Figure 2. The tight link between efficacy and toxicity with historical CLL therapy. This figure is a summary illustrating the link between efficacy and
toxicity with historical CLL treatments. It cannot be used to compare regimens directly because results are drawn from across trials with different
patient characteristics. In some cases, multiple trials testing the same regimen found slightly different PFS and rates of grade 3/4 toxicity; the
representative experience is indicated in such cases.
unlikely to be a single treatment regimen that will be an optimal fit
for all older patients. After determining the goals of treatment, the
best strategy to achieve these goals must be determined. Here the
characteristics of the treatment regimen (efficacy, toxicity, mechanism drug elimination/metabolism) and the patient’s underlying
organ function become substantial considerations. Tables providing
an extensive cataloging of the experience of elderly CLL patients
treated in past and ongoing clinical trials have been published by
multiple authors and will not be reproduced here.14,74-76
The GCLLSG has used the combination of the CIRS assessment of
comorbidities and creatinine clearance as useful parameters to
identify older patients fit for aggressive treatment approaches.
Those with a CIRS score ⱕ 6 and preserved creatinine clearance
(ⱖ 70 mL/min) have generally been considered candidates for
aggressive therapy independent of age, whereas patients with higher
CIRS scores are considered to be less fit and are therefore
candidates for less intense treatment strategies.74 A recent report
from the Australian CLL Study Group in a cohort of fit CLL patients
age ⱖ 65 (median age, 72) found no difference in the frequency of
grade ⱖ 3 adverse events among individuals with a CIRS score of
0-2, 3-4, or 5-6, providing some justification that a CIRS score ⱕ 6
identifies elderly patients able to tolerate more aggressive CIT
treatment strategies.77
In contrast to the findings of 4 randomized trials in younger
patients,58-61 several recent observations have challenged the notion
that purine analogs are superior to chlorambucil in all age
groups.63,75,78 The CLL5 trial of the GCLLSG randomized patients
age ⱖ 65 to fludarabine monotherapy or single-agent chlorambucil.16 Although a higher overall (72% vs 51%, P ⫽ .003) and
complete response rate (7% vs 0%, P ⫽ .11) were observed for the
fludarabine arm, no difference in the median PFS was observed
between groups (19 months for fludarabine and 18 months for
chlorambucil, P ⫽ .7). Time to treatment failure, however, did favor
the fludarabine arm (18 months vs 11 months, P ⫽ .004) because
⬃ 30% of patients randomized to chlorambucil crossed over to
fludarabine before disease progression. No difference in grade 3-4
162
neutropenia or infection was observed between the arms and a
higher proportion of patients in the chlorambucil arm discontinued
therapy due to treatment side effects. Greater improvements in
quality of life were observed in the fludarabine arm at both 6 and 12
months. Although no difference in OS was observed, interpreting
this finding is confounded because patients randomized to chlorambucil were markedly more likely to received salvage therapy
compared with those randomized to fludarabine (50% vs 77%,
P ⫽ .006). Nonetheless, in the absence of evidence suggesting an
OS advantage, either a fludarabine- or chlorambucil-based strategy
could be considered an appropriate platform from which to
build.63,74,78-80 Some favor administering the most active treatment
first (when the patient is younger and may be better able to tolerate
it), whereas others favor administering the less toxic treatment first
(even if it is less efficacious) and salvaging patients at the time of
recurrence. It should also be noted that there are a variety of doses
and schedules of chlorambucil that have been evaluated and that
higher dosing strategies appear to have greater efficacy.81 Higherdose strategies may also have greater side effects, indicating a
trade-off between efficacy and toxicity.
The data on life expectancy at the population level (Table 2) raises
concerns that many elderly CLL patients are undertreated. The PFS
rates with both fludarabine and chlorambucil monotherapy (⬍ 18
months) are disappointing and inadequate for most patients.16,58,63 A
retrospective analysis of 5 CALGB trials found that the addition of
rituximab to fludarabine improved OS irrespective of age,79 arguing
for the inclusion of rituximab for elderly patients regardless of
which chemotherapy backbone is selected. Rituximab has been
added to both chlorambucil and fludarabine platforms in efforts to
improve disease control.82 A pivotal phase 3 trial by the GCLLSG
has now demonstrated that the addition of rituximab to chlorambucil in elderly CLL patients (median age 73) doubles the overall
response rate and prolongs PFS (16 months vs 11 months) without
increasing the rates of infection.83 This trial also suggested that the
third-generation type II anti-CD20 antibody obinutuzumab may
have even greater efficacy, with a PFS of 23 months for the
obinutuzumab-chlorambucil combination compared with 11 months
American Society of Hematology
Figure 3. An approach to selecting first-line therapy for CLL patients age ⱖ 70 years.
