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Zilioli, V.R.; Muzi, C.; Pagani, C.; Ravano, E.; Meli, E.; Daffini, R.; Ravelli, E.; Cairoli, R.; Re, A. Classical Hodgkin Lymphoma in Older Adults. Encyclopedia. Available online: https://encyclopedia.pub/entry/41944 (accessed on 13 June 2025).
Zilioli VR, Muzi C, Pagani C, Ravano E, Meli E, Daffini R, et al. Classical Hodgkin Lymphoma in Older Adults. Encyclopedia. Available at: https://encyclopedia.pub/entry/41944. Accessed June 13, 2025.
Zilioli, Vittorio Ruggero, Cristina Muzi, Chiara Pagani, Emanuele Ravano, Erika Meli, Rosa Daffini, Erika Ravelli, Roberto Cairoli, Alessandro Re. "Classical Hodgkin Lymphoma in Older Adults" Encyclopedia, https://encyclopedia.pub/entry/41944 (accessed June 13, 2025).
Zilioli, V.R., Muzi, C., Pagani, C., Ravano, E., Meli, E., Daffini, R., Ravelli, E., Cairoli, R., & Re, A. (2023, March 07). Classical Hodgkin Lymphoma in Older Adults. In Encyclopedia. https://encyclopedia.pub/entry/41944
Zilioli, Vittorio Ruggero, et al. "Classical Hodgkin Lymphoma in Older Adults." Encyclopedia. Web. 07 March, 2023.
Classical Hodgkin Lymphoma in Older Adults
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15051515

Along with the fact that classical Hodgkin lymphoma (cHL) in older adults is frequently considered biologically different from cHL in younger patients, its most distinctive feature is its dismal clinical outcome due to the decreased effectiveness and greater toxicity of therapies. Although strategies to mitigate specific toxicities (e.g., cardiological and pulmonary) have obtained some results, in general, reduced-intensity schemes, proposed as an alternative to ABVD, have proved to be less effective. The addition of brentuximab vedotin (BV) to AVD, especially in a sequential scheme, has demonstrated good efficacy. However, the problem of toxicity persists even with this new therapeutic combination, with comorbidities remaining an important prognostic factor. The adequate stratification of functional status is necessary to distinguish between those patients who will benefit from full treatment and those who will benefit from alternative strategies.

Hodgkin lymphoma elderly comorbidity functional status geriatric assessment

1. Epidemiology and General Characteristics

Classical Hodgkin lymphoma (cHL) in older adults is seen in the second peak of the incidence of cHL. Although there is no shared definition of “older patient” in the cHL setting, most studies agree that a patient ≥60 years of age is “older”.
Despite accounting for about one-fifth of all new diagnoses of cHL, older patients are under-represented in clinical trials, which typically include less than 5–10% of patients aged ≥60 years. This may be due to the “biological diversity” of cHL in older adults as well as to the difficulty of treating these patients, who have poor tolerance and a reduced response to first-line therapy [1]. Furthermore, this under-representation is very unlike what occurs in the setting of diffuse large B-cell non-Hodgkin lymphoma (DLBCL), for example.

2. First-Line Therapy: Reduced-Intensity Regimens

The issue of therapy toxicity in older cHL patients is so important that there have been multiple attempts over the last 20 years to create the so-called low-intensity treatment regimens, including ChLVPP (chlorambucil, vinblastine, procarbazine, and prednisolone) [2], VEPEM-B (vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone, bleomycin, and prednisolone) [3][4], P-VAG (prednisone, vinblastine, doxorubicin, and gemcitabine) [5], and others. These regimens do not start from the ABVD backbone but are alternative polychemotherapy combinations, some including an anthracycline, while others do not. These regimens have almost always been the subject of small, prospective phase 2 studies whose aim was to find an adequate cycle and then ideally be able to compare the regimen with ABVD. A rare example of a randomized clinical trial compared ABVD and VEPEMB in 54 older patients with cHL (17 localized and 37 advanced); in this selected patient population, it was possible to observe in patients a superiority of ABVD over VEPEMB that, while not statistically significant, was certainly clinically significant, with a 5-year progression-free survival (PFS) of 70% versus 48% (p = 0.06) [6]. All these low-intensity regimens aimed to (1) be less toxic and therefore better tolerated, (2) be completed while maintaining an adequate dose rate, (3) lead to a high rate of overall and complete responses, and (4) lead to an improvement in overall (OS) and disease-free survival (DFS).
However, while reduced acute toxicity and a high rate of completion of chemotherapy protocols with adequate dose rates have almost always been observed, the high overall response rates (ORRs) and complete response rates (CRRs) observed did not translate into an improvement in survival curves due to the high recurrence rates seen. Ultimately, less intensity means less toxicity, but it also seems to mean less cure, at least in the setting of older cHL patients.

