Peripheral T-cell lymphoma in older patients: a narrative review of initial and subsequent treatments and clinical outcomes

Introduction

Recent advances in the understanding of the pathobiology of mature T-cell and NK-cell neoplasms (MTNKNs) have improved the classification of these rare diseases. The 2022 Internal Consensus Criteria and World Health Organization Classification of Haematolymphoid Tumours, 5th edition refined the number of subtypes that are recognized to no fewer than 35 distinct entities (1,2). The median age of diagnosis is typically in the 6th decade of life, with some variability depending upon subtype or geographic location (3). Current guidelines recommend early clinical trial enrollment, if available, or initial treatment with intensive cytotoxic chemotherapy for fit patients. However, the advanced age at which most patients are diagnosed presents unique challenges when treating older patients with MTNKN. Patient comorbidities and toxicities associated with cytotoxic chemotherapy mean that these patients are often not candidates to receive curative-intent chemotherapy and are also ineligible for clinical trial enrollment. We present this article in accordance with the Narrative Review reporting checklist (available at https://aol.amegroups.com/article/view/10.21037/aol-23-18/rc).

Methods

This is a retrospective narrative review describing treatment strategies and clinical outcomes in older patients with peripheral T-cell lymphoma (PTCL), which are referred to here as the MTNKNs in accordance with the World Health Organization Classification of Haematolymphoid Tumours, 5th edition. As summarized in Table 1, we developed a comprehensive search strategy to identify original research articles pertaining to the topic of interest. Medical Subject Headings (MeSH) terms were used to query the largest medical subject databases, including Wiley, EMBASE, PubMed/MEDLINE, Cochrane Library, and Clinical Key. Articles were selected for review by the study authors if written in English and published after January 1, 1990. Specific areas of focus during data extraction included study characteristics and study design, patient demographics (including age, gender, disease histology), treatment regimens, and clinical outcome measures [including overall response rates (ORRs), progression-free survival (PFS), overall survival (OS), and adverse events (AEs)]. A narrative approach was used to summarize extracted data.

Discussion

General approach and special considerations in the treatment of older patients with MTNKN

Randomized data supporting an optimal treatment approach in older patients with MTNKN are limited. This stands in contrast to other more common lymphoid malignancies, such as diffuse large B-cell lymphoma (DLBCL), where randomized trials involving only older patients have shaped treatment guidelines in this high-risk population. Comprehensive geriatric assessment (GA) tools have been developed to identify oncology patients at increased risk of adverse outcomes (4). Most have been studied or adapted for use in patients with non-Hodgkin lymphoma (NHL), most commonly DLBCL. Shared among these is an assessment of a recurring set of functional and psychosocial domains that is used to characterize a patient’s “fitness” to receive cancer-directed therapy. As illustrated in Table 2, patients with MTNKN are under-represented or absent in most studies on GA tools (5-14). Moreover, many of these studies included patients who were treated only in the front-line setting with cytotoxic chemotherapy alone, thereby raising questions regarding their utility in patients treated in relapsed/refractory (R/R) settings or with novel or targeted agents.

In 2018, the American Society of Clinical Oncology (ASCO) released inaugural guidelines for the care of older patients with cancer. The original guidelines called for the use of a comprehensive GA to “identify vulnerabilities that are not routinely captured in oncology assessments”, while noting that evidence “supports an assessment of function, comorbidity, falls, depression, cognition, and nutrition” (15). These recommendations were refined in 2023 to reflect that all cancer patients ≥65 years old with GA-identified impairments “should have GA-guided management included in their care plan” (16). This update also emphasized that any assessment should include aging-related domains known to be associated with clinical outcomes in older patients, including physical and cognitive function, emotional health, comorbidities, polypharmacy, nutrition, and social support. The Practical Geriatric Assessment (PGA) is recommended as one such GA tool for routine clinical use. In addition, sarcopenia is increasingly recognized as an important predictor of adverse clinical outcomes in oncology patients receiving systemic therapies. Various definitions and measures of sarcopenia have been proposed, but in general sarcopenia refers to the progressive loss of lean muscle mass and muscle function related to aging (17). A prior meta-analysis by Surov et al. demonstrated that sarcopenia is associated with lower OS in patients with DLBCL [simple regression: hazard ratio (HR) =3.05, P<0.001] (18). The prognostic significance of sarcopenia in patients with MTNKN is poorly defined. A recent retrospective study examining the impact of sarcopenia (as defined by MRI-based assessment of masticatory muscle index) in patients with extra-nodal NK/T-cell lymphoma (ENKTL), nasal type is one of few studies to address this (19). This study demonstrated that the presence of sarcopenia was negatively associated with OS (HR =4.59, P=0.003) and PFS (HR =3.048, P=0.002) on multivariate analysis. Interestingly, age >60 vs. ≤60 years was associated with OS on univariate analysis (HR =2.398, range, 1.105–5.204, P=0.03) but not on multivariate analysis (HR =1.73, range, 0.737–4.095, P=0.12), suggesting that other factors beyond age alone were contributing to worse outcomes in older patients. Although limited by its retrospective nature and potential for selection bias, these findings suggest that sarcopenia may be an important prognostic factor in ENKTL patients and potentially other MTNKN subtypes as well. Practical approaches to assess sarcopenia are increasingly being explored in patients with hematologic malignancies. The Timed Up and Go (TUG) Test¹ is one such low-cost, easily administrable test (20). Data presented at the 2023 American Society of Hematology annual meeting highlighted the role of the TUG test in predicting severe toxicity in older NHL patients receiving systemic chemotherapy (21). Most patients had DLBCL (72%), but a small proportion (2%) had angioimmunoblastic T-cell lymphoma (AITL). Patients with abnormal TUG scores prior to treatment initiation experienced a higher incidence of severe toxicity than patients with normal TUG scores (72% vs. 51%, P=0.01), highlighting the potential role of this functional test in treatment planning among older patients.

