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Review

Appropriate Treatment Intensity for Diffuse Large B-Cell Lymphoma in the Older Population: A Review of the Literature

by
Satoshi Yamasaki
1,2,3
1
Department of Hematology, St. Mary’s Hospital, 422 Tsubukuhonmachi, Kurume 830-8543, Japan
2
Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu 874-0838, Japan
3
Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka 810-0065, Japan
Hematol. Rep. 2024, 16(2), 317-330; https://doi.org/10.3390/hematolrep16020032 (registering DOI)
Submission received: 29 March 2024 / Revised: 13 May 2024 / Accepted: 22 May 2024 / Published: 24 May 2024
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Abstract

:
Most patients with diffuse large B-cell lymphoma (DLBCL) are >65 years of age, with the number of patients expected to increase in the coming years. A comprehensive geriatric assessment that carefully evaluates fitness status and comorbidities is essential for selecting the appropriate treatment intensity. Although generally healthy patients or those <80 years of age may benefit from standard immunochemotherapy, unfit/frail patients or patients >80 years old may require reduced-intensity chemotherapy or less-toxic drugs. Some new drugs are currently being tested as single or combined agents for first-line treatment, aiming to improve the outcomes of conventional chemotherapy. This review systematically collates and discusses the outcomes associated with the use of immunochemotherapy in older patients with DLBCL, as well as considering the impact of full-dose immunochemotherapy on quality of life in older and frail patients, summarizing the rationale for reduced dosing in the older population, and presenting recommendations for selecting patients likely to benefit from reduced dosing. If preliminary efficacy and safety data are confirmed in future clinical trials, non-chemotherapy-based immunotherapy approaches could become an alternative potentially curative option in frail patients and those >80 years of age with DLBCL.

1. Introduction

Common comorbidities and limited organ reserves (e.g., bone marrow, heart, kidneys, liver) in older patients lead to common problems in treating older patients and place them at higher risk of toxicity compared with younger patients. Clinicians should also consider issues related to impairments in physical and cognitive function, which might compromise their ability to attend hospital or manage treatment at home, especially in the absence of a caregiver. In addition to factors related to patient fitness, unfavorable biological properties of the disease may also contribute to a poor prognosis. This section introduces the definition and epidemiology of diffuse large B-cell lymphoma (DLBCL) and highlights its increasing frequency and incidence, especially in older people, as well as presenting the characteristics of older patients (comorbidities, frailty, and decreased organ reserve) that might complicate management decisions and reduce tolerance to full-dose chemotherapy.

2. Chemotherapy Options

The aim of first-line treatment in fit patients ≤80 years old should be curative, with a total-dose anthracycline-based regimen. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has been used as an initial treatment for over 20 years [1], and most attempts to improve its results by adding new biological agents to immunochemotherapy, especially in patients with non-germinal center B (GCB) DLBCL, have failed to show any significant advantage [2]. The PHOENIX trial found no improvement in event-free survival by adding ibrutinib to R-CHOP in patients with newly diagnosed non-GCB DLBCL, and ibrutinib plus R-CHOP was associated with increased toxicity in patients >60 years old, leading to compromised R-CHOP administration and worse outcomes [3]. No improvement was observed in the ROBUST trial in previously untreated patients with activated B-cell-type DLBCL receiving lenalidomide plus R-CHOP [4]. The POLARIX study is the only randomized phase III trial that has demonstrated significantly improved progression-free survival (PFS) in patients with DLBCL [5]. In this trial, replacement of vincristine with polatuzumab vedotin (Pola), an antibody-drug-conjugate targeting CD79b, in the R-CHOP scheme (Pola-R-CHP) improved the 2-year PFS to 76.7% compared with 70.2% for standard R-CHOP in patients aged 18–80 years with intermediate-risk or high-risk DLBCL, with similar safety profiles; however, the 2-year overall survival (OS) rates did not differ between the groups (88.7% in the Pola-R-CHP group and 88.6% in the R-CHOP group). Exploratory subgroup analysis revealed greater benefit in patients aged 60 years and older and in patients with non-GCB types, double expression, and high international prognostic index (3–5). The modest PFS benefit of Pola-R-CHP and similar OS has led to some concerns about the broad application of this regimen. Although Pola-R-CHP is a good choice, especially in certain patient subgroups, R-CHOP is likely to remain the standard of care in future clinical trials and an effective backbone for new combinations.
Dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) is one of the most suitable therapies for patients with high-grade B-cell lymphoma (double or triple hit). This intensive treatment, however, may not be acceptable for patients >80 years old and those <80 years with significant comorbidities [6,7], and there were no advantages of dose-adjusted R-EPOCH in patients >65 years with double/triple expression [8].
Although the cells of origin, molecular features, genetic features/expression (such as MYC, BCL-2, BCL-6, TP53, CDKN2A, and primary histocompatibility class II), and positron emission tomography-directed treatment approaches may contribute to the overall prognosis [9,10,11,12], there are currently few systems or treatment guidelines for patients aged >65 years, including in the European Society for Medical Oncology guidelines [13] and National Comprehensive Cancer Network guidelines [14], and R-CHOP remains an effective and appropriate therapeutic option for older patients with DLBCL [15].

3. Considerations in the Older Population

Aging is a complex natural process leading to progressive loss of physiological integrity, organ dysfunction, increased inflammation, and susceptibility to genetic damage and epigenetic modification. Some patients do not receive standard-dose chemotherapy because of their own preference or that of their physician, and the lack of this treatment may thus not be due strictly to patient age or comorbidities, leading to potential bias in terms of the relationship between older age and poor outcome risks, as previously noted [16]. There may thus be selection bias regarding the ineligibility for standard-dose chemotherapy because no proper randomization could be achieved. R-CHOP is not standardized for older patients with DLBCL, particularly for those aged ≥80 years [17,18].
Several characteristics of older patients may impact their ability to tolerate standard curative therapy, including comorbidities and organ reserve, the impact of age on pharmacokinetics (therapeutic index, reduced drug metabolism, and elimination), concomitant medication, and nutritional status/frailty [17,19,20]. Older patients at high risk, as defined by higher international prognostic index scores, low albumin, and Cumulative Illness Rating Scale for Geriatrics score ≥6, may be at higher risk of infection-related morbidity and mortality [21]. Some reports have also suggested differences in disease characteristics between younger and older patients, including dominance of the activated B-cell subtype [19,22]. There is also a distinction between poor clinical outcomes, such as lower OS, PFS, and complete remission (CR) rates (CRRs), and quality-of-life (QoL) outcomes, including capacity for daily activity, social functioning, and patients’ general health perception, with QoL factors potentially influencing individual preferences independent of clinical outcomes.
In addition, sarcopenia is a crucial factor affecting the physical fitness of the older population. Skeletal muscle index was recently reported to be the most appropriate assessment method for evaluating sarcopenia and a critical prognostic factor in terms of OS and PFS in older patients with DLBCL [23].

4. Management of Frail, Older Patients

Although outcomes differ in older compared with younger patients with DLBCL, OS may be improved with appropriate treatment [24], and age alone should not be a contraindication to chemotherapy [17,25]. Although reduced-intensity chemotherapy is associated with poorer outcomes in the general population, reduced dosing intensity does not consistently affect survival in patients aged >80 years compared with full-dose chemotherapy [26]. Although OS following attenuated-dose R-CHOP (R-mini-CHOP) is inferior compared with that of R-CHOP [27], R-mini-CHOP is being increasingly used as an initial treatment in the older population. Eligibility criteria other than age should thus be carefully considered when choosing a treatment for unfit/frail patients or patients >80 years old. A list of first-line immunochemotherapy regimens suitable for older patients with DLBCL is shown in Table 1.

