treatmentofolderpatientswithchroniclymphocytic...

Treatment of older patients with chronic lymphocyticleukemia: 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 newlydiagnosed patients. The management of elderly patients with CLL is more complex than that of younger patients due to thegreater frequency of comorbidities and functional impairment as well as reduced organ function. Many of the recentadvances in the care of CLL patients (prognostication, more intense combination therapy regimens) are of unclear relevancefor elderly patients. This review addresses 5 key questions in the management of elderly patients with CLL: (1) why isclassifying the “fitness” of CLL patients necessary; (2) what criteria should be used to classify patient fitness; (3) whenshould elderly patients be treated; (4) how should therapy be selected for elderly patients; and (5) which therapy is best (forthis patient)?

IntroductionThe last 2 decades have been a time of tremendous progress inthe care of patients with chronic lymphocytic leukemia (CLL).Most patients are diagnosed with early-stage disease beforedeveloping symptoms after they are incidentally found to havelymphocytosis. Insights into the molecular biology and geneticsof the leukemic CLL B cell have not only led to a betterunderstanding of disease biology,1-3 but have also enhanced theaccuracy of prognostication4,5 and identified potential newtherapeutic targets.6 The development of chemoimmunotherapy(CIT) combining purine nucleoside analogs with the anti-CD20monoclonal 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 achievea minimal residual disease–negative disease state, a depth ofremission rarely achieved with historical treatments.9,10

Unfortunately, these advances do not benefit all patients uni-formly. CLL is a disease of the elderly, with a median age ofonset of � 70 years. According to the Surveillance Epidemiol-ogy and End Results (SEER) registry, � 75% of patients aremore than 65 years of age at the time of diagnosis. Despite theadvanced age at onset, CLL shortens the life expectancy of themajority of newly diagnosed patients,11-13 with survival relativeto the age-matched population reduced for those � age 75 atdiagnosis, including those with Rai stage 0 disease.13 Althoughstudies suggest that there has been an improvement in survivalfor CLL patients � age 70 at diagnosis over the past severaldecades, no improvement has been observed for older patients.11,12

Because most patients have early-stage disease at diagnosis and areobserved for several years before starting treatment, the median ageat the time therapy is initiated is closer to 75 years. Elderly patientshave been underrepresented in previous clinical trials, which hasresulted in uncertainty regarding the optimal treatment approachesfor these individuals.14 Although select elderly individuals may beable to tolerate aggressive treatment approaches,8 standard fludara-bine, cyclophosphamide, rituximab (FCR) CIT cannot be toleratedby the majority of CLL patients who have comorbid healthconditions and begin treatment after the age of 70.15 Despite

advanced age, efficacious treatment is needed for these individualsbecause a majority of patients beginning treatment for CLL will dieas a direct result of the disease or its complications.16

This review addresses 5 key questions in the management of elderlypatients with CLL: (1) why is classifying the “fitness” of CLLpatients necessary; (2) what criteria should be used to classifypatient fitness; (3) when should elderly patients be treated; (4) howshould therapy be selected for elderly patients; and (5) whichtherapy is best (for this patient)?

Why is classifying the “fitness” of CLL patientsnecessary?There are several purposes for classifying fitness level in patientswith CLL. The first is to accurately categorize the patient’s lifeexpectancy unrelated to CLL (eg, due to other health problems).This information can then be used for patient counseling and tohelp define the importance of durable disease control whenselecting treatment. An 18-month remission in a symptomaticCLL patient is acceptable for an individual with a life expectancyof 24 months due to other health problems, whereas it would beconsidered inadequate for an individual with a 10-year lifeexpectancy unrelated to CLL.

Physicians often underestimate the life expectancy of older adults.For example, the life expectancy of the average 70-year-old man inthe United States according to the actuarial calculations of theUnited States Social Security Office is � 15 years.17 The lifeexpectancy for the average 80-year-old man is � 8 years (Table1).17 These data illustrate the limitations of using chronologicage alone to estimate survival in patients with CLL.

