Blood Reviews
Volume 26, Issue 1 , Pages 15-23, January 2012

Optimal management of older patients with chronic lymphocytic leukemia: Some facts and principles guiding therapeutic choices

  • Tamar Tadmor

      Affiliations

    • Hematology Unit, Bnai-Zion Medical Center, Haifa, Israel
    • Corresponding Author InformationCorresponding author at: Hematology Unit, Bnai-Zion Medical Center, 47 Golomb Street, Haifa, 31048, Israel. Tel.: +972 48359407; fax: +972 48359962.
    • ,
  • Aaron Polliack

      Affiliations

    • Department of Hematology, Hadassah University Hospital, Hebrew University Medical School, Jerusalem, Israel

published online 28 September 2011.

Article Outline

Abstract 

Chronic lymphocytic leukemia (CLL) is a disease of older patients and median age at diagnosis is 72years. This older group is under-represented in clinical trials, (median age 58–62years). Here we review background data on incidence, survival, definitions of older age, fitness criteria, frailty and co-morbidities. Issues influencing the choice of therapy in older patients are also addressed and different therapeutic options are highlighted based on recent available data. Fit older patients with less co-morbidities benefit most from the very effective chemoimmunotherapy (FC-R) given for younger patients today, but whether other novel drug combinations or new agents are more suitable for less fit patients is still unsettled. Based on careful evaluation of published data from larger clinical trials and major referral centers we present our concept of therapy as a guide to optimal management for subgroups of older patients with CLL.

Keywords: Chronic lymphocytic leukemia (CLL), Elderly, Old, Therapy, Chemoimmunotherapy, Clinical trials, Rituximab, Purine analogs, Fludarabine

 

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1. General introduction 

During recent years and particularly over the past decade our understanding of the pathophysiology of CLL has greatly improved. Advances in revealing the basic mechanisms of the underlying defects in molecular biology and regulation of the leukemic clone, and the significance of interactions between the CLL cell and its microenvironment, the possible role of antigenic stimulation in the pathogenesis of the disease, have all contributed to the improved understanding of this common form of leukemia. These developments have directly affected approaches to daily management and have led to improved risk adapted targeted therapy for CLL. Increases in overall survival have been reported for the first time using chemoimmunotherapy, resulting in a wave of optimism for future innovative therapeutic options.1 The robust development of a variety of novel agents and candidate drugs for continuing therapy and possible use in the near future has revitalized interest in CLL, raising hopes for even greater improvements in quality of life and survival for all age groups including the elderly. Although age is a factor in prognosis as well as outcome, therapy, biological frailty and co-morbidities and even which criteria should be used to define fitness and eligibility for treatment are all interlinked in CLL. How best to treat and administer optimal supportive care for older patients in the general community is still an issue today. This relates to the fact that there appears to be some bias in outcome in favor of patients included in trials, who appear to benefit more from closer and more frequent follow-up and the attention given to them during the trial and because they are more carefully selected and generally younger than patients in the community . As a result it is indeed possible that the accepted “gold standard” therapy proposed for this age group may not always be applicable to all CLL patients in daily practice who are not generally included in clinical trials undertaken within larger referral centers.

The first part of this review provides some background data on CLL in elderly patients and also addresses a few selected issues which influence choices of therapy and patient management in this age group. These include incidence and survival data in older patients, problems relating to the definition of terms like “old or elderly”, how fitness criteria are determined in this age group and what part frailty and co-morbidities play in the basic decision-making in CLL and in determining who is able to receive optimal therapy. In this respect, older age until quite recently has traditionally been regarded as a poor prognostic factor and a major reason for withholding optimal combination therapy from many patients, who may have been regarded as fit enough to receive more aggressive therapy if other criteria were used. In this regard attitudes to age have changed in recent years.

The second part of this review deals with the different options of therapy available for patients with CLL and highlights the results obtained in the older age group until now. Based on careful evaluation of reported data from the major centers and clinical trials we propose our concept of therapy as a guide to optimal management for the different subgroups of older patients.

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2. Background 

2.1. Incidence and survival in older patients 

CLL is still the commonest adult leukemia of the western world and comprises about 11% of all hematological cancers affecting mostly elderly patients, with a median age of 72years at diagnosis.[2], [3], [4], [5] The incidence of CLL impressively increases with advancing age and according to the SEER clinical statistics review data (1975–2008) from the USA, the adjusted incidence rate at diagnosis is 3.9/100,000 increasing significantly in the elderly to 22.3/100,000 above the age of 65years and is even higher for patients above the age of 80years.[2], [5] It is important to realize that 75% of CLL patients in the USA are over the age of 65years while about 50% are 75years or older. At the time of diagnosis about 30% of patients are between the ages of 70 and 79 and close to 23% are above the age of 80years.[3], [6], [7]

