Treatment pathways and clinical outcomes in Hodgkin lymphoma outside Europe and North America: results from the international, multicenter, retrospective, B-HOLISTIC study

Abstract Information on Hodgkin lymphoma (HL) is mostly limited to Europe and North America. This real-world, retrospective study assessed treatment pathways and clinical outcomes in adults with stage IIB–IV classical HL receiving frontline treatment (n = 1598) or relapsed/refractory HL (RRHL, n = 426) in regions outside Europe and North America between January 2010 and December 2013. The primary endpoint was progression-free survival (PFS) in the RRHL group. Among patients with RRHL, 89.0% received salvage chemotherapy; most common regimen was etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP; 26.3%). Median PFS in the RRHL group was 13.2 months (95% confidence interval [CI]: 9.9–20.2) and was longer in patients with vs. without stem cell transplantation (SCT; 20.6 vs. 7.5 months; p = 0.0071). This large-scale study identified a lower PFS for RRHL in the rest of the world compared with Europe and North America, highlighting the need for novel targeted therapies and SCT earlier in the treatment continuum. Clinical trial registration: NCT03327571.


Introduction
The incidence and clinical outcome of Hodgkin lymphoma (HL) vary according to age, sex, race, genetics, and geographic location [1][2][3]. More than 80% of patients with classical HL (cHL) achieve long-term remission with contemporary frontline chemotherapy that is now response-adapted using positron emission tomography/ computed tomography (PET-CT) scans [4]. However, 30% of patients with advanced-stage disease (IIB-IV) experience relapse or have primary refractory disease [5]. For patients with relapsed/refractory HL (RRHL), salvage chemotherapy followed by stem cell transplantation (SCT) is the current standard of care [6,7]. Despite this, $50% of patients experience progressive disease, with poor prognosis and survival [8,9]. Disease characteristics, treatment pathways, and clinical outcomes in HL vary significantly between developed and developing regions, which may be related to differences in the availability and access to resources, countrylevel healthcare policies, and quality of cancer treatment [10]. In developing regions, the burden of RRHL is further complicated by late diagnosis, lack of awareness, gaps in using diagnostic techniques and novel therapeutic agents, and financial issues [11][12][13]. Moreover, in developing countries there is a distinct lack of reliable statistics and proper documentation of geographic differences in treatment and outcomes [10,14]. Health data on epidemiology, treatment, and outcome in HL from diverse geographic regions is important to understand the disease, determine if healthcare programs and treatment protocols from developed countries can be extrapolated to resource-limited settings, and to guide country-specific healthcare infrastructure.
Real-world information regarding treatment pathways and clinical outcomes in RRHL is mostly confined to studies in Europe and North America [9,[15][16][17][18][19]. Extrapolating these results to patient populations outside Europe and North America is confounded by the limited provision of basic healthcare and the availability of lifesaving chemotherapy regimens [10]. The few studies that have been undertaken in developing countries are limited by sample size, single-center experiences, data quality, or lack of comprehensive information on patients, treatment, or clinical outcomes [11,[20][21][22].
In the absence of robust real-world data outside Europe and North America, the B-CD30þ HOdgkin Lymphoma International Multi-center Retrospective Study of Treatment PractIces and OutComes (B-HOLISTIC) study assessed treatment pathways and clinical outcomes in RRHL and cHL in a large cohort of patients from East Asia, Latin America, the Middle East, and South Africa, Australia, and Russia. The primary results of the study are presented here with an emphasis on RRHL.

Materials and methods
Study design and patients B-HOLISTIC (ClinicalTrials.gov, NCT03327571) is an international, multicenter, observational study involving the retrospective review of medical records of patients with advanced-stage IIB-IV cHL who received frontline chemotherapy (frontline cHL), with or without radiotherapy, and/or patients diagnosed with RRHL. Participating centers (Supplementary Table 1) were selected based on the physician's interest, startup information, resource availability, and accessibility to a defined minimum data set (Supplementary Table 2) for all patients with RRHL and frontline cHL. Highly specialized treatment centers and physicians able to provide extensive retrospective data from hospitals, cancer institutes, and academic medical centers were included. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guideline for Good Clinical Practice. The relevant independent ethics committees or institutional review boards at each center approved the study. Patients provided written informed consent according to local regulations.
Data were collected retrospectively for all patients (!18 years) with RRHL or frontline cHL between 1 January 2010 and 31 December 2013, until death or last follow-up (whichever occurred first). Patients initially diagnosed as cHL, with subsequent progression to RRHL during the study, were included in both groups. Patients without a minimum study dataset or with participation in an interventional clinical trial at any stage of their HL management were ineligible. Patients were identified at each center using central management information systems or paper-based medical charts. Pseudonymized data were collected using a web-based electronic case report form and assessed for random selection, pooled analysis, and reporting. To adequately compare progression-free survival (PFS) across regions, the initial target sample size in each country was 50 patients in each group. However, because target patient numbers were not achievable in every center and country, oversampling was allowed in countries with larger populations of eligible patients.

