Diffuse large B-cell lymphoma among the elderly: a narrative review of current knowledge and future perspectives

Introduction

Diffuse large B-cell lymphoma (DLBCL) is predominantly a disease of the elderly, with incidence increasing with age (1). The number of very old patients with DLBCL in the Western World is expected to rise significantly in coming years due to evolving demographics (2). The world population aged 80 years and above tripled in size between 1980 and 2010, an increase that is projected to continue (3). Although DLBCL is a potentially curable disease, and although there are robust clinical trial data of frontline therapy in the elderly (ages 60–80) (4-6), there is a paucity of data in the very elderly (>80 years of age). Patients with DLBCL >60 years of age are heterogeneous, which limits their widespread inclusion in clinical trials. The few trials focusing exclusively on the very elderly have generated a limited evidence base informing optimal therapies in this group of patients. For example, in a systematic review of frontline therapies in DLBCL, only 6 out of 41 phase II/III clinical trials included patients over the age of 80 years (7). Recent improvements in cancer and lymphoma care have primarily been achieved in younger patient groups (2,8), and it is unclear whether these also apply to the elderly population. The aim of this review is to provide an overview of the epidemiology, prognosis, frailty assessment and current and future treatment options for elderly DLBCL patients with a focus on the very elderly patients for whom evidence-based practice is limited.

We present the following article in accordance with the Narrative Review reporting checklist (available at https://aol.amegroups.com/article/view/10.21037/aol-22-2/rc).

Methods

Relevant studies were identified using the PubMed database with the keywords reported above, searched alone and in combination. While there were no filters used to specify text language or publication dates, the evidence included in the review was limited to studies published in English in peer-reviewed international journals (Table 1).

Discussion

Epidemiology and survival in elderly DLBCL patients

DLBCL is the most common lymphoma subtype among adults in the Western World. With a median age at diagnosis of 70 years and increasing incidence with advanced age, the number of newly diagnosed elderly patients with DLBCL becomes larger every year as life expectancy increases. In a Swedish population-based study the incidence of DLBCL increased 2.2% per year between 2004 and 2016 (9). The definition of elderly has varied over time in the literature with no universally accepted age cut-off to define this population, although age ≥80 years is often used to define a very elderly subgroup (10,11).

Data describing patient characteristics and survival of older patients with lymphoma are mostly limited to retrospective and observational data. In published reports, patient characteristics for elderly patients with DLBCL are similar to those of younger patients with the exception of a higher fraction of patients with poor performance status (12,13). Females numerically exceed males in elderly cohorts due to the longer life expectancy of women, but male-to-female incidence rate ratio remains higher among older patients when calculating sex-specific incidence rates of DLBCL (14,15). Some studies report a higher proportion of stage III-IV disease among elderly patients, which may indicate a more protracted diagnostic workup with delayed diagnosis or a more aggressive disease biology (12,13,16). As expected, the comorbidity burden is high among elderly DLBCL patients (12,16,17). Prognostic factors among elderly patients with DLBCL are similar to those observed in other studies including a broader range of patients with DLBCL, including Eastern Cooperative Oncology Group performance status (ECOG PS) score 2–4, elevated lactate dehydrogenase (LDH), advanced stage and Charlson comorbidity index (CCI) >1 (14).