However, incidence assessments for CLL based on data from cancer registries are mostly underestimated by about 10% as they rely on diagnostic histopathological reports and in daily practice outside the larger referral centers, less biopsies are performed and diagnosis is usually established on the basis of a blood film or flow cytometry (FCM) analyses . Furthermore most patients are not treated at diagnosis and because of this there is generally underreporting to cancer registries. A recent Swedish study 8 has shown that case documentation is about 10% lower for CLL than for other lympho-proliferative disorders while some reports from the USA indicate that over a 10year period, 37% of patients diagnosed with CLL were not even reported.9 In older patients this is yet a greater problem since many samples are not even sent for FCM to confirm the diagnosis and as a result the true incidence of CLL in the general community is incomplete in many countries. Today, establishing the true incidence of CLL is further complicated by the recent redefinitions of the criteria for monoclonal B cell lymphocytosis (MBL) and early stage CLL,[10], [11] using absolute numbers of circulating CLL cells present in the peripheral blood according to FCM (>5×109 B lymphocytes/L) as the basis for diagnosis which will also alter the true reported incidence of CLL in the future.12

When the 1980s are compared with the early period of this century [3], [4] a trend to increased long term survival is evident in CLL. In 2008, Brenner and colleagues 3 reported that, there were steady increases of about 10% in 5year survival over time, evenly distributed across all age groups. However, after 10years increased survival patterns from diagnosis were only evident in patients diagnosed <80years. It is very probable that these trends can be attributed to earlier diagnosis of CLL rather than to improved management of co-morbidity, and possibly to therapeutic advances which may also have contributed to ongoing improvement. Today, there are even more long term survival expectations for patients in the future, particularly after the impressive results obtained with the combination chemoimmunotherapy regimen — FCR. 3

2.2. The burden of co-morbidities, age and fitness criteria 

Co-morbidities are frequent in elderly patients with cancer and may significantly affect the survival of patients with CLL requiring treatment constituting an important prognostic factor in the elderly and adversely affecting decisions to treat. This seems to be particularly significant for patients with >2 co-morbidities or with severe co-morbidity.[13], [14] The number and severity of existing co-morbidities are not always related to age and appear to be independent predictors of survival in some studies and the extent of co-morbidity in the USA appears to be higher than in Europe.15 Some studies have implied that age and disease stage rather than co- morbidities are associated with shorter OS. However very different patient populations have been compared in the various reports and as a result these issues have not yet been completely resolved [13], [16] and may also contribute to some selection bias in clinical trials performed in CLL. In this respect it is important to acknowledge that the renowned German CLL Study Group 1 employs, in addition to age itself, the Cumulative Illness Rating Scale (CIRS) and a modified Charlson scoring system, to measure co-morbidity and assess physical fitness before including or excluding patients from their studies.[1], [13], [16]

The studies from the German CLL Study Group have basically defined what is now accepted almost worldwide as the “gold standard” therapy for patients for CLL, including the elderly, with a slight bias towards the “fit”patients (the so called “Go-Go” group). However the medically less fit older patients with a greater co-morbidity burden, (the so called “Slow Go” group), are generally under-represented in clinical trials and need to be to be recruited into future clinical studies as emphasized recently by Del Giudice et al.17 A third group, of frail patients (so called “No-Go” group) who have three or more co-morbidities, individual dependence on one or more activities in life and a shorter life expectancy, and who should probably only receive palliative therapy, has also been defined.[13], [16], [18] In practice however, this approach is limited by the fact that the scoring systems can often be difficult to apply in patients with malignancies and can be problematic when it comes to correlating results because different methods have been used in the various studies.19 Taking all the above into consideration, it is also important to realize that clinical stage and bio-markers may perhaps be even more relevant for predicting responses and prognosis in CLL. Consequently all aspects should be considered when therapeutic decisions have to be made in elderly patients because management and risk stratification is indeed problematic.

Age on its own can also be regarded as an independent risk factor for poorer prognosis in CLL but this is variable and differs considerably in individual patients within the same age group.[9], [20] This variability may relate to the increased number of co-morbidities and to loss of end organ reserve developing with older age. Accordingly, exact chronological age does not always reflect fitness or performance status or “biological age” and individual function, as clearly evident from some of the Mayo Clinic data.20

The evaluation of who is indeed “fit for therapy” can be undertaken using different scores and scales such as the ECOG performance status criteria, the Instrumental Daily Living Scale or the Activities of Daily Living Scale — all of which when applied do not always correlate well with what has been reported.19 In this regard when dealing with therapeutic issues in unselected newly diagnosed patients with CLL the treating hemato-oncologists tend to link “co-morbid conditions and survival”,21 or “co-morbidities and functional status” but these are often unrelated in the elderly.12 As Zent has so elegantly described 20, some symptoms may be caused by anemia and extreme asthenia which are disease related and if the patient is not treated “frailty” and performance status may decline even more. This raises the important issue of how to balance the risks and benefits of treatments in older patients who display reduced tolerance for therapy or have decreased life expectancy. Because of all the above it is best to rely on a combination of good clinical judgment, practical application of the performance/fitness scales and a careful assessment of co-morbidities, during the difficult decision-making in individual cases.

