Abstract
Patients with classic Hodgkin lymphoma (cHL) with primary refractory disease, early relapse, or extranodal disease have a higher risk of relapse after salvage therapy and autologous stem cell transplant (ASCT). Post-ASCT brentuximab vedotin (BV) maintenance improved progression-free survival (PFS) in high-risk relapsed/refractory (R/R) cHL in the AETHERA trial, but subgroup analysis suggested that the benefit in patients transplanted in complete metabolic response (CMR) is unclear. In a large international real-world cohort, we assessed the efficacy of BV maintenance stratified by pre-ASCT metabolic response and by the number of clinical risk factors as defined in the AETHERA trial. Adult patients with R/R cHL who met AETHERA risk criteria were included. Utilizing propensity score analyses, PFS and OS were assessed overall and in subgroups of CMR (442 pts) and partial metabolic response (PMR, 249 pts). We observed that post-ASCT BV maintenance was associated with significantly higher PFS in the subgroup with PMR (5-year PFS: 59.6% vs 43.3% HR = 0.52, CI95: 0.33–0.82; p = 0.007). In the subgroup of patients with CMR, BV maintenance did not significantly improve PFS (5-year PFS: 75.8% vs 62.3% HR = 0.88, CI95: 0.59–1.32; p = 0.29). However, when focusing on patients with CMR treated post-FDA approval of BV, there was a significant PFS benefit observed in those treated with BV maintenance vs. not (5-year PFS: 81.2% vs 55.2% HR = 0.40, CI95: 0.22–0.72; p = 0.003). Overall, BV maintenance after ASCT remains an important therapy for high-risk R/R cHL patients, especially for those in PMR or those in CMR.
Subject terms: Hodgkin lymphoma, Hodgkin lymphoma
Introduction
Classic Hodgkin lymphoma (cHL) is curable with frontline chemotherapy in about 80–90% of cases [1, 2]. For patients who relapse, salvage therapy and autologous stem cell transplant (ASCT) lead to a 3-year freedom from treatment failure rate of 50–60% [3–6]. Patients with relapsed/refractory cHL (R/R cHL) who have high-risk features such as primary refractory disease (PRD), relapse within 1 year, and extranodal disease are more likely to relapse [3, 7–9].
Post-ASCT brentuximab vedotin (BV) maintenance has improved outcomes of high-risk R/R cHL [10, 11]. In the randomized phase 3 AETHERA trial enrolling patients with R/R cHL with primary refractory disease (PRD), relapse within 1 year of frontline therapy, and extranodal disease, post-ASCT BV maintenance led to 5-year progression-free survival (PFS) of 59% (CI95: 51–66), significantly higher than the placebo arm (5-year PFS of 41% (95% CI, 33–49)) [10, 11]. With long-term follow-up of the AETHERA trial, additional factors such as pre-ASCT partial response or stable disease, receipt of more than 1 line of salvage therapy, and presence of B symptoms were incorporated into survival analysis [11]. BV maintenance was associated with higher 5-year PFS in patients with 2 or more risk factors, but not in patients with only a single risk factor at relapse, with caveats of a small sample size [11].
Pre-ASCT fluorodeoxyglucose positron emission tomography (FDG-PET) response is significantly associated with post-ASCT survival [12–14]. Multiple studies have suggested that patients who undergo ASCT in complete metabolic response or with a negative FDG-PET scan have significantly higher PFS and overall survival (OS) compared to patients who undergo ASCT in partial metabolic response or persistently positive FDG-PET scan [12–14]. In a subgroup analysis of the AETHERA trial, the effect of BV maintenance on PFS was less substantial in patients who underwent ASCT in complete metabolic response (CMR- negative pre-ASCT PET scan), although the small available sample size may limit statistical power [10]. Hence, the impact of BV maintenance on patients who are transplanted in CMR is uncertain. Using a multicenter cohort, we sought to analyze efficacy of post-ASCT BV maintenance by pre-ASCT metabolic response. Furthermore, we sought to understand whether number of AETHERA risk factors would have differential effect on efficacy of post-ASCT BV maintenance in patients with pre-ASCT CMR. Herein, we report the final results of efficacy of BV maintenance in a large, international real-world cohort of high-risk R/R cHL patients with outcomes stratified by pre-ASCT metabolic response.