The addition of rituximab to standard chemotherapy has benefited both young and elderly DLBCL patients, although possibly to a lesser extent in the latter group (15,18-21). Three randomized clinical trials have demonstrated that R-CHOP is generally well tolerated and associated with improved outcomes exclusively in patients >60 years of age, although the proportion of patients >75 years of age included in these studies has ranged been 0 and 20% (4-6). A nation-wide study from the Netherlands included 4,737 DLBCL patients aged ≥80 years (10% ≥90 years) treated in the period 1989–2015. Five-year relative survival (RS) for patients who received treatment was 45%, 44% and 36% in age groups 80–84 years, 85–89 years and ≥90 years, respectively. Relative survival is the overall survival (OS) in a patient cohort divided by the expected survival (ES) of an equivalent group from the general population, matched to the patients with respect to age, sex, and period (15). The improvement was particularly pronounced in the cohort treated with immunochemotherapy, with a 5-year RS of 69% (15). A Surveillance, Epidemiology, and End Results (SEER) database study of DLBCL patients aged 80 years and above demonstrated improved 2-year OS of 39% in the rituximab era compared to 25–32% in the pre-rituximab era (22). In another SEER-study of 1,156 DLBCL patients aged 80 and above, R-CHOP was the only treatment associated with improved survival, but only 51% of the cohort received R-CHOP, indicating that elderly lymphoma patients may be at risk of undertreatment (12). Several other studies also report possible suboptimal treatment of elderly patients with DLBCL with as few as 30–50% receiving treatment in some studies, although it is difficult to retrospectively identify subgroups who may have benefited from more curative treatment approaches (16,23-25).

In a collaborative Nordic study of lymphoma patients aged 85 years and above, 2,347 Danish and Swedish patients were identified, of which 924 had DLBCL. Overall, 69% of DLBCL patients received active treatment which was associated with an improved survival with a 2-year RS of 51% for treated DLBCL patients as compared to 10% for untreated (Figure 1) (14). For patients who were selected for R-CHOP or R-CEOP (data on potential dose reductions not available), survival was even better with a 2-year RS of 64% (14). That treatment is beneficial also among the oldest old and should be administered when feasible is supported by other observational studies. A French retrospective study of 164 patients aged 90 years and above with all lymphoma subtypes showed that 56% of patients received systemic therapy which was associated with improved OS for aggressive subtypes (26). In another Swedish study of 1,194 DLBCL patients aged 80 years and above, curative intent treatment was associated with superior 2 year RS of 64% as compared to low-intensive treatment or palliative treatment (2-year RS 33% and 7%) (27). Similar results were seen in a retrospective cohort study of DLBCL patients aged 80 years and above from MD Anderson; 70% received treatment with R-CHOP, which was associated with a 3-year OS of 54% (28).

Figure 1 Cumulative relative survival stratified by active treatment (green line) or no active treatment (orange line) for patients with DLBCL aged 85 years and above, with courtesy of Wästerlid et al., unpublished data from (14). DLBCL, diffuse large B-cell lymphoma.

Is biology in elderly DLBCL different?

There is mounting evidence that tumour biology differs between younger and elderly patients with DLBCL. Klapper et al. demonstrated that cytogenetic complexity increases with age, and that the prognostically inferior ABC-subtype is more common among elderly patients (29). This was confirmed by other groups, where one also found a higher MYC expression among older DLBCL patients (30,31). A report that proposed a new subtype stratification of DLBCL based on genetic alterations, found that most mutations were caused by mutational processes associated with aging (32). Finally, a recent study from the Munich Leukemia laboratory with comprehensive genetic analyses on 3,069 patients with hematologic disorders, found a higher median number of mutations and different distribution of genetic aberrations among patients ≥60 years (33). Although this study only included a few cases of B-cell non-Hodgkin lymphoma (B-NHL), it indicates that biological differences may partially explain the worse survival of elderly DLBCL patients (33).

Frailty and prognostic scores in elderly DLBCL patients

The clinical evaluation of elderly patients with DLBCL can be complicated by poor performance status and higher frailty scores, often related to lymphoma-associated symptoms (34,35). Because the international prognostic index (IPI) (36) incorporates age >60 years as a factor, its applicability for elderly lymphoma patients may be suboptimal. The NCCN-IPI, proposed in 2014, enhanced stratification by extending age and LDH categorisation, with patients aged >75 years grouped separately, and differentiating between specific extranodal presentations (37). However, it has not yet proven to predict prognosis more accurately than the original IPI for elderly patients (19). A Danish study showed that an age-cut off of 70 years was more discriminatory in a population-based cohort of patients with DLBCL (38). However, neither the IPI nor the NCCN-IPI incorporate other measures of frailty.