3. First-Line Therapy: Is There a Reference Treatment?

A second strategy is to work on the ABVD backbone to reduce its most frequent toxicities. An interesting attempt in this sense is the one published by Salvi F et al., who replaced the standard doxorubicin in the ABVD scheme with a non-pegylated liposomal formulation, known for its lower incidence of acute and late toxicity (especially as hypokinetic heart disease) in other histologies. In this experience, 47 older and/or cardiac patients were treated. Although neither OS nor PFS was greater than the known rates for these indicators (3-year OS 70%, 3-year PFS 43%), the authors documented how a “standard” ABVD-like therapy in this “protective formulation” was feasible even in patients who would perhaps not have been candidates for anthracycline therapy [7].
Another direction of research is obviously to reduce or omit bleomycin. In the RATHL trial [8], the authors stated that the omission of bleomycin from the ABVD regimen (AVD) after negative findings on interim PET resulted in a lower incidence of pulmonary toxic side effects compared with continued ABVD but not in significantly lower efficacy (3-year PFS 84.4% in the AVD arm versus 85.7% in the ABVD arm). In another study, carried out by the German Hodgkin Study Group (GHSG) [9], the upfront omission of bleomycin from the front-line therapy actually led to a reduction in cure rates, although much smaller than that with the omission of dacarbazine. However, the need to reduce and even eliminate bleomycin toxicity is much greater in older patients. In this setting, in a retrospective series of 147 patients [10], a French group observed how the reduction in or omission of bleomycin (chosen on a clinical basis) did not translate into worse survival rates in the entire population (hazard ratio (HR) for OS: 1.74; 95% confidence interval (CI) 1.0–3.0; p = 0.051), while reporting a worse outcome for patients in an advanced stage versus those in a localized stage. A recent Nordic group study [11] retrospectively evaluated registry data from ≥60-year-old patients treated between 2000 and 2021 in Sweden, Norway, and Denmark, who received ABVD (n = 671), AVD (n = 122), CHOP (n = 465), or other regimens (n = 296).

4. “AVD Plus” Chemotherapy: Attempts to Improve Efficacy

The greatest advance in the treatment of cHL in recent years has undoubtedly been the optimization of first-line therapy with the addition of brentuximab vedotin (BV) to AVD in the ECHELON-1 study [12]. In this phase 3 study, patients with advanced newly diagnosed cHL were 1:1 randomized to receive ABVD or BV + AVD. Of the entire study population, 186 (14%) patients were aged ≥60 years (median age 67 years, range 60–83); an analysis of this subgroup was published in 2022 [13]. With regard to toxicity, the majority of these patients were given a dose reduction or modification of both BV (80% of patients in the BV + AVD arm) and bleomycin (71% of patients in the ABVD arm). The most relevant findings were the high treatment-related mortality in both groups (3.6% BV + AVD vs. 5.1% with ABVD) and the high rate of febrile neutropenia (37% BV + AVD vs. 17% ABVD). The authors reported that the high incidence of febrile neutropenia decreased after the mandatory introduction of primary prophylaxis with G-CSF. Eighteen percent of the patients in the BV + AVD arm experienced grade ≥3 peripheral polyneuropathy but also a substantial reduction in pulmonary toxicity (2% versus 13% in the ABVD arm). In terms of efficacy, 5-year PFS was 67.1% in the BV + AVD group versus 61.6% in the ABVD group (p = 0.443). Based on these findings on the older population included in ECHELON-1, BV + AVD can be proposed as an effective bleomycin-free alternative for these patients.
The combination of BV and AVD was also proposed as a sequential therapy (BV 1.8 mg/kg every 21 days for 2 cycles, followed by AVD for 6 cycles, followed by BV 1.8 mg/kg every 21 days for 4 cycles) in a phase 2 study on 48 consecutive newly diagnosed older cHL patients [14].
Although the main side effects of the combination of BV + AVD are apparently lower in sequential combination therapy, they should not be overlooked. Along with febrile neutropenia, which can be effectively prevented with G-CSF primary prophylaxis and adequately treated with early empiric antibiotic therapy, grade 3 peripheral polyneuropathy is also an important side effect. Although it is often transient and frequently resolves or improves over time, it can result in a reduction in the ability to perform common activities of daily living (ADLs) [15] and must therefore be appropriately assessed in older patients.
Furthermore, despite the most modern therapies, some factors specific to older patients, such as the presence of comorbidities, continue to play an important prognostic role in terms of overall survival [14], probably due to their influence on chemotherapy-related toxicity and on the possibility of achieving adequate dose intensity. It is therefore clear that correct patient selection must be addressed.