In the absence of randomized studies to guide treatment decisions, the approach to older patients is like the approach to younger patients, but with important considerations that must be taken into account. Most notably, both extremes of age and increasing comorbidity burden have been repeatedly shown be associated with inferior outcomes in large registry studies (22-24). Retrospective data from the Swedish Lymphoma Registry (SLR) and California Cancer Registry (CCR) provide some of the earliest robust evidence for the inferior outcomes of older patients with extensive comorbidities (23). Among 775 patients in the CCR/SLR who were ≥70 years old and received multi-agent therapy, median OS rates were 18.3, 14.4, and 9.2 months for patients with Charlson Comorbidity Index (CCI) scores of 0, 1, or >1, respectively (P<0.001). Furthermore, multivariate analysis showed worse survival outcomes for patients (regardless of treatment modality) who were 75–84 vs. 70–74 years old (HR =1.32, P<0.001) and 85+ vs. 70–74 years old (HR =1.41, P<0.001). Very similar findings were recently reported in a retrospective review of patients from the United States Surveillance, Epidemiology, and End Results (SEER)-Medicare database (25). This large cohort (n=2,546) of exclusively older patients (median age 77 years old; range, 77–81) included a diverse mixture of MTNKN subtypes. Among patients who received first-line treatment, multivariate analysis showed worse OS for patients who were 76–80 (HR =1.30, P=0.008), 81–85 (HR =1.66, P<0.001), and ≥86 (HR =2.36, P<0.001) years old compared to patients who were 66–70 years old. Multivariate analysis also showed that presence of comorbidities was negatively associated with OS (CCI =1 vs. CCI =0, HR =1.23, P=0.01; CCI ≥2 vs. CCI =0, HR =1.34, P<0.001). Interestingly, male vs. female sex (HR =1.16, P=0.04) and residence within higher income census tracts were associated with better OS outcomes. The improved outcomes seen in higher earning patients were hypothesized to be due to higher rates of CHOEP (cyclophosphamide, hydroxydaunorubicin, oncovin, etoposide, prednisone) usage and stem-cell transplantation in this group. The negative impact of comorbidity burden on treatment outcomes in older patients cannot be understated, as prior studies have also shown increasing comorbidity burden to be correlated with lower probability of receiving intensive therapy. Another striking finding from the SLR and CCR is that ~43% of patients received no treatment at all. This compares similarly to the ~40% of patients in the SEER-Medicare database who also were reported to have received no treatment. Whether or not this is due to delayed diagnosis, which may have a disproportionately negative impact on older patients compared to younger patients due to lower physiologic reserve, or other cancer-specific factors in older patients remains unclear. Furthermore, as shown in Figure 1, a significant decline in treatment rates has been observed in older U.S. patients who experience disease progression following first-line therapies (25). Such trends highlight a persistent unmet need and area of opportunity for improvement in older patients. Unsurprisingly, it has been shown that outcomes in older patients treated with curative-intent chemotherapy are significantly better than those treated with palliative-intent chemotherapy. In a sub-analysis of 246 patients >70 years old from the International T-cell Lymphoma Project, median OS for patients treated with curative vs. palliative intent chemotherapy was 59 months compared with 4.7 months (P=0.001), and median PFS for patients treated with curative vs. palliative intent chemotherapy was 37 months compared with 3.7 months (P=0.004) (26). This stark difference highlights the critical importance of assessing older patients’ fitness to receive intensive chemotherapy with curative intent, and considering early enrollment in clinical trials or treatment with novel agents whenever possible for those patients unfit to receive curative-intent therapies.

Figure 1 Proportion of US patients >65 years old who received first-, second-, and third-line treatments in a retrospective review of the SEER-Medicare database (n=2,546) (25). SEER, Surveillance, Epidemiology, and End Results.

Key points

• Comprehensive GA tools can identify older patients with MTNKN who are at increased risk for adverse clinical outcomes. However, most of these tools have been validated in patients with hematologic malignancies other than MTNKN.
• Extremes of age and increasing comorbidity burden are associated with worse survival outcomes among older patients with MTNKN.
• On average, up to 40% of older patients with the most common nodal MTNKN subtypes (i.e., PTCL-NOS, ALCL, AITL, TFh-PTCL) will never receive cancer-directed therapies for their disease.
• Increased treatment intensity is associated with improved survival outcomes in older patients.