5. Reduced-Intensity Chemotherapy

Unfit and frail patients usually require an adapted therapeutic regimen. R-miniCHOP is the most popular treatment for DLBCL in patients aged >80 years without severe comorbidities, with a 2-year PFS of 47% and a 2-year OS of 59% [28]. The LYSA group attempted to improve the outcomes of R-mini-CHOP by using ofatumumab instead of rituximab [29], but the 2-year OS (64.7%) was only slightly better. Nevertheless, this study confirmed the importance of a systematic pre-stage using prednisone and vincristine before immunochemotherapy, which could improve performance status and reduce treatment-related mortality in the first cycle [30]. Based on the promising results of the POLARIX trial, the Nordic Lymphoma Group is currently randomizing patients aged ≥80 years or frail patients aged ≥75 years to R-mini-CHOP or R-mini-CHP plus polatuzumab vedotin in phase III trials (ClinicalTrials.gov Identifier: NCT04332822).
Many older patients have cardiac comorbidities and multiple cardiovascular risk factors (e.g., hypertension, diabetes mellitus, chronic kidney disease), which are associated with an increased risk of anthracycline-related cardiotoxicity [16,31]. In these cases, replacing traditional doxorubicin with a non-pegylated liposomal form may reduce the risk of cardiac events without compromising efficacy [32,33,34,35].
For patients with a complete contraindication to anthracyclines, the European Society for Medical Oncology (ESMO) guidelines suggest that substituting doxorubicin with gemcitabine or etoposide [13], and omitting doxorubicin altogether (e.g., the R-CVP regimen), may be an option in frail older patients; however, it is generally less effective, and this option has a palliative purpose [36]. Tucci et al. recently reported that including rituximab within palliation improved the outcome in terms of 2-year OS (42% with rituximab vs. 22% without rituximab; p = 0.008) [37].
The safety and efficacy of rituximab and bendamustine in indolent lymphoma has prompted their evaluation as a first-line treatment in frail older patients with DLBCL, with an overall response rate (ORR) of 62% (53% CRR) in a phase II trial of 49 patients with DLBCL aged >70 years with significant comorbidities and declining health; however, the PFS was disappointing (38% at 2 years) [38]. The phase II ReRi study tested the combination of rituximab plus lenalidomide in 68 patients with newly diagnosed DLBCL who were not eligible for conventional cytotoxic therapy. The ORR was 41%, and the 12-month PFS and OS were 55% and 69%, respectively. Although the initial endpoint was not confirmed in this study, activity was observed in many cases, justifying its further exploration as the backbone of new chemotherapy-free combination therapy in older and frail patients [39].
Park et al. concluded that clinical outcomes following reduced-intensity R-CHOP chemotherapy were comparable to those of standard-dose R-CHOP in patients with DLBCL aged ≥65 years [20]. Eyre et al. examined a cohort of patients across eight centers in the United Kingdom and concluded that R-mini-CHOP resulted in similar OS, PFS, and relapse rates to full-dose R-CHOP in patients aged ≥80 years [40]. Peyrade et al. evaluated and recommended R-mini-CHOP as standard therapy in patients aged >80 years with DLBCL [28]. Liao et al. retrospectively compared R-CHOP, R-mini-CHOP, and R-CVOP in patients aged ≥75 years and concluded that OS was comparable and differences in PFS were insignificant [18]. Verner et al. undertook a phase 2 study of R-mini-CHOP plus ibrutinib in patients aged >75 years and showed that, although 2-year OS was 68%, ibrutinib was discontinued in 25% of patients, primarily because of adverse events [41].
Regimens other than R-CHOP that may be used at lower dose intensities have been introduced to treat frail older patients with DLBCL. Peyrade et al. demonstrated a 2-year OS of 64.7% in patients aged >80 years with DLBCL treated with ofatumumab, pre-phase treatment (oral vincristine followed by oral prednisone), and reduced-intensity CHOP [29]. Pola-R-miniCHP [5,42], as well as other chemotherapy options, including R-mini-CEOP, R-split CHOP, R-CVOP, and R-GCVP [18,43], may also be promising therapies for older patients with DLBCL.

6. New, Novel, and Chemotherapy-Free Regimens

A limited number of older patients with R/R DLBCL receive the traditional standard approach based on salvage chemotherapy (usually a platinum-containing regimen), followed by high-dose therapy and autologous stem cell transplantation (ASCT) in chemosensitive cases, ideally in patients with CR at re-staging with positron emission tomography/computed tomography. The upper age limit in most studies was 60 or 65 years [44,45], and only a few retrospective series, subgroup post hoc analyses, and data from international registries have described the outcomes of older patients [46,47,48]. In general, ASCT appears to be a feasible option in selected fit older patients ≤75 years of age, but the 1-year non-relapsed mortality in older patients was only 6.0%, suggesting that age should not be the sole factor determining a patient’s eligibility for ASCT [49]. Transplant-ineligible but chimeric antigen receptor (CAR) T-eligible older patients could soon become an accurate and relevant population [50]. Despite significant efficacy, many issues can limit the widespread application of CAR T-cells in clinical practice, particularly in older patients, including the need for specialized centers that may be far from the patient’s residence, a long turnaround time from leukapheresis to product release, and the cost of the entire treatment [51]. Evidence from randomized trials supports the use of a comprehensive geriatric assessment (CGA) to reduce treatment-related toxicities and guide treatment intensity in the care for solid tumors, while its use for evaluation of cellular therapies is less evidence-based.
The combination of tafasitamab–lenalidomide represents another possible salvage option for patients with DLBCL who are not eligible for transplant or CAR T-cells. Although tafasitamab, a new anti-CD19 antibody with an enhanced Fc portion, and lenalidomide have limited single-agent activity, in vitro and in vivo studies showed synergistic effects with limited toxicity [52]. The phase II single-arm L-MIND study enrolled 81 patients with DLBCL who had relapsed after one to three prior systemic regimens, including a minority of primary refractory cases [53]. Tafasitamab was administered in combination with lenalidomide for 12 cycles, followed by tafasitamab monotherapy until progression or toxicity. Updated analysis after ≥35 months of follow-up showed an ORR of 57.5%, including CR in 40% of cases, a median OS of 33.5 months, and a median PFS of 11.6 months. Tafasitamab–lenalidomide thus appears to allow long-term responses with a well-tolerated immuno-modulatory combination [54].
CD19 antigen is the target of loncastuximab tesirine, a novel antibody–drug conjugate that delivers a pyrrolobenzodiazepine dimer after binding to the B-cell surface and entering the cell [55]. The phase II LOTIS-2 study enrolled 145 patients with relapsed or refractory (R/R) DLBCL who had received at least two lines of therapy, including 20% of patients with primary refractory disease, 20% with transformed lymphoma, and 10% with double or triple hit lymphoma. The ORR in this study was 48.3%, with CR occurring in 24.1% of cases and a median duration of response of 10.3 months. The safety profile was acceptable, with the most relevant adverse events being neutropenia, thrombocytopenia, increased gamma-glutamyl transferase, and pleural effusions [56].
New drugs have recently emerged that may provide more effective treatment. Polatuzumab vedotin is a novel antibody–drug conjugate that delivers the microtubule inhibitor monomethyl auristatin E (MMAE) to B-cells and targets the CD79b antigen [57]. In a phase II study, 80 patients with R/R transplant-ineligible DLBCL were randomly assigned to receive Pola-BR (polatuzumab vedotin, bendamustine, rituximab) combination or BR alone [58]. The median number of prior treatment lines was two (range 1–7), and most patients (75–85%) were refractory to their last treatment. Pola-BR resulted in a significantly higher CRR (40.0% vs. 17.5%), longer PFS (9.5 vs. 3.7 months; p < 0.001), and longer OS (12.4 vs. 4.7 months; p = 0.002) compared with BR alone; however, Pola-BR patients had a higher rate of hematological toxicity but similar grade 3–4 infections. Peripheral neuropathy, usually associated with MMAE, was grade 1–2 in all cases and resolved in most patients. Updated outcomes from the randomized arm with a median follow-up of 48 months and the results for an extension cohort of 106 additional patients that received Pola-BR showed no new safety signals and confirmed a significant survival benefit [59].
Chemotherapy-free regimens, targeted therapies such as Bruton’s tyrosine kinase inhibitors, immunotherapies such as lenalidomide, and bispecific antibodies are novel options that may offer promising strategies in older patients (Table 2) [60,61,62]. The safety and effectiveness of chemotherapy-free strategies, such as ibrutinib, rituximab, and lenalidomide, have been tested as first-line options in frail or unfit patients aged ≥75 years [63]. The treatment landscape for B-cell lymphoma has recently been expanded by bispecific anti-CD20xCD3 antibodies that can engage and redirect patients’ T-cells to eliminate malignant B-cells [64,65,66,67]. The main advantage of this approach is its ready-made, rapid availability and toxicity similar but generally inferior to CAR T-cells. Glofitamab, a bispecific antibody characterized by a novel 2:1 CD20–CD3 binding configuration, showed a high response rate (ORR 52%, CRR 39%) in 154 patients (median age 66 years) with R/R DLBCL after treatment, who had received at least two prior treatments, and 52 had already received CAR T-cell therapy. CR continued at 12 months in 78% of cases, and the most frequent adverse event expected of this class of drugs was cytokine-release syndrome (all grades 63% of patients, grade ≥3 4%) [64]. Epcoritamab is a good choice for older patients because of its subcutaneous mode of administration. The phase I/II dose-expansion cohort included 157 patients with DLBCL (median age 64 years), who showed an ORR of 63%, a CRR of 39%, and a median duration of response of 12 months with continued treatment. Cytokine-release syndrome occurred frequently but was only grade 1–2 in most cases (97%) [65]. These novel and chemotherapy-free options may thus be valid first-line therapy choices for older/frail patients and may play a more significant role in older relapsed patients, including as second-line and third-line therapies.