5. The Need for Patient Selection and the Role of Simplified Geriatric Assessment

Adequate patient selection for treatments with different intensities or intent should be pursued for a number of reasons, including the possible toxicity of “standard” first-line treatments (as discussed above), the growing incidence of different types of frailty in the older population, and the availability of new effective therapies even for patients not eligible for standard therapy.
There is no univocal definition of frailty in the literature, much less in the setting of patients suffering from hematological cancers, especially in the specific case of patients suffering from cHL. Nevertheless, the literature does demonstrate that frailty, no matter how it is defined, increases as a person ages. The data of Fogg et al. [16], part of a large national study on over 2 million patients in England, showed that frailty (measured with a multiparametric electronic frailty score) was found in 10% of patients aged 50–64 years but in 43.7% of those over age 64 years, reaching very high percentages in the older segments of the population.
Along with fragility, it is also very important to perform an accurate assessment of a patient’s life expectancy. The life expectancy of an older patient with lymphoma is the number of years that separates that patient from the target age that he or she would reach without lymphoma or if the lymphoma can be adequately treated. For a correct estimate of life expectancy, using the reference tables of many Departments of Health, which are updated yearly, and/or online calculators, which are based on these tables, is suggested [17]. By way of an example, in 2023, an 80-year-old woman newly diagnosed with cHL has a life expectancy, in the absence of lymphoma, of about 9.6 more years.
Finally, in the specific setting of cHL, it has been demonstrated that full-dose first-line therapy can produce the best survival results in patients who can tolerate it, resulting in a reduction in mortality from all causes [18]. Indeed, Orellana-Noia et al. observed that receiving conventional therapy had a survival advantage over receiving alternative therapy [19].
In light of the above, it is clear that the accurate assessments of present frailty and life expectancy allow clinicians to distinguish between those patients who will benefit from full-dose treatment and those who will benefit from other treatment options.
A method to stratify patients based on their frailty was developed and tested by the Fondazione Italiana Linfomi (FIL) group, who recently published their results on the usefulness of a simplified geriatric assessment (sGA) in patients with DLBCL. In the FIL study, a baseline assessment of ADL [20], instrumental ADL (IADL) [21], and Cumulative Illness Rating Scale—Geriatric (CIRS-G) [22] made it possible to divide patients into three functional status groups (FIT, UNFIT, and FRAIL), with different outcomes (3-year OS of 75%, 58%, and 43% for FIT, UNFIT, and FRAIL, respectively) [23]. Moreover, very similar to what was found in a study conducted by Isaksen et al. [24], the FIL group showed that it was possible to use the stratification of a patient’s functional status for therapeutic indications as well. For example, in patients defined as UNFIT, it was observed that there were no differences in terms of outcome between patients treated with full-dose R-CHOP therapy and those treated with the same therapy at reduced doses (i.e., R-mini-CHOP) [24][25]. The usefulness of such a tool is also related to its practicality: It takes less than 10 min to perform sGA, even in an outpatient setting. The applicability and usefulness of the sGA have yet to be validated in the setting of cHL in older adults; to this end, a prospective study is currently being conducted by the FIL group [26].

6. New Ways to Improve Defining Patients’ Functional Status: Sarcopenia and Immunosenescence

Beyond the extremely useful, practical tools to stratify patients in terms of their fitness, it is increasingly evident that functional status is a complex concept involving multiple factors.
Sarcopenia (defined as a mainly cancer-related reduction in muscle mass, strength, and performance) has been widely demonstrated to be a reproducible, effective indicator of the outcome and, to some extent, the tolerance to therapy of patients of any age undergoing chemotherapy in the oncological setting [27][28][29]. More recently, sarcopenia, particularly as a CT-scan measured reduction in muscle mass, was demonstrated to be useful in predicting the outcome of patients with lymphomas as well [30][31][32][33][34][35].
Immunosenescence—an age-related decrease in immune function—is emerging as another important aspect related to lymphoma prognosis and cure. This complex biological process occurs in both the innate and adaptive components of the immune system and results in increased sensitivity to infections, increased autoimmune disorders, reduced immune surveillance, and cancer development [36][37]. Little is known about any possible correlation between immunosenescence and frailty, but it is worth mentioning that in the FIL study published by Tucci et al. [38], the non-FIT DLBCL patients did not benefit from potentially life-saving therapies: The OS of patients treated with a curative regimen was the same as that for those treated with a palliative regimen (2-year OS 19.8% vs. 26.1% for patients treated with curative or with palliative intent, respectively; p = 0.85).