Frailty is defined as a state of decreased physical reserves, affecting the body’s tolerance to stressors due to deteriorated physical systems (39). Comprehensive geriatric assessment (CGA) is considered a gold standard to assess for frailty in elderly cancer patients (40). In DLBCL, it has been shown to predict both survival and treatment toxicity in DLBCL and has potential to guide treatment choice (41,42). Still, its use has been limited in clinical practice as it is time consuming (40,43,44). Therefore, several screening tools to identify patients appropriate for a full CGA have been developed, including the Vulnerable-Elders Survey-13 (VES-13), Geriatric-8 (G8) and Triage Risk Screening Tool. These screening tools have been found to have high sensitivity to predict frailty and prognosis, but in a systematic review they had low specificity and poor positive prognostic values in identifying individual patients who might benefit from a full CGA (45,46). The G8-score has subsequently proved to predict prognosis among patients with hematological malignancies and could represent a useful tool in treatment choice (40,47,48). However, a Japanese group demonstrated that the cut-off value for when the G8 score should affect treatment choice was different among patients with DLBCL compared to solid malignancies, as it includes variables that may be affected by the lymphoma itself (48). That frailty according to the VES-13 is associated with poorer survival regardless of age has also been shown (49). Ultimately, the use of CGA and similar tools has not been adopted widely because (I) some of their components such as PS and nutritional scores may both be affected by the lymphoma itself, and (II) it is unclear how to best adapt therapy in response to results (48,50). Still, it is evident that CGA and simplified screening tools are associated with survival and need to be incorporated in future trials to evaluate the feasibility of these tools to guide treatment choice.

Several prognostic scores specifically developed to assess frailty and treatment tolerability for elderly patients with DLBCL have been proposed and are summarised in Table 2. The Fondazione Italiana Limfomi have previously demonstrated that a simplified version of geriatric assessment (sGA) correlates with DLBCL survival and identifies a group of frail patients who may not benefit from treatment (52). In a subsequent prospective observational study, sGA significantly predicted survival as did the IPI and hemoglobin level <12 g/L, which led to the construction of the Elderly prognostic index (EPI) (10). The authors found that patients with a low-risk EPI benefit from full-dose treatment with curative intent. In the group with intermediate EPI score, full-dose therapy with curative intent was feasible but reduced dose-intensity was not associated with worse outcomes. For patients with a high-risk EPI, treatment benefit remains uncertain (10). Data on socioeconomics and other factors such as marriage status, shown to be important for survival and treatment tolerability, were not accounted for. When stratifying patients into fit, unfit and frail using a frailty score proposed in a retrospective Norwegian study of 742 patients aged 70–100 (51), administration of R-CHOP was beneficial for all cohorts without significantly increased treatment related mortality. However, attenuated R-CHOP (defined as relative dose intensity ≤80%) was as effective as full dose R-CHOP among unfit and frail patients (51). Thus, both this and the EPI may function as tools to define treatment goals for elderly patients, although further prospective validations are needed (10,51).

Several other methods to assess frailty have been proposed. For example, gait speed, measured on a 4-meter walk, has been found to be associated with both mortality and need for in-hospital stays for patients with hematologic malignancies (29% with DLBCL) (53). With a mortality increase of 20% for every 0.1 m/s decrease in gait speed, this measure appears to capture several different physiological aspects such as function of the central and peripheral nervous system, perception, muscle mass and energy production (54). How these simple tests can guide treatment selection in elderly patients with DLBCL tolerability remains to be prospectively studied.

Optimal dosing of R-CHOP in elderly patients

R-CHOP has been the standard of care for patients over the age of 60 for the last two decades based on randomized data (4-6). However, elderly patients are at increased risk of toxicity from R-CHOP, often requiring dose reductions and/or premature treatment discontinuations (21). Standard doses of R-CHOP cannot be consistently used in all elderly patients outside of clinical trials, especially in the very elderly or frail. In a study of 3,149 Swedish DLBCL patients, age >75 years and comorbidity were predictors of premature treatment discontinuation. Patients unable to complete the full six cycles of R-CHOP experienced substantially worse OS even when discontinuations were unrelated to disease progression; five-year OS for 1–3 cycles was 26% (95% CI: 19–33%), 49% (95% CI: 41–57%) for 4–5 cycles, and 76% (74–77%) for completion of treatment (55).