The second reason to classify fitness is to help determine thepatient’s ability to tolerate aggressive therapy. A 70-year-oldwoman with CLL in need of treatment may have an average lifeexpectancy unrelated to CLL of greater than 15 years. Although thisimplies that the goal of treatment should be durable remission andprolongation of life, it does not necessarily indicate that she will beable to tolerate an aggressive therapeutic regimen that has beendeveloped and tested in younger individuals. Rather than chrono-logic age, the patient’s comorbid health conditions, organ function

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and the pharmacokinetics (absorption, metabolism, excretion) of thedrugs to be used become key considerations in evaluating thesuitability of a given treatment approach. This principle is wellillustrated by the Cancer and Leukemia Group B (CALGB) 9011trial, which found that creatinine clearance rather than age was theprimary predictor of higher toxicity with fludarabine-based therapyin CLL patients.18

The third reason for classification of patient fitness is to allow moreconsistent stratification and selection of patients across clinicaltrials. Historically, trials have primarily used an exclusionary (ratherthan a stratification) approach declaring patients above an age cutoffor with any decrease in organ function or performance statusineligible.19 These criteria have excluded those with the characteristicstypical of real-world CLL patients from participating.20 A stratificationapproach allows trials to be designed with more liberal eligibility and touse alternative dosing strategies or different treatments for thosedeemed unable to receive aggressive regimens. A consistent approachto stratification in CLL trials that can also be applied in practice wouldhelp oncologists more readily interpret the relevance of trial results tothe patient they are evaluating and facilitate more rapid translation oftrial 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 inCLL patients. Although patients were traditionally classified based onage alone, it is now well recognized that chronologic age is not areliable surrogate for physiologic age or fitness.21 Although organfunction, 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 onestrategy used to assess fitness/frailty more accurately. CGA includesevaluation of function, coexisting health problems, level of socialsupport, cognitive ability, nutritional status, and common syndromesthat affect geriatric patients (dementia, delirium, falls, neglect, failure tothrive, depression, polypharmacy).21,22 Although there is limited infor-mation on the use of CGA to predict outcomes in patients with CLL,standardized scales to perform CGA are available23,24 and theseassessments have been shown to reliably predict the ability of elderlypatients to tolerate chemotherapy in other malignancies.25

The number and severity of comorbid health conditions also providesimportant information regarding patient fitness. A Mayo Clinic study of373 unselected CLL patients found that 89% of newly diagnosedpatients had at least one comorbid condition and 46% had at least onemajor comorbidity (eg, coronary artery disease, peripheral vasculardisease, diabetes mellitus, pulmonary disease [COPD], etc).20 Anadditional 9% of patients reported having difficulty in performingactivities of daily living independently (eg, eating, bathing, dressing,walking, toileting). Although the presence of a major comorbidityaffected OS on univariate analysis, it was not a significant predictor onthe multivariate analysis adjusting for CLL-specific characteristics (eg,stage).20 This finding underscores that CLL-related characteristics areoften the major factor influencing survival even when substantialcomorbidities are present. Although it enrolled only fit older patients(performance status 0-2, no severe organ disfunction), the presence of 2or more comorbid health conditions was still associated with shorterPFS and shorter OS in the German CLL5 trial.16 There are a variety ofmethods to assess comorbidity,26 of which the Cumulative IndexRating Scale (CIRS)27 and the Charlson Comorbidity Index28 areamong the most widely used.

Organ function is a third factor in assessing patients’ suitability foraggressive treatment. It is well recognized that renal function decreaseswith age.29,30 Analysis of � 15 000 adults participating in the NationalHealth 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 inRenal Disease (MDRD) equation.30 Common methods to estimaterenal function, such as the Cockcroft-Gault method, are heavilyinfluenced by age and lose precision among elderly patients. Forexample, a study of � 100 000 individuals from Japan found that� 80% of those � age 70 had a calculated creatinine clearance � 60mL/min/1.73 m2 when estimated by the Cockcroft-Gault method.31 Inthe Mayo Clinic series of unselected, newly diagnosed CLL patients,� 4% had decreased organ function (ie, total bilirubin � 2 mg/dL or aserum creatinine � 1.5 times the upper limit of normal).20

