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Multicenter analysis of geriatric fitness and real-world outcomes in older patients with classical Hodgkin lymphoma

: We performed a multicenter retrospective analysis across 10 US academic medical centers (2010 - 2018) to evaluate current treatment patterns and outcomes in patients age >/=60 with classical Hodgkin lymphoma (cHL). Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 14% had ECOG performance status (PS) 2-4, and 12% had documented loss of >/=1 activity of daily living (ADLs). Medical comorbidities were assessed by the Cumulative Illness Rating Scale - Geriatric (CIRS-G), where n=44 (18%) had total scores >/=10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; HR 2.13, p=0.007) and overall survival (OS; HR=2.52, P=0.02). Most patients (n=203, 83%) received conventional chemotherapy regimens, including ABVD (56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P=0.0007) and OS (HR 0.31, p=0.0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs >/=70: PFS HR 0.88, p=0.63; OS HR 0.73, p=0.55. Early treatment discontinuation due to toxicity was more common with CIRS-G >/=10 (28 vs 12%, p=0.016) or documented geriatric syndrome (28 vs 13%, p=0.02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, p=0.02) and higher mortality from causes other than disease or treatment in those with high CIRS-G or geriatric syndromes. These data suggest conventional chemotherapy regimens be considered standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward. ABSTRACT We performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had ECOG performance status (PS) 0-2, and 12% had documented loss of ≥1 basic or instrumental activities of daily living (ADLs). Medical comorbidities were assessed by the Cumulative Illness Rating Scale – Geriatric (CIRS-G), where n=44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; HR 2.13, p=0.007) and overall survival (OS; HR=2.52, P=0.02). Most patients (n=203, 83%) received conventional chemotherapy regimens, including ABVD (56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P=0.0007) and OS (HR 0.31, p=0.0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, p=0.63; OS HR 0.73, p=0.55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥ 10 (28 vs 12%, p=0.016) or documented geriatric syndrome (28 vs 13%, p=0.02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, p=0.02) and higher mortality from causes other than disease or treatment in those with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.


ABSTRACT
We performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had ECOG performance status (PS) 0-2, and 12% had documented loss of ≥1 basic or instrumental activities of daily living (ADLs). Medical comorbidities were assessed by the Cumulative Illness Rating Scale -Geriatric (CIRS-G), where n=44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; HR 2.13, p=0.007) and overall survival (OS; HR=2.52, P=0.02). Most patients (n=203, 83%) received conventional chemotherapy regimens, including ABVD (56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P=0.0007) and OS (HR 0.31, p=0.0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, p=0.63; OS HR 0.73, p=0.55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥ 10 (28 vs 12%, p=0.016) or documented geriatric syndrome (28 vs 13%, p=0.02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, p=0.02) and higher mortality from causes other than disease or treatment in those with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.

INTRODUCTION
Patients over age 60 represent 20-30% of new cHL diagnoses annually but remain vastly under-represented in clinical trials, comprising only 5-13% of participants in modern phase III studies [2][3][4][5][6] . These individuals more commonly present with advanced stage, mixed cellularity subtype, as well as varying burdens of age-related medical comorbidities, all of which may impact the fitness for and outcomes with conventional cHL regimens such as ABVD and Stanford V 3,7,8 . Older patients have historically experienced inferior efficacy and greater toxicity with these regimens compared to younger individuals with cHL 9 . However, it remains unclear how these experiences compare in the context of novel combinations without a conventional chemotherapy backbone [10][11][12] , particularly in those who otherwise seem fit enough to receive intensive therapy.
Geriatric fitness measures have been increasingly studied across oncologic settings and may allow for more objective insight into a patient's candidacy for a proposed treatment intensity 13 . While geriatric assessments (GA) have been studied extensively in the management of older patients with solid tumors, data are more limited in hematologic malignancies and it is unknown how widely GAs are used in the US to inform decisions on lymphoma-directed therapy in routine practice 14 . Medical comorbidity burden, a key component to geriatric fitness testing, has been shown in multiple cHL studies to affect tolerability and efficacy of a given regimen 15,16 . Functional impairment of basic and/or instrumental ADLs has likewise shown significant impact on treatment tolerability and disease-related outcomes, for geriatric oncology more broadly and for cHL in particular [16][17][18] .
Given the wide range of current treatment options available to older cHL patients as well as the impact that a more nuanced assessment of geriatric fitness may have on treatment consideration and outcomes, we performed a large retrospective analysis to assess real-world outcomes in this population.