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3. Prognostic factors and their impact in the elderly 

The “classical” or traditional prognostic factors recognized as being important for younger patients with CLL include numerous clinical and biologic parameters predictive of time to first treatment, prognosis and survival 22 (Fig. 1). Until recently these were essentially based on readily obtainable clinical parameters such as clinical stage of disease, age, lymphocyte doubling time and simple laboratory data including serum beta 2 microglobulin and possibly LDH levels.[22], [23], [24] However in recent years biological and molecular markers (some probably still needing standardization), including IgVH mutational status, CD 38, ZAP-70 and CLLU1 expression, cytogenetics and particularly FISH, have been shown to be significant complementary parameters which provide vital prognostic information.[22], [25], [26] FISH findings particularly those relating to chromosome 17p deletion and TP53 mutations and to some extent 11q deletion, are clearly of the greatest importance in this regard and will probably form the basis for the first genotype-specific risk adapted therapy for patients with CLL.27 The above factors serve as independent predictors of time to first treatment and/or overall survival and their distribution appears to be independent of age. The impact of these factors in elderly patients >65 and >75years has not been definitively demonstrated in all studies 23 and it is still justified to ask questions about the links between the “conventional” biomarkers, older age and performance status and eventual outcome. Is their individual impact on prognosis in the older patients markedly different? Have they been evaluated sufficiently well enough to be significant? Nevertheless, simple clinical factors like stage and age still appear to be relevant and of prognostic and predictive significance and as a result cannot be overlooked.

3.1. Clinical stage and age 

Clinical stage of disease which is simple and easy to define in CLL, is clearly a very good guide to eventual prognosis and is an independent important predictive factor in many cases. Obviously diagnosis established at an early stage of disease has very different implications than disease diagnosed in a more advanced clinical stage which will mostly have a greater negative impact on survival. Because of the established heterogeneity in the clinical course of the disease, stage alone does not reliably predict the risk of progression for individual patients even when they are diagnosed with very early disease. In this regard, it has been shown, that there is still a strong “age gradient” in relation to survival in CLL when co-morbidities and individual health frailty issues in elderly patients are taken into consideration.23 Expected 10year survival patterns are grossly different and are about 60% for patients below the age of 60 and about 6% for those >80years old.3 Accordingly the benefit of risk stratification under similar clinical circumstances using many of the classical molecular biomarkers as a basis for therapeutic decisions may be maximal for a patient <60years but much less significant for a >70year old.

When carefully reviewing the issues relating to prognosis and prediction of life expectancy in the elderly CLL, it is evident that most of the data reported in the major clinical studies were derived from much younger patients (median age of <65–60).23 In this respect the Mayo Clinic data is of particular interest as they attempted to determine differences in the natural history of CLL based on age at diagnosis, comparing survival of patients with CLL to that of age matched individuals in the general population.23 They also attempted to assess the value of age-stratified prognostic prediction for CLL using age groups <55, 55–64, 65–74, >75years of age . The latter age group constituted 17.4% of the 2487 patients, and the 65–74year old age group made up 30.1% of the entire cohort, while 47.5% of the entire group was >65years old. In this study, the majority of patients at the time of diagnosis were older and had early disease [3], [13], [16], [28], [29] whereas most of the published data relating to prognostic factors in CLL are derived from studies comprising younger patient cohorts, often with more advanced disease. This paradox is not always appreciated when deciding on whether to apply prognostication in daily clinic experience.

3.2. Other bio-molecular markers 

Although some trials included appreciable numbers of elderly patients the impact of the newer molecular prognostic factors in elderly patients (>65 and >75years) has not yet been convincingly demonstrated until most recently.[23], [30], [31], [32] In fact whether FISH/cytogenetic aberrations particularly p53 mutations and alterations in chromosome 17 have the same prognostic implications for the elderly as they have in younger patients may still be unclear. In this respect it is of interest to note that in a study by Joseffson et al. 25 analyzing CLLU1 expression in CLL, it was evident that this gene was only prognostically significant in patients younger than 70years of age and that its prognostic impact was lost above the age of 70. Similarly the same study showed that strong expression of ZAP 70 and CD 38, also lacked significance with older age, 25while other studies also suggested that the poor prognostic cytogenetic/FISH findings (e.g. 11q deletions) also identified a subset of patients with poorer prognosis may not have the same impact in patients >55years.26 It is important to realize that TP53 mutations and 17p deletions, which are clearly indicative of high risk and shorter survival in CLL, are only encountered in 8–12% of patients needing front-line therapy for their disease, and because of this it is difficult to obtain a large series of patients and verify whether it is also so impressively predictive of failure to respond and poorer survival in older patients as well.33 Accordingly, it remains unclear from all published studies whether the very obvious poor prognostic implications of 17p deletions and p53 mutations present in the younger patients with CLL apply equally to elderly patients with the disease. Limited data from Zenz et al. 27 imply that it is the most important single parameter determining efficacy of treatment for CLL in all age groups and that these patients do not respond well to standard routine chemoimmunotherapy. Furthermore studies by Shanafelt et al. investigating the influence of age at diagnosis on the utility of prognostic testing in patients with CLL suggest that, CD 38, ZAP 70 IGHV mutation status and FISH were useful for predicting time to treatment in all age cohorts but were less reliable for predicting overall survival in patients >75years and older.23 These results imply that the biology of the disease itself influences the clinical course of the disease in the elderly and that survival is affected by a combination of variables including impaired organ function and poorer therapeutic tolerance, decreased life expectancy and co-morbidities which do not allow patients to benefit even from the optimal risk adapted therapy.33 They indicate that these markers assist in selecting high risk early stage patients (<75years old) for clinical trials designed for early therapeutic intervention and can predict OS independent of stage reliably for all age groups <75years of age.23 On the other hand for patients above the age of 75years they can predict for time to first treatment but not for OS independently of clinical stage, implying that it does not seem correct to enroll patients aged >75 in clinical trials according to these prognostic factors if the intent is to improve OS.