Management of fit patients in the front-line setting

Following the completion of a comprehensive GA, the next crucial step is to define the intent of treatment. For fit patients, treatment with anthracycline-based regimens (i.e., CHOP² or CHOP-like) has remained a standard of care, curative-intent approach for most MTNKN subtypes since the original study by Fisher et al. in 1993 (27). This study notably included only ~25% of patients who were ≥65 years old and relied upon the now outdated working group classification from the Non-Hodgkin’s Lymphoma Pathologic Classification Project (28). As summarized in Table 3 and Figure 2, several retrospective registry studies have since been published describing treatment outcomes of older patients treated with CHOP or CHOP-like chemotherapy, with each containing a heterogeneous mixture of subtypes and chemotherapy regimens. The German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) published one of the earliest such reviews (29). A total of 96 patients >60 years old with MTNKN were analyzed who were treated with chemotherapy. A key finding was that in patients <60 years old the addition of etoposide to CHOP-21 or CHOP-14 significantly improved response rates and 3-year event-free survival (EFS) (75.4% vs. 51.0%, P=0.003), but did not improve OS (P=0.18). However, in older patients, the addition of etoposide to CHOP (CHOEP) did not improve EFS or OS. The incorporation of etoposide into CHOP-based regimens has since remained an acceptable approach for young, fit patients with most nodal subtypes other than systemic anaplastic large T-cell lymphoma (ALCL). However, for older patients such an approach should be considered on a case-by-case basis that carefully considers the patient’s overall fitness and ability to tolerate intensive chemotherapy. In the retrospective analysis of US patients by Gordon et al., treatment with CHOEP compared to CHOP showed a nonsignificant trend toward improved OS [HR =0.78, 95% confidence interval (CI): 0.54–1.11] (25). However, sensitivity analysis of patients with no comorbidities (CCI score =0) did show an association with improved OS among those who received CHOEP compared to CHOP (HR =0.52, 95% CI: 0.30–0.91). The Hematology Association of South East Korea (HASEK) published a similar review examining outcomes of 81 patients ≥60 years old who were treated with CHOP or CHOP-like chemotherapy between 2001 and 2014 (30). Median age was 71 (range, 60–88) years and a majority (80.2%) of patients had stage III/IV disease. Among treated patients, approximately 84% received an anthracycline-containing regimen. An ORR of 70.2% was observed [complete response (CR) 37.8%, partial response (PR) 32.4%] for patients treated with chemotherapy with an estimated 5-year OS rate of 45.9%. Median PFS and OS of all patients were 7.3 and 21.9 months, respectively. Extreme age (≥80 years old, HR =5.60, P=0.006) and increased comorbidity burden (CCI ≥3, HR =2.24, P=0.03) were associated with inferior survival. In 2019 the Thai Lymphoma Study Group (TLSG) also published similar findings in their registry of 127 patients ≥60 years old who were treated between 2007 and 2014 (22). In contrast to the HASEK registry, the TLSG included patients with ENKTL (21%) in addition to other PTCL subtypes (79%). Out of 127 total patients, 103 (81.1%) received at least one modality of therapy, with 76% receiving chemotherapy, 13.4% receiving radiotherapy, and 8.6% receiving combined chemotherapy and radiation. Two-year PFS and OS for the entire cohort were 38.1% and 48.5%, respectively. Patients who received intensive chemotherapy had longer PFS and OS than patients who received less intensive chemotherapy or best supportive care alone (2-year PFS 41.7% vs. 33.8%, P=0.05; 2-year OS 54.3% vs. 39.1%, P=0.01). Multivariate analysis showed that absence of intensive multi-agent chemotherapy, age >75, and poor Eastern Cooperative Oncology Group (ECOG) status were each associated with significantly worse PFS and OS. Finally, a larger review published by UCLA and Skane University Hospital produced similar findings to those seen in the previous studies (23). In this review, 891 patients ≥70 years old (median age 77) diagnosed with primarily nodal MTNKN subtypes between January 2010 and December 2015 were identified from the SLR and CCR. Treatment data were available for 98% of patients, with 47% of patients receiving multiagent treatment, 5.8% receiving single-agent treatment, 2.6% receiving unspecified chemotherapy, and 43% receiving no treatment. Median OS for all patients was 9 months. An ORR of 55% was noted among 87 patients within the SLR, with 43.7% achieving complete remission and 11.5% achieving partial remission. Overall prognosis was poor and increasing comorbidity burden and age were associated with worse survival. Like other registry studies, multivariate analysis demonstrated a negative association between advanced disease stage and extremes of age with OS.

Figure 2 Representation of various MTNKN subtypes in registry studies of older patients (22,23,25,30). TLSG, Thai Lymphoma Study Group; HASEK, Hematology Association of South East Korea; SLR, Swedish Lymphoma Registry; CCR, California Cancer Registry; SEER, Surveillance, Epidemiology, and End Results; PTCL, peripheral T-cell lymphoma; NOS, not otherwise specified; AITL, angioimmunoblastic T-cell lymphoma; ENKTL, extra-nodal NK/T-cell lymphoma.