Eligibility
Following IRB approval at each site, we collected detailed clinical and pathologic data from patients with cHL across 10 US academic medical centers. Eligible patients were age ≥ 60 at time of cHL diagnosis and started on lymphoma-directed therapy between January 2010 -December 2018. 264 cases were identified, of whom 244 met full eligibility for inclusion. Those with a preceding hematologic malignancy (N=4) or inadequate clinicopathologic or outcomes data (N=16) were excluded; no cases of nodular lymphocyte-predominant HL were submitted. The study was conducted in accordance with the Declaration of Helsinki.

Variables and Endpoints
Medical comorbidities were quantified by CIRS-G, a validated assessment tool specifically designed to capture comorbidities in older individuals 19 ; cHL was not included in CIRS-G scoring. Data regarding ADLs and presence of geriatric syndromes (dementia, delirium, depression, osteoporosis, incontinence, falls, failure to thrive, and/or neglect/abuse) were abstracted from patient charts. Treatment response and progression were determined by local investigators and clinical documentation. Survival estimates were calculated for PFS (time from cHL diagnosis to disease progression, death, or last follow-up) and OS (time from diagnosis to death or last follow-up).
In assessing frontline therapy, we compared recipients of conventional cHL regimens (defined here as ABVD, AVD with or without BV, or Stanford V) versus those who received alternative regimens (i.e., all other therapies). While anthracyclines are considered necessary for curative intent therapy in cHL 20 , we did not consider CHOP a conventional cHL regimen for these analyses given substantial differences in dose density between CHOP and A(B)VD, which has been shown in cHL to impact response rates and survival 21 . Based on this decision, a separate three-arm comparison was also performed to assess PFS and OS following CHOP relative to conventional and non-CHOP alternative therapies. Growth factor use and chemotherapy dose adjustments were not collected.

Statistical Methods
Data was de-identified prior to submission for analysis, including the censoring of age as "90 or greater" for relevant cases. Categorical data were analyzed using chi-square tests, Fisher's exact test, and logistic regression modeling.

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Continuous variable data was compared using two-sample T-tests. Kaplan-Meier estimates and log-rank tests were used for time-to-event analyses. Findings significant on univariate analysis were subsequently assessed in multivariable logistic regression models. Associations of baseline patient characteristics with survival were further evaluated using a multivariable Cox proportional hazards model, using backward elimination to help mitigate potential collinearity between factors and using a variable retention threshold of 0.05. Analyses were performed in SAS 9.4 (SAS institute, Cary NC) and figures were created using GraphPad Prism v8 (GraphPad Software, Inc., San Diego, CA).
Multivariate competing risks regression based on the Fine-Gray method 22 was conducted using the cmprsk package in R (R Core Team, Vienna, Austria. https://www.R-project.org) to compare the cumulative incidence of disease-related deaths and treatment-related deaths between groups, accounting for death from other causes as a competing event.
Associations for each analysis were considered significant at a two-sided P value < 0.05.
Trial eligibility, treatment standards, and disease-related outcomes generally differ in stage I cHL from those with stage II-IV disease 23 . As such, outcomes for these individuals (n=22) were analyzed separately; unless otherwise stated, reported analyses include stages II-IV (N=222).

Geriatric Fitness
Prior to initiation of therapy, 31 patients (12%) had documented loss of at least one basic or instrumental ADL; 40 (16%) had a documented geriatric syndrome; and 16 (6.3%) had both ADL impairment and a geriatric syndrome. In terms of medical comorbidities, median CIRS-G score was 5 (range 0-22). One hundred eleven (45%) had at least one comorbidity classified as "severe" (i.e., individual CIRS-G category score of 3-4) and 44 (18%) had a total score of ≥10 indicating increased overall burden. Geriatric fitness markers varied by age; patients over 70 were more likely to have impaired ADLs (OR 1.78, P=0.09), CIRS total score ≥10 (OR 2.27, P=0.001) and/or geriatric syndromes (OR 2.82, P=0.0002). Further analysis of ECOG status was limited by a small number of patients with PS 3-4 (n=7), and notably only one patient underwent a formal geriatric assessment prior to treatment.