Methods
Patients
Consecutive patients with R/R cHL, who received salvage therapy and underwent ASCT, from January 1st, 2011, through December 31st, 2020, were enrolled in a multicenter international cohort from 18 participating institutions: 14 centers in the United States and 4 centers in the Czech Republic. Patients with nodular lymphocyte predominant Hodgkin lymphoma and patients who did not undergo ASCT were excluded. Out of this parent cohort, patients with the presence of at least one of the following high-risk features were deemed eligible and included in this study: presence of primary refractory disease (inability to achieve complete remission at the end of frontline therapy), relapse within 1 year of completing frontline therapy, or presence of extranodal disease. In retrospective studies, PD1-based salvage regimens are associated with improved post-ASCT outcomes compared to chemotherapy-based and BV-based regimens, and there is no significant difference in the post-ASCT outcomes of BV-based and chemotherapy-based salvage regimens [14, 15]. Therefore, we excluded patients who had received PD1-based salvage regimens from this study to prevent confounding from salvage regimens.
Data were collected through retrospective review of electronic health records at participating sites. Clinical variables were recorded, including age at relapse, sex, stage, bulky disease, receipt of BV maintenance, and the following risk factors reported in the AETHERA trial: primary refractory disease, early relapse within 1 year of completing frontline therapy, B symptoms at relapse, extranodal disease at relapse, pre-ASCT response by PET, and number of salvage therapies received.
Ethics approval and consent to participate
Mayo Clinic served as the leading site for this multicenter international effort. Data transfer agreements were executed between Mayo Clinic and all other participating sites according to each institution’s requirements. The study was approved by the Institutional Review Board (IRB, STUDY00012928) of each participating institution and conducted in accordance with the Declaration of Helsinki. Since this is a retrospective study, informed consent was waived by the IRB of each participating institution.
Objectives
Study objectives were to evaluate PFS and OS from the date of ASCT and assess if there were differences in these survival outcome distributions based on post-ASCT BV maintenance. PFS was defined as the time from ASCT to progression or death due to any cause, whichever occurred first; patients who were progression-free and alive at their last disease evaluation were censored at that time point. OS was defined as the time from ASCT to death due to any cause, with patients alive at last follow-up censored at that time.
Secondary objectives were to assess the influence of post-ASCT BV maintenance treatment on PFS and OS distributions in subgroups based on pre-ASCT metabolic response, as well as the number of AETHERA risk factors summarized above. Interactions between pre-ASCT metabolic response and the number of AETHERA risk factors were analyzed in each subgroup to assess the impact of increasing the number of AETHERA risk factors on the efficacy of BV maintenance in each subgroup.
Statistical analysis
Data met the assumptions of statistical tests and the normal distribution. Variance was the same between the two groups that were compared. Patient characteristics were summarized overall as well as by receipt of BV maintenance therapy; these variables were compared using chi-square tests for categorical data or Kruskal–Wallis tests for continuous measures between groups. Kaplan–Meier methods were used to estimate PFS and OS distributions overall and between groups of interest, as well as to estimate medians, 5-year outcomes, and 95% confidence intervals. Propensity score analyses were used to mitigate the influence of potential confounding factors in comparisons of survival between groups. Logistic regression models were used to generate propensity scores based on age at time of relapse, time to relapse, presence of extranodal disease, and number of salvage therapies (≥2 vs. <2). Inverse probability treatment weights (IPTW) were generated based on the propensity scores and whether the patient had received BV maintenance. These IPTW weight variables were then used in Cox regression models to evaluate the influence of treatment on survival outcomes (PFS, OS), and modified log-rank tests were used to accommodate the weighted model comparisons. Model-based hazard ratios (HRs) were also calculated from these weighted models along with corresponding 95% confidence intervals [16]. (See Supplementary Methods section for more details on the analytic approaches used.) Pre-ASCT PET-assessed metabolic response was also evaluated and included in this analysis cohort (1): complete metabolic response (CMR, defined as Deauville score 1–3) or FDG-PET negative, and (2) partial metabolic response (PMR, Deauville score 4–5) or FDG-PET positive. Differences in PFS and OS distributions based on BV maintenance were evaluated and compared in these propensity score-weighted models across all patients, but also in subgroups based on metabolic response and AETHERA risk factors, as well as in subgroup analyses focusing only on those treated post-FDA approval of BV therapy.
All analyses were done using SAS software version 9.4 and R statistical software version 4.2.2.