It seems clearly evident now that for the subgroup of patients needing treatment and have unmutated IGHV, 11 q deletion, V3-21 usage and high levels of serum B2MG, poor median survival of about 4.5years can be predicted once therapy has been started, while the patients who have none of these and mutated IGVH status have a very favorable outcome.34 Obviously those patients who have TP53 mutations (even without 17p deletion) and those who have 17p-genotype have the worst prognosis with a median survival of less than 24months from first therapy indication.35 It is still unclear whether all the above are applicable to elderly patients above the age of 70years and this needs to be investigated very carefully as the median age of diagnosis of CLL is over 70years of age.

3.3. Beta 2 microglobulin 

The cumulative reported data from the MDACC group from Keating and co-workers have shown consistently just how valuable the levels of serum beta microglobulin are in relation to prognosis and prediction of PFS and OS as well as to response to Fludarabine-containing regimens. Very high levels of B2M are indeed an independent predictive factor in terms of poor response rates and poorer survival and could indeed be most appropriate for use in the elderly subgroup of patients seeing that it is so easy a laboratory test to perform and use routinely.[36], [37], [38]

One should bear in mind, that in the community, and outside clinical trials, not all the more sophisticated and expensive bio-markers are performed, and less of them are done in the elderly patients. Taking all the above in consideration a simple marker such as B2MG could certainly be used as a useful surrogate of tumor load and progression in the older patient with CLL.

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4. Treatment of elderly CLL patients 

4.1. Under representation of the more elderly in trials 

Today, when planning risk-adapted therapy for elderly patients with CLL in the light of published results in this age group, one has to take into consideration that there is an obvious under representation of the more elderly group of patients in many of the reported trials. This is linked to the issue of co-morbidities, as some include unselected cases while others exclude patients with more than one co-morbidity, accepting only fit patients or those with only mild co-morbidities.[9], [15] Furthermore the median age for patients with CLL in the general community is 72years while it is lower (58–66years) in the large centralized studies [39], [40] and even less in trials using chemoimmunotherapy.[28], [41] Because of the different criteria in the various studies there is obviously some bias in the reported data which may affect decisions to recommend the proposed therapy for all patients in community practice. Bearing this in mind and considering the fact that age may be considered a major prognostic factor, it is apparent that not all elderly patient subgroups can benefit in the same way as selected and slightly younger subgroups do from the same therapy regimens proposed. This remains a very basic issue that will continue to influence therapeutic decisions in the elderly in the future.

4.2. Are the indications for treatment and up-front therapeutic options the same for younger and older patients? 

The process of decision-making for treating both younger and elderly patients with CLL is similar and both share a common initial approach. Firstly a decision has to be made about whether patients should only be followed without therapeutic intervention or whether treatment should be initiated. There is general agreement that newly diagnosed patients with asymptomatic early-stage disease should be followed without therapy independent of age, as early intervention does not appear to prolong survival. Indications for initiating treatment in CLL are still based on the appearance of CLL-related symptoms, and only symptomatic patients or those with progressive or advanced stage disease should be considered for therapy. At this point a second crossroad decision must be made about the choice of recommended therapy. Decisions are best made based on all the background facts and considerations discussed earlier here and based on evidence based medical data relating to older patients. However the problems relating to discordance between the true median age of patients with CLL in the general population and of those included in clinical trials must be taken into account. When evaluating clinical trials that included only elderly patients with CLL, it is surprisingly unexpected to find, only one phase III trial specifically designed and tailored for the older populations with CLL for such a prevalent form of leukemia of the elderly 42. This is clearly evident and summarized in Table 1, Table 2. In fact it is noteworthy that most of the current treatment recommendations are based on a sub-analysis of results obtained from the largest clinical trials, the majority of which include only about 25–30% of patients above the age of 65years, and only about 10% are 70years old and above. In order to be included in these studies, generally patients have to have no evidence of significant renal or liver disease and no history of viral infections such as hepatitis B and C or HIV which is obviously a situation very different from the reality encountered in the general community.