Randomized controlled trials comparing full vs. reduced intensity R-CHOP in elderly/frail patients have not been performed. The efficacy of attenuated R-CHOP (mini-CHOP) was established in a single-arm trial of 150 DLBCL patients >80 years (11). The attenuated R-CHOP regimen (R-mini-CHOP) consisted of six cycles of R-CHOP-21 with 375 mg/m² rituximab, 400 mg/m² cyclophosphamide, 25 mg/m² doxorubicin, and 1 mg vincristine on day 1 of each cycle, and 40 mg/m² prednisone on days 1–5 (11). The median age of enrolled patients was 83 years (range 80–95 years) with intermediate-high to high risk by IPI in 71%. Functional limitations according to the IADL were documented in 54% of the patients. The relative median dose-intensity for the 108 patients completing six cycles was 97% for doxorubicin, suggesting that this dose is tolerable for many elderly. The 2-year OS was 59% (95% CI, 49–67%) (11). Despite the reduced intensity R-CHOP, 13 patients died between first and second cycle. Prophylactic granulocyte colony-stimulating factor (G-CSF) and/or antibiotics were left to the discretion of the treating physician, but later studies have shown reduction of early mortality from infectious complications if used consistently in elderly patients (56). Ongoing studies of novel agents against DLBCL in elderly patients have implemented the dose-attenuated R-CHOP-21 regimen as standard treatment, confirming that this regimen is now widely accepted as first line treatment in elderly patients.

A major challenge for clinicians is to identify elderly DLBCL patients for full dose R-CHOP. A recent systematic review included studies of DLBCL where survival was reported for at least 100 R-CHOP-21 treated patients with available data on dose intensity (57). Thirteen relevant studies including a total of 5,188 patients were identified, all retrospective and many single center. Relative dose intensity (RDI) was defined as the ratio of delivered dose to the planned dose multiplied by a time factor (the ratio of planned treatment time to the actual time taken to complete chemotherapy) in 10/13 studies (57). Seven of nine studies evaluating the impact of RDI on OS found that OS was reduced in patients receiving reduced RDI. This association was most evident in patients <80 years, whereas reduced dose intensity in patients 80 years or older did not consistently appear to compromise survival outcomes (57).

Four of the largest studies of dose intensity and outcomes are summarized in Table 3. The two studies that based treatment intensity of the dosing of first cycle of R-CHOP both consistently showed that full dose R-CHOP was not associated with better outcomes in patients ≥80 years (13,16). Thus, an intention to treat with less than full dose in this population did not adversely affect outcomes in this age group. Further, patients ≥80 years treated with R-CHOP at an intended dose intensity (IDI) of ≤80% did not experience more relapses suggesting that reduced dose is sufficient for durable remissions in elderly patients. This was not the case for patients <80 years, where reduced dose was associated with increased relapse risk (13). Importantly, R-CHOP of any dose appeared to be better than milder regimens such as R-CVP for patients up to 85 years, with exception of patients 80–84 with severe comorbidity (16). Therefore, R-CHOP should be pursued regardless of the need for dose reductions in healthy patients up to 85 years. For the very elderly ≥85 years, treatment decisions will have to be on individual case basis with careful evaluation of patient preferences and comorbidities, as results are conflicting for this group. In a Nordic study of lymphoma patients ≥85 years where dose intensity was not reported, standard treatment (R-CHOP or R-CEOP) for DLBCL was associated with a 2-year relative survival (RS) of 64% (95% CI, 60–73%) whereas low-intensive systemic therapies were associated with a 2-year RS of 40% (95% CI, 34–47%) (14). In a recent Japanese multi-center study, a linear relation between dose-intensity and OS was observed in 127 patients. Median follow-up was short at 15 months, 22/64 deaths were unrelated to lymphoma and some patients with treated with pirarubicin instead of doxorubicin. The results showed that patients in the <50% dose intensity group (based on anthracycline, cyclophosphamide, and vincristine) had poorer response rates and survival. The median dose of anthracycline in the <50% dose intensity group was 31%, and thus far below the mini-CHOP dosing schedule, which provides a dose intensity >50% due to cyclophosphamide of 400 mg/m² (60). Main drivers for <50% dose intensity were, among others, patient specific factors such as dementia, comorbidity, and age. This study suggests that R-CHOP doses <50% are associated with worse outcomes in patients 80 years or older, despite adjustments for confounders such IPI and comorbidity, but do not provide evidence against the efficacy of R-miniCHOP in patients 80 years or older.