The sub-optimal long-term results of standard-dose CHOP seen in most MTNKN subtypes have led to the augmentation of anthracycline-based regimens through the addition of novel or targeted agents. The ECHELON-2 trial is the largest prospective, randomized front-line trial ever conducted where such an approach was adopted (31). Patients with treatment-naïve, CD30 positive MTNKN³ were randomized to receive six or eight 21-day cycles of either Bv in combination with cyclophosphamide, doxorubicin, prednisone (Bv-CHP) or CHOP. Although not exclusively limited to older patients [median age 58 years, interquartile range (IQR) 45–67 years], a substantial proportion (n=139, 31%) was ≥65 years old. Updated 5-year analysis of ECHELON-2 has confirmed a continued benefit of Bv-CHP over CHOP, with patients more than 65 years old having a significant improvement in OS (HR =0.62, range, 0.39–0.98). However, it is important to note that subgroup analyses have shown the survival benefit to be driven largely by the benefit seen in patients with systemic ALCL who comprised ~70% of patients enrolled in both study arms. Considering this, many experts feel that the benefit of adding Bv to CHOP in subtypes other than ALCL is not definitive. Older patients with non-ALCL subtypes can thus reasonably be offered CHOP as initial induction therapy, however routine incorporation of Bv into frontline chemotherapy remains a standard of care for all patients, irrespective of age, with ALCL. In contrast to the encouraging results seen with Bv-CHP in ECHELON-2, the addition of other novel or targeted agents to anthracycline-based chemotherapy has often produced unsatisfactory results, particularly among older patients. The efficacy of adding the anti-CD52 monoclonal antibody, alemtuzumab, to CHOP in the front-line setting was evaluated in the ACT-2 trial (32). In this randomized, phase 3 trial, 116 patients aged 61–80 (median age 69 years) were randomized 1:1 to receive 6 cycles of CHOP (CHOP-14) or alemtuzumab plus CHOP (A-CHOP). After median follow up of 54 months, the primary endpoint of EFS was not met (3-year EFS 27% in A-CHOP arm vs. 24% in CHOP-14 arm, P=0.25). Failure to meet the primary endpoint was at least partially attributed to the increased toxicity of A-CHOP as the incidence of grade 3–4 hematologic AEs was higher along with the number of grade 3 or higher infections (40% vs. 21%, P=0.03), highlighting the critical importance of balancing treatment efficacy with tolerability in older patients. The role of the class I selective histone deacetylase (HDAC) inhibitor, romidepsin, in combination with CHOP was similarly evaluated in a randomized phase 3 trial (33). In this open-label study, 421 patients with previously untreated MTNKN⁴ were randomly assigned in a 1:1 ratio to receive romidepsin plus CHOP (Ro-CHOP) or CHOP alone. Median age was 65 years, and most patients (n=276, 65.6%) were >60 years old. Randomization was stratified by both International Prognostic Index (IPI) and age (≤60 vs. >60 years), ensuring that older patients were equally represented in both arms. After a median follow up of 27.5 months, the primary end point of PFS was not met, and median PFS for Ro-CHOP vs. CHOP was 12.0 vs. 10.2 months, respectively (P=0.10). In the Ro-CHOP vs. CHOP arms, the median OS for all patients, regardless of age, was 51.8 vs. 42.9 months and the ORR was 63% vs. 60% with CR plus unconfirmed CR rates of 41% vs. 37% (P>0.1 in all comparisons), respectively. Initial subgroup analysis showed no difference in PFS outcomes for patients >60 years old in the overall study population. Accelerated approval status for romidepsin was subsequently withdrawn by the Food and Drug Administration (FDA) in the United States in May 2022. Despite this, romidepsin continues to be used off-label or in clinical trials in the absence of other more efficacious agents and remains a reasonable option for older patients with R/R disease. Interestingly, a more recent post hoc analysis of the Ro-CHOP study subsequently confirmed a PFS benefit among patients with TFh-like PTCL who received Ro-CHOP vs. CHOP (median PFS 19.5 vs. 10.6 months, respectively, HR =0.703, P=0.04) (34). Subgroup analysis of TFh-like PTCL patients who were ≤60 and >60 years old also suggested a possible trend toward improved 2-year PFS among older patients, but this did not meet the specified boundary for significance (HR =0.705, 95% CI: 0.48–1.05). Another epigenetic modifier, 5-azacitidine, has also been evaluated in combination with CHOP in patients with treatment-naïve disease (35). This single-arm, phase 2 study included a total of only 21 patients with median age 66 (including ~57% who were ≥65 years old) and was enriched for patients with PTCL with T-follicular helper (TFh) phenotype (17/21 or 81% of patients). Although no age-specific analysis was performed, an impressive CR rate of 75% was observed, with corresponding 2-year PFS and OS rates of 65.8% and 68.4%, respectively. No treatment-related deaths occurred and treatment was well tolerated, with all patients able to tolerate standard dose CHOP. Additional clarity on the effectiveness of 5-azacitidine in combination with CHOP as initial therapy for PTCL is forthcoming from an ongoing randomized phase 2 trial (ClinicalTrials.gov #NCT04803201), which is a 3-arm study comparing CHOP to duvelisib + CHOP or 5-azacitidine + CHOP in treatment-naïve patients (36).

