Chronic lymphocytic leukemia (CLL) mainly affects older people: the median age at diagnosis is > 70 years. Elderly patients with CLL are heterogeneous with regard both to the biology of their disease and aging. Following the diagnosis of CLL in an elderly individual, careful risk assessment is essential when treatment options are evaluated. This includes not only clinical staging and evaluation of disease-specific prognostic biomarkers such as 17p deletion and TP53 mutation, but also of comorbidities, physical capacity, nutritional status, cognitive capacity, ability to perform activities of daily living and social support. Comorbidity scoring and geriatric assessment tools are helpful in achieving such multidimensional evaluation in a systematic manner. The introduction of new drugs including novel monoclonal antibodies and kinase inhibitors offers enhanced opportunities for the treatment of elderly patients with CLL. This position paper of a Task Force of the International Society of Geriatric Oncology (SIOG) reviews currently available evidence relevant to such patients. All types of elderly patient (i.e. chronological age > 65–70 years) are considered, from robust (fit) to vulnerable (unfit) to the terminally ill. Among the topics covered are the following: (i) the relationship between chronological age, prognosis and survival, (ii) assessment of biological aging, (iii) biological age as a determinant of treatment feasibility and tolerance and (iv) tailoring of both first and further-line treatment to the circumstances of the individual patient.

introduction

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in western countries. Incidence rates are 4–6 per 100 000/year in USA and in Europe [1, 2]. Numbers rise dramatically with age, exceeding 30 cases per 100 000/year in people >80 years; almost 70% of patients with CLL in USA are over 65 years at diagnosis, and the median age at diagnosis is 71 years [3]. In Europe, median age at diagnosis is 71 years in men and 74 years in women [4]. Since most patients are diagnosed at an early, asymptomatic stage and therapy is delayed, the median age at first treatment is higher still. As older people are a rapidly increasing proportion of the population, the number of elderly CLL patients will rise in parallel.

A majority of elderly patients with CLL die from this disease rather than from other causes. For instance, age-specific excess hazard ratios for 5-year relative survival using data from USA and UK registries demonstrate that CLL increased risk of death even in patients aged 85 years or more [5]. In an analysis of 2487 patients (most with early or intermediate disease stage), survival was shorter than in the age-matched general population for ages up to 74 years [6]. Hence, although CLL is indolent, it shortens survival in the elderly. Women aged 75 years unaffected by cancer can expect 13 years of further life, and men a further 11 years [7]. Enabling elderly patients with CLL to realize this life expectancy while preserving good function and quality of life is the aim of treatment. Realizing this goal poses a considerable challenge, especially since elderly patients with CLL have been under-represented in many clinical trials due to restrictive exclusion criteria [8–10].

With these issues in mind, a Task Force of the International Society of Geriatric Oncology (SIOG) met to consider the management of elderly CLL patients. Members conducted literature searches in their areas of expertise. The initial article underwent several rounds of review by authors and a panel appointed by SIOG (see acknowledgements). We do not formally assign levels of evidence to recommendations since the number of randomized trials in elderly CLL patients is still small. The applicability of recommendations will vary between countries depending on the availability of finances, specialized staff and drugs. Our recommendations are in accord with existing guidelines published by other international expert panels such as the International Workshop on CLL and the European Society for Medical Oncology [11, 12]. This article complements these guidelines by providing detailed advice on elderly patients. It should be considered an expert position paper, and a basis for further discussion.

optimal risk assessment in elderly patients with CLL

Diagnosis is based on blood count, microscopy and immunophenotyping of lymphocytes [11, 12]. In elderly patients, suspicion of CLL should be followed by establishment of a firm diagnosis, and methodology should not differ between young and old. Following diagnosis, risk assessments help to predict the course of the disease and form a basis for deciding treatment. Prognostication in CLL has been based mainly on disease-specific parameters. In the elderly, assessment of patient-related parameters linked to aging is also important.

clinical staging

The Rai and Binet systems, based on leukemia burden, are widely used [13, 14]. Compared with their younger counterparts, elderly patients more often present with advanced disease stage [6, 15]. Binet and Rai staging are of similar prognostic value in young and old patients [6, 15].