In addition to showing a general adverse impact of reduced dose-intensity of doxorubicin (<70% of full dose) on OS, a Swedish study of 541 patients treated with CHOP or CHOEP showed that omission of vincristine, was not associated with inferior outcomes (HR for OS 1.30, 95% CI, 0.53–3.16) (58). This is important, as neurotoxicity is seen in 20% of elderly patients and this group is likely less able to cope with the neurological decline which can have a detrimental impact on physical functioning (11).

Most of the patients analyzed in the UK study of IDI in 690 DLBCL patients were also analyzed by the authors for infection-related morbidity and mortality in a subsequent study; among 331 patients receiving an IDI ≥80%, 33% were hospitalized with ≥1 infection(s) as compared with 23.3% of 355 patients receiving an IDI of <80% (OR, 1.61; 95% CI, 1.15–2.25; P=0.006). The use of primary quinolone prophylaxis also independently reduced the risk of infection-related hospital admission (61). Therefore, less than full dose in patients ≥80 years as well as prophylactic antibiotics can reduce risk of hospitalizations in this fragile elderly group and thereby likely increase quality of life during treatment.

Recent real-world data from England comparing R-mini-CHOP to standard R-CHOP in 904 patients ≥80 years have confirmed equivalent survival with the two regimens in this age-group with a completely overlapping 3-year OS of 54%. Interestingly, patients treated with non-anthracycline (mostly R-CEOP but also R-GCVP) had a similar 3-year OS to patients treated with R-mini-CHOP of 49% (95% CI, 38–60%) suggesting that elderly with risk factor for anthracycline-induced cardiotoxicity can be managed successfully without anthracyclines (62).

For future research in dose-intensity in DLBCL and its impact on outcomes, randomized trials would be of major importance to establish the benefit/risk of full-dose R-CHOP in patients ≥80 years, although this trial may never be performed due to the increasing number of novel therapies that may prove to be particularly relevant in elderly patients at risk of chemo-induced toxicity. Based on available data, we recommend reduced intensity R-CHOP for the majority of patients ≥80 years, as lymphoma outcomes are encouraging and risk of complications are less than with full dose. Patients ≥85 years need to be carefully evaluated, but reduced intensity R-CHOP should be considered in the healthy and fit subpopulation.

How to treat elderly patients with DLBCL despite frailty and comorbidities: alternatives to R-CHOP in 1st line

As reviewed above, older patients with DLBCL are more likely to have multiple comorbidities, associated with increased rates of treatment toxicity and risk of severe adverse events (28). Safe and effective options in those patients unable to tolerate standard or reduced doses of R-CHOP are limited. Table 4 lists single-arm studies of modified R-CHOP for first-line treatment of DLBCL using dose-reduced chemotherapy and/or anthracycline alternatives.

The R-COMP studies, substituting non-pegylated liposomal doxorubicin (NPLD) in patients with both normal heart function (63) and those with pre-existing significant cardiac comorbidities (64), showed similar efficacy to R-CHOP (66). It is important to note, however, that even in the population selected for their history of cardiac dysfunction, median left ventricular ejection fraction (LVEF) was 60% (IQR 12) and only 7 patients (12%) had a LVEF<50% (64). These results may therefore not be readily applicable to older adults with underlying cardiac dysfunction.