Key points

• Fit, older patients with the most common MTNKN subtypes (excluding ALCL) should be preferentially offered clinical trial enrollment, where available, or maximum-intensity treatment with CHOP or a CHOP-like regimen in the front-line setting.
• Fit, older patients with ALCL should be preferentially offered Bv-CHP as initial therapy.
• Intensification of CHOP with etoposide improves outcomes in younger patients based on retrospective data.
• Among older patients, the incorporation of etoposide into CHOP-based regimens should preferentially be considered in patients with limited or no comorbidities who have been adequately assessed to be fit by comprehensive GA, and these patients should be closely monitored for treatment-related toxicities.
• Except for brentuximab-vedotin in ALCL, the addition of other novel or targeted agents to CHOP, including alemtuzumab and romidepsin, has not improved outcomes in older patients compared to treatment with CHOP alone.
• Post hoc analysis of the randomized Ro-CHOP trial has shown a PFS benefit in patients with TFh-like PTCL who received Ro-CHOP, suggesting that the biology of this subtype should be considered in future trial designs. Older patients with TFh-like PTCL showed a non-significant trend toward greater benefit than younger patients.

Management of fit patients in the R/R setting

To improve upon the efficacy of novel agents used as monotherapy, increased attention is being given to the identification of combinations that synergistically expand upon the activities of those agents. Response rates approaching 50–60% or higher with select combinations have been observed (see Table 4). The median age of study subjects is often in the 6th decade of life, with several studies enrolling patients in their 80s, highlighting the potential for these agents to be safe and effective even at extremes of age. The combination of 5-azacitidine and romidepsin warrants particular attention. The results of both a phase 2 trial and a real-world retrospective case series have demonstrated encouraging results (42,45). In the phase 2 trial, a total of 25 patients with treatment-naïve and R/R disease were enrolled. Median age was 63 years (range, 42–88 years) and the study was enriched for patients with TFh phenotype (17/25 or 68% classified as AITL or PTCL-TFh). An ORR of 61% (CR rate 43%) was observed among treated patients, leading to median PFS of 8.0 months and median OS not reached (42). The results of this phase 2 study compare similarly to a retrospective review of real-world usage of the combination in patients treated outside of a trial setting (45). In the real-world study, an ORR of 76.9% and CR rate of 53% were observed among evaluable patients. This included 4 patients >60 years old who achieved CR and who underwent consolidative HSCT, including 3 who underwent allogeneic stem cell transplantation (allo-SCT). The tolerability of 5-azacitidine and romidepsin in combination among reported patients distinguishes it from many of the other combinations listed in Table 4 (37-45). Dose reductions or treatment discontinuation occurred in only 28% and 4% of patients in the phase 2 study, respectively. Furthermore, despite including 33% of patients with reduced performance status (ECOG 2–3), treatment discontinuation occurred in only 7.4% of patients in the real-world study. The most common grade 3–4 toxicities seen in the phase 2 study included thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), which were similar to the most common toxicities reported in the real-world study. In other studies that have examined combinatorial approaches, the rates of grade 3–4 AEs in patients treated with the combinations of romidepsin/duvelisib, romidepsin/lenalidomide, and panobinostat/bortezomib were 65%, 71%, and 78%, respectively; while these numbers do not reflect the true rate of toxicity in older patients alone, the fact that such high rates were observed in studies that included younger patients highlights a key challenge of treating older patients with combinatorial approaches—the added toxicity. A randomized, phase 2B study comparing the combination of 5-azacitidine/romidepsin vs. investigator’s choice (single agent romidepsin, pralatrexate, gemcitabine, belinostat) in R/R MTNKN is ongoing, and the results of this will provide further clarity on both the safety and efficacy of this combination (ClinicalTrials.gov #NCT04747236). More recently, the benefit of adding Bv to bendamustine has also been described in a multicenter, retrospective review of 82 patients with R/R MTNKN (46). Median age was 60 years (range, 25–85 years), with ~39% of patients >60 years and ~15% of patients >70 years old. Nearly all (96%) patients had received prior treatment with a CHOP-based regimen. An ORR of 68% was observed, with CR rate of 49%, resulting in median PFS and OS of 8.3 and 26.3 months, respectively. Univariate analysis showed no difference in response rates between patients ≤60 and >60 years old (OR 1.13, P=0.82). These results suggest a potential role for this regimen to act as bridging therapy in older patients who have progressed after prior anthracycline-based chemotherapy, but who otherwise remain fit enough for consideration of intensive therapy and even hematopoietic stem cell transplantation (HSCT).

In most cases the evidence supporting the use of these novel agents in combination comes from small, phase 1/2 studies which did not include comparator arms and which also included patients <60 years old. Several other novel agents with significant activity remain in clinical development with promising early results. Discussion of each goes beyond the aim of this review, however it is important to note that older patients remain under-represented in clinical trials due to comorbidities and overall performance status. Nevertheless, these agents with favorable toxicity profiles and potential synergistic activity hold the promise of a better therapeutic landscape for older patients.