Study endpoints
The primary endpoint was PFS in patients with RRHL, defined as the time from initiation of first salvage treatment for RRHL to first documentation of relapse or disease progression or death. Patients without a relapse or disease progression, and who did not die, were censored on the date when they were last known to be alive.
Secondary endpoints in the RRHL group included overall survival (OS), best clinical response (e.g. complete remission [CR], partial remission [PR], stable disease [SD], or progressive disease [PD]) to first salvage treatment, time to achieve objective response (CR or PR), number of lines of chemotherapy to achieve first response, duration of response, adverse events (AEs, assessed by severity and line of treatment), PFS in patients with and without SCT, and treatment pathways. OS in the RRHL group was defined as either (a) the time from the first relapse after frontline treatment to death in the relapsed group or (b) the time from initial diagnosis of cHL to death in the entire RRHL group to include patients with refractory disease and those not receiving any salvage treatment. Additionally, an exploratory analysis was performed for the RRHL group only (i.e. excluding patients initially diagnosed as cHL who subsequently progressed to RRHL) to understand the impact of inclusion criteria on PFS.
All the above parameters were also assessed in the frontline cHL group. In this group, OS was defined as the time from diagnosis of cHL to death, and PFS was defined as the time from initiation of frontline treatment to the first documentation of relapse, disease progression, or death.

Statistical analysis
All analyses for the overall population and individual regions were performed separately. Patient and disease characteristics, treatment pathways, and AEs were presented as descriptive statistics, including measures of central tendency (median) and spread (range or interquartile range) for continuous variables and frequency distributions (number, %) for categorical variables using the number of subjects with available data. PFS and OS were analyzed using the Kaplan-Meier method. PFS and OS between patient groups were compared by calculating p-values using the log-rank test from the Kaplan-Meier analysis, considering a 5% significance level. Both univariate and multivariate analyses were performed in each group to identify various patient-and disease-related risk factors for PFS and OS. For the multivariate analysis, only significant factors in the univariate analysis with a pvalue of <0.2 were retained in the final model, and hazard ratios (HRs) were estimated from Cox regression models. All analyses were conducted using Statistical Analysis System (SAS V R ) Software, Version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results
A total of 1703 patients (RRHL: n ¼ 426; frontline cHL: n ¼ 1598) from 74 centers in 13 countries across five regions participated in the study: East Asia (n ¼ 426), Latin America (n ¼ 366), the Middle East and South Africa (n ¼ 694), Australia (n ¼ 56), and Russia (n ¼ 161). The data cutoff date was 4 March 2020, with a median follow-up of 4.4 years (range: 0.03-134.7 months) for the RRHL group and 5.4 years (range: 0.2-118.6 months) for the frontline cHL group.

Patient demographics and characteristics in the RRHL group
The median age of patients with RRHL was 31.0 years (range: 15.0-92.0). At the regional level, Russia had the lowest median age (28. (Table 1). Overall, there were more males (56.8%), and the most prominent ethnicity was White/Caucasian (38.3%). The prevalence of stage III and stage IV disease at presentation was not very different (30.5 and 37.5%, respectively). PET or PET-CT scans at baseline were performed in 32.8% of patients in the RRHL group. The proportion of baseline PET or PET-CT scans performed was lowest in Russia (1/11; 9.1%) and highest in East Asia (33/81; 40.7%). In total, 177 (41.5%) patients had primary refractory disease only, 182 (42.7%) had relapsed disease only, and 67 (15.7%) had both refractory and relapsed disease.