7. Geriatric and QoL Assessments, and Tailoring Therapy in DLBCL

CGA has been used to help identify older patients with lymphoma suitable for standard-dose chemotherapy [71]. The American Society of Clinical Oncology expert panel suggested that clinicians should consider CGA for older chemotherapy patients [72]; however, few reports have considered the CGA as an effective tool for guiding therapeutic strategies in patients aged ≥80 years with lymphoma who received reduced-intensity chemotherapy [73].
Treating older patients with DLBCL presents the clinical dilemma of balancing the potential for cure while minimizing toxicity. Although age itself is not a contraindication to full-dose curative therapy, comorbidities or functional impairments may suggest the need for dose reduction or drug substitution to improve tolerance. There is wide heterogeneity among older patients, and traditional measures of performance status are not accurate enough to define treatment goals and adjust treatment intensity. ESMO guidelines recommend the application of a geriatric assessment to avoid the risk of under- or over-treatment [74]. The Fondazione Italiana Linfomi recently conducted a simplified geriatric assessment (sGA) in a large prospective series of patients with DLBCL aged >64 years (the Elderly Project), based on age (≥ or <80 years), Cumulative Illness Rating Scale for Geriatrics (CIRS-G), activities of daily living, and instrumental activities of daily living (IADL) [75]. The sGA is an objective and reproducible tool that can be easily administered by a single hematologist (in <10 min) and permits the classification of older patients as fit (54%), unfit (28%), or frail (18%), with significantly different outcomes.
Choosing between these different options may be difficult in clinical practice, and real-world data report poorer outcomes than those seen in clinical trials, likely due to the smaller number of patients selected [76,77]. In the absence of randomized trials, comparisons between drugs are only derived from retrospectively matched cohorts, and the results should thus be interpreted cautiously. The main factors affecting treatment decisions are the aim of the therapy (CR, duration of response, QoL), patient characteristics (age, fitness, comorbidities), logistic and social aspects (presence of caregiver, distance from hospital), and disease characteristics (previous treatment line, refractoriness).
The assessment options, supporting evidence demonstrating the relative complexity of the assessment tools, and their crucial evaluation components are summarized in Table 3. The relative complexity of a CGA necessitates the use of sGAs and evidence for the use of components of the CGA (e.g., IADL [78]) [79] and the development of screening tests (e.g., G8 [80]). Additional clinical criteria that may aid therapeutic decision making include cell subtypes such as GCB-cell-like and non-GCB subtypes [81] and lymphocyte/monocyte ratio [82].
Clinical prognosis alone might be insufficient to individualize therapy, and significant improvements in daily activity and social attitude scores (QOL-ACD) and general health perception and social functioning (SF-36) in terms of QoL have been demonstrated in lymphoma patients aged ≥80 years [86]. No other studies, however, have investigated improvements in QoL in relation to reduced-intensity chemotherapy.
In the future, it may be necessary to consider treatment strategies that emphasize QoL from the perspective of patient communication and consent to treatment, in parallel with or in addition to the known clinical benefits of chemotherapy for DLBCL.
There is currently no standard therapy for older patients with DLBCL, particularly those aged >80 years, and the treatment choice is based on a combination of information, such as G8, IADL, Charlson comorbidity index, daily life, and cognitive status [87] supporting immunochemotherapy, alternatives to chemotherapy, impact on QoL, and evaluation of frailty/fitness. There is a need to proactively consider critical features that will help select appropriate patients for alternatives to standard treatments, and the roles of formal or informal pre- and post-treatment QoL assessments in guiding practice. Careful administration of attenuated immunochemotherapy was shown to improve clinical outcomes and QoL in clinical practice, compared with no treatment, and CGA, abbreviated frailty assessment, and improvement in QoL were observed in a small number of cases [88]. Performance of standardized, systematic CGA by geriatricians permits older patients with lymphoma to be classified according to frailty, with significant differences in terms of clinical outcomes across groups [89]. I present my clinical approach for older patients with DLBCL (Figure 1) and a paradigm shift (from management to independent) in lymphoma treatment in the older population (Figure 2). It is expected that the involvement of multiple individuals in multiple areas, such as nursing care (from requirement to prevention), purpose of treatment (from disease to QoL), patient’s role (from compliance to self-selection), doctors’ role (from treatment to support), and place (from hospital to home) may play an important role when selecting less intensive immunochemotherapy for frail patients, especially those >80 years of age.

8. Future Directions and Conclusions

As noted above, many efforts have been made to improve the standard R-CHOP regimen by adding new targeted drugs (so-called R-CHOP plus X trials), but these still need to demonstrate better OS. Future trials will attempt to achieve better outcomes by combining R-CHOP with new Bruton’s tyrosine kinase inhibitors characterized by a more favorable profile, such as zanubrutinib (ClinicalTrials.gov Identifier: NCT05189197). In addition, the front-MIND phase III trial (ClinicalTrials.gov Identifier: NCT04824092) has tested the efficacy and safety of the combination of tafasitamab–lenalidomide and R-CHOP in patients aged 18–80 years with newly diagnosed DLBCL, with high/intermediate or high-risk disease.
Investigators at the MD Anderson Cancer Center have proposed a different strategy, based on an initial phase with biological agents alone (RLI: rituximab, lenalidomide, and ibrutinib) administered for two cycles to patients with non-GCB DLBCL, followed by the addition of conventional chemotherapy (either R-CHOP or R-EPOCH). Despite the small number of patients (60 in total, of which 28% ≥70 years), this “Smart Start study” paves the way for targeted therapy before chemotherapy, showing an impressive response rate after RLI alone (ORR 86%, CRR 36%), with a final ORR of 100% and a 2-year PFS of 91% [90].
Chemotherapy-free treatments based on new antibodies and small molecules represent an emerging approach for unfit/frail older patients who are not eligible for standard chemotherapy. A phase I/II study explored the use of the bispecific antibody mosunetuzumab as first-line treatment in patients with DLBCL aged >80 years, or aged >60 years with comorbidities precluding full-dose chemoimmunotherapy. The ORR and CRR were 56% and 43%, respectively, in 54 patients with a median age of 83, with no grade ≥3 cytokine-release syndrome and no neurotoxicity [91]. An incoming phase II trial will assess epcoritamab alone and in combination with lenalidomide as first-line treatment in older patients with DLBCL who are considered ineligible for anthracycline treatment (ClinicalTrials.gov Identifier: NCT05660967).
Comparison and validation of pre-, intra-, and post-treatment QoL assessments in older patients with DLBCL and the consideration of a combination of pre-and post-treatment measurements are needed. There is thus a need to establish evaluation methods for R-mini-CHOP/reduced-intensity R-CHOP alternatives in patients who cannot tolerate full-dose chemotherapy. A comparison of QoL outcomes between new alternative therapies is required, especially when clinical outcomes are similar.
Although the management of older patients with DLBCL continues to present a challenge, a new era has begun. Objective parameters defining patient fitness status provide the basis for establishing the correct treatment intensity and should be included in future clinical trials. Additionally, a QoL assessment and patient-reported outcomes should be considered as important endpoints. Novel agents with immunological mechanisms of action may help to improve outcomes for patients who have relapsed or become refractory after standard immunochemotherapy and those who are unable to receive standard immunochemotherapy due to comorbidities.
Treatment is not standardized for selected patients, particularly those >80 years old and frail patients, and reduced-intensity chemotherapy may achieve clinical outcomes comparable to full-dose chemotherapy in this population, while avoiding adverse effects. The selection of patients for reduced-intensity chemotherapy or chemotherapy-free regimens is predominantly undertaken using comprehensive or simplified frailty assessments based on evidence measuring clinical outcomes; however, baseline QoL and anticipated gains in QoL may also play important roles in selecting patients with DLBCL for individualized treatment among the older population.