Key points

• Fit patients with R/R MTNKN should be preferentially offered clinical trial enrollment when available.
• Combinatorial approaches with novel or targeted agents are the subject of intense investigation, and may represent safe and effective options for older patients who have progressed after intensive cytotoxic chemotherapy but who remain fit for more intensified regimens.
• The optimal sequencing of therapies for R/R disease in older patients who remain fit for intensive therapy is not well-defined, and the choice of agent is guided by disease subtype, patient comorbidities, and provider experience with managing toxicities.

Management of less fit patients in front-line or R/R settings

The treatment of older patients who are not fit to receive standard-dose anthracycline-based therapies, either because of comorbidities or overall performance status, represents a particular challenge. A small number of limited case series or early-phase trials have explored anthracycline-free or dose-reduced chemotherapy approaches (Table 5), and most of these studies were enriched for patients >60 years old (47-50). A dose-attenuated CHOP regimen⁵ has been described in a case series of 44 patients >70 years old or 65–70 years old with comorbidities precluding treatment with standard CHOP (49). Among 35 evaluable patients, an ORR of 61.4% was reported (CR 47.7%, PR 13.7%) with median PFS and OS of 8.2 and 11.7 months, respectively. Rates of hematologic toxicity were comparatively high and 44.2% of patients required dose reductions; whether further dose reduction could ameliorate toxicity without compromising efficacy is unknown. An alternative gemcitabine-based regimen, GemOD⁶ produced an ORR of 25% in a prospective series of 31 patients (all over 60 years old) with R/R MTNKN (47). Importantly, only 25% of patients experienced treatment delays due to myelosuppression and no treatment-related deaths occurred. The efficacy of single-agent bendamustine was evaluated in a retrospective study of 138 patients with primarily R/R AITL and PTCL-NOS (48). In this study, PFS with bendamustine was similar among patients <65 and ≥65 years of age (P=0.64). Interestingly, among 22 patients ≥75 (representing 16% of the overall cohort), an ORR of 50% (CR 28%, PR 22%) was observed, with median duration of response (DOR) of 5.9 months, suggesting that single-agent bendamustine can be used even at extremes of age with careful attention to dosing and toxicity monitoring. The efficacy of DEVEC (Deltacortene^®, etoposide, vinorelbine, cyclophosphamide), an all-oral, metronomic regimen, has also been described in a study of 17 older patients with both treatment-naïve and R/R disease (50). ORRs were 80% and 58% in patients with treatment-naive and R/R disease, respectively, with CR achieved in 1/5 (20%) of patients with treatment-naive disease and 3/12 (25%) in patients with R/R disease. In this highly selected cohort, median PFS was 20 and 11 months in patients with treatment-naïve and R/R disease, respectively. In highly selected patients, an oral, metronomic regimen thus could offer palliative benefit to less fit patients.

The disappointing results of chemotherapy in patients with T-cell lymphomas compared to the results achieved in patients with B-cell lymphomas can be attributed to the intrinsic chemo-resistance of the malignant cells and the indiscriminate translation of B-cell treatment approaches to T-cell malignancies without consideration of the disease-specific pathobiology. Therefore, the development of novel therapeutics for MTNKN is critical. The recognition that mutations in key epigenetic regulators contribute to the pathogenesis of MTNKN has led to the development and approval of several epigenetic modifiers. The significance of these breakthroughs cannot be understated, particularly for patients who are unfit to receive intensive therapies or SCT. Highlighting this, a retrospective review of 219 patients (including 33% ≥65 years old) demonstrated that exposure to novel agents in the R/R setting was associated with improved OS, with median OS of 3.8 years for patients treated with novel agents vs. 2.5 years for patients treated with chemotherapy (P=0.04) (51). Studies of selected novel agents as monotherapy are summarized in Table 6 (52-58). As of this writing, three agents, including belinostat, pralatrexate, and Bv (in ALCL only), continue to hold FDA approval in the R/R setting. In the case of belinostat, ~49% of patients >65 years old (median age 64, range, 29–81) were included in the phase 2 study which led to its approval (54). However, no subgroup analysis of younger vs. older patients was included. A subsequent meta-analysis of belinostat usage in patients with both solid and hematologic malignancies showed that cardiac toxicity, including arrhythmias and QTc prolongation, was rare (4.3%) with only 2.1% of patients experiencing grade 3 or 4 cardiac AEs (59). For older patients where cardiovascular toxicity is a concern, belinostat thus represents a safe option given its established cardiovascular toxicity profile. Despite the removal of its FDA label in R/R disease, romidepsin continues to be available for use in the absence of other more effective therapies. In the pivotal phase 2 study of romidepsin in R/R disease, a majority of patients were older (median age 61, range 20–83 years) with patients ≥65 years old comprising 54.2% of the study population (53). Subgroup analysis of age groups showed no difference in ORR in patients ≥65 years old when compared to patients <65 (ORR 27% vs. 25%, respectively, P=0.84), and there was no difference in median PFS (4.6 months in the older population vs. 3.7 months in the younger population, P=0.92). An increasing body of literature suggests that TFh-like PTCL exhibits increased sensitivity to histone deacetylase inhibitors (HDACi) such as romidepsin and belinostat (34,60). HDACi should therefore be prioritized in older patients with TFh-like PTCL who are unfit to receive more intensive therapies. Pralatrexate, a novel anti-folate, has similarly been evaluated in single-arm, phase 2 PROPEL study (52). The mean age of patients was 58 (range, 21–85) years and only a minority (36%) were ≥65. Responses were higher in the subgroup of patients <65 when compared to patients ≥65 (64% vs. 36%, respectively), however the study was not powered to detect a difference between age groups. Median PFS and OS were 3.5 and 14.5 months, respectively, and pralatrexate was well tolerated. Like belinostat and romidepsin, pralatrexate is another reasonable option for older patients with R/R disease given its established cardiovascular toxicity profile. Several other novel agents have been described in patients with R/R MTNKN, including valemetostat, ruxolitinib, duvelisib, and many others beyond the scope of this review. While older patients were represented in the studies evaluating these agents, currently published results generally do not describe any significant differences in efficacy or safety between older vs. younger subgroups in each study.