In a retrospective analysis of R-CVP (R-CHOP without doxorubicin) in elderly, comorbid DLBCL patients with contraindications to anthracyclines, outcomes were inferior to those in studies of R-COMP, R-miniCHOP, and R-CEOP (65). Those poor outcomes may indeed be related to the very elderly and comorbid patients enrolled, and it is uncertain if this group would have had more favorable outcomes with the addition of etoposide or NPLD to R-CVP.

Table 5 summarizes studies comparing frontline DLBCL treatment alternatives to full-dose R-CHOP in elderly and comorbid patients. None of the various R-CHOP alternatives out-performed full-dose R-CHOP. The less intensive regimens of bendamustine plus rituximab (BR) or R-CVP had inferior efficacy. In a retrospective study comparing BR to R-CHOP as first-line therapy in elderly patients with DLBCL, BR was an independent poor prognostic factor for OS (71). Subgroup analyses of a retrospective study comparing BR to R-CHOP showed that patients age 80 and older benefitted from R−CHOP compared to BR, regardless of performance status (median PFS 59 vs. 11 months) (70). In a large retrospective, multi-centre study of DLBCL treatment in adults age ≥80 that compared R-CHOP, R-CVP, CHOP, and CVP, use of R-CHOP was independently associated with improved OS (69).

The long-term follow up of R-CEOP, substituting etoposide for doxorubicin, compared to matched controls treated with R-CHOP shows encouraging results with comparable disease-specific and progression-free survival between groups (68). Despite the limitations of this retrospective study, the >10 years of follow-up suggest R-CEOP may be a reasonable alternative to R-CHOP in patients with cardiac comorbidity.

Treatment of relapsed DLBCL in elderly patients

While DLBCL is a curable disease, a large cohort study of 4,805 patients published in 2021 showed that 25% of patients aged 70 or older experienced relapse of their disease or had disease that was refractory to first-line therapy (72). Relapsed disease is that which recurs after an initial response to treatment. Thirty-one percent of those either relapsed or refractory (R/R) patients exhibited primary refractory disease, defined as stable disease as the best response to treatment at post-treatment assessment (73).

To achieve durable disease remissions in the R/R setting, the standard of care therapy includes intensive salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, more than half of relapsing patients will not be eligible for ASCT, and the best next treatment step for transplant-ineligible patients is less clear (73). This is not least true for the cohort of elderly patients with DLBCL where very few will be eligible for ASCT and data on ASCT in elderly patients is limited. A retrospective study from Japan looked at 484 R/R DLBCL patients age 60 or older treated with salvage chemotherapy and ASCT (66). To examine outcomes, the authors stratified patients by ages 60 to 64, 65 to 69, and 70 years or older. Non-relapse mortality at day 100 was not significantly different between age groups, but age >65 was associated with decreased OS. The relapse rate was significantly higher among patients age ≥70, as well as for those not in remission, and those with ECOG PS 2–4 at time of transplant (66). ASCT may be a good option in fit elderly patients, but the toxicity profile requires careful risk assessment due to the likely diminishing returns of transplant above the age of 70 (74).

Patients deemed ineligible for ASCT have a variety of therapeutic options, but there is no accepted standard of care. Table 6 outlines therapeutic options for elderly patients with R/R DLBCL ineligible for or relapsed post ASCT. The combination R-gemcitabine and oxaliplatin (R-GemOx) is often applied and has demonstrated a median OS of 10 months in a retrospective French cohort of 196 patients ineligible for transplant (75). In a phase II study of 49 patients with R/R DLBCL R-GemOx led to complete remission for 44% of patients (76).

Recently, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an attractive, curative-intent option for patients who are refractory to salvage regimens, relapse post-ASCT, and for select older patients deemed transplant-ineligible due to age or comorbidities. Patients with R/R DLBCL who received CAR-T cells targeting CD19 were studied in the ZUMA-1 and JULIET trials and, based on those results, CAR-T products were approved for R/R DLBCL following failure of two or more lines of therapy, including prior stem cell transplant. In the ZUMA-1 and JULIET trials, 27 patients (25%) and 25 patients (23%), respectively, were age 65 or older. CAR-T activity did not seem to be impacted by age, therefore it may be an option for older patients with R/R DLBCL (77,78).