prognostic biomarkers

CLL-specific biomarkers include serum markers (e.g. ß2-microglobulin, thymidine kinase), CD38 and ZAP-70, and molecular parameters such as IGVH mutational status, 11q and 17p deletion, and TP53, NOTCH1, SF3B1 or other mutations [16, 17]. These provide prognostic information beyond clinical staging. Until recently, no great differences in the prevalence of these biomarkers had been detected in older versus younger patients [6, 15]. However, a recent analysis suggested that 17p deletions (Del(17p)) and TP53 mutations (TP53mut) as well as simultaneous presence of other unfavorable risk factors may be more frequent in the elderly [18]. Some of the biomarkers have been reported to lose prognostic power with advancing age [6]. However, for Del(17p) and TP53mut there is accumulating evidence that these parameters are significant determinants of adverse prognosis in older as well as younger patients [15]. The finding that high-risk CLL might be more common in older than in younger patients [18] is important since novel targeted therapies can successfully treat unfavorable disease even when age or comorbidity preclude allogeneic stem cell transplantation. Emerging prognostic models integrate established clinical parameters such as stage and disease-specific biomarkers [19–21]. Among these is the CLL International Prognostic Index (CLL-IPI) [19] which currently is validated in elderly CLL specifically.

life expectancy

The age-adjusted life expectancy of an elderly patient is important when deciding treatment. Chronological age provides only a rough estimate since individual life expectancy depends on physiological aging (e.g. renal function, cellular senescence, stem cell exhaustion, persistent low-grade inflammation), comorbidities, functional capacities and lifestyle. Assessment tools that include such parameters have been proposed as means of estimating individual life expectancy [22, 23]. Molecular biomarkers of aging such as inflammation markers, telomere length or p16INK4a expression have also been suggested. In the future, these may provide additional help in estimating individual life expectancy. However, presence of malignancy may confound such biomarker profiles. Hence careful evaluation in the cancer setting including CLL will be necessary [24, 25].

comorbidity assessment

Along with shortening life expectancy, comorbidities [26] may reduce treatment tolerance and increase risk of dose-reduction and treatment delay or discontinuation. Hence comorbidities may increase both treatment- and disease-related mortality. Comorbidities are frequent in elderly CLL patients [8, 15]. Common assessment tools are the Cumulative Illness Rating Scale (CIRS), Charlson Comorbidity Index (CCI), National Cancer Institute (NCI) Comorbidity Index, and Hematopoietic Stem Cell Transplantation Comorbidity Index (HCT-CI) [27–30]. CIRS is the most frequently used in CLL trials. However, no comorbidity score has been prospectively validated in CLL so far. Several studies have demonstrated correlations between comorbidities and shorter overall survival (OS) in CLL [8, 15, 31–35]. The impact of comorbidity on treatment tolerance and feasibility (dose reductions, treatment delay or discontinuation) is less well studied and results are inconsistent [31, 33, 36, 37]. Given that purine nucleoside analogues are cleared by the kidney, surrogates of renal comorbidity such as glomerular filtration rate (GFR) and creatinine clearance (CrCl) have, historically, been the most important determinants of dose [38, 39]. Studies in CLL exploring impact on outcome provided inconsistent results, however. In a retrospective analysis of 143 CLL patients aged over 65 years treated with fludarabine- and rituximab-based regimens or with chlorambucil, patients with a CrCl of <60 ml/min had shorter progression-free survival (PFS) than patients with less impaired renal function [40]. In a study of dose de-escalated treatment with fludarabine, cyclophosphamide and rituximab in elderly patients, CrCl had no effect on PFS, OS or toxicity [41]. In a study of 64 patients over 69 treated with pentostatin, cyclophosphamide and rituximab, a CrCl of 70 ml/min or less was associated with greater dose reduction or delay but not with increased toxicity or reduced efficacy [36]. Robak et al. [42] reported an increase of adverse events in relapsed CLL patients with renal impairment treated with fludarabine and cyclophosphamide±rituximab.

geriatric assessment

Geriatric assessment (GA) encompasses cognition, emotion, nutrition, mobility, basic and instrumental activities of daily living (IADL), and social functioning. In geriatrics, GA is part of routine diagnostic workup and used to plan targeted interventions. In prospective studies, its use reduced mortality and rates of hospitalization and institutionalization [43]. There has been increasing interest in the potential of GA in predicting outcome of cancer patients and deciding cancer treatment. Reviews have summarized the results of over 100 studies [44–48]. One systematic review was specific to hematological malignancies where geriatric impairments such as reduced IADL, physical or cognitive capacity, and malnourishment detected by GA predicted OS [47]. Some studies in hematological malignancies found associations between GA and treatment toxicity [49, 50]. These findings can be applied to CLL only by extrapolation and with caution since the number of CLL patients in these studies was either not indicated or very low. To date, only one study has examined GA specifically in CLL [51]. It revealed associations between impaired physical and cognitive capacity with reduced OS. Of note, this study did not include patients treated with chemoimmunotherapies or targeted drugs. Nevertheless, and based on evidence in cancer in general, SIOG has developed recommendations for the routine use of GA in older patients [52]. GA is generally recommended prior to cancer treatment since it identifies age-related health problems that might remain undetected by standard oncological workup. Based on this, GA may alter planned oncological treatment [53] or result in additional geriatric interventions. Moreover, GA contributes to risk scores such as CRASH or CARG that estimate the risk of chemotherapy toxicity [54, 55]. As GA is demanding, frailty screening has been introduced with the aim of selecting patients who might benefit most from a full GA. Frailty screening can predict treatment toxicity, dose modification and all-cause mortality in cancer patients [56]. The G8 screening tool detected relevant geriatric impairments and predicted survival in a study specific to elderly patients with hematological malignancy [50] and is among the most favored.