Funding

This work was supported by JSPS KAKENHI, Grant Number 22K12887. The article processing charges were funded by the author.

Institutional Review Board Statement

This was a retrospective review study with no experimental interventions.

Informed Consent Statement

This was a retrospective review study with no requirement for informed consent.

Conflicts of Interest

The author declares no conflicts of interest.

References

  1. Coiffier, B.; Lepage, E.; Brière, J.; Herbrecht, R.; Tilly, H.; Bouabdallah, R.; Morel, P.; Van Den Neste, E.; Salles, G.; Gaulard, P.; et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 2002, 346, 235–242. [Google Scholar] [CrossRef] [PubMed]
  2. Goy, A. Succeeding in breaking the R-CHOP ceiling in DLBCL: Learning from negative trials. J. Clin. Oncol. 2017, 35, 3519–3522. [Google Scholar] [CrossRef] [PubMed]
  3. Younes, A.; Sehn, L.H.; Johnson, P.; Zinzani, P.L.; Hong, X.; Zhu, J.; Patti, C.; Belada, D.; Samoilova, O.; Suh, C.; et al. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non–germinal center B-cell diffuse large B-cell lymphoma. J. Clin. Oncol. 2019, 37, 1285–1295. [Google Scholar] [CrossRef] [PubMed]
  4. Nowakowski, G.S.; Chiappella, A.; Gascoyne, R.D.; Scott, D.W.; Zhang, Q.; Jurczak, W.; Özcan, M.; Hong, X.; Zhu, J.; **, J.; et al. ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients with ABC-Type Diffuse Large B-Cell Lymphoma. J. Clin. Oncol. 2021, 39, 1317–1328. [Google Scholar] [CrossRef] [PubMed]
  5. Tilly, H.; Morschhauser, F.; Sehn, L.H.; Friedberg, J.W.; Trněný, M.; Sharman, J.P.; Herbaux, C.; Burke, J.M.; Matasar, M.; Rai, S.; et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N. Engl. J. Med. 2022, 386, 351–363. [Google Scholar] [CrossRef]
  6. Friedberg, J.W. How I treat double-hit lymphoma. Blood 2017, 130, 590–596. [Google Scholar] [CrossRef] [PubMed]
  7. Oki, Y.; Noorani, M.; Lin, P.; Davis, R.E.; Neelapu, S.S.; Ma, L.; Ahmed, M.; Rodriguez, M.A.; Hagemeister, F.B.; Fowler, N.; et al. Double hit lymphoma: The MD Anderson cancer center clinical experience. Br. J. Haematol. 2014, 166, 891–901. [Google Scholar] [CrossRef] [PubMed]
  8. Dodero, A.; Guidetti, A.; Tucci, A.; Barretta, F.; Novo, M.; Devizzi, L.; Re, A.; Passi, A.; Pellegrinelli, A.; Pruneri, G.; et al. Dose-adjusted EPOCH plus rituximab improves the clinical outcome of young patients affected by double expressor diffuse large B-cell lymphoma. Leukemia 2019, 33, 1047–1051. [Google Scholar] [CrossRef]
  9. Schmitz, R.; Wright, G.W.; Huang, D.W.; Johnson, C.A.; Phelan, J.D.; Wang, J.Q.; Roulland, S.; Kasbekar, M.; Young, R.M.; Shaffer, A.L.; et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N. Engl. J. Med. 2018, 378, 1396–1407. [Google Scholar] [CrossRef]
  10. Sehn, L.H.; Salles, G. Diffuse large B-cell lymphoma. N. Engl. J. Med. 2021, 384, 842–858. [Google Scholar] [CrossRef]
  11. Susanibar-Adaniya, S.; Barta, S.K. 2021 Update on diffuse large B cell lymphoma: A review of current data and potential applications on risk stratification and management. Am. J. Hematol. 2021, 96, 617–629. [Google Scholar] [CrossRef] [PubMed]
  12. Persky, D.O.; Li, H.; Stephens, D.M.; Park, S.I.; Bartlett, N.L.; Swinnen, L.J.; Barr, P.M.; Winegarden, J.D.; Constine, L.S.; Fitzgerald, T.J.; et al. Positron emission tomography-directed therapy for patients with limited-stage diffuse large B-cell lymphoma: Results of Intergroup National Clinical Trials Network Study S1001. J. Clin. Oncol. 2020, 38, 3003–3011. [Google Scholar] [CrossRef] [PubMed]
  13. Tilly, H.; Gomes da Silva, M.; Vitolo, U.; Jack, A.; Meignan, M.; Lopez-Guillermo, A.; Walewski, J.; André, M.; Johnson, P.W.; Pfreundschuh, M.; et al. Diffuse large B-cell lymphoma (DLBCL): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2015, 26 (Suppl. 5), v116–v125. [Google Scholar] [CrossRef] [PubMed]
  14. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): B-Cell Lymphomas. Available online: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf (accessed on 16 November 2023).
  15. Alvarez, R.; Esteves, S.; Chacim, S.; Carda, J.; Mota, A.; Guerreiro, M.; Barbosa, I.; Moita, F.; Teixeira, A.; Coutinho, J.; et al. What determines therapeutic choices for elderly patients with DLBCL? Clinical findings of a multicenter study in Portugal. Clin. Lymphoma Myeloma Leuk. 2014, 14, 370–379. [Google Scholar] [CrossRef] [PubMed]
  16. Lyon, A.R.; Dent, S.; Stanway, S.; Earl, H.; Brezden-Masley, C.; Cohen-Solal, A.; Tocchetti, C.G.; Moslehi, J.J.; Groarke, J.D.; Bergler-Klein, J.; et al. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: A position statement and new risk assessment tools from the cardio-oncology study group of the heart failure association of the European society of cardiology in collaboration with the international cardio-oncology society. Eur. J. Heart Fail. 2020, 22, 1945–1960. [Google Scholar] [CrossRef] [PubMed]
  17. Moccia, A.A.; Thieblemont, C. Curing diffuse large B-cell lymphomas in elderly patients. Eur. J. Intern. Med. 2018, 58, 14–21. [Google Scholar] [CrossRef]
  18. Liao, P.-H.; Kuo, C.-Y.; Ma, M.-C.; Liao, C.-K.; Pei, S.-N.; Wang, M.-C. Oral chemotherapy application in elderly patients with diffuse large B-cell lymphoma: An alternative regimen in retrospective analysis. J. Hematol. 2022, 11, 176–184. [Google Scholar] [CrossRef]
  19. Sarkozy, C.; Coiffier, B. Diffuse large B-cell lymphoma in the elderly: A review of potential difficulties. Clin. Cancer Res. 2013, 19, 1660–1669. [Google Scholar] [CrossRef] [PubMed]
  20. Park, S.; Jo, J.-C.; Do, Y.R.; Yang, D.-H.; Lim, S.-N.; Lee, W.-S.; Kim, W.S.; Lee, H.S.; Hong, D.-S.; Kim, H.J.; et al. Multicenter phase 2 study of reduced-dose CHOP chemotherapy combined with rituximab for elderly patients with diffuse large B-cell lymphoma. Clin. Lymphoma Myeloma Leuk. 2019, 19, 149–156. [Google Scholar] [CrossRef]
  21. Eyre, T.A.; Wilson, W.; Kirkwood, A.A.; Wolf, J.; Hildyard, C.; Plaschkes, H.; Griffith, J.; Fields, P.; Gunawan, A.; Oliver, R.; et al. Infection-related morbidity and mortality among older patients with DLBCL treated with full- or attenuated-dose R-CHOP. Blood Adv. 2021, 5, 2229–2236. [Google Scholar] [CrossRef]
  22. Rosenwald, A.; Wright, G.; Chan, W.C.; Connors, J.M.; Campo, E.; Fisher, R.I.; Gascoyne, R.D.; Muller-Hermelink, H.K.; Smeland, E.B.; Giltnane, J.M.; et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 2002, 346, 1937–1947. [Google Scholar] [CrossRef] [PubMed]
  23. Niiyama-Uchibori, Y.; Okamoto, H.; Miyashita, A.; Mizuhara, K.; Kanayama-Kawaji, Y.; Fu**o, T.; Tsukamoto, T.; Mizutani, S.; Shimura, Y.; Teramukai, S.; et al. Skeletal muscle index impacts the treatment outcome of elderly patients with diffuse large B cell lymphoma. Hematol. Oncol. 2024, 42, e3252. [Google Scholar] [CrossRef] [PubMed]