Table 1. Articles on Phase II and III clinical trials — only for elderly patients with CLL.
AuthorScheduleStudy phaseAge (yrs)No. of PtsCR%/ORR%Reference/no.
Chlorambucil vs FludarabineEichhorstChl: P.O. 0.4–0.8mg/kg for 14days, every 28days (up to 24 cycles)III65–80
(median 70)		193
100		0%
51%		Blood 2009 114;338214
GCLLSG
CLL5		 F: I.V. 25mg/m2 for 5days, every 28days. (up to 6 cycles) 937%
72%
CladribineRobakCladribine: I.V :0.12mg/kg daily
Day 1–5, every 28days		II70–92
Median 70		4330.2%
69.8%		Leuk Lymphoma 1999;34:151–749
Low dose Fludarabine+CyclophosphamideMarrotaF: I.V 15mg/m2
C: I.V 200mg/m2
Days 1–4, every 28days		II61–87
Median 75		2015%
85%		Hematologica 2000; 85:1268–7044
Fludarabine +/− Cyclophosphamide+/− MitoxantroneShvidelF: 25mg/m2; days 1–5
+/− C: 250mg/2 days 1–3
+/− M: 8mg/m2 day 1
Every 28days		II65–87
Median 70		320
59%		Leuk Lymphoma 2003;44;1947–5073
Low dose Fludarabine+CyclophosphamideForconiF: P.O: 25mg/m2
C: P.O 120mg/m2
Day 1–4, every 28days		II65–80
Median 71		2646%
92%		Hematol Oncol 2008 26;247–5145
LenalidomideBadouxLEN: P.O 5mg daily for 56days, titrated up to 25mg per dayII66–85
Median 71		6010%
65%		Blood 2011; July 154

I.V. = Intravenous, P.O. = oral, S.C. = subcutaneous, Chl = Chlorambucil, F = Fludarabine, C = Cyclophosphamide, M = Mitoxantrone, LEN = Lenalidomide.

Table 2. Abstracts of clinical trials — only for elderly patients with CLL.
AuthorScheduleStudy phaseAgeNo. of PtsCR%/ORR%Reference no.
Subcutaneous low-dose AlemtuzumabPitiniS.C. 10mg three times per week for up to 18weeksIIMedian 74487%
40%		J Clin Oncol 26: 2008, 704874
Rituximab+GM-CSFFerrajoliR: I.V. 375mg/m2 weekly for 4weeks
GM-CSF S.C. 250 mcg. three times weekly for 8weeks		IIAge ≥70years397%
61%		J Clin Oncol 2006 24,18S: 660275
Rituximab+MethylPrednisoneBadouxR: I.V. 375–750mg/m2
MP IV; 500–2000mg weekly for 4weeks		II65–87
Median 71		2450%
67%		Blood 2010; 116 463662
Chlorambucil+RituximabFoaChl: P.O. 8mg/m²/day days 1–7
R: I.V: 375mg/m² R for cycle 3 and 500mg/m² for cycles 4–8.		II61–84
Median 70.5		9716.5%
81.2%		Haematologica 2011; 96(s2) 053253
Followed by Rituximab maintenance Responsive patients were subsequently randomized to receive
R maintenance every 2months for 2years or clinical observation
Fludarabine±oral Cyclophosphamide and IV RituximabMulliganF: 24mg/m2 po D1-5+R:(375mg/m2C1, 500mg/m2C2-6) (FR5)
F: 24mg/m2 po and C: 150mg/m2 po D1-3+R: iv D1 (FCR3)
F: 24mg/m2 po+C:150mg/m2po D1-5+R: I.V. D1 (FCR5)		III65–85
Median 72		65 Blood 2010 116: 69946

I.V. = Intravenous, P.O. = oral, S.C. = subcutaneous, A = Alemtuzumab, R = Rituximab, Chl = Chlorambucil, = Fludarabine, C = Cyclophosphamide, MP = Methylprednisolone.

4.3. Some of the available therapeutic options 

4.3.1. Fludarabine-based regimens and other purine analogs 

In the recently published phase III trial (CLL8) of the German CLL Study Group 1 which enrolled 817 patients, comparing the combination of Fludarabine and Cyclophosphamide (FC) to FC+Rituximab (FCR), there was a clear advantage to the FCR arm in terms of response evaluation, and for the first time ever in CLL therapy, for overall survival. Based on these impressive results, FCR has now been accepted and adopted almost everywhere as the “gold standard” frontline therapy for medically fit patients with CLL of all ages. However if we relate to the older patients in this study, only 29% and 31% of all patients enrolled to the FC or FCR arms respectively, were 65years or older while only 9 and 11% were 70years or older . This study was clearly not primarily planned for older patients but enrolled large numbers of patients under the age of 70years, while only 74 patients older than 70years (30 and 44 in each arm respectively) were included. Because of this it is unclear whether the “gold standard” regimen suggested for all patients will necessarily achieve the same survival advantages in the oldest group when given in the framework of a larger series of fit patients or whether this is in fact the most suitable regimen for this particular subgroup of elderly patients with CLL. In this study adverse effects were more frequently seen in patients older than 65years and bacterial infections were significantly more common. The results obtained with FCR in the above study followed on those reported in the non randomized MD Anderson study reported by Keating et al. in 2005, who first introduced the combination FCR regimen for CLL.28 This study included 224 patients but only 30 (13%) were 70years old or more. So, these two major studies together only have data on just over 100 patients above the age of 70.