conclusions and recommendations

Following CLL diagnosis in an elderly patient, decision-making regarding therapy warrants a careful risk assessment. Clinical staging is required to decide between immediate therapy and active surveillance. In patients requiring therapy, Del(17p) and TP53mut status are needed to select treatment even in the elderly. Patients with one or both of these adverse factors need special consideration. Other prognostic biomarkers are optional at the present time. The value of prognostic biomarkers should be studied further in elderly CLL, particularly given the increasing use of novel agents.

To ensure appropriate dosage, measurement of renal function by calculation of GFR/CrCl using a formula such as Cockcroft–Gault is mandatory in patients receiving fludarabine. Comorbidity assessment is highly recommended in elderly CLL. Outside trials, use of a comorbidity score is not mandatory and careful history taking and physical examination may be sufficient. In clinical trials, the comorbidity burden should be systematically reported. In past trials, CLL was sometimes included in the comorbidity score, hence confounding the true burden of co-existing diseases. To avoid this, and to harmonize reporting, the index disease, in this case CLL, should not contribute to the score. Following the recommendation for older cancer patients in general [52], assessment of geriatric impairments by GA is recommended in CLL. Available data in CLL and extrapolation from studies in other hematological malignancies [47, 50, 51] suggest that assessment of physical and cognitive capacity, nutritional status and activities of daily living (ADL) provides helpful guidance. The CRASH and CARG toxicity scores [54, 55] should be used only with caution. The same is true for G8 frailty screening. These specific tools and GA in general warrant prospective studies in CLL.

Elderly patients with CLL can be categorized according to Table 1. Patients with normal renal function, no comorbidity and absence of geriatric impairments can be considered ‘robust’ or ‘fit’ for intensive therapy. Patients with impaired renal function, multiple or severe comorbidities, or impaired physical or cognitive capacity, nutritional status or IADL/ADL can be regarded as ‘vulnerable’ and likely to be ‘unfit’ for intense CLL therapy. Such patients were under-represented or excluded from landmark trials investigating intensive therapies [57–59] and therefore should be considered for alternative treatments. Patients with a life expectancy of a few weeks or months due to comorbidities and based on GA assessment can be regarded as ineligible for specific CLL therapy. CLL-related life expectancy (estimated by clinical staging and prognostic biomarkers) and age-adjusted life expectancy (estimated by comorbidity and GA) should be carefully compared in elderly patients.

Table 1

Recommendation for categorization of elderly patients with CLL according to risk assessments (SIOG position)

Robust/fit Vulnerable/unfit Terminally ill 
Consider for intensive therapya Unsuitable for intensive therapya Unsuitable for antileukemic therapy 
 Consider for adapted therapyb Consider for best supportive care 
Normal renal function Abnormal renal function Age-adjusted life expectancy unrelated to CLL <3 monthse 
and or 
No/minor comorbidityc Moderate/severe comorbidity or multimorbidityc 
and or 
Lack of geriatric impairmentsd Geriatric impairmentsd 
Robust/fit Vulnerable/unfit Terminally ill 
Consider for intensive therapya Unsuitable for intensive therapya Unsuitable for antileukemic therapy 
 Consider for adapted therapyb Consider for best supportive care 
Normal renal function Abnormal renal function Age-adjusted life expectancy unrelated to CLL <3 monthse 
and or 
No/minor comorbidityc Moderate/severe comorbidity or multimorbidityc 
and or 
Lack of geriatric impairmentsd Geriatric impairmentsd 
a

See Table 3 for intensive therapies available.

b

See Table 3 for adapted therapies available.

c

As assessed by careful history taking and physical examination (outside clinical trial) or as assessed by comorbidity scoring (optional outside clinical trial, mandatory inside clinical trial); severe comorbidity and/or multimorbidity will be indicated by comorbidity score.