Frontline therapy
Key clinical features are listed in Table 1, overall and by frontline therapy. Common regimens (Figure 1) included ABVD (n=136; 56%), AVD (n=31; 13%), and CHOP (n=17; 7%  Table 2 were then included in backward-elimination multivariable Cox proportional hazards models for PFS and OS respectively, where only ADL impairment continued to correlate significantly with either endpoint (PFS mvHR 2.13, p=0.007; OS mvHR 2.52, p=0.02). Alternative CIRS-G total score thresholds were not predictive of PFS, nor were previously-reported scoring systems in elderly lymphoma focusing on individual CIRS-G categories 7,24 (Supplement).

Conventional versus alternative frontline therapy
Recipients of conventional cHL regimens showed superior PFS (HR 0.46, p=0.0007) and OS (HR 0.31, p=0.0003) versus those treated with alternative regimens (Figure 2 Stage I disease Twenty-two patients (9% of total cohort) had stage I disease at diagnosis; median age was 71 (range 60-88) with 13 (59%) above age 70. The majority (n=21, 95%) received radiation and 14 (64%) received systemic therapy (range 2-4 cycles). Latter was most commonly ABVD (n=9) and also included AVD (n=2) and CHOP (n=1), all with radiation. Two patients received BV, one with radiation and one with bendamustine. Overall response for stage I was 95% (n=21), with 91% (n=20) achieving a complete response (CR). Two-year PFS and OS were 82% and 95% respectively; relapses within the first 2 years of completing therapy (n=4, 18%) were evenly divided between recipients of ABVD with radiation and those who received radiation alone. Long-term outcomes in this cohort remain unknown due to excellent early outcomes and limited follow-up thus far.

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TLT was associated with shorter treatment duration by a median of 2 cycles (6 vs 4 cycles, p<0.0001

Bleomycin lung injury (BLI)
ABVD recipients received a median of 7 bleomycin doses (range 1-14) and 26 (18.4%) had documented pulmonary toxicity. Though uncommon, incidence of BLI was higher among males (25.4 vs 11.4%, p=0.03) and was not significantly associated with any other individual factor, including age, stage, smoking history, pulmonary CIRS-G score, number of bleomycin doses, or number of chemotherapy cycles (data not shown).

Treatment-related mortality
Eight patient deaths (3.3% of total cohort) were attributed to complications of HL therapy. Median age of patients who experienced a TRM was 72.5 (range: 61-83). This was most common following receipt of ABVD (n=7), of which 3 were attributed to BLI. One patient had a pre-treatment ECOG PS of 3, 3 (37.5%) had CIRS-G of ≥10 (each with ECOG PS 0-2), and 2 (25%) had impaired IADLs and/or known geriatric syndrome prior to frontline therapy. Three patients experienced TRM after presenting initially with ECOG PS 0-2, CIRS-G < 10, and intact ADLs.
A competing risk analysis was performed to compare deaths due to disease-related, treatment-related, and other causes, which showed significant improvement in disease-related survival following conventional cHL regimens (HR 0.29, p=0.02). While there was a suggestion that high CIRS-G or a geriatric syndrome were at increased risk for death due to alternative causes, this was not significant on multivariate analysis (Supplement).

DISCUSSION
To the best of our knowledge, these data represent one of the largest detailed analyses of older cHL patients in the modern era. Most patients in this study derived significant benefit from conventional cHL regimens, many of whom remained disease-free at time of last follow-up. We believe a significant portion of these individuals may be cured of their lymphoma as their responses have been observed beyond 5 years. Importantly, a number of these individuals with durable responses are above age 70, a group which if treated according to their chronological age may not have been offered potentially curative therapy. Given the substantial survival benefit seen with conventional therapies, undertreatment based solely on age thus presents a major risk to older cHL patients and such decision should require justification based on physiologic measures of fitness rather than age alone.
This in many ways echoes modern experiences treating older patients with diffuse large B cell lymphoma (DLBCL), where anthracycline-based therapy even with advanced patient age is a clear standard of care 25,26 . Due to low numbers, analysis was limited for those over age 80 in this cohort and warrants further study. Notably there is no mini-CHOP equivalent when prescribing an AVD-based regimen, and as mentioned there are significant differences in dose-density between AVD and CHOP (e.g., every 3-versus every 2-week chemotherapy, respectively) which can impact respective therapeutic outcomes in cHL 21,27 . Common dose modifications in older cHL patients include avoidance of chemotherapy escalation (no patient in this cohort received standard or escalated BEACOPP) as well as limiting bleomycin exposure to a maximum of 4 doses 23 . The latter was clearly not observed in this cohort, where the median bleomycin course was 7 doses and 86 of 136 ABVD recipients (63%) got 5 or more doses. Of note, BLI as an entity is not well-defined; we considered this diagnosis as any reported pulmonary toxicity in a bleomycin recipient, though numerous definitions have been employed with rates varying from 9.3 -91% across studies 9,28,29 . We interpret the relatively low rates of BLI in this context to be in part a consequence of this lack of consensus definition as well as a byproduct of retrospective collection, though administration of up to 4 bleomycin doses, which the current NCCN guidelines 23 list as appropriate for select older patients, appeared to be well-tolerated in this study.