Another alternative approach to therapy which attempts to maintain and exploit the known efficacy of FCR and at the same time avoid the price of toxicity, employed lower doses of chemotherapy in what was termed the FCR-LITE regimen.[43], [44], [45] Most recently other groups have also employed this “lighter” regimen with additional modifications of the dose and timing schedule. This and subsequent modifications of the same combination schedule using even lower doses of Fludarabine and Cyclophosphamide were shown to be well tolerated and associated with less toxicity with comparable efficacy.[43], [46], [47], [48]

Other purine analogs have also been reported to be effective in older patients with CLL, in phase II clinical trials and these include Cladribine and Pentostatin used as monotherapy or in combination with Cyclophosphamide and Rituximab.[49], [50] Shanafelt et al. reported on the use of Pentostatin, Cyclophosphamide and Rituximab (PCR) in 64 previously untreated patients. The regimen was well tolerated by this small group of older patients, however only 18 patients were aged 70years or more in this study [43]. Furthermore, Robak et al., initially reported on the use of Cladribine in 43 patients aged 70years or more, showing that the drug toxicity profile was acceptable and similar for older and younger patients alike. The same Polish group performed a study comparing the combination of Cladribine and Cyclophosphamide with Fludarabine and Cyclophosphamide as first-line therapy for CLL.51 The above combinations appear comparable in their efficacy for CLL and could indeed be considered for general use in a similar fashion as FCR for all age groups.

4.3.2. Chlorambucil 

A revived interest in Chlorambucil, traditionally the drug of choice for elderly patients with CLL in many European countries in the past has now emerged again during the last few years. In this respect it is interesting to note that the only published phase III study for the elderly reported by Eichhorst et al. failed to demonstrate an advantage for first line therapy with Fludarabine (F) compared to Chlorambucil (Clb).42 Furthermore very recently Catovsky and co-workers have published a retrospective analysis of data supporting the use of Chlorambucil in a paper entitled “Chlorambucil — still not bad: a reappraisal”,52in which the UK CLL study group summarize the last 30years experience with the drug. In the CLL3 and LRF CLL4 studies 33%, and 35% of the patients respectively were 70years or older and results of Chlorambucil therapy in the elderly compare favorably with those obtained with Fludarabine and Bendamustine. They stress the fact that higher doses of Chlorambucil correlated with better overall response rates than lower doses, and in the light of these results, Chlorambucil used in the correct dose may well be a suitable choice for elderly patients with CLL.52

The Italian CLL Study Group also reported an interesting study recently, using the CLB-R combination (Chlorambucil and Rituximab with Rituximab maintenance) as first-line treatment for elderly patients and discussed the role of maintenance in CLL. In this study 97 elderly patients received CLB (8mg/m²/day p.o., d1-7, courses 1–8) and R (375mg/m², course 3 and 500mg/m², courses 4–8) every 28days. The median number of R-CLB cycles administered was six. Responsive patients were subsequently randomized to receive R maintenance every 2months for 2years or to clinical observation. This study concluded that this regimen was effective in this subgroup of patients and well tolerated.[17], [53]

4.3.3. Lenalidomide and Bendamustine 

Among the new drugs now under evaluation, Lenalidomide seems to be a promising and attractive alternative or an addition for induction therapy and even for maintenance in elderly patients in particular. Badoux recently published a phase II clinical trial, where 60 patients aged 65years and older received treatment with oral Lenalidomide.54 The median follow-up of the study is still short, only 29months, but results already seem interesting, with an ORR of 65% including 10% complete responses.54 Currently Lenalidomide is under investigation, as induction therapy as well as for maintenance in older patients. The “old new drug” Bendamustine (B) is another revitalized drug for use in B cell malignancies including CLL.55 In a phase III study it was compared with Chlorambucil in previously untreated patients with CLL, and found to offer significantly better r efficacy than Chlorambucil as a single agent and with a manageable toxicity profile.56 Based on all the above, the German CLL Study Group (CLL 10) protocol was designed to compare FCR and BR in patients with previously untreated CLL. The study hypothesis is that BR may be non inferior in terms of efficacy, but may have a better safety profile. The drug has also been evaluated in combination with Mitoxantrone and Rituximab in elderly patients with CLL (median age, 69years) and shown to have a good safety profile. In this study 49% of the patients were older than 70years and 33% were 75years or older. It appears that Bendamustine may indeed be considered an effective and safe drug for the elderly patient with CLL, but longer follow up is still needed in order to determine the degree of myelosuppression seen as late toxicity in this group.57

4.3.4. Alemtuzumab 

In previously untreated patients with CLL Alemtuzumab (A) (anti CD52 monoclonal antibody), had significantly higher efficacy compared to Chlorambucil in terms of PFS, ORR and CR.58 Due to its toxicity profile, the use of A, is restricted to high risk patients, who carry the 17p deletion or p53 mutation, and it is not widely used in the older population. Pitini et al presented results, using A at low doses of 10mg, thrice weekly, for 48 elderly patients with CLL (median age 74years). Complete response was obtained in 7% of the patients and 16 patients. (33%) had a partial response. The toxicity profile of this regimen and schedule of the antibody were favorable. The role of A as consolidation therapy, was also evaluated in a preliminary study in a small cohort of elderly patients and striking reduction of CLL was recorded with the achievement of impressively low MRD.59