d

As assessed by geriatric assessment (desirable outside and inside clinical trial); presence of geriatric impairments will be indicated by abnormal results in any of the following geriatric domains: activities of daily living, physical capacity, nutritional status, cognitive capacity.

e

As anticipated based on history, clinical examination and other health conditions; the presence of geriatric impairments per se does not necessarily imply ineligibility for adapted therapy.

optimal treatment in elderly patients with CLL

Treatment options for elderly patients with CLL have changed fundamentally during recent years. Single-agent chlorambucil (Clb) was standard for several decades and demonstrated noninferiority to fludarabine or bendamustine with regard to OS [60–62]. Recent studies have resulted in new treatment standards which include the use of monoclonal antibodies and kinase inhibitors. The most common regimens are summarized in Table 2.

Table 2

Currently available evidence from trials of chemoimmunotherapy and novel agentsa in elderly patients with CLL

Treatment-regimen Study type Patients
 
Efficacy
 
Tolerability
 
N Treatment line Median age Co- morbidity Complete remission Progression- free survival Survival- benefit? Neutropenia ≥Grade 3 Infection ≥Grade 3 Other 
Modified FCRb            
Smolej [41Phase 2d 108 First 69 Increased 37% 28 months NA 56% 15% – 
  94 Salvage 71 Increased 30% 15 months NA 50% 18% – 
Mulligan [67Phase 2d 200 First 71 Little 20% NR NA ∼50% ∼6% – 
Nikitin [69Phase 3d 48 First 69 Increased 43% 37 months No 38% NR – 
BR Phase 3 121 First 72 Moderate 24% 40 months No 43% 19% – 
Michallet [70          – 
R-CLBc            
Hillmen [74Phase 2 100 First 70 NR 10% 24 months NA 41% NR (in %) – 
Foa [75Phase 2 85 First 70 NR 17% 35 months NA   – 
Goede [76Phase 3 330 First 73 Increased 7% 15 months Yes 28% 9% – 
O-CLB            
Hillmen [79Phase 3 221 First 69 Increased 14% 22 months No 26% 9% IRR (10%) 
G-CLB            
Goede [77Phase 3 333 First 74 Increased 21% 29 months Yes 33% 12% IRR (20%) 
IBRU            
OBrien [106Phase 2 31 First 71 NR 13% Not reached NA 3% 10% Diarrhea 
Burger [81Phase 3 136 First 72 Partially increased 4% Not reached Yes 10% NR (in %) Diarrhea 
Byrd [91Phase 2 85 Salvage 66 NR 2% Not reached NA 15% NR (in %) Diarrhea 
Byrd [92Phase 3 195 Salvage 67 NR 0% Not reached Yes 16% 24% Bleeding, AF 
IDELA            
Zelenetz [82Phase 2 41 First 71 NR 0% Not reached NA 17% NR (in %) Colitis 
IDELA-R            
OBrien [83Phase 2d 64 First 71 NR 19% Not reached NA NR 19% Diarrhea 
Furman [93Phase 3 110 Salvage 71 Increased 0% Not reached Yes 3% NR (in %) Diarrhea 
Treatment-regimen Study type Patients
 
Efficacy
 
Tolerability
 
N Treatment line Median age Co- morbidity Complete remission Progression- free survival Survival- benefit? Neutropenia ≥Grade 3 Infection ≥Grade 3 Other 
Modified FCRb            
Smolej [41Phase 2d 108 First 69 Increased 37% 28 months NA 56% 15% – 
  94 Salvage 71 Increased 30% 15 months NA 50% 18% – 
Mulligan [67Phase 2d 200 First 71 Little 20% NR NA ∼50% ∼6% – 
Nikitin [69Phase 3d 48 First 69 Increased 43% 37 months No 38% NR – 
BR Phase 3 121 First 72 Moderate 24% 40 months No 43% 19% – 
Michallet [70          – 
R-CLBc            
Hillmen [74Phase 2 100 First 70 NR 10% 24 months NA 41% NR (in %) – 
Foa [75Phase 2 85 First 70 NR 17% 35 months NA   – 
Goede [76Phase 3 330 First 73 Increased 7% 15 months Yes 28% 9% – 
O-CLB            
Hillmen [79Phase 3 221 First 69 Increased 14% 22 months No 26% 9% IRR (10%) 
G-CLB            
Goede [77Phase 3 333 First 74 Increased 21% 29 months Yes 33% 12% IRR (20%) 
IBRU            
OBrien [106Phase 2 31 First 71 NR 13% Not reached NA 3% 10% Diarrhea 
Burger [81Phase 3 136 First 72 Partially increased 4% Not reached Yes 10% NR (in %) Diarrhea 
Byrd [91Phase 2 85 Salvage 66 NR 2% Not reached NA 15% NR (in %) Diarrhea 
Byrd [92Phase 3 195 Salvage 67 NR 0% Not reached Yes 16% 24% Bleeding, AF 
IDELA            
Zelenetz [82Phase 2 41 First 71 NR 0% Not reached NA 17% NR (in %) Colitis 
IDELA-R            
OBrien [83Phase 2d 64 First 71 NR 19% Not reached NA NR 19% Diarrhea 
Furman [93Phase 3 110 Salvage 71 Increased 0% Not reached Yes 3% NR (in %) Diarrhea 
a