It should be emphasized that functional status (CGA), performancestatus, comorbidities, and organ function are related but distinctdimensions. Measuring only one of these dimensions can lead to aninaccurate assessment of overall patient fitness.32,33 Although East-ern Cooperative Oncology Group (ECOG) performance status, themost widely used assessment of patient fitness in oncology practice,has a moderate correlation with more formal CGA instruments,32 itis an inadequate measure of function for most older adults.33,34

Although not yet defined, the optimal method to assess fitness forpatients with CLL will likely involve a combination of CGA, comorbid-ity evaluation, and assessment of organ function (Table 2). Given theimportance of assessing fitness/frailty in the management of CLLpatients, the International Workshop on CLL (IWCLL) recently

Table 1. Life expectancy in the United States17

Current age, y

Life expectancy, y

Men Women

65 18.9 20.970 15.0 16.775 11.5 12.980 8.5 9.685 5.9 6.8

Table 2. Selected standardized tools to evaluate various dimensions of patient fitness

CGA and functional assessment Comorbidities Quality of life

Activity of Daily Living (ADL)101

CIRS-G27 European Organization for Research and Treatmentof Cancer (EORTC) QLQ-C30102

Instrument of Activities of Daily Living (AIDL)103,104 Charlson Comorbidity Index28 Functional assessment of cancer therapy-general(FACT-G)105

ECOG performance status106 Adult Comorbidity Evaluation (ACE-27)107 Patient Reported Outcome MeasurementInformation System (PROMIS)108

Others26 Others109

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launched an international initiative to bring greater consistency to thisassessment. It is hoped that this effort will identify standard criteria bywhich both fit and less fit CLL patients may be selected for trials andthat can be used to stratify patients within a trial to evaluate how fitnessrelates to response and toxicity. This effort will also explore how suchcriteria may be used to inform therapy selection in routine clinical practice.

When should elderly patients be treated?The indications to initiate therapy for elderly patients with CLL aregenerally the same as those for younger patients.35 These indicationsinclude cytopenias due to BM failure (hemoglobin � 11.0 g/dL,platelets � 100 � 109/L), massive/symptomatic lymphadenopathy ororganomegaly, and disease-related constitutional symptoms (disablingfatigue, unintentional weight loss, drenching night sweats, feversunrelated to infectious complications).35 Care should be used whenapplying these criteria in elderly patients because they are at higher riskfor having other disease processes that may contribute to fatigue orweight loss (eg, second cancer, malnutrition, neglect, other organdysfunction). Up to 50% of older patients have been found to havedepression,34,36 and patients should be specifically screened for depres-sion and other disorders associated with fatigue (eg, hypothyroid, sleepapnea, anemia from a cause unrelated to CLL) before attributing fatigueto CLL. Although a lymphocyte doubling time of less than 6 months isconsidered an acceptable indication for treatment,35 treatment on thisbasis alone is rarely indicated in the absence of other indications fortherapy. CLL experts appear to have a greater tolerance for delayingtherapy when it is not indicated,37 particularly in elderly patients.13

It is also worth emphasizing several features that are not acceptablereasons to initiate therapy. The degree of elevation in the absolutelymphocyte count, regardless of magnitude, is not an acceptablereason to initiate therapy in the absence of other indications.35 It isalso not necessary to initiate treatment for asymptomatic lymphnode enlargement or slow, progressive lymphadenopathy. Becausetreatment increases rather than decreases the risk of infection,frequent or recurrent infections are also not a reason to initiatetherapy.35 Rather, patients with frequent or recurrent infectionsshould undergo assessment for hypogammaglobulinemia or othercauses of immunocompromise.38,39