In older transplant-ineligible patients for whom CAR-T cell therapy is not yet accessible or not appropriate, several newer approaches may better balance efficacy and tolerability. Polatuzumab vedotin (pola) in combination with BR has activity in R/R DLBCL and is approved for transplant-ineligible patients after two lines of therapy (88). This regimen demonstrates significantly improved efficacy over BR alone with a similar toxicity profile, making it an attractive choice in the R/R setting (81). Interestingly, in the study comparing pola-BR to BR alone, when analyzed by age group pola-BR demonstrated a particular improvement in OS and PFS in patients age ≥65 (81).

Lenalidomide (len) has modest single-agent activity in R/R DLBCL and can be considered as a bridging therapy to ASCT or CAR-T, or as a palliative treatment with or without the addition of rituximab (82). The regimen is well tolerated with a favorable toxicity profile, though somewhat limited effectiveness (84). A study comparing len to single-agent palliative-intent chemotherapy suggests the efficacy of len may be more pronounced in non-germinal centre B-cell (GCB) type DLBCL, and demonstrated a minor benefit over chemo monotherapies, but none of the responses were durable, making an argument for preferential use of len in combination with another agent (84). For example, the addition of anti-CD19 monoclonal antibody tafasitamab (tafa) has offered improved efficacy over lenalidomide monotherapy without significantly increasing toxicity (86). Tafa has demonstrated activity as a single agent, but by itself it has not shown a robust disease response (85). Using tafa and len together achieves a significantly more impressive response than either agent alone (86). This synergistic combination represents a tolerable and effective chemotherapy-free option for R/R disease.

While there are second- and later-line therapies available for older, transplant-ineligible patients with DLBCL, there is no established standard of care therapy. CAR-T cell therapy can offer a potentially curative option to patients considered ineligible for ASCT. Newer agents in combination with established regimens, like pola-BR, and novel combinations such as tafa-len are emerging as potential therapeutic options in R/R DLBCL.

Novel therapies in DLBCL with potential in elderly patients

Many novel therapies with activity in R/R DLBCL, especially those with favourable single-agent toxicity profiles, represent opportunities to improve frontline therapy in the elderly. There are four strategies to potentially integrate novel therapies into frontline therapy: (I) as additions to the chemoimmunotherapy (CIT) backbone, most commonly in the form of R-CHOP or R-miniCHOP, (II) as replacements of some or all the components of CIT, (III) as maintenance or consolidation therapy after CIT, or (IV) as lead-in therapy prior to CIT.

Table 7 lists various novel agents tested in combination with standard doses of R-CHOP or R-EPOCH in adult patients. Approximately half of the patients accrued in these studies were ≥65 years old, although few patients were >80 years old. For example, in the ROBUST trial, 33% patients receiving lenalidomide + R-CHOP were age ≥70, but only 3% were age ≥80 (93). These studies show that a proportion of robust elderly patients are eligible for novel agents in combination with CIT, although efficacy and toxicity were not evaluated in elderly subgroups in most of these studies. These studies also highlight the heterogeneity of elderly patients with DLBCL, and do not inform management of the very old or the very frail.

Table 8 lists clinical trials evaluating novel agents, with or without CIT, exclusively in elderly patients although eligibility criteria and definitions of elderly or frailty were variable. Two studies have evaluated novel agents in combination with R-miniCHOP. In the randomized phase III SENIOR study, which only enrolled patients over the age of 80, the addition of lenalidomide to R-miniCHOP was associated with increased toxicity compared to R-miniCHOP alone (102). This combination was not associated with improved PFS or OS, in line with the ROBUST trial in adult patients (93). Similarly, in the Australasian Leukaemia & Lymphoma Group NHL29 phase II study, which only enrolled patients over the age of 75, the addition of ibrutinib to R-miniCHOP was associated with significant toxicity requiring treatment modifications or interruptions (103). A similar observation was made in the subgroup of patients over the age of 60 randomized to ibrutinib + R-CHOP in the PHOENIX trial, in whom the greater toxicity and treatment discontinuation rates may have abrogated the impact of this combination on outcomes (92).