Selected studies with median age > 65 years are listed.

b

Diverse dosing schedules were used for modified FCR.

c

Diverse dosing schedules were used for CLB.

d

Only preliminary results reported.

F, Fludarabine; C, Cyclophosphamide; B, Bendamustine; CLB, Chlorambucil; R, Rituximab; O, Ofatumumab; G, Obinutuzumab (GA101); IBRU, Ibrutinib; IDELA, Idelalisib; IRR, Infusion-related Reaction; AF, atrial fibrillation; NR, not reported; NA, not applicable.

chemoimmunotherapy in previously untreated CLL

Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) remains the current standard of care in young and fit patients with previously untreated CLL [57, 58, 63]. Standard-dose FCR or FCR-like therapy (e.g. pentostatin, cyclophosphamide and rituximab—PCR) is feasible in selected patients aged >65 or 70 years who are fit and have little comorbidity [36, 58]. However, there is also evidence that the majority of patients over 65 or 70 years—even if they have few or no comorbidities—do not tolerate standard-dosed FCR very well. Therapy-related toxicity, dose reductions and treatment discontinuations are more common in these patients than in those who are younger [57–59, 63] and may result in a loss of treatment efficacy [57, 35, 64, 65].

To reduce toxicity, modified FCR regimens were proposed [66] and studied in older patients with or without comorbidity [41, 67, 68]. Results were encouraging, but trials were nonrandomized and have not set a new standard of care. On an exploratory basis, one randomized trial reported greater efficacy of such modified FCR (FCR lite) compared with chlorambucil–rituximab in elderly patients [69]. However, this trial was small (n = 92), had an unknown primary endpoint, and final results remain unpublished.

A recent trial comparing standard-dose bendamustine plus rituximab (BR) against standard-dose FCR in young and fit patients (median age 62 years, median CIRS 2) found that BR was inferior to FCR in efficacy (median PFS 42 versus 55 months) but produced less toxicity (59% versus 84% grade 3–4 neutropenia, 14% versus 22% grade 3–4 thrombocytopenia, 27% versus 39% grade 3–4 infections) [59]. In a subgroup analysis of patients aged >65 years, median PFS with BR was not different from that with FCR, while causing significantly fewer severe infections. This subgroup analysis lacked power to compare the two regimens in the elderly but lends some support to using BR instead of FCR in older patients with CLL with little or no comorbidity. Another trial compared standard-dose BR against chlorambucil plus rituximab (R-Clb) in elderly patients [70], demonstrating superiority of BR over R-Clb in PFS (median 40 versus 30 months) but not OS. Grade 3–4 infections were significantly more frequent with BR than with R-Clb (20% versus 10%). Of note, bendamustine was dosed at 90 mg/m2 in these two trials, and there are as yet no trial data on first-line BR with bendamustine 70 mg/m2 in elderly CLL. Trials combining bendamustine with ofatumumab (BO) or obinutuzumab (BG) have mainly been conducted in younger patients [71–73]. There is to date no evidence that these regimens are superior to BR in CLL.

Two nonrandomized trials have demonstrated the feasibility of combining rituximab and chlorambucil (R-Clb) in older patients with CLL [74, 75]. The benefit of adding novel anti-CD20 antibodies to Clb in older treatment-naive patients has been studied in two phase 3 trials. One [76] enrolled older patients with increased comorbidity (median age 73 years, median CIRS 8). R-Clb prolonged PFS (16 versus 11 months) and OS compared with Clb alone [77]. Addition of the glycoengineered and type 2 anti-CD20 antibody obinutuzumab (GA101) to Clb (G-Clb) resulted in prolonged PFS (29 versus 11 months) and OS compared with Clb chemotherapy alone. There was a clinically meaningful prolongation of PFS (29 versus 15 months) and time-to-next-treatment (51 versus 38 months) compared with R-Clb [78]. The second trial [79] which also enrolled older patients with increased comorbidity (median age 69 years, median CIRS-G 8) found longer PFS (22 versus 13 months) when ofatumumab plus Clb (O-Clb) was compared with Clb. This trial did not investigate the benefit of ofatumumab over rituximab, however, and used a higher Clb dose than the German trial. All three therapies explored (R-Clb, O-Clb, G-Clb) had an acceptable safety profile. Infusion-related reactions are the most important adverse events encountered with novel anti-CD20 antibodies. They are more frequently noted with obinutuzumab. Prehydration and steroid prophylaxis are generally recommended to prevent infusion-related reactions.