  24. Feugier, P.; Van Hoof, A.; Sebban, C.; Solal-Celigny, P.; Bouabdallah, R.; Fermé, C.; Christian, B.; Lepage, E.; Tilly, H.; Morschhauser, F.; et al. Long-term results of the R-CHOP Study in the treatment of elderly patients with diffuse large b-cell lymphoma: A study by the Groupe d’Etude des Lymphomes de l’Adulte. J. Clin. Oncol. 2005, 23, 4117–4126. [Google Scholar] [CrossRef] [PubMed]
  25. Wasterlid, T.; Oren Gradel, K.; Eloranta, S.; Glimelius, I.; El-Galaly, T.C.; Frederiksen, H.; Smedby, K.E. Clinical characteristics and outcomes among 2347 patients aged ≥85 years with major lymphoma subtypes: A Nordic Lymphoma Group study. Br. J. Haematol. 2021, 192, 551–559. [Google Scholar] [CrossRef]
  26. Bataillard, E.J.; Cheah, C.Y.; Maurer, M.J.; Khurana, A.; Eyre, T.A.; El-Galaly, T.C. Impact of R-CHOP dose intensity on survival outcomes in diffuse large B-cell lymphoma: A systematic review. Blood Adv. 2021, 5, 2426–2437. [Google Scholar] [CrossRef] [PubMed]
  27. Al-Sarayfi, D.; Brink, M.; Chamuleau, M.E.D.; Brouwer, R.; van Rijn, R.S.; Issa, D.; Deenik, W.; Huls, G.; Mous, R.; Vermaat, J.S.P.; et al. R-miniCHOP versus R-CHOP in elderly patients with diffuse large B-cell lymphoma: A propensity matched population-based study. Am. J. Hematol. 2024, 99, 216–222. [Google Scholar] [CrossRef]
  28. Peyrade, F.; Jardin, F.; Thieblemont, C.; Thyss, A.; Emile, J.-F.; Castaigne, S.; Coiffier, B.; Haioun, C.; Bologna, S.; Fitoussi, O.; et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: A multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011, 12, 460–468. [Google Scholar] [CrossRef]
  29. Peyrade, F.; Bologna, S.; Delwail, V.; Emile, J.F.; Pascal, L.; Fermé, C.; Schiano, J.-M.; Coiffier, B.; Corront, B.; Farhat, H.; et al. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: An open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017, 4, e46–e55. [Google Scholar] [CrossRef]
  30. Pfreundschuh, M.; Trümper, L.; Kloess, M.; Schmits, R.; Feller, A.C.; Rübe, C.; Rudolph, C.; Reiser, M.; Hossfeld, D.K.; Eimermacher, H.; et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: Results of the NHL-B2 trial of the DSHNHL. Blood 2004, 104, 634–641. [Google Scholar] [CrossRef]
  31. Hershman, D.L.; McBride, R.B.; Eisenberger, A.; Tsai, W.Y.; Grann, V.R.; Jacobson, J.S. Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-hodgkin’s lymphoma. J. Clin. Oncol. 2008, 26, 3159–3165. [Google Scholar] [CrossRef]
  32. Luminari, S.; Montanini, A.; Caballero, D.; Bologna, S.; Notter, M.; Dyer, M.J.S.; Chiappella, A.; Briones, J.; Petrini, M.; Barbato, A.; et al. Nonpegylated liposomal doxorubicin (Myocet™) combination (R-COMP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL): Results from the phase II EURO18 trial. Ann. Oncol. 2010, 21, 1492–1499. [Google Scholar] [CrossRef] [PubMed]
  33. Sancho, J.M.; Fernández-Alvarez, R.; Gual-Capllonch, F.; González-García, E.; Grande, C.; Gutiérrez, N.; Peñarrubia, M.; Batlle-López, A.; González-Barca, E.; Guinea, J.; et al. R-COMP versus R-CHOP as first-line therapy for diffuse large B-cell lymphoma in patients ≥60 years: Results of a randomized phase 2 study from the Spanish GELTAMO group. Cancer Med. 2021, 10, 1314–1326. [Google Scholar] [CrossRef] [PubMed]
  34. Rigacci, L.; Annibali, O.; Kovalchuk, S.; Bonifacio, E.; Pregnolato, F.; Angrilli, F.; Vitolo, U.; Pozzi, S.; Broggi, S.; Luminari, S.; et al. Nonpeghylated liposomal doxorubicin combination regimen (R-COMP) for the treatment of lymphoma patients with advanced age or cardiac comorbidity. Hematol. Oncol. 2020, 38, 478–486. [Google Scholar] [CrossRef] [PubMed]
  35. Visco, C.; Pregnolato, F.; Ferrarini, I.; De Marco, B.; Bonuomo, V.; Sbisà, E.; Fraenza, C.; Bernardelli, A.; Tanasi, I.; Quaglia, F.M.; et al. Efficacy of R-COMP in comparison to R-CHOP in patients with DLBCL: A systematic review and single-arm metanalysis. Crit. Rev. Oncol. Hematol. 2021, 163, 103377. [Google Scholar] [CrossRef]
  36. Laribi, K.; Denizon, N.; Bolle, D.; Truong, C.; Besançon, A.; Sandrini, J.; Anghel, A.; Farhi, J.; Ghnaya, H.; de Materre, A.B. R-CVP regimen is active in frail elderly patients aged 80 or over with diffuse large B cell lymphoma. Ann. Hematol. 2016, 95, 1705–1714. [Google Scholar] [CrossRef]
  37. Tucci, A.; Merli, F.; Fabbri, A.; Marcheselli, L.; Pagani, C.; Puccini, B.; Marino, D.; Zanni, M.; Pennese, E.; Flenghi, L.; et al. Diffuse large B-cell lymphoma in octogenarians aged 85 and older can benefit from treatment with curative intent: A report on 129 patients prospectively registered in the elderly project of the fondazione italiana linfomi (FIL). Haematologica 2023, 108, 1083–1091. [Google Scholar] [CrossRef] [PubMed]
  38. Storti, S.; Spina, M.; Pesce, E.A.; Salvi, F.; Merli, M.; Ruffini, A.; Cabras, G.; Chiappella, A.; Angelucci, E.; Fabbri, A.; et al. Rituximab plus bendamustine as front-line treatment in frail elderly (>70 years) patients with diffuse large B-cell non-Hodgkin lymphoma: A phase II multicenter study of the fondazione italiana linfomi. Haematologica 2018, 103, 1345–1350. [Google Scholar] [CrossRef]
  39. Gini, G.; Tani, M.; Bassan, R.; Tucci, A.; Ballerini, F.; Sampaolo, M.; Merli, F.; Re, F.; Olivieri, A.; Petrini, M.; et al. Lenalidomide and rituximab (ReRi) as front-line chemo-free therapy for elderly frail patients with diffuse large b-cell lymphoma. A phase II study of the fondazione italiana linfomi. Blood 2021, 138, 305. [Google Scholar] [CrossRef]
  40. Eyre, T.A.; Martinez-Calle, N.; Hildyard, C.; Eyre, D.W.; Plaschkes, H.; Griffith, J.; Wolf, J.; Fields, P.; Gunawan, A.; Oliver, R.; et al. Impact of intended and relative dose intensity of R-CHOP in a large, consecutive cohort of elderly diffuse large B-cell lymphoma patients treated with curative intent: No difference in cumulative incidence of relapse comparing patients by age. J. Intern. Med. 2019, 285, 681–692. [Google Scholar] [CrossRef]
  41. Verner, E.; Johnston, A.; Pati, N.; Hawkes, E.; Lee, H.-P.; Cochrane, T.; Cheah, C.-Y.; Filshie, R.J.; Purtill, D.; Sia, H.; et al. Efficacy of ibrutinib, rituximab and mini-CHOP in very elderly patients with newly diagnosed diffuse large b cell lymphoma: Primary analysis of the Australasian Leukaemia & Lymphoma Group NHL29 Study. Blood 2021, 138 (Suppl. 1), 304. Available online: https://ashpublications.org/blood/article/138/Supplement%201/304/479579/Efficacy-of-Ibrutinib-Rituximab-and-Mini-CHOP-in (accessed on 29 March 2024).