4.3.5. Steroids 

Steroids used as monotherapy or as part of other regimens are among the most frequently used therapeutic agents in CLL. Regimens such as Chlorambucil and Prednisone or COP/CVP are still being used for elderly patients with CLL but mostly outside of clinical trials. Based on the effectiveness of steroids on the disease, both Catovsky et al., and Kipps et al. have published regimens based on the combination of pulse therapy with high dose Methylprednisone and Rituximab.[60], [61] However once again, both of these studies included only a minority of patients above the age of 65years. A retrospective analysis, was also presented by the MD Anderson group, who identified 24 patients aged 65years or more who received Rituximab and Methylprednisone 62 and higher response rates were seen in a small group of previously untreated patients, but this involved only 6 patients. The efficacy of this regimen still needs to be evaluated in larger cohorts of elderly patients but taking into consideration the toxicity and side effects profile of this regimen.

After reviewing all the reported data for the elderly patients with CLL we stress the need for more clinical trials using both “old” and “new” drugs, which should be specifically designed and tailored for use in elderly patients with CLL, seeing that, until now, only a very small minority of all the clinical trials are indeed specifically intended and tailored for use in this population.

Ongoing clinical trials which target elderly patients are summarized in Table 3.

Table 3. Ongoing clinical trials for elderly patients with CLL: data of registered studies at “Clinical Trials.Gov” and ERIC: clinical trials in Europe.
Name of the study and drugAge limitationUntreated vs relapsedStudy phaseRecruitment
1CAL-101 and Rituximab in untreated elderly patients with CLL or SLL
CAL-101: 150mg BID for 12months or until progression
Rituximab 375mg/m2 weekly for 8weeks		>65yearsUntreatedIIActive 60 patients 08/2010-03/2013
2The ORIGIN Trail: Effectiveness and safety of Lenalidomide versus Chlorambucil as first line therapy for elderly patients with B-CLL.>65yearsUntreatedIIIActive 428 patients 05/2009-03/2013
3Rituximab in combination with low dose Fludarabine and Cyclophosphamide as primary therapy in elderly patients with CLL>65yearsUntreatedIIOpening now 40 patients 07/2011-01/2016
4Standard dose and low dose Rituximab with Alemtuzumab in treating older patients with progressive CLL>70yearsUntreatedII90 patients 10/2010-02/2012
5Fludarabine or Chlorambucil as first line therapy in treating older patients with previously untreated CLL.65-79yearsUntreatedIII205 patients 10/2003
6Multicenter trial of Revlimid and Rituximab, for first line treatment of CLL.>65yearsUntreatedII80 patients 02/2008-07/2011
7Study role of Lenalidomide in improving sleep in CLL patients 65+ years experiencing clinically significant fatigue.>65years 12 patients 11/2008-11/2011
8Phase III in previously untreated patients with CLL unfit for Fludarabine‐combinations; Chlorambucil versus Chlorambucil+ofatumumab (NCRI CLL sub‐group, UK)>18years Unfit patientsUntreatedIII444 patients

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5. Future therapeutic agents for use in CLL and their possible role in treating elderly patients 

We are now in a prosperous era for CLL and there has been much progress in the understanding of the biology of the disease with impressive development of new drugs which are also under intensive evaluation. Some of these new drugs may indeed have a potential role in the treatment of older patients. A summary of these relevant agents is presented in Table 4.

Table 4. Future agents in CLL with possible role for therapy of elderly patients.
ClassName of the drug
Anti-CD20 antibodyGa-101, Ofatumumab, Veltuzumab
CDK inhibitorFlavopiridol
BCL-2 interventionABT-263, Oblimerson, Obatoclax
Bruton's tyrosine kinase inhibitorPCI-32765
PI3KCAL-101
Anti CD74Milatuzumab (hLL1)
Purine nucleoside phosphorylase (PNP) inhibitorForodesine

5.1. D4: Do herbal medicines have a place in therapy for older patients? 

In recent years, there has been an increasing use of herbal remedies and other complementary and alternative medicine (CAM) therapies reported in patients with hemato-oncological malignancies. Some of these agents are being used during or in parallel with conventional treatment of CLL. Hensel et al. reported that, 44% of patients with CLL used alternative medicine 63 and the treating physician should always bear this in mind when planning “conventional” therapy as many patients do not declare this openly to their doctors while on therapy. In CLL in particular, the interactions between CAM and traditional medicine may even be more complex and the situation in this respect is interesting, as some of the leading clinical centers, including the Ohio State University and the Mayo Clinic, have widened their interests and even integrated their approaches in this respect and in addition to their studies with novel conventional therapy have also investigated the effects of some of these herbal compounds for use in CLL both in vitro and in vivo.[64], [65], [66] In general this approach is of interest and may even be more attractive for the elderly population, some of these herbs have been thoroughly studied and are reviewed here but we have been selective in our approach, choosing only the more promising natural compounds which may be included in the planning of future therapy for CLL especially in elderly patients (Table 5).