Progression-free survival in the RRHL group
Median PFS in the RRHL group was 13.2 months (95% confidence interval [CI]: 9.9-20.2), ranging from 8.8 months (95% CI: 5.0-15.0) in the Middle East and South Africa to 37.4 months (95% CI: 6.5-not reached [NR]) in Russia ( Figure 1). A univariate analysis revealed that the following were associated with a higher risk of disease progression, relapse, or death: time to recurrence within 3-12 months after the end of first-line treatment, clinical stage III/IV at first RRHL diagnosis, hemoglobin level at first RRHL diagnosis (<10.5 g/dL for females and <12 g/dL for males), B symptoms at first RRHL diagnosis, and inadequate response to first salvage chemotherapy (defined as response < PR or PET positivity). However, in the adjusted multivariate model the risk of disease progression, relapse, or death was only statistically significant for the 'hemoglobin level at the time of RRHL diagnosis' (p ¼ 0.0002) and 'inadequate response to salvage chemotherapy' (p < 0.0001) ( Figure 2).

Treatment pathways in the RRHL group
Intensive first salvage chemotherapy was given to 89.0% of patients with RRHL. The most common salvage regimens were etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP; 26.3%), followed by cHL: classical Hodgkin lymphoma; CT: computed tomography; ECOG PS: Eastern Cooperative Oncology Group performance status; PET: positron emission tomography; RRHL: relapsed/refractory Hodgkin lymphoma. a 321 patients with an initial diagnosis of cHL progressed to RRHL during the study period and were included in both groups. b The 'Other' category in 'Ethnicity/race' combines the following categories: Black or African American, American Indian or Alaska Native, Native Hawaiian or another Pacific Islander, and Other. c There is no entry in the medical record or patient chart relating to an item as confirmed by the site. d Patients who were both refractory and relapsed were defined as the percentage of patients who were refractory during frontline treatment but relapsed sometime later after receiving and responding to second-line treatment or the percentage of patients who responded to frontline treatment but then relapsed, and when given second-or third-line treatment were refractory to treatment. e Josting score parameters are defined as time to relapse 12 months, clinical stage III or IV at relapse, anemia (hemoglobin <10.5 g/dL for females and <12 g/dL for males) at relapse. dexamethasone, cytarabine, cisplatin (DHAP; 17.5%) (           common frontline regimen (overall: 6.5%). Radiotherapy was administered as part of frontline treatment in 22.3% of patients.
Median PFS was not reached and CR was achieved in 60.6% of patients following frontline treatment, and the median time to response (CR or PR) following frontline treatment was 3.9 months (IQR: 2.6-5.6).  Table 3).