novel agents in previously untreated CLL

The kinase inhibitors ibrutinib and idelalisib target receptor signalling cascades relevant to CLL. Treatment with ibrutinib was feasible and highly efficacious in a small nonrandomized trial in older patients (median age 71 years, comorbidity burden not reported) [80]. Importantly, this drug appeared active in patients with Del(17p) or TP53mut. A recent phase 3 trial compared ibrutinib with chlorambucil in elderly patients, several of whom met criteria for lack of fitness. The trial demonstrated superiority of ibrutinib over chlorambucil for both PFS (median not reached versus 18 months) and OS [81], resulting in a recent approval for frontline treatment. Ibrutinib toxicities (bleeding complications, atrial fibrillation and diarrhea, see below) were observed.

Two small nonrandomized trials explored idelalisib alone or in combination with rituximab in elderly patients with untreated CLL (median age 70 and 71 years, respectively, comorbidity not reported) [82, 83]. Response rates and PFS were promising. However, even with short follow-up, a number of patients discontinued due to colitis. This toxicity becomes increasingly common with longer duration of idelalisib. A warning was also issued regarding frontline usage of idelalisib after observation of increased mortality rates due to opportunistic infections in trials.

Other targeted agents (lenalidomide, venetoclax) have been investigated as frontline therapy in elderly patients with CLL [84, 85]. A phase 3 trial of lenalidomide versus Clb was closed due to lack of benefit and greater toxicity. The role of these drugs in first-line elderly CLL remains to be determined.

chemoimmunotherapy in previously treated CLL

Few randomized trials have explored chemoimmunotherapy in elderly patients with relapsed or refractory CLL. A trial comparing FCR with FC in younger patients with relapsed and fludarabine-/rituximab-naïve CLL (median age 63 years, comorbidity not reported) demonstrated superiority of FCR for PFS but not OS [42]. Two recent trials comparing BR with BR plus ibrutinib or BR plus idelalisib also enrolled predominantly younger patients [86, 87]. Results from nonrandomized studies suggest that chemoimmunotherapy with dose-reduced FCR, BR (70 mg/m2) or G-Clb may provide some benefit in elderly patients [41, 88, 89]. The same is true for single antibody therapy (e.g. ofatumumab, alemtuzumab)±steroids [90].

novel agents in previously treated CLL

There are convincing efficacy and toxicity data for ibrutinib and idelalisib plus rituximab in elderly patients with relapsed/refractory CLL. Following early evidence of feasibility and efficacy [91], a phase 3 trial in heavily pre-treated patients (median age 67 years) demonstrated superiority of (continuous) ibrutinib over (standard-duration) ofatumumab for PFS (median not reached versus 8 months) and OS [92]. Benefit was seen across high-risk subgroups including Del(17p) or TP53mut. Another phase 3 trial explored idelalisib plus rituximab in heavily pre-treated elderly patients and increased comorbidity (median age 71 years, median CIRS 8). The combination of idelalisib and rituximab prolonged PFS (median not reached versus 6 months) and OS when compared with rituximab monotherapy [93]. Comparable data came from a trial comparing idelalisib plus ofatumumab with ofatumumab alone, although this study was not specific to elderly patients [94]. Again, benefits of the combination treatment were also seen in high risk subgroups such as patients with Del(17p) or TP53mut.

In contrast to chemotherapy, ibrutinib and idelalisib cause mild hematological toxicity, making them attractive for elderly patients with prior myelosuppressive chemoimmunotherapy. However, other side effects are relevant. Hematomas of the skin occur frequently in patients treated with ibrutinib [92, 95, 96]. More significant bleeding has been reported, especially in patients on antithrombotic agents such as aspirin, warfarin and heparin [95]. Co-medication with anticoagulants is not an absolute contra-indication to ibrutinib therapy but it should be used with caution [86, 95]. Patients with cardiac comorbidity are at a slightly increased risk of atrial fibrillation. Ibrutinib is metabolized via hepatic CYP3A4 and inducers or inhibitors of this enzyme may decrease or increase its serum level indicating the need for careful medication review. The idelalisib metabolite is also a strong inhibitor of CYP3A4 and pharmacovigilance is important [97]. Idelalisib is associated with a gradually increasing risk of late-onset colitis (see above). Noncompliance may occur more often with long-term oral kinase inhibitors than with infusional chemoimmunotherapy, particularly in patients with cognitive impairments and/or polypharmacy.