While under observation, older patients should receive aggressivesupportive care measures to minimize disease-related complications.This includes age-appropriate cancer screening and regular evaluationfor skin cancer specifically.40,41 Given the heightened risk of bothmelanoma and nonmelanoma skin cancer, patients should also becounseled regarding sun protection and avoidance.42 Approximately50% of adults are vitamin D deficient43-45 and counseling to avoid sunexposure can exacerbate this problem. Studies from both the UnitedStates and Italy suggest that low vitamin D levels may be associatedwith more rapid CLL disease progression and shorter survival,46,47 afinding that has also been found in other malignancies.48-50 It isunknown whether screening for vitamin D deficiency and/or vitamin Dreplacement reverses this association. Nonetheless, vitamin D assess-ment in patients at risk can be considered good general care for elderlypatients due to bone health51 as well as to reduce falls52,53 and weroutinely perform vitamin D assessment at the time of diagnosis.46,47

Vaccination strategies should also be employed in CLL patients totry to reduce infectious complications.38,39 In the United States, theCenter for Disease Control vaccination guidelines (updated in2012) suggest that all immunocompromised patients, such asthose with leukemia, receive initial pneumococcal vaccinationwith the Prevnar 13 vaccine followed 8 weeks later by the

pneumococcal 23 vaccine.54 The pneumococcal 23 vaccineshould then be repeated at 5-year intervals. Adult patients whohave previously had the pneumococcal 23 vaccine should receivethe Prevnar 13 vaccination at least once during their lifetime(administer 12 months after the most recent pneumococcal 23vaccine).54 Although annual influenza vaccination is also recom-mended, live attenuated vaccines, including Zostavax, are contra-indicated in patients with CLL (Table 3).

Although the genetic and biologic characteristics of CLL B cellshave been found to predict outcome in younger CLL patients, thereis limited information on the utility of these molecular biomarkersfor predicting outcome in older CLL patients.55,56 The Mayo Clinicevaluated the utility of prognostic testing based on age at diagnosisin a cohort of � 2500 CLL patients, including 748 patients age65-74 and 433 patients age � 75.13 After adjusting for disease stage,IGHV, ZAP-70, and CD38 remained powerful predictors of time tofirst treatment in patients of all ages, including those age � 75. Incontrast, prognostic testing had minimal to no value for predictingOS among patients age � 75 after adjusting for stage.13 Thesefindings suggest that these molecular biomarkers remain relevant tothe biology and natural history of CLL in elderly patients, but that

Table 3. Supportive care considerations for CLL patients

Suggestions

Cancer screening ● Whole-body skin examinationannually.41,42

● Age-appropriate screening for breast,colon, and cervical cancer should bedone.

Vaccination strategies54 ● Prevnar 13 pneumococcal vaccinationshould be given at diagnosis followed 8weeks later by Pneumovax (23-valent)vaccine.

● Repeat Pneumovax approximately every5 years.

● Patients who have previously receivedPneumovax but who have neverreceived Prevnar 13 should receive asingle dose of Prevnar 13 at least 12months after last pneumococcalvaccination.

● Annual influenza vaccination should begiven.

● Avoid live attenuated vaccines includingvaccines for zoster, yellow fever, andlive attenuated typhoid vaccines.

Fatigue ● Fatigue must be carefully evaluatedbefore attributing to CLL, particularly inolder adults.

● Consider evaluation for depression,second cancers, hypothyroidism, sleepapnea, anemia due to causes unrelatedto CLL before attributing fatigue toCLL.

Other considerations ● Provide education regarding skinprotection and avoidance of sunexposure to reduce risk of skin cancer.Consider evaluation of vitamin D levelsbecause this recommendationincreases risk of vitamin D deficiency.

● Smoking cessation should be advisedgiven apparent increased risk ofsmoking-related cancers in CLLpatients.110,111


competing causes of death may decrease their direct relevance forpredicting OS with increasing age.