Key points

• Palliative chemotherapy options for less fit patients, regardless of line of therapy, include gemcitabine- or bendamustine-based regimens. There are no randomized data to suggest one regimen is superior over another in older patients.
• Several novel agents used as monotherapy have been evaluated in early-phase clinical trials that included varying proportions of older patients. In general, advanced age alone has not been shown to be independently associated with worse efficacy or safety outcomes among studies of novel agents which have reported subgroup analysis of different age groups.
• Patients with PTCL with TFh phenotype who are not fit to receive intensive chemotherapy or combination-based approaches should be preferentially offered treatment with HDACi as monotherapy.

Role of SCT in older patients with MTNKN

For young and old patients alike, current practice patterns and guidelines regarding consolidative autologous stem cell transplantation (ASCT) or allo-SCT in patients achieving first remission (CR1) are generally based on weak-quality evidence. Among older patients, the available evidence is even weaker, reflecting a lack of randomized studies and the potential bias from retrospective studies. Moreover, the rarity of the disease and narrow window of transplant eligibility mean that older patients with MTNKN are under-represented in retrospective studies on HSCT. Highlighting this, a randomized phase 3 trial evaluating consolidative autologous vs. allogeneic SCT in poor-risk MTNKN showed no difference in 3-year OS in either arm (57% vs. 70% after allo-SCT and ASCT, respectively, P=0.41) (61). The lack of superiority of allo-SCT, as compared with ASCT, was at least partially attributed to the high rate of transplant-related mortality (31%) among allo-SCT patients. Moreover, this study was conducted in only younger patients who were 18–60 years old, leaving unanswered questions for older patients who otherwise remain fit for consideration of consolidative HSCT in CR1. Available data among US patients have shown that ~4% of US patients with MTNKN underwent HSCT, and these patients all had either PTCL-NOS or AITL (25). Median age among this group was 69 years and most were <75 years old. Landmark analysis at 1-year from diagnosis demonstrated improved OS among patients who underwent HSCT vs. those who did not (5-year OS 61.5% vs. 49.7% among patients with and without HSCT, respectively, P=0.01). Otherwise, the COMPLETE report represents the only non-retrospective data examining outcomes following ASCT in CR1 (62). Forty-eight percent (n=57) of the cohort was older than 65 years, and 23% (n=13) of this older population underwent ASCT. There were no differences in 2-year OS or PFS among all disease subtypes, though a notable trend toward improved OS was observed in the ASCT group (median OS in ASCT group was not reached, vs. 57.6 months in non-ASCT group, P=0.06). Cox regression analysis showed no impact of age on OS (HR =1.02 for age <65 vs. ≥65 years, P=0.09). The SLR included 457 patients older than 60 (66%) among whom a total of 89 (13%) underwent planned ASCT following treatment with CHOP or CHOEP (63). The presence of at least one comorbidity was the only factor associated with worse OS. Interestingly, univariate analysis suggested that diabetes mellitus had a particularly negative impact on OS outcomes following ASCT (HR =4.7, P=0.001), but advancing age did not.

Data regarding outcome differences between ASCT and allo-SCT in older patients are similarly limited. A retrospective study by Sterling et al. examining the role of allogeneic transplantation with post-transplant cyclophosphamide included 32 patients (49%) ≥60 years old (64). Univariate analysis based on age at time of transplantation (increment per 10 years) showed no difference in PFS, OS, relapse, or non-relapse mortality. In a separate study of 29 patients (among whom 39% were ≥55 years of age) who successfully underwent allo-SCT after achieving CR or PR with chemotherapy, univariate analysis showed no difference in PFS or OS in patients <50 or >50 years of age (P=0.46 for PFS and P=0.98 for OS) (65). However, remission status at time of allo-SCT was significantly associated with both PFS and OS [relative risk (RR) =4.7 for PFS, P=0.03; RR =6.1 for OS, P=0.05]. Another retrospective study published by Mehta et al. evaluated outcome differences among nodal PTCL patients who were treated with the intention of undergoing ASCT or allo-SCT in CR1 (66). This study included 65 patients with median age of 58 years (range, 22–75 years), with 52% undergoing allo-SCT vs. 8% undergoing ASCT. Four-year OS was similar between ASCT and allo-SCT, with 67% of patients in either cohort surviving four years or longer. High baseline IPI score and lack of interim response to induction chemotherapy were associated with worse PFS outcomes, but the effect of age on PFS or OS was not specifically evaluated. Perhaps most importantly, more recent data suggest a trend in declining non-relapse mortality among older lymphoma patients undergoing ASCT (2000–2010 vs. 2011–2016, HR =6.54, 95% CI: 1.37–31.31, P=0.02), reflecting improvements in patient selection, toxicity management and supportive care in the peri-transplant period (67).