for chlorambucil alone.83 The fludarabine-rituximab (FR) combination appears to result in even more impressive overall and complete
response rates and a median PFS of ⬃ 42 months.84,85 The British
Columbia experience with FR confirmed this PFS in a community
setting in a cohort of 98 patients (27% were age ⱖ 70).85 Age did
not affect the number of FR cycles administered, the need to stop
treatment early, or OS.85
Although it represents a minority of older patients, the German
CLL8 experience indicates that select, fit elderly patients with
preserved organ function may be able to tolerate aggressive
FCR-type therapy.8 On subanalysis, FCR resulted in superior PFS
(but not OS) relative to FC therapy among patients age ⱖ 65,
although it was also associated with greater hematologic toxicity
and bacterial infections. The LRF4 trial also found that the more
intense FC regimen provided better outcomes than fludarabine or
chlorambucil monotherapy in all patient age groups, including those
age ⬎ 70.63 Data from the Australian CLL study group also support
that older patients with preserved organ function and low comorbidity can be treated aggressively.77
Alternative or reduced-intensity versions of FCR-like regimens
have also been developed. FCR-LITE decreases fludarabine and
cyclophosphamide doses and increases the amount of rituximab
administered.86 Although pilot data suggest that this regimen is
efficacious, the median age of patients in the pilot trial was 58 years,
and 3 of the 7 patients age ⱖ 70 had to discontinue treatment early,
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making the suitability of this regimen for elderly patients unclear.86
Investigators from the Czech Republic have developed an alternative reduced-intensity FCR type strategy with even greater reduction in the fludarabine dose, which was tested in a cohort of fit, older
patients (median age 70, median CIRS score ⫽ 4). Although these
investigators reported the regimen was reasonably well tolerated,
the overall response rate was only 70% and data on PFS and OS data
are not yet available.87 The pentostatin, cyclophosphamide, rituximab (PCR) regimen is another highly efficacious CIT approach that
appears to be well tolerated in elderly patients and those with
moderately decreased renal function (CrCl 35-70 mL/min), where
age does not appear to affect the number of cycles administered, the
number of adverse events experienced, or the efficacy of therapy.73
On balance, there remains a fairly strong correlation between
efficacy and toxicity with historical CLL treatment regimens
(Figure 2). Regimens offering deeper remission and greater PFS
tend to induce greater myelosuppression and have more grade 3-4
toxicity. As outlined in the accompanying chapter in this publication
by Hallek,88 it is hoped that novel targeted therapies currently in
clinical testing (eg, ibrutinib,89 and GS110190) may uncouple the
link between efficacy and toxicity and provide a wider menu of
effective therapy options for older and more frail patients.
The apparent relative equivalence of fludarabine and chlorambucil
for elderly patients74,78 raises the question of whether other therapies
that have proven superior to chlorambucil in randomized, controlled
163
trials may also be good platforms upon which to build for elderly
individuals. Both bendamustine91 and alemtuzumab92 have demonstrated higher overall and complete response rates as well as longer
PFS in randomized comparisons with chlorambucil. Additional
studies with these drugs in elderly patients are ongoing.
Nonchemotherapy regimens such as alemtuzumab-rituximab,93-95
lenalidomide monotherapy,96 lenalidomide in combination with
rituximab,97 rituximab monotherapy,98 rituximab–GM-CSF,99 and
high-dose methylprednisolone ⫾ rituximab100 have also been explored in clinical trials. With the exception of the alemtuzumabrituximab regimen for patients with nonbulky disease and/or
del(17p13) and the methylprednisolone-rituximab regimen, there
are currently inadequate data to recommend the routine use of these
regimens.
An approach to selecting therapy for elderly patients that considers
life expectancy, the result of genetic testing, and performance
status/comorbidities is provided in Figure 3. Although a personal
interpretation, all regimens listed are considered standard treatment
options for CLL patients by current National Comprehensive
Cancer Network (NCCN) guidelines. When selecting among different CIT regimens (FR, PCR, BR, reduced-intensity FCR strategies)
for more fit elderly patients, subtle trade-offs among tolerability,
toxicity, and durability of remission may lead different providers to
favor subtly different approaches. All of these strategies could be
considered a high-activity approach, where some variation in
practice is acceptable.
Conclusion
The management of elderly patients with CLL is more complex than
that of younger patients due to the greater frequency of comorbidities and functional impairment as well as reduced organ function.
The actuarial life expectancy of 70- to 80-year-old individuals is
longer than most physicians estimate. CLL will ultimately become
the cause of death for a majority of elderly patients once they
progress to the point that they require treatment. Although they may
not be able to tolerate regimens of the same intensity as younger
CLL patients, fit elderly adults should be treated with highly active
CIT approaches with the goal of achieving a reasonable depth of
remission and a several-year PFS. Several rituximab-containing
CIT platforms fit this profile and are appropriate treatment options.
Cytogenetic abnormalities are an important consideration in treatment selection, even among elderly patients. Clinical trials designed
specifically for elderly patients are under way and will help to better
define optimal management for these individuals. Priority should be
given to enrolling patients in these studies, particularly because
several novel, targeted therapies currently in testing have the
potential to transform the care of CLL patients in the near future.
Disclosures
Conflict-of-interest disclosure: The author has received research
funding from Genentech, Glaxo-Smith-Kline, Celgene, Cephalon,
Hospira, and Polyphenon E International. Off-label drug use:
Off-label use of fludarabine, pentostatin, rituximab, ofatumuamb,
lenalidomide, cyclophosphamide, ibrutinib, GS1101, and methylprednisolone for treatment of CLL.
Correspondence
Tait Shanafelt, MD, Mayo Clinic, 200 First St, Rochester, MN
55902; Phone: 507-266-1154; Fax: 507-266-4972; e-mail:
[email protected].
164
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