Table 8 shows two studies evaluating upfront strategies that do not include CIT. The combination of lenalidomide + rituximab appears to be active although response rates and outcomes were lower than expected in this study, likely related to the selection of frail patients as defined by the sCGA (104). Single agent mosunetuzumab also appears to be active and well-tolerated in those unfit for CIT and may represent an opportunity to improve frontline therapy in the elderly, although the data currently available require larger sample size and longer follow-up (105).

Because of the additional toxicity of novel agents when combined with CIT, strategies employing them after or before CIT could improve outcomes while reducing toxicity. In the randomized phase III REMARC trial, maintenance lenalidomide for 2 years after full-dose R-CHOP was associated with improved PFS but not OS, and with expected toxicity for this agent (101). However, only patients aged 60–80 and fit for full-dose R-CHOP were included in this study, limiting applicability across the broader range of elderly patients. Approximately half of the patients with high-risk large B-cell lymphoma enrolled in the ZUMA-12 study were over the age of 60 and able to tolerate axicabtagene ciloleucel after two cycles of CIT and achieve excellent early responses (98).

Novel agents could also be used to establish initial disease control and improve performance status, allowing patients to better tolerate CIT. In the Start Smart trial, the ORR was 86% (CR 36%) after two cycles of lenalidomide + ibrutinib + rituximab prior to CIT. Even though only 28% patients were over the age of 70, this study suggests this strategy could be feasible in a broader elderly population (95). Not all novel agents might be suitable for this approach, especially those which elicit slow tumor responses with the passage of time such as single agent BTK inhibitors or PD1 inhibitors.

Novel agents alone or in combinations will play an increasingly important role in the management of DLBCL in the elderly, especially in those unable to tolerate R-CHOP or R-miniCHOP. Selection of appropriate novel agent strategies will need to incorporate assessments based on frailty/organ function, patient preferences, and the biologic heterogeneity of DLBCL.

Conclusions

Age itself is not a contraindication to standard treatment of DLBCL, but its association with frailty and presence of comorbidity means that individual assessment is necessary to determine treatment feasibility and safety. Several novel scoring systems have been proposed to improve frailty assessment in the clinical setting, although the optimal algorithm to adjust therapy based on these results, especially in newly diagnosed patients, remains unclear. In elderly patients with newly diagnosed DLBCL, R-CHOP with or without modifications, is the most appropriate first-line therapy even for the very old patients. However, for patients older than 80 years, there is no clear benefit of full-dose R-CHOP over reduced dose R-CHOP and reduced dose R-CHOP is associated with a lower risk of complications. In patients with contraindications to anthracyclines, R-CEOP seems to result in comparable long-term outcomes, although with the limitation of small sample sizes and observational data. Less intensive therapies such as BR or R-CVP are generally associated with poor outcomes but can be considered in the very old (≥85 years) or in those who are not eligible for reduced doses of R-CHOP or R-CEOP. In the relapsed setting, data regarding optimal treatment for older patients with DLBCL are sparse although several novel agents with favorable single-agent activity may provide options that balance efficacy against toxicity. Moving forward, prospective, randomised studies performed exclusively in elderly patients, ideally with easily applicable assessments of frailty and disease biology, will identify the most appropriate treatment options in this population.

Acknowledgments

We wish to thank the Danish Cancer Society (TCEG). TW was supported by Region Stockholm (clinical postdoctoral appointment).

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aol.amegroups.com/article/view/10.21037/aol-22-2/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aol.amegroups.com/article/view/10.21037/aol-22-2/coif). DV has participated in advisory boards and has received honoraria from Roche, Janssen, Kite/Gilead, BMS/Celgene, Kyowa Kirin, Abbvie, AstraZeneca. DV has received research funding from Roche and AstraZeneca (institutional funding). TCEG serves as an unpaid editorial board member of Annals of Lymphoma from October 2020 to September 2022, and was previously employed by Roche Ltd (Basel) and has received a speaker’s fee from Abbvie. The other authors have no conflicts of interest to declare.

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