  42. Jerkeman, M.; Leppä, S.; Hamfjord, J.; Brown, P.; Ekberg, S.; Ferreri, A.J.M. Initial safety data from the phase 3 POLAR BEAR trial in elderly or frail patients with diffuse large cell lymphoma, comparing R-pola-mini-CHP and R-mini-CHOP. In Proceedings of the European Hematology Association 2023 Hybrid Congress, Frankfurt, Germany, 8–11 June 2023. Abstract S227. [Google Scholar] [CrossRef]
  43. Kumar, A.; Fraz, M.A.; Usman, M.; Malik, S.U.; Ijaz, A.; Durer, C.; Durer, S.; Tariq, M.J.; Khan, A.Y.; Qureshi, A.; et al. Treating diffuse large B cell lymphoma in the very old or frail patients. Curr. Treat. Options Oncol. 2018, 19, 50. [Google Scholar] [CrossRef] [PubMed]
  44. Philip, T.; Guglielmi, C.; Hagenbeek, A.; Somers, R.; van der Lelie, H.; Bron, D.; Sonneveld, P.; Gisselbrecht, C.; Cahn, J.-Y.; Harousseau, J.-L.; et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-hodgkin’s lymphoma. N. Engl. J. Med. 1995, 333, 1540–1545. [Google Scholar] [CrossRef] [PubMed]
  45. Gisselbrecht, C.; Glass, B.; Mounier, N.; Gill, D.S.; Linch, D.C.; Trneny, M.; Bosly, A.; Ketterer, N.; Shpilberg, O.; Hagberg, H.; et al. Salvage regimens with autologous transplantation for relapsed large b-cell lymphoma in the rituximab era. J. Clin. Oncol. 2010, 28, 4184–4190. [Google Scholar] [CrossRef] [PubMed]
  46. Chihara, D.; Izutsu, K.; Kondo, E.; Sakai, R.; Mizuta, S.; Yokoyama, K.; Kaneko, H.; Kato, K.; Hasegawa, Y.; Chou, T.; et al. High-dose chemotherapy with autologous stem cell transplantation for elderly patients with relapsed/refractory diffuse large b cell lymphoma: A nationwide retrospective study. Biol. Blood Marrow Transplant. 2014, 20, 684–689. [Google Scholar] [CrossRef]
  47. Davison, K.; Chen, B.E.; Kukreti, V.; Couban, S.; Benger, A.; Berinstein, N.; Kaizer, L.; Desjardins, P.; Mangel, J.; Zhu, L.; et al. Treatment outcomes for older patients with relapsed/refractory aggressive lymphoma receiving salvage chemotherapy and autologous stem cell transplantation are similar to younger patients: A subgroup analysis from the phase III CCTG LY.12 trial. Ann. Oncol. 2017, 28, 622–627. [Google Scholar] [CrossRef]
  48. Munshi, P.N.; Chen, Y.; Ahn, K.W.; Awan, F.T.; Cashen, A.; Shouse, G.; Shadman, M.; Shaughnessy, P.; Zurko, J.; Locke, F.L.; et al. Outcomes of autologous hematopoietic cell transplantation in older patients with diffuse large b-cell lymphoma. Transplant. Cell Ther. 2022, 28, 487.e1–487.e7. [Google Scholar] [CrossRef] [PubMed]
  49. Wudhikarn, K.; Johnson, B.M.; Inwards, D.J.; Porrata, L.F.; Micallef, I.N.; Ansell, S.M.; Hogan, W.J.; Paludo, J.; Villasboas, J.C.; Johnston, P.B. Outcomes of Older Adults with Non-Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation: A Mayo Clinic Cohort Analysis. Transplant. Cell Ther. 2023, 29, 176.e1–176.e8. [Google Scholar] [CrossRef]
  50. Vic, S.; Lemoine, J.; Armand, P.; Lemonnier, F.; Houot, R. Transplant-ineligible but chimeric antigen receptor T-cells eligible: A real and relevant population. Eur. J. Cancer 2022, 175, 246–253. [Google Scholar] [CrossRef]
  51. Neuendorff, N.R.; Khan, A.; Ullrich, F.; Yates, S.; Devarakonda, S.; Lin, R.J.; von Tresckow, B.; Cordoba, R.; Artz, A.; Rosko, A.E. Cellular therapies in older adults with hematological malignancies: A case-based, state-of-the-art review. J. Geriatr. Oncol. 2024, 15, 101734. [Google Scholar] [CrossRef]
  52. Mougiakakos, D.; Voelkl, S.; Bach, C.; Stoll, A.; Bitterer, K.; Beier, F.; Endell, J.; Boxhammer, R.; Bittenbring, J.T.; Mackensen, A.; et al. Mechanistic characterization of tafasitamab-mediated antibody-dependent cellular phagocytosis alone or in combination with lenalidomide. Blood 2019, 134, 4064. [Google Scholar] [CrossRef]
  53. Salles, G.; Duell, J.; Gonzalez-Barca, E.; Tournilhac, O.; Jurczak, W.; Liberati, A.M.; Nagy, Z.; Obr, A.; Gaidano, G.; Andre, M.; et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): A multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020, 21, 978–988. [Google Scholar] [CrossRef] [PubMed]
  54. Duell, J.; Maddocks, K.J.; González-Barca, E.; Jurczak, W.; Liberati, A.M.; de Vos, S.; Nagy, Z.; Obr, A.; Gaidano, G.; Abrisqueta, P.; et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica 2021, 106, 2417–2426. [Google Scholar] [CrossRef]
  55. Zammarchi, F.; Corbett, S.; Adams, L.; Tyrer, P.C.; Kiakos, K.; Janghra, N.; Marafioti, T.; Britten, C.E.; Havenith, C.E.G.; Chivers, S.; et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood 2018, 131, 1094–1105. [Google Scholar] [CrossRef] [PubMed]
  56. Caimi, P.F.; Ai, W.; Alderuccio, J.P.; Ardeshna, K.M.; Hamadani, M.; Hess, B.; Kahl, B.S.; Radford, J.; Solh, M.; Stathis, A.; et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): A multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021, 22, 790–800. [Google Scholar] [CrossRef]
  57. Deeks, E.D. Polatuzumab vedotin: First global approval. Drugs 2019, 79, 1467–1475. [Google Scholar] [CrossRef] [PubMed]
  58. Sehn, L.H.; Herrera, A.F.; Flowers, C.R.; Kamdar, M.K.; McMillan, A.; Hertzberg, M.; Assouline, S.; Kim, T.M.; Kim, W.S.; Ozcan, M.; et al. Polatuzumab vedotin in relapsed or refractory diffuse large b-cell lymphoma. J. Clin. Oncol. 2020, 38, 155–165. [Google Scholar] [CrossRef]
  59. Sehn, L.H.; Hertzberg, M.; Opat, S.S.; Herrera, A.F.; Assouline, S.; Flowers, C.R.; Kim, T.M.; McMillan, A.K.; Ozcan, M.; Safar, V.; et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: Survival update and new extension cohort data. Blood Adv. 2022, 6, 533–543. [Google Scholar] [CrossRef]
  60. Miura, K.; Takahashi, H.; Nakagawa, M.; Hamada, T.; Uchino, Y.; Iizuka, K.; Ohtake, S.; Iriyama, N.; Hatta, Y.; Nakamura, H. Ideal dose intensity of R-CHOP in diffuse large B-cell lymphoma. Expert Rev. Anticancer. Ther. 2022, 22, 583–595. [Google Scholar] [CrossRef] [PubMed]
  61. Jardin, F.; Tilly, H. Chemotherapy-free treatment in unfit patients aged 75 years and older with DLBCL: Toward a new paradigm? Lancet Health Longev. 2022, 3, e453–e454. [Google Scholar] [CrossRef]
  62. Arcari, A.; Cavallo, F.; Puccini, B.; Vallisa, D. New treatment options in elderly patients with Diffuse Large B-cell Lymphoma. Front. Oncol. 2023, 13, 1214026. [Google Scholar] [CrossRef]
  63. Xu, P.-P.; Shi, Z.-Y.; Qian, Y.; Cheng, S.; Zhu, Y.; Jiang, L.; Li, J.-F.; Fang, H.; Huang, H.-Y.; Yi, H.-M.; et al. Ibrutinib, rituximab, and lenalidomide in unfit or frail patients aged 75 years or older with de novo diffuse large B-cell lymphoma: A phase 2, single-arm study. Lancet Health Longev. 2022, 3, e481–e490. [Google Scholar] [CrossRef] [PubMed]