Results
Patient characteristics
A total of 1168 patients with R/R cHL had received salvage therapy and undergone ASCT between January 1st, 2010, and December 31st, 2021. Of these, 870 had at least 1 of the three major AETHERA risk factors and were eligible for inclusion in this analysis. Of those 870 patients, 818 had endpoint and characteristics data available to calculate propensity scores and evaluate survival outcomes. We excluded 85 patients who had received PD1 based salvage therapy, resulting in a total of 733 patients included in the final analysis cohort (Fig. 1). Of these 733 patients, the median age was 33.4 years (range: 26–45), 396 (54.0%) were male, 196 (26.7%) had bulky disease, 319 (43.5%) had B symptoms, 346 (47.2%) had extranodal disease, 195 (26.6%) received 2 or more lines of salvage therapies, 442 (60.3%) underwent ASCT in CMR, 249 (34.0%) underwent ASCT in PMR, 379 (51.8%) patients had 3 or more high-risk disease factors per the AETHERA trial. Twelve patients received BV-based chemoimmunotherapy in the frontline, and none of them received BV maintenance. The group of patients who received BV maintenance had a significantly higher proportion of male patients but no differences in other disease characteristics (Table 1). Further, 322 of the 733 patients were treated after FDA approval of BV (2015) in this setting, with 135 (42%) receiving BV maintenance post-ASCT, 118 (37%) received it in 2018 or afterward. Of the 369 treated prior to FDA approval of BV, only 35 (9.5%) received BV maintenance treatment. Supplementary Table 1 describes BV maintenance by institutions.
Fig. 1. Consort diagram.
*AETHERA criteria, eligibility criteria of AETHERA study: presence of one of these three risk factors: primary refractory disease, relapse within a year of frontline treatment, or extranodal disease.
Table 1.
Patient characteristics.
| Patient characteristics | No BV maintenance (total N = 556) | BV maintenance (total N = 177) | Total (N = 733) | P-value |
|---|---|---|---|---|
| Age at relapse in years | 0.4939a | |||
| Median | 33.9 | 32.6 | 33.4 | |
| IQR | 25.6, 46.0 | 26.4, 42.1 | 25.8, 45.4 | |
| Sex, n (%) | 0.0151b | |||
| F | 242 (43.5) | 94 (53.1) | 336 (45.8) | |
| M | 314 (56.5) | 82 (46.3) | 396 (54.0) | |
| Bulky disease, n (%) | 149 (26.8) | 47 (26.6) | 196 (26.7) | 0.3209b |
| B symptoms, n (%) | 242 (43.5) | 77 (43.5) | 319 (43.5) | 0.4466b |
| Extranodal disease, n (%) | 262 (47.1) | 84 (47.5) | 346 (47.2) | 0.9380b |
| No. therapies, n (%) | 0.5465b | |||
| <2 | 405 (72.8) | 133 (75.1) | 538 (73.4) | |
| ≥2 | 151 (27.2) | 44 (24.9) | 195 (26.6) | |
| FDA approval, n (%) | <0.0001b | |||
| Pre-approval | 362 (65.1) | 35 (19.8) | 397 (54.2) | |
| Post-approval | 194 (34.9) | 142 (80.2) | 336 (45.8) | |
| Final response, n (%) | 0.8066b | |||
| CMR | 334 (60.1) | 108 (61.0) | 442 (60.3) | |
| PMR | 187 (33.6) | 62 (35.0) | 249 (34.0) | |
| SD or NMR | 10 (1.8) | 1 (0.6) | 11 (1.5) | |
| PD | 20 (3.6) | 4 (2.3) | 24 (3.3) | |
| NA | 5 (0.9) | 2 (1.2) | 7 (1.0) | |
| Number of ATHERA risk factors, n (%) | 0.4034b | |||
| 1 | 95 (17.1) | 31 (17.5) | 126 (17.2) | |
| 2 | 183 (32.9) | 45 (25.4) | 228 (31.1) | |
| 3 | 140 (25.2) | 52 (29.4) | 192 (26.2) | |
| 4 | 94 (16.9) | 37 (20.9) | 131 (17.9) | |
| 5 | 33 (5.9) | 10 (5.6) | 43 (5.9) | |
| 6 | 11 (2.0) | 2 (1.1) | 13 (1.8) | |
| ATHERA risk factorsc, n (%) | 0.1015b | |||
| <3 | 278 (50.0) | 76 (42.9) | 354 (48.3) | |
| 3+ | 278 (50.0) | 101 (57.1) | 379 (51.7) | |
| Prior salvage therapy | ||||
| BV-based | 151 (27%) | 63 (35%) | 214 (29%) | 0.03b |
IQR interquartile range, BV brentuximab vedotin, F female, M male, CMR complete metabolic response, PMR partial metabolic response, SD stable disease, NMR no metabolic response, PD progressive disease, NA not available, n number of patients, % percentage of total patients.
aKruskal–Wallis p-value.
bChi-Square p-value.
cATHERA risk factors: primary refractory disease, early relapse, presence of B symptoms, pre-ASCT response, number of salvage therapy lines, and extranodal disease.