How to select therapy for older patientsIn younger patients without comorbidities, genetic characteristics of theclonal B cells (del[17p13], TP53 gene mutations, del[11q23]) are theprimary factor influencing therapy selection. Deep remission (evenminimal residual disease–negative remission) is the goal of treatment57

and the treatment strategies offering the best PFS and OS should beprioritized. Based on a series of phase 3 trials,8,58-64 most patients (withexception of those having TP53 defects) should receive an FCR8 orFCR-like65,66 treatment regimen. The German CLL Study Group(GCLLSG) CLL10 trial will determine whether bendamustine andrituximab (BR)67 is an acceptable alternative in these patients. Inclusionof an alkylating agent appears to be important for patients with deletion11q23.68 Although associated with PFS, this cytogenetic defect doesnot appear to effect OS when these patients are treated with FCR-likeplatforms.69 As outlined in the accompanying chapter in this publica-tion by Gribben and Riches,70 suitable young patients with del(17p13)in need of treatment should be debulked and proceed to reducedintensity allogeneic stem cell transplantation.71,72

As discussed, the selection of therapy in older patients is morecomplex because they are more likely to have coexistent healthconditions that affect organ function and the ability to toleratetreatment. Establishing the goals of treatment is the first step intherapy selection (Figure 1). Patient characteristics (rather than the

characteristics of the treatment regimen) determine the goals oftherapy. The combination of performance status, comorbidityassessment, CGA (such as independence with activities of dailyliving), and organ function (primarily creatinine clearance) are moreimportant factors than age in determining treatment goals.

In patients with a long life expectancy unrelated to CLL and goodfunctional status, deep remission remains an appropriate goalregardless of age. For those with short life expectancy due to otherhealth conditions, palliation is appropriate. Most older patients withCLL fall somewhere in between and require that clinicians balance avariety of considerations when selecting therapy. It must also be kept inmind that, with the exception of allogeneic stem cell transplantation,the current treatments for CLL are noncurative. Although achieving thelongest remission duration possible is an appropriate strategy inyounger patients, intermediate durations of remission (eg, 3-4 years)with salvage therapy at relapse may be more appropriate for someelderly patients if this approach offers less toxicity and better quality oflife. Selecting a too aggressive approach that requires extensive dosereduction or results in discontinuation of treatment may be lessbeneficial than choosing a better tolerated treatment that allowsadministration 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 conditionsand greater than half have at least one major comorbidity under-scores that therapy selection must be individualized. There is

Figure 1. Determining the goals of treatment for older patients with CLL.

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unlikely to be a single treatment regimen that will be an optimal fitfor all older patients. After determining the goals of treatment, thebest strategy to achieve these goals must be determined. Here thecharacteristics of the treatment regimen (efficacy, toxicity, mecha-nism drug elimination/metabolism) and the patient’s underlyingorgan function become substantial considerations. Tables providingan extensive cataloging of the experience of elderly CLL patientstreated in past and ongoing clinical trials have been published bymultiple authors and will not be reproduced here.14,74-76

The GCLLSG has used the combination of the CIRS assessment ofcomorbidities and creatinine clearance as useful parameters toidentify older patients fit for aggressive treatment approaches.Those with a CIRS score � 6 and preserved creatinine clearance(� 70 mL/min) have generally been considered candidates foraggressive therapy independent of age, whereas patients with higherCIRS scores are considered to be less fit and are thereforecandidates for less intense treatment strategies.74 A recent reportfrom the Australian CLL Study Group in a cohort of fit CLL patientsage � 65 (median age, 72) found no difference in the frequency ofgrade � 3 adverse events among individuals with a CIRS score of0-2, 3-4, or 5-6, providing some justification that a CIRS score � 6identifies elderly patients able to tolerate more aggressive CITtreatment strategies.77

In contrast to the findings of 4 randomized trials in youngerpatients,58-61 several recent observations have challenged the notionthat purine analogs are superior to chlorambucil in all agegroups.63,75,78 The CLL5 trial of the GCLLSG randomized patientsage � 65 to fludarabine monotherapy or single-agent chloram-bucil.16 Although a higher overall (72% vs 51%, P � .003) andcomplete response rate (7% vs 0%, P � .11) were observed for thefludarabine arm, no difference in the median PFS was observedbetween groups (19 months for fludarabine and 18 months forchlorambucil, P � .7). Time to treatment failure, however, did favorthe fludarabine arm (18 months vs 11 months, P � .004) because� 30% of patients randomized to chlorambucil crossed over tofludarabine before disease progression. No difference in grade 3-4