prophylaxis of infection

Infection risk is related to therapy-induced immunosuppression and immune defects inherent to CLL [98]. Hypogammaglobulinaemia is more pronounced with advanced stage and longer disease duration. The spectrum of infections has evolved with the therapeutics utilized and their impact on immune function. Most infections in alkylator-treated patients are caused by common bacteria (S. aureus, S.s pneumoniae, enteric Gram negatives). As purine analogues cause T-cell abnormalities, occasional opportunistic infections (systemic fungi, herpesviruses) may occur [99]. FC resulted in more infections in some series [100]. With FCR, grade 3–4 infections, including a few opportunistic infections, occur in 20–30% of patients [63, 101]. Late infections may arise several months after FCR therapy, especially in those patients with prolonged cytopenia [102]. Cytomegalovirus (CMV) reactivation occurs in 10–25% of patients on alemtuzumab and was recently also observed with idelalisib. General recommendations on antimicrobial prophylaxis [103–105] apply also to the elderly and are summarized in

, available at Annals of Oncology online.

conclusions and recommendations

In patients aged 65–70 years and above, first-line therapy with standard-dose FCR/FCR-like (e.g. PCR) is possible in those judged very fit and robust [58, 67]. However, such regimens should be administered only with great caution as toxicity could be substantial. BR may offer a better risk-benefit ratio [59]. For elderly patients judged vulnerable and unfit, large phase 3 trials support chemoimmunotherapy with Clb plus anti-CD20 antibody (G-Clb, O-Clb, R-Clb) [59, 67, 76, 78, 79]. Use of bendamustine instead of chlorambucil as the chemotherapy backbone may be an option [70]. Dose-reduced BR is possible based on clinical experience but not yet in trials. Modified FCR regimes are possible but have only been evaluated in nonrandomized trials [39]. Ibrutinib is a new option with phase 3 trial evidence [81]. Untreated elderly patients with Del(17p) or TP53mut and indication for therapy should be treated upfront with ibrutinib [81, 106]. Idelalisib should not be used frontline at the present time. Ibrutinib or idelalisib plus rituximab are indicated if older patients with or without comorbidity experience relapsed or refractory CLL (with or without Del(17p) or TP53mut) [92, 93]. Venetoclax is another option to treat recurrent CLL with Del(17p) or TP53mut (including progressive CLL after treatment with ibrutinib or idelalisib plus rituximab). In patients relapsing late after chemoimmunotherapy, repetition of that therapy is an option (albeit not based on trial evidence). These recommendations are summarized in Table 3.

Table 3

Treatment options and recommendations for elderly patients with CLL (SIOG position)

Elderly patient Treatment 
Treatment-naive CLL 
 Binet A/B and not symptomatic None 
 Binet C or symptomatic  
  Robust/Fita FCRb or BRb (standard dose or dose-modified) 
  Vulnerable/Unfita G-CLBb,c 
O-CLBb,c 
R-CLBb,c 
BRc (standard dose or dose modified) 
FCRc (dose-modified) 
IBRU (recently approved) 
  17p-deletion/p53-mutation IBRU 
Relapsed/Refractory CLL (regardless of a) 
 Early or with 17p-deletion/p53-mutation IBRU, IDELA-R 
 Late without 17p-deletion/p53-mutation IBRU, IDELA-R, Chemoimmunotherapy 
Elderly patient Treatment 
Treatment-naive CLL 
 Binet A/B and not symptomatic None 
 Binet C or symptomatic  
  Robust/Fita FCRb or BRb (standard dose or dose-modified) 
  Vulnerable/Unfita G-CLBb,c 
O-CLBb,c 
R-CLBb,c 
BRc (standard dose or dose modified) 
FCRc (dose-modified) 
IBRU (recently approved) 
  17p-deletion/p53-mutation IBRU 
Relapsed/Refractory CLL (regardless of a) 
 Early or with 17p-deletion/p53-mutation IBRU, IDELA-R 
 Late without 17p-deletion/p53-mutation IBRU, IDELA-R, Chemoimmunotherapy 
a

Categories as determined by means of Table 1.

b

No full agreement among experts about most preferred regimen for this group or about optimal dose.

c

No full agreement among experts about most preferred regimen for this group; order of listing reflects level of trial evidence.