  64. Dickinson, M.J.; Carlo-Stella, C.; Morschhauser, F.; Bachy, E.; Corradini, P.; Iacoboni, G.; Khan, C.; Wróbel, T.; Offner, F.; Trněný, M.; et al. Glofitamab for relapsed or refractory diffuse large b-cell lymphoma. N. Engl. J. Med. 2022, 387, 2220–2231. [Google Scholar] [CrossRef]
  65. Thieblemont, C.; Phillips, T.; Ghesquieres, H.; Cheah, C.Y.; Roost Clausen, M.; Cunningham, D.; Do, Y.R.; Feldman, T.; Gasiorowski, R.; Jurczak, W.; et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large b-cell lymphoma: Dose expansion in a phase I/II trial. J. Clin. Oncol. 2023, 41, 2238–2247. [Google Scholar] [CrossRef] [PubMed]
  66. Budde, L.E.; Assouline, S.; Sehn, L.H.; Schuster, S.J.; Yoon, S.-S.; Yoon, D.H.; Matasar, M.J.; Bosch, F.; Kim, W.S.; Nastoupil, L.J.; et al. Single-agent mosunetuzumab shows durable complete responses in patients with relapsed or refractory b-cell lymphomas: Phase I dose-escalation study. J. Clin. Oncol. 2022, 40, 481–491. [Google Scholar] [CrossRef] [PubMed]
  67. Kim, W.-S.; Kim, T.M.; Cho, S.-G.; Jarque, I.; Iskierka-Jazdzewska, E.; Limei Poon, M.; Prince, H.M.; Oh, S.Y.; Lim, F.; Carpio, C.; et al. Odronextamab in patients with relapsed/refractory (R/R) diffuse large b-cell lymphoma (DLBCL): Results from a prespecified analysis of the pivotal phase II study ELM-2. Blood 2022, 140, 1070–1071. [Google Scholar] [CrossRef]
  68. Locke, F.L.; Miklos, D.B.; Jacobson, C.A.; Perales, M.-A.; Kersten, M.-J.; Oluwole, O.O.; Ghobadi, A.; Rapoport, A.P.; McGuirk, J.; Pagel, J.M.; et al. Axicabtagene ciloleucel as second-line therapy for large b-cell lymphoma. N. Engl. J. Med. 2022, 386, 640–654. [Google Scholar] [CrossRef]
  69. Abramson, J.S.; Solomon, S.R.; Arnason, J.; Johnston, P.B.; Glass, B.; Bachanova, V.; Ibrahimi, S.; Mielke, S.; Mutsaers, P.; Hernandez-Ilizaliturri, F.; et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: Primary analysis of the phase 3 TRANSFORM study. Blood 2023, 141, 1675–1684. [Google Scholar] [CrossRef] [PubMed]
  70. Bishop, M.R.; Dickinson, M.; Purtill, D.; Barba, P.; Santoro, A.; Hamad, N.; Kato, K.; Sureda, A.; Greil, R.; Thieblemont, C.; et al. Second-line tisagenlecleucel or standard care in aggressive b-cell lymphoma. N. Engl. J. Med. 2022, 386, 629–639. [Google Scholar] [CrossRef] [PubMed]
  71. Tucci, A.; Ferrari, S.; Bottelli, C.; Borlenghi, E.; Drera, M.; Rossi, G. A comprehensive geriatric assessment is more effective than clinical judgment to identify elderly diffuse large cell lymphoma patients who benefit from aggressive therapy. Cancer 2009, 115, 4547–4553. [Google Scholar] [CrossRef]
  72. Mohile, S.G.; Dale, W.; Somerfield, M.R.; Schonberg, M.A.; Boyd, C.M.; Burhenn, P.S.; Canin, B.; Cohen, H.J.; Holmes, H.M.; Hopkins, J.O.; et al. Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology. J. Clin. Oncol. 2018, 36, 2326–2347. [Google Scholar] [CrossRef]
  73. Bai, J.-F.; Han, H.-X.; Feng, R.; Li, J.-T.; Wang, T.; Zhang, C.-L.; Liu, H. Comprehensive Geriatric Assessment (CGA): A Simple Tool for Guiding the Treatment of Older Adults with Diffuse Large B-Cell Lymphoma in China. Oncologist 2020, 25, E1202–E1208. [Google Scholar] [CrossRef] [PubMed]
  74. Buske, C.; Hutchings, M.; Ladetto, M.; Goede, V.; Mey, U.; Soubeyran, P.; Spina, M.; Stauder, R.; Trneny, M.; Wedding, U.; et al. ESMO consensus conference on malignant lymphoma: General perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma. Ann. Oncol. 2018, 29, 544–562. [Google Scholar] [CrossRef] [PubMed]
  75. Merli, F.; Luminari, S.; Tucci, A.; Arcari, A.; Rigacci, L.; Hawkes, E.; Chiattone, C.S.; Cavallo, F.; Cabras, G.; Alvarez, I.; et al. Simplified geriatric assessment in older patients with diffuse large b-cell lymphoma: The prospective elderly project of the fondazione italiana linfomi. J. Clin. Oncol. 2021, 39, 1214–1222. [Google Scholar] [CrossRef] [PubMed]
  76. Northend, M.; Wilson, W.; Osborne, W.; Fox, C.P.; Davies, A.J.; El-Sharkawi, D.; Phillips, E.H.; Sim, H.W.; Sadullah, S.; Shah, N.; et al. Results of a United Kingdom real-world study of polatuzumab vedotin, bendamustine, and rituximab for relapsed/refractory DLBCL. Blood Adv. 2022, 6, 2920–2926. [Google Scholar] [CrossRef] [PubMed]
  77. Qualls, D.; Buege, M.J.; Dao, P.; Caimi, P.F.; Rutherford, S.C.; Wehmeyer, G.; Romancik, J.T.; Leslie, L.A.; Merrill, M.H.; Crombie, J.L.; et al. Tafasitamab and lenalidomide in relapsed/refractory large b cell lymphoma (R/R LBCL): Real world outcomes in a multicenter retrospective study. Blood 2022, 140, 787–789. [Google Scholar] [CrossRef]
  78. Yamasaki, S.; Matsushima, T.; Minami, M.; Kadowaki, M.; Takase, K.; Iwasaki, H. Clinical impact of comprehensive geriatric assessment in patients aged 80 years and older with diffuse large B-cell lymphoma receiving rituximab-mini-CHOP: A single-institute retrospective study. Eur. Geriatr. Med. 2022, 13, 195–201. [Google Scholar] [CrossRef] [PubMed]
  79. Lawton, M.P.; Brody, E.M. Assessment of older people: Self-maintaining and instrumental activities of daily living. Gerontologist 1969, 9, 179–186. [Google Scholar] [CrossRef] [PubMed]
  80. Martinez-Tapia, C.; Paillaud, E.; Liuu, E.; Tournigand, C.; Ibrahim, R.; Fossey-Diaz, V.; Culine, S.; Canoui-Poitrine, F.; Audureau, E.; Caillet, P.; et al. Prognostic value of the G8 and modified-G8 screening tools for multidimensional health problems in older patients with cancer. Eur. J. Cancer 2017, 83, 211–219. [Google Scholar] [CrossRef] [PubMed]
  81. Hans, C.P.; Weisenburger, D.D.; Greiner, T.C.; Gascoyne, R.D.; Delabie, J.; Ott, G.; Müller-Hermelink, H.K.; Campo, E.; Braziel, R.M.; Jaffe, E.S.; et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004, 103, 275–282. [Google Scholar] [CrossRef]
  82. Bento, L.; Díaz-López, A.; Barranco, G.; Martín-Moreno, A.M.; Baile, M.; Martín, A.; Sancho, J.M.; García, O.; Rodríguez, M.; Sánchez-Pina, J.M.; et al. New prognosis score including absolute lymphocyte/monocyte ratio, red blood cell distribution width and beta-2 microglobulin in patients with diffuse large B-cell lymphoma treated with R-CHOP: Spanish Lymphoma Group Experience (GELTAMO). Br. J. Haematol. 2020, 188, 888–897. [Google Scholar] [CrossRef]
  83. Hohloch, K.; Ziepert, M.; Truemper, L.; Buske, C.; Held, G.; Poeschel, V.; Chapuy, B.; Altmann, B. Low serum albumin is an independent risk factor in elderly patients with aggressive B-cell lymphoma: Results from prospective trials of the German High-Grade Non-Hodgkin’s Lymphoma Study Group. eJHaem 2020, 1, 181–187. [Google Scholar] [CrossRef]
  84. Ribi, K.; Rondeau, S.; Hitz, F.; Mey, U.; Enoiu, M.; Pabst, T.; Stathis, A.; Fischer, N.; Clough-Gorr, K.M. Cancer-specific geriatric assessment and quality of life: Important factors in caring for older patients with aggressive B-cell lymphoma. Support. Care Cancer 2017, 25, 2833–2842. [Google Scholar] [CrossRef] [PubMed]