neutropenia or infection was observed between the arms and ahigher proportion of patients in the chlorambucil arm discontinuedtherapy due to treatment side effects. Greater improvements inquality of life were observed in the fludarabine arm at both 6 and 12months. Although no difference in OS was observed, interpretingthis finding is confounded because patients randomized to chloram-bucil were markedly more likely to received salvage therapycompared with those randomized to fludarabine (50% vs 77%,P � .006). Nonetheless, in the absence of evidence suggesting anOS advantage, either a fludarabine- or chlorambucil-based strategycould be considered an appropriate platform from which tobuild.63,74,78-80 Some favor administering the most active treatmentfirst (when the patient is younger and may be better able to tolerateit), whereas others favor administering the less toxic treatment first(even if it is less efficacious) and salvaging patients at the time ofrecurrence. It should also be noted that there are a variety of dosesand schedules of chlorambucil that have been evaluated and thathigher dosing strategies appear to have greater efficacy.81 Higher-dose strategies may also have greater side effects, indicating atrade-off between efficacy and toxicity.

The data on life expectancy at the population level (Table 2) raisesconcerns that many elderly CLL patients are undertreated. The PFSrates with both fludarabine and chlorambucil monotherapy (� 18months) are disappointing and inadequate for most patients.16,58,63 Aretrospective analysis of 5 CALGB trials found that the addition ofrituximab to fludarabine improved OS irrespective of age,79 arguingfor the inclusion of rituximab for elderly patients regardless ofwhich chemotherapy backbone is selected. Rituximab has beenadded to both chlorambucil and fludarabine platforms in efforts toimprove disease control.82 A pivotal phase 3 trial by the GCLLSGhas now demonstrated that the addition of rituximab to chloram-bucil in elderly CLL patients (median age 73) doubles the overallresponse rate and prolongs PFS (16 months vs 11 months) withoutincreasing the rates of infection.83 This trial also suggested that thethird-generation type II anti-CD20 antibody obinutuzumab mayhave even greater efficacy, with a PFS of 23 months for theobinutuzumab-chlorambucil combination compared with 11 months

Figure 2. The tight link between efficacy and toxicity with historical CLL therapy. This figure is a summary illustrating the link between efficacy andtoxicity with historical CLL treatments. It cannot be used to compare regimens directly because results are drawn from across trials with differentpatient characteristics. In some cases, multiple trials testing the same regimen found slightly different PFS and rates of grade 3/4 toxicity; therepresentative experience is indicated in such cases.


for chlorambucil alone.83 The fludarabine-rituximab (FR) combina-tion appears to result in even more impressive overall and completeresponse rates and a median PFS of � 42 months.84,85 The BritishColumbia experience with FR confirmed this PFS in a communitysetting in a cohort of 98 patients (27% were age � 70).85 Age didnot affect the number of FR cycles administered, the need to stoptreatment early, or OS.85

Although it represents a minority of older patients, the GermanCLL8 experience indicates that select, fit elderly patients withpreserved organ function may be able to tolerate aggressiveFCR-type therapy.8 On subanalysis, FCR resulted in superior PFS(but not OS) relative to FC therapy among patients age � 65,although it was also associated with greater hematologic toxicityand bacterial infections. The LRF4 trial also found that the moreintense FC regimen provided better outcomes than fludarabine orchlorambucil monotherapy in all patient age groups, including thoseage � 70.63 Data from the Australian CLL study group also supportthat older patients with preserved organ function and low comorbid-ity can be treated aggressively.77