F, fludarabine; C, cyclophosphamide; R, rituximab; G, obinutuzumab (GA101); O, ofatumumab; CLB, chlorambucil; IBRU, ibrutinib; IDELA, idelalisib.

future perspectives

Overall, management of older patients with CLL has improved during the last decade due to a growing number of available treatments and a more differentiated view on patient fitness and vulnerability. However, many important questions remain and should be addressed. These include:

  • Do new prognostic tools developed for CLL apply equally to older and younger patients?

  • How are comorbidity and geriatric assessment tools best implemented in routine practice?

  • How can our current categorization of older patients (fit versus unfit versus terminally ill) be further refined?

  • What are the best chemotherapy-free treatments and their true benefits in older patients?

  • Do the generally higher costs of novel treatments justify their widespread use in older patients who do not have Del(17p) or TP53mut?

Improving risk assessment and treatment in elderly patients with CLL will rely on clinical research that must ensure the following:
  • Older patients should be adequately represented in clinical trials and outcome fully evaluated by age [107].

  • Both disease-specific and all-cause mortality should be reported.

  • Progression-free survival should to be reported since it often translates into treatment-free survival.

  • Additional endpoints relevant to the elderly must be considered including quality of life, capacity for independent living, objective measures of physical functioning, and health care utilization [108].

  • Further investigation of the role of targeted antibodies and kinase inhibitors.

Importantly, associated costs cannot be ignored. Even if trials suggest novel agents have efficacy or toxicity advantages, treating large numbers of patients for long periods with these agents at today’s costs would cripple most healthcare systems [109]. This problem will vary from country to country and a uniform prioritization of treatments by costs is not currently possible. Further evaluation of the health economic impact of the new drugs is needed to prioritize treatments not just by their efficacy and toxicity, but—when appropriate—also their expense. In a rapidly evolving field, the position of SIOG on the management of elderly patients with CLL will have to be constantly adapted to meet future needs.

acknowledgements

Rob Stepney, medical writer, Charlbury, UK, acted as rapporteur at the initial meeting of the Task Force and assisted in drafting this article. We are also grateful to the following people (in alphabetical order) who commented on the article as part of an internal SIOG review panel: Harvey Jay Cohen, Christian Geisler, Michael Hallek, Emili Montserrat and Ulrich Wedding.

funding

This project was made possible by unrestricted grants from Janssen, Gilead and TRM oncology.

disclosure

RS has received research grants and honoraria from Celgene, Novartis, Teva and Janssen Cilag, and served as scientific advisor for Celgene. VG conflicts of interest are: Roche—speaker fees, advisory board, consultancy; Gilead and Janssen—advisory board; Mundipharma, GSK and BMS—speaker fees. AO has received scientific grants and/or payments for scientific lectures or advisory boards from Janssen, Gilead, Celgene and Abbvie. IP: Roche—advisory board, consultancy; Janssen—advisory board; Takeda—advisory board, speaker fees. LY: Roche and Gilead—consultancy, advisory board; Janssen and BMS—speaker fees. LS: Roche—honoraria, travel grants, advisory boards; Janssen—honoraria, travel grants, advisory boards; Gilead—honoraria, travel grants, advisory boards; Abbvie—advisory boards. VM: Celgene—consultant, speakers bureau; Genentech—speakers bureau; Pharmacyclics—consultant, speakers bureau. KK: Gilead and Janssen Cilag—scientific support. TS has received research funding from Genentech, Janssen, Pharmacyclics, GlaxoSmithKline, Celgene, Cephalon and Hospira. TS is a Clinical Scholar of the Leukemia and Lymphoma Society. BE is on the advisory boards of Janssen, Gilead, Mundipharma, GSK, Roche; has received honoraria from Roche, Mundipharma, GSK, Gilead, Janssen, Celgene and has received scientific grants from Roche, Mundipharma, Janssen, Abbvie. JW has no COI for this article but has received research funding from Acerta, Karyopharm and Morphosys. MH has no conflicts of interest to declare.

CLL Fact Box

• Most common leukemia in Western countries.

• Incidence 4–6 per 100 000 people per year.

• Majority of newly diagnosed patients are >70 years.

• Establish diagnosis as in younger patients (blood count, immunophenotyping).

• Clinical staging has prognostic value in elderly patients.

• Del(17p) and TP53 mutation are prognostic in elderly patients.

• Comorbidity is common and prognostically relevant in elderly patients.

• Geriatric impairments may impact prognosis.

• Various effective and well-tolerated treatments available.

• Choice of treatment depends on disease- and patient-specific risk factors.

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Supplementary data