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While older patients showed significant benefit overall with more aggressive therapy, this is not to say that age and agerelated factors do not impact treatment consideration. ADL impairment was seen more commonly with advancing age, and the impact of other geriatric measures on treatment efficacy by itself appears more nuanced and challenging to quantify. Toxicities showed a consistent relation to presence of geriatric syndromes and high burden of medical comorbidities, especially for toxicities which limited further planned therapies. Risk of such treatment-limiting toxicity showed a clear increase with advancing age, and the truncation of treatment length even by one cycle led to inferior responses and, by extension, to shorter PFS and OS. Of note, few patients (15%) received novel agents with frontline therapy, and it remains unclear whether 6 cycles will remain the optimal treatment duration when such agents are included in the upfront setting.
Only one patient in this large sampling of US academic cancer centers underwent a formal geriatric assessment prior to therapy. Despite rising calls for GA incorporation into clinical trials and routine care for older cancer patients across the board 13,18 , this lack of GA utilization may reflect the paucity of data regarding how such measures would inform therapy in lymphoma patients, including cHL. Several cHL studies have incorporated at least some GA components, with the emergence of medical comorbidities and ADL status as the most straightforward predictors of treatment outcome 10,11,15,16 . The recently reported Elderly Prognostic Index (EPI), developed for older patients with DLBCL, highlights one potential framework to consider 30 ; biological and functional differences likely exist between older populations with DLBCL and cHL, and further study is needed to assess the EPI's utility in the latter context. We compared the CIRS-G criteria used in the EPI and found total score to be more predictive of severe toxicity, though histologies differ between studies and our finding is potentially biased due to retrospective collection. Other factors such as gait speed, cognition, and nutrition have all been evaluated in geriatric hematology if not specifically in the context of cHL [31][32][33][34] , and all are notably omitted from the EPI. Our data suggest that routine clinical practice at least in large academic centers in the US rarely leverages these fitness markers at present to guide therapy for older cHL patients. This is a key area for future study, perhaps most importantly how GAs may help guide decisions of therapeutic intensity and which test(s) and scoring thresholds to use in order to optimize disease-related outcomes and tolerability with cHL-directed therapy.
This study had several important limitations, in part due to its retrospective design and the biases inherent to this approach. As mentioned, only one patient underwent CGA; we otherwise relied on retrospective collection of comorbidities, geriatric syndromes, and ADL impairment, which was dependent on provider documentation. As such, we suspect our study underestimates these geriatric measures by identifying only the most significant impairments, and that more sensitive documentation and/or higher utilization of geriatric assessments may produce different outcomes. Our cohort included low numbers of patients above age 80, which is likely due to referral patterns of this patient population to academic medical centers in the US. Regarding use of novel agents, this study was not powered to compare sequential versus concurrent administration of BV with AVD chemotherapy, though cross-trial comparisons suggest sequential administration may be better tolerated in older patients. We were also unable to adequately capture incidence, severity, and functional implications of treatment-related neuropathy; this remains of critical interest especially with BV-based therapy and warrants further study, especially with prolonged exposure. Given the alreadyextensive data collection for each patient per site, we were unable to collect additional treatment details such chemotherapy dose levels or growth factor use. Patients were all seen at academic medical centers; while a subset received at least some of their treatment at affiliated community sites, this does select for individuals willing and able to seek care at such locations.
Conventional chemotherapy (ABVD, AVD, or BV-AVD) should be considered standard of care for fit older patients with cHL, irrespective of chronological age. Risk of inferior outcomes due to treatment-limiting toxicity are higher in those with high medical comorbidities or a geriatric syndrome. Further prospective study is needed to define fitness in this context using geriatric assessments and to evaluate their potential role in guiding therapeutic intensity as frontline treatments evolve.