  85. Go, S.-I.; Park, S.; Kang, M.H.; Kim, H.-G.; Kim, H.R.; Lee, G.-W. Clinical impact of prognostic nutritional index in diffuse large B cell lymphoma. Ann. Hematol. 2019, 98, 401–411. [Google Scholar] [CrossRef] [PubMed]
  86. Pergolotti, M.; Deal, A.M.; Williams, G.R.; Bryant, A.L.; Bensen, J.T.; Muss, H.B.; Reeve, B.B. Activities, function, and health-related quality of life (HRQOL) of older adults with cancer. J. Geriatr. Oncol. 2017, 8, 249–254. [Google Scholar] [CrossRef]
  87. Mizutani, T.; Nakamura, K.; Fukuda, H.; Ogawa, A.; Hamaguchi, T.; Nagashima, F.; Geriatric Study Committee/Japan Clinical Oncology Group. Geriatric Research Policy: Japan Clinical Oncology Group (JCOG) policy. Jpn. J. Clin. Oncol. 2019, 49, 901–910. [Google Scholar] [CrossRef] [PubMed]
  88. Yamasaki, S. Feasibility of Quality of Life Assessment in Patients with Lymphoma Aged ≥80 Years Receiving Reduced-Intensity Chemotherapy: A Single-Institute Study. Hematol. Rep. 2023, 16, 1–10. [Google Scholar] [CrossRef] [PubMed]
  89. Hormigo-Sanchez, A.I.; Lopez-Garcia, A.; Mahillo-Fernandez, I.; Askari, E.; Morillo, D.; Perez-Saez, M.A.; Riesco, M.; Urrutia, C.; Martinez-Peromingo, F.J.; Cordoba, R.; et al. Frailty assessment to individualize treatment in older patients with lymphoma. Eur. Geriatr. Med. 2023, 14, 1393–1402. [Google Scholar] [CrossRef] [PubMed]
  90. Westin, J.; Davis, R.E.; Feng, L.; Hagemeister, F.; Steiner, R.; Lee, H.J.; Fayad, L.; Nastoupil, L.; Ahmed, S.; Rodriguez, A.; et al. Smart start: Rituximab, lenalidomide, and ibrutinib in patients with newly diagnosed large b-cell lymphoma. J. Clin. Oncol. 2023, 41, 745–755. [Google Scholar] [CrossRef]
  91. Olszewski, A.J.; Avigdor, A.; Babu, S.; Levi, I.; Eradat, H.; Abadi, U.; Holmes, H.; McKinney, M.; Woszczyk, D.; Giannopoulos, K.; et al. Mosunetuzumab monotherapy continues to demonstrate promising efficacy and durable complete responses in elderly/unfit patients with previously untreated diffuse large b-cell lymphoma. Blood 2022, 140, 1778–1780. [Google Scholar] [CrossRef]
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Figure 1. My approach to older patients with DLBCL. DLBCL, diffuse large B-cell lymphoma; CGA, comprehensive geriatric assessment; QoL, quality of life; PET, positron emission tomography.
Figure 1. My approach to older patients with DLBCL. DLBCL, diffuse large B-cell lymphoma; CGA, comprehensive geriatric assessment; QoL, quality of life; PET, positron emission tomography.
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Figure 2. Paradigm shift in lymphoma treatment in the older population. QoL, quality of life.
Figure 2. Paradigm shift in lymphoma treatment in the older population. QoL, quality of life.
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Table 1. First-line immunochemotherapy regimens for older patients with DLBCL.
Table 1. First-line immunochemotherapy regimens for older patients with DLBCL.
Therapy TypeAgeDevelopment StatusReference(s)
R-CHOP60–80 yearsPhase 3 trialCoiffier et al., 2002 [1]
R-mini-CHOP≥80 yearsPhase 2 trialPeyrade et al., 2011 [28]
Peyrade et al., 2017 [29]
Pola-R-CHP<80 yearsPhase 3 trialTilly et al., 2022 [5]
Pola-R-mini-CHP≥80 years or frail patients aged ≥75 yearsPhase 3 trial, ongoingClinicalTrials.gov
Identifier: NCT04332822
Abbreviations: DLBCL, diffuse large B-cell lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-mini-CHOP, attenuated-dose R-CHOP; Pola-R-CHP, of vincristine with polatuzumab vedotin (Pola), an antibody-drug-conjugated targeting CD79b, in the R-CHOP scheme.
Table 2. New, novel, and chemotherapy-free regimens.
Table 2. New, novel, and chemotherapy-free regimens.
Therapy TypeExample(s)Development StatusReference(s)
BTK inhibitorIbrutinibPhase 2 trialXu et al., 2022 [63]
Tafa-LenTafa-LenPhase 2 trialSalles et al., 2020 [53]
Duell et al., 2021 [54]
CD19 antibody–drug conjugateLoncaPhase 2 trialCaimi et al., 2021 [55]
Bispecific antibodyGlofitamab
Epcoritamab		Phase 2 trialDickinson et al., 2022 [64]
Thieblemont et al., 2023 [65]
CAR T-cellsAxi-cel
Liso-cel
Tisa-cel		Phase 3 trialCocke et al., 2022 [68]
Abramson et al., 2022 [69]
Bishop et al., 2022 [70]
Abbreviations: BTK, Bruton’s tyrosine kinase; Tafa, tafasitamab; Len, lenalidomide; Lonca, loncastuximab; CAR, chimeric antigen receptor.
Table 3. Evaluation of frailty in older patients.
Table 3. Evaluation of frailty in older patients.
Assessment ToolKey ParametersBenefitsLimitations
Comprehensive geriatric assessmentADL, IADL, CCI, CIRS-GRecommended by ASCO (Mohile et al., 2018 [72])Complexity, time (Moccia and Thieblemont, 2018 [17])
Simplified geriatric assessment (Merli et al., 2021 [75])ADL, IADL, age, (≥80 years), CIRS-G, IPI, hemoglobinOS, CR rate (Bai et al., 2020 [73])Complexity
IADL (Lawton and Brody, 1969 [79])IADLPredicts OS with R-mini-CHOP therapy (Yamasaki et al., 2022 [78])Reproducibility
G8 screening test (Martinez-Tapia et al., 2017 [80])G8OS, treatment toxicityReproducibility
Age, comorbidities, albumin index, and IADL (Hohloch et al., 2020 [83])Age, CCI, albumin (≤3.5 g/dL)OS, mean chemotherapy dose, treatment toxicity, treatment-related toxicityReproducibility
Vulnerable elders survey-13 (Ribi et al., 2015 [84])Vulnerable elders survey-13OS, response rateReproducibility
Prognostic nutritional index (Go et al., 2019 [85])Prognostic nutritional indexOSReproducibility
Abbreviations: ADL, activities of daily living; CCI, Charlson comorbidity index; ASCO, American Society of Clinical Oncology; CIRS-G, Cumulative Illness Rating Scale for Geriatrics; IADL, Instrumental Activities of Daily Living; MCIRS-G, modified CIRS-G; OS, overall survival; IPI, international prognostic index.
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Yamasaki, S. Appropriate Treatment Intensity for Diffuse Large B-Cell Lymphoma in the Older Population: A Review of the Literature. Hematol. Rep. 2024, 16, 317-330. https://doi.org/10.3390/hematolrep16020032

AMA Style

Yamasaki S. Appropriate Treatment Intensity for Diffuse Large B-Cell Lymphoma in the Older Population: A Review of the Literature. Hematology Reports. 2024; 16(2):317-330. https://doi.org/10.3390/hematolrep16020032

Chicago/Turabian Style

Yamasaki, Satoshi. 2024. "Appropriate Treatment Intensity for Diffuse Large B-Cell Lymphoma in the Older Population: A Review of the Literature" Hematology Reports 16, no. 2: 317-330. https://doi.org/10.3390/hematolrep16020032

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