Table 5. Preliminary and promising data on natural products used in vitro or in vivo for CLL.
Natural compound (reference)ActiveMechanism of action
Gossypol (cottonseed oil)76A phenolic compoundBinds BCL-2 and BCL-Xl and induces apoptosis, reducing lymphocyte count
Polyphenon E 65Polyphenons or catechins are active chemical compounds present in green-tea.Induce down regulation of anti apoptotic proteins: MCL1 and XIAP and decreases vascular endothelial growth factor (VEGF) receptor (R1 and R2) phosphorylation.
Curcumin[64], [67], [68], [69]Diferuloylmethane, an active ingredient in the spice turmeric.Inhibit constitutively active pro-survival pathways, including signal transducers and activators of transcription 3 (STAT3), AKT, and nuclear factor κB.
Suppresses the expression of the anti-apoptotic proteins MCL-1 and XIAP.
Up-regulates the pro-apoptotic protein BIM.
Silvestrol[66], [77]Soluble extract of the stem bark of Aglaia foveolataCauses early reduction in MCL-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization.
Vitamin D[70], [71]Calciferol and analogs (EB1089)Induces apoptosis by activation of p38 mitogen-activated protein (MAP) kinase and suppression of extracellular signal-regulated kinase (ERK) activity, associated with downstream activation of caspase-3.

Curcumin is the active ingredient of the dietary spice turmeric (Curcuma longa), one of the more important spices in Middle-East, India and the Far East. Several groups have investigated its ability both in vitro and in vivo to modulate the growth of B cell malignancies particularly lymphoma and CLL 67 and demonstrated that it induces apoptosis in vitro through several mechanisms. Liu et al. showed that the curcumin ingredient functions as a histone deacetylase inhibitor (HDAC) and that it can in fact be included and regarded as a new member of this class of drugs which is currently under investigation in some hematological malignancies as well as CLL 68. Additional studies have been reported and shown that curcumin suppresses activation of nuclear factor-kB and down modulates Syc activity.69 An interesting study was performed at the Mayo Clinic using the combination of curcumin and green tea (Camellia sinensis), epigallocatechin-3 gallate (EGCG) 64 showing a synergistic effect against CLL cells.65 These results led to the design of a Phase I clinical trial using oral Polyphenon E daily in patients with asymptomatic Rai Stage 0 to II CLL which was published in 2009 showing some some clinical efficacy manifested as a decline in absolute lymphocyte count or decrease in lymphadenopathy, observed in the majority of patients.65

Vitamin D insufficiency has also been described quite recently to be associated with inferior survival in CLL patients, while in vitro studies demonstrated that EB1089, a vitamin D3 analog, is a potent inducer of apoptosis for B-CLL cells. It is still preliminary to conclude whether normalizing vitamin D levels, or even increasing serum levels of vitamin D would improve outcome in CLL patients. However these results are encouraging and have stimulated more interest in the topic of Vitamin D and CLL.[70], [71]

Other possible natural compounds that are under evaluation, with their possible mechanisms of action and related references are summarized in Table 4.

5.2. Treatment recommendations and our own paradigm 

It is indeed difficult to propose a scheme of therapy for all elderly patients that would be acceptable to all hemato-oncologists treating CLL without disagreement and some argument. This is because there is still not enough data available and also due to the fact that CLL experts tend to have their own personal approach to therapy in this age group and often rely on their individual experience. In this respect the recommendations of the German CLL Study Group [18], [72] have taken the field one big step forward, changing the more traditional approach from an “age based” to a” fitness based approach” according to scoring systems and well defined fitness assessment criteria commonly used as guidelines for therapy of older patients in geriatric hemato-oncology. Based on this approach patients independent of their age were included in the following categories: “GO-GO, “SLOW-GO and “NO-GO” which were used as a guide to therapy. These have been adopted by many worldwide despite the fact that these recommendations were not specifically designed for older patients with CLL nor clinically tested in a larger series of patients above the age of 70years and particularly in patients older than 75years of age. From other studies we now appreciate that biological age still remains a central factor in this therapeutic equation as illustrated diagrammatically in Fig. 1. Older “frail” patients defined as “NO-GO” at evaluation may benefit from appropriate and suitable supportive therapy. Most importantly optimal choices for “less fit” patients defined as the “Slow-Go” category remain problematic in terms of what therapeutic approach would be best to use. In this group age plays a fundamental role which should be taken into account when therapy is chosen. Taking all studies into consideration there seems to be little disagreement about the fact that patients above the age of 75 and particularly 80years generally do not benefit from optimal therapy in terms of overall survival. After considering results summarized in the second half of this review and the relevant background data detailed in the first section, taking into account fitness, age, stage and existing co-morbidities we suggest a schematic paradigm (Fig. 2) for therapy of the different older subgroups which is presented below.

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Conflict of interest 

The authors have no conflicts of interest to declare.

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PII: S0268-960X(11)00067-1

doi:10.1016/j.blre.2011.09.002

Blood Reviews
Volume 26, Issue 1 , Pages 15-23, January 2012

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