Alternative or reduced-intensity versions of FCR-like regimenshave also been developed. FCR-LITE decreases fludarabine andcyclophosphamide doses and increases the amount of rituximabadministered.86 Although pilot data suggest that this regimen isefficacious, the median age of patients in the pilot trial was 58 years,and 3 of the 7 patients age � 70 had to discontinue treatment early,

making the suitability of this regimen for elderly patients unclear.86

Investigators from the Czech Republic have developed an alterna-tive reduced-intensity FCR type strategy with even greater reduc-tion in the fludarabine dose, which was tested in a cohort of fit, olderpatients (median age 70, median CIRS score � 4). Although theseinvestigators reported the regimen was reasonably well tolerated,the overall response rate was only 70% and data on PFS and OS dataare not yet available.87 The pentostatin, cyclophosphamide, ritux-imab (PCR) regimen is another highly efficacious CIT approach thatappears to be well tolerated in elderly patients and those withmoderately decreased renal function (CrCl 35-70 mL/min), whereage does not appear to affect the number of cycles administered, thenumber of adverse events experienced, or the efficacy of therapy.73

On balance, there remains a fairly strong correlation betweenefficacy and toxicity with historical CLL treatment regimens(Figure 2). Regimens offering deeper remission and greater PFStend to induce greater myelosuppression and have more grade 3-4toxicity. As outlined in the accompanying chapter in this publicationby Hallek,88 it is hoped that novel targeted therapies currently inclinical testing (eg, ibrutinib,89 and GS110190) may uncouple thelink between efficacy and toxicity and provide a wider menu ofeffective therapy options for older and more frail patients.

The apparent relative equivalence of fludarabine and chlorambucilfor elderly patients74,78 raises the question of whether other therapiesthat have proven superior to chlorambucil in randomized, controlled

Figure 3. An approach to selecting first-line therapy for CLL patients age � 70 years.

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trials may also be good platforms upon which to build for elderlyindividuals. Both bendamustine91 and alemtuzumab92 have demon-strated higher overall and complete response rates as well as longerPFS in randomized comparisons with chlorambucil. Additionalstudies with these drugs in elderly patients are ongoing.

Nonchemotherapy regimens such as alemtuzumab-rituximab,93-95

lenalidomide monotherapy,96 lenalidomide in combination withrituximab,97 rituximab monotherapy,98 rituximab–GM-CSF,99 andhigh-dose methylprednisolone � rituximab100 have also been ex-plored in clinical trials. With the exception of the alemtuzumab-rituximab regimen for patients with nonbulky disease and/ordel(17p13) and the methylprednisolone-rituximab regimen, thereare currently inadequate data to recommend the routine use of theseregimens.

An approach to selecting therapy for elderly patients that considerslife expectancy, the result of genetic testing, and performancestatus/comorbidities is provided in Figure 3. Although a personalinterpretation, all regimens listed are considered standard treatmentoptions for CLL patients by current National ComprehensiveCancer Network (NCCN) guidelines. When selecting among differ-ent 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 tofavor subtly different approaches. All of these strategies could beconsidered a high-activity approach, where some variation inpractice is acceptable.

ConclusionThe management of elderly patients with CLL is more complex thanthat of younger patients due to the greater frequency of comorbidi-ties and functional impairment as well as reduced organ function.The actuarial life expectancy of 70- to 80-year-old individuals islonger than most physicians estimate. CLL will ultimately becomethe cause of death for a majority of elderly patients once theyprogress to the point that they require treatment. Although they maynot be able to tolerate regimens of the same intensity as youngerCLL patients, fit elderly adults should be treated with highly activeCIT approaches with the goal of achieving a reasonable depth ofremission and a several-year PFS. Several rituximab-containingCIT platforms fit this profile and are appropriate treatment options.Cytogenetic abnormalities are an important consideration in treat-ment selection, even among elderly patients. Clinical trials designedspecifically for elderly patients are under way and will help to betterdefine optimal management for these individuals. Priority should begiven to enrolling patients in these studies, particularly becauseseveral novel, targeted therapies currently in testing have thepotential to transform the care of CLL patients in the near future.

DisclosuresConflict-of-interest disclosure: The author has received researchfunding 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 methyl-prednisolone for treatment of CLL.

CorrespondenceTait Shanafelt, MD, Mayo Clinic, 200 First St, Rochester, MN55902; Phone: 507-266-1154; Fax: 507-266-4972; e-mail:[email protected].

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