7. Alternative First-Line Therapies (Mainly) for Non-FIT Patients

7.1. Brentuximab Vedotin

One type of therapy is based on the use of BV alone or in combination. BV monotherapy as a first-line treatment in older cHL patients has been shown to achieve a good ORR and CRR (92% and 73%, respectively), although of short duration, with a median duration of response and PFS of around 10 months [39]. The good efficacy and low toxicity of BV have led to its evaluation in combination with monochemotherapy, in particular with bendamustine and dacarbazine. BV + bendamustine has proved extremely effective in achieving high ORR and CRR (100% and 88%, respectively) and has very good disease control over time, with a median PFS not reached after a follow-up of approximately 1 year. However, a total of 65% of the patients examined experienced adverse events, and 10% died of treatment-induced toxicity, resulting in the discontinuation of the BV + bendamustine arm of the study [40]. In the same study by Friedberg et al. [40], the combination of BV and dacarbazine proved to be less toxic but adequately effective: for the 22 treated patients, the ORR was 100% (CRR 62%), with a median PFS of 17.9 months (not reached in patients obtaining CR versus 10.8 months in patients without CR) [40].

7.2. Anti-PD1-Containing Therapies

Anti-PD1-containing therapies represent a great opportunity, especially given their extreme efficacy in cHL (greater than that observed in any other histology of oncological disease) and their good toxicity profile, making them an extremely interesting pharmacological class, especially for older patients.
Considering their use as first-line therapy in this population, anti-PD1-containing combinations have been primarily studied in order to improve the efficacy of standard treatments: the combination of nivolumab with AVD in the phase 2 CheckMate 205 study obtained an 84% ORR (CRR 67%) in a cohort of 51 patients, with 9-month PFS of 92% and 9-month OS of 98% [41].
The use of anti-PD1-containing therapy alone or in combination with other drugs allows clinicians to offer appropriate treatment to those patients who are not candidates for standard therapy and who therefore may not be offered treatment at all. In this context, the combination of BV + nivolumab has proved to be well tolerated and effective. Although the ACCRU trial [42] discontinued its enrollment after the interim analysis because it had not achieved the primary CRR objective (at the final evaluation of 46 patients, the authors observed an ORR of 61% and a CRR of 48%), it illustrated that the responses obtained were long-lasting (median PFS 18.3 months for the entire population, in particular, not reached for patients with CR, versus 6 months for patients with PR, with a median follow-up of 21.2 months). The efficacy of this combination was also demonstrated by Yasenchak et al. [43], who documented an ORR of 95% (CRR 79%) in their 19 patients, with a median PFS not reached at a median follow-up of 19.4 months.
The French NIVINHO trial on 56 patients consisted of a first phase of treatment with nivolumab monotherapy (240 mg flat dose) every 14 days for 6 administrations and subsequent continuation based on response: The patients in complete metabolic response continued nivolumab monotherapy for an additional 18 cycles, while those in partial response or stable disease were treated with a combination of nivolumab and vinblastine every 14 days for 18 cycles. Thanks to this scheme, this difficult-to-treat population (median age 75 years, median CIRS-G 10) achieved an ORR of 46.5% and a CRR of 28.6% (16% post-nivolumab in monotherapy), with a median PFS of 9.8 months at a median follow-up of over 20 months [44].
Finally, several study protocols are about to be activated (e.g., the GHSG HD20 study “Indie trial” NCT04837859 and the announced GHSG HD19 and UK RATIFY trials) in which anti-PD1-containing therapies will be used to reduce the toxicity or duration of first-line therapy and, in some cases, to allow the omission of chemotherapy in patients in complete metabolic response.

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Subjects: Hematology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Vittorio Ruggero Zilioli
,
Cristina Muzi
,
Chiara Pagani
,
Emanuele Ravano
,
Erika Meli
,
Rosa Daffini
,
Erika Ravelli
,
Roberto Cairoli
,
Alessandro Re
View Times: 603
Revisions: 3 times (View History)
Update Date: 15 Mar 2023
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