Key points

• No randomized data exist to show the superiority of consolidative HSCT in patients >60 years old who achieve CR1 compared with observation alone.
• Comorbidity burden is associated with negative outcomes among older patients who undergo HSCT.
• Improvements in supportive care and treatment of peri-transplant complications have led to reduced rates of transplant-related mortality in lymphoma patients undergoing HSCT.

Conclusions

The treatment of older patients with MTNKN presents many challenges. The presence of comorbidities has repeatedly been shown to negatively impact treatment outcomes, and the optimum approach for patients who are ineligible to receive aggressive, curative-intent therapy is poorly defined. Particularly challenging is the approach older patients who achieve initial remissions with up-front therapies, but who are otherwise unfit to undergo allogeneic or ASCT in the event of disease relapse. Acknowledging these limitations, a proposed algorithm for treating older patients with the most common nodal MTNKN subtypes (i.e., PTCL-NOS, AITL, ALCL, TFh-like PTCL) is shown in Figure 3. Future randomized studies exploring the potential for established, or emerging, novel agents to improve long-term outcomes in such cases are greatly needed. Rapidly accumulating data obtained from gene expression profiling (GEP) and next generation sequencing (NGS) in patients with MTNKN have led to the rapid development of many novel or targeted therapy options. Cellular therapies, including novel chimeric antigen receptor (CAR)-T cell therapies and bispecific T-cell engager (BiTE) therapies are also the subject of intense investigation but currently their role remain purely investigational (68). The inclusion and adequate representation of older patients in clinical studies will be crucial to the development of evidence-based guidelines to guide the management of these patients. Certainly, the continued development of targeted agents and novel therapeutic strategies in MTNKN will have profound benefits to older patients who need more efficacious and less toxic therapies.

Figure 3 Proposed algorithm for the management of older patients with the most common nodal MTNKN subtypes. sALCL, systemic anaplastic large-cell lymphoma; Bv, brentuximab vedotin; CHP, cyclophosphamide, doxorubicin, prednisone; CHOP, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone; EPOCH, etoposide, prednisolone, oncovin, cyclophosphamide, hydroxydaunorubicin; SCT, stem cell transplantation; CR, complete response; MTNKN, mature T-cell and NK-cell neoplasm.

Acknowledgments

Funding: This work was supported by the University of Virginia Comprehensive Cancer Center.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Jonathon B. Cohen and Craig Portell) for the series “Management of Elderly Patients with HL and NHL” published in Annals of Lymphoma. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aol.amegroups.com/article/view/10.21037/aol-23-18/rc

Peer Review File: Available at https://aol.amegroups.com/article/view/10.21037/aol-23-18/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aol.amegroups.com/article/view/10.21037/aol-23-18/coif). The series “Management of Elderly Patients with HL and NHL” was commissioned by the editorial office without any funding or sponsorship. E.M. has received research funding from Merck, Celgene/BMS, Kymera Therapeutics/Dren Bio: Research Funding. E.M. is a scientific advisor for Vittoria Biotherapeutics, Seagen, and Acrotech. E.M. is a member of the data safety monitoring committee for Everest clinical research. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

¹TUG test is administered by (I) having patient first sit in a standard arm chair and identify a line 3 meters (10 feet) away on the floor, then (II) rise from a seated position following “go” command and walk to the marker, turn around, walk back, and sit down again. Patients are timed with a stopwatch from the “go” command until returning to a seated position.

²Cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, and prednisone 40 mg/m2 on days 1–5 administered every 21 days.

³CD30 positivity ≥10%; represented subtypes included ALK+ ALCL (22%) with an IPI score 2, ALK- ALCL (48%), PTCL-NOS (16%), AITL (11.9%), adult T-cell leukemia/lymphoma (1.5%), and enteropathy-associated T-cell lymphoma (0.6%).

⁴Represented histologic subtypes included PTCL-NOS (30.2%), AITL (46.3%), ALK– ALCL (10.0%), enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous gamma-delta T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic lymphoma, primary cutaneous CD4+ small or medium T-cell lymphoproliferative disorder, and other non-classifiable T-cell lymphoma.

⁵Cyclophosphamide 562.5 mg/m2 on day 1 (25% reduction), doxorubicin 37.5 mg/m2 on day 1 (25% reduction), vincristine 1.4 mg/m2 on day 1, and prednisolone 50 mg twice per day for five days given every 21 days.

⁶Gemcitabine 1,000 mg/m2 on day 1, oxaliplatin 100 mg/m2 on day 1, and dexamethasone 20 mg/day from day 1 to day 4 administered every 21 days.

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