Discussion
The B-HOLISTIC study is the largest observational study assessing treatment pathways and long-term clinical outcomes in patients with HL in East Asia, Latin America, the Middle East and South Africa, Australia, and Russia. Considering the paucity of longterm clinical data in HL, particularly in regions outside Europe and North America, the present study contributes additional and relevant real-world data to the literature.
The salvage chemotherapy regimens used in the current study (ESHAP, DHAP, and ICE) were generally consistent with those reported in other real-world studies in RRHL from developed [9,18] and developing regions [20,23] around the time of this study. To improve outcomes in RRHL, novel agents and their combinations as salvage regimens have been increasingly used, especially in developed regions [15,16,18,19]. Real-world evidence suggests that, despite the advancement in treatment options, some developing regions still rely heavily on conventional salvage regimens for RRHL due to limitations associated with the availability, costs, and access to novel targeted therapies [10,20,23]. Given that the European Society for Medical Oncology and National Comprehensive Cancer Network guidelines do not recommend any specific salvage regimen for RRHL [6,7], and given the existing limitations with modern diagnostic techniques and novel agents in resource-limited settings [10,11,20,23], our study findings can help guide salvage treatment choices in RRHL in these developing regions.
In our RRHL cohort, the overall proportion of PET or PET-CT scans performed at baseline was low (32.8%) because the now-standard practice of PET-guided treatment was not common during 2010-2013. The low proportion of PET or PET-CT-guided treatment for RRHL still holds true for some developing regions with limited availability of PET-CTs [10,11,24].
The clinical outcomes of patients with RRHL in the current study were suboptimal compared with those reported in European and North American real-world studies conducted during a similar period [9,18,19,25]. This difference may be partly attributed to the lower use of novel agents in salvage settings in the current study. Additionally, the proportion of patients with refractory disease (41.5%) was higher than that reported in other studies (15%) [26][27][28]. This may have contributed to higher treatment resistance and inferior clinical outcomes. However, the 5-year PFS rate (33.9%) was in line with that reported in real-world studies in developing regions [11,21]. The risk of disease progression in RRHL was significantly associated with the hemoglobin level at the time of RRHL diagnosis and inadequate response to salvage chemotherapy, both of which have been previously reported as prognostic factors in RRHL patients [29,30]. Real-world clinical outcomes from regions outside Europe and North America are expected to be less favorable than outcomes in randomized controlled trials in Western countries where conventional and novel therapies and more advanced diagnostic tools are easily accessible. Nevertheless, they provide a benchmark for comparing outcomes in clinical practice.
We observed a significant improvement in PFS for patients with RRHL who underwent SCT compared with those who did not undergo SCT, which concurs with other real-world studies [21,25,31]. SCT following salvage chemotherapy is the current standard of care for patients with RRHL [6,7] and was undertaken in 52.1% of patients in the RRHL cohort of this study. Although the proportion of SCT was consistent with that in developed countries (44%) [16], the clinical outcomes with SCT were less optimal compared with those from developed regions [16,26,31]. The most important parameter predicting SCT outcomes is the pre-SCT complete metabolic response rate based on PET/PET-CT imaging [32,33], which was achieved in only 49% of patients with RRHL in this study. Prior evidence suggests that the 4-year event-free survival rates were better in transplanted patients with negative (77%) vs. positive (33%) functional imaging [34]. Accordingly, the low pre-SCT response rates are likely to have contributed to the lower PFS rates post-SCT in this study. Additionally, the delay in undergoing SCT due to limitations with its access in some of the developing countries could have influenced the suboptimal post-SCT outcomes.
The most common treatment regimens in the frontline cHL group were ABVD and BEACOPP, which is in line with treatment recommendations for cHL [6,7]. The 5-year PFS and OS rates (65.0 and 84.7%, respectively) were largely comparable to those reported in real-world studies of patients with advanced-stage cHL in Europe and North America [35,36] and in developing regions [10,22]. With Asian ethnicity as a reference, White/Caucasian and Other ethnicities were statistically associated with a longer time-to-first event from initiation of frontline treatment. However, this likely reflects socioeconomic differences and access to healthcare rather than observed ethnic differences.
This study has several limitations due to its retrospective nature. The data set spans from 2010 to 2013 and may not be applicable to the current HL treatment landscape, especially in developed regions. However, this study evaluated a large body of patients from several regions hereto underrepresented in the literature. The patients enrolled were predominantly from specialized treatment centers with the necessary resources to undertake clinical trials. Therefore, the results may not reflect the entire patient population in a certain region. Selection bias due to the retention of patients with minimal data was unavoidable. Clinical outcomes were based on the study investigator's assessment, without specific criteria provided. Country-and institution-specific differences in the choice of initial and subsequent therapies may have influenced clinical outcomes, making it difficult to generalize results. Additionally, information on the relative dose intensities (RDIs) for different chemotherapy regimens was not collected, which could have influenced overall clinical outcomes. However, current evidence in HL suggests that reduced RDI does not significantly impact outcomes [37], and generally RDI <85% is considered an issue in patients aged >60 years [38]. In our study, most patients were <60 years old. Additionally, this study does not address the delays from diagnosis to treatment initiation resulting from different referral patterns that may have influenced the poor clinical outcomes. However, limited evidence suggests that the diagnosis to treatment interval is not a significant prognostic factor for HL [39]. The AE data presented here may only include actively managed SAEs and AEs recorded in the medical records, and this may not include common or expected AEs not formally recorded, such as alopecia or nausea. Lastly, although this study focused on developing regions, some developed countries like Australia and South Korea are included, which may have influenced the overall results.
In conclusion, PFS rates for RRHL patients from the developing regions in this study are lower than those reported in real-world studies from Europe and North America. Recent evidence has shown that using novel agents in earlier treatment lines has clinical benefits in HL patients [15,18,19]. The results among high-risk RRHL patients emphasize the importance of considering the use of novel targeted therapies in salvage settings as well as timely SCT. However, given that the management of patients with HL has changed dramatically since 2013, further investigation into diagnostic modalities and treatment pathways in developing regions is needed.