Clinical outcomes
Median follow-up for the analysis cohort was 3.9 years with a total of 295 PFS events and 113 OS events. There was no significant difference in the PFS and OS distributions between US patients and Czech patients (Supplementary Figs. 1 and 2).
For the overall cohort, receipt of BV maintenance was significantly associated with improved PFS and OS compared to no receipt of maintenance therapy (Fig. 2a, b). Patients who received BV maintenance had significantly better PFS than those without maintenance (HR = 0.71, CI95: 0.53–0.94; p = 0.014). The estimated 5-year PFS rate for those who received BV maintenance was 68.4% (CI95: 59.8–75.5) vs. 52.9% (CI95: 48.2–57.2) for those without maintenance. Moreover, patients who received BV maintenance had significantly higher 5-year OS of (93.1%, CI95: 85.1–96.9) compared to patients who did not receive BV maintenance (5-year OS: 79.9%, CI95: 75.7–83.5, HR = 0.47, CI95: 0.28–0.81; p = 0.025).
Fig. 2. Efficacy of post-ASCT BV maintenance in the entire cohort.
a PFS by BV maintenance. PFS progression-free survival, BV brentuximab vedotin, ASCT autologous stem cell transplant, HR hazard ratio, CI95 95% confidence interval. b OS by BV maintenance. OS overall survival, BV brentuximab vedotin, ASCT autologous stem cell transplant, HR hazard ratio, CI95 95% confidence interval.
Efficacy of BV maintenance by pre-ASCT PET-based response
In the subgroup of patients who underwent ASCT in CMR between 2010 through 2021, BV maintenance was associated with a trend toward higher PFS that did not reach statistical significance (HR = 0.88, CI95: 0.59–1.32; p = 0.29; Fig. 3a). Patients who had achieved CMR and received BV maintenance had an estimated 5-year PFS rate of 75.8% (CI95: 65.2–83.5) vs. 62.3% (CI95: 56.1–67.8) without maintenance. Similarly, BV maintenance did not significantly improve OS for CMR patients (HR = 0.48, CI95: 0.22–1.07; p = 0.16; Supplementary Fig. 3), with 5-year OS rates of 95.6% (CI95: 86.8–98.6) and 85.4% (CI95: 80.0–89.4), with and without maintenance, respectively.
Fig. 3. Effect of BV maintenance on PFS stratified by pre-ASCT metabolic response.
a Progression-free survival by BV maintenance in the subgroup of CMR. PFS progression-free survival, BV brentuximab vedotin, ASCT autologous stem cell transplant, CMR complete metabolic response, HR hazard ratio, CI95 95% confidence interval. b Progression-free survival by BV maintenance in the subgroup of PMR. PFS progression-free survival, BV brentuximab vedotin, ASCT autologous stem cell transplant, PMR partial metabolic response, HR hazard ratio, CI95 95% confidence interval.
In the subgroup of patients who underwent ASCT in PMR, BV maintenance was significantly associated with higher PFS (HR = 0.52, CI95: 0.33–0.82; p = 0.007; Fig. 3b). Patients who achieved a PMR pre-ASCT who received BV maintenance had an estimated 5-year PFS rate of 59.6% (CI95: 43.8–72.3) versus 43.3% (CI95: 35.9–50.5) without maintenance. There was no significant difference between the OS distributions of patients who received BV maintenance versus those who did not receive maintenance [5-year OS rates: 88.9% (CI95: 69.4–96.3) vs 76.0% (CI95: 68.5–82.0), respectively; HR = 0.54, CI95: 0.25–1.19; p = 0.12; Supplementary Fig. 4].
Finally, since receipt of BV maintenance therapy was strongly associated with the timing of therapy in relation to FDA approval of BV therapy in this setting, we conducted subgroup analyses focusing only on the 336 patients who received post-ASCT treatment after the FDA approval of BV therapy. The significant improvement in PFS for those who received BV maintenance (vs. not) still maintained significance with a similar effect (HR = 0.45, CI95: 0.30–0.67; p < 0.001), with corresponding 5-year PFS rates of 73.5% (CI95: 64.3–80.7) in those who received BV maintenance vs. 48.8% (CI95: 38.0–58.8) in those who did not. Significant differences in OS were also seen in this post-FDA approval cohort (5-year OS 95.7% vs 83.7%, HR = 0.26, CI95: 0.10–0.66; p = 0.006), although we note that the number of OS events in this subgroup (26 deaths) was more limited and thus requires caution in its interpretation. In the patients who underwent ASCT in CMR in post-FDA approval era, BV maintenance was associated with significant improvement in 5-year PFS (81.2%, CI95 69.2–88.9%) compared to no maintenance (55.2%, CI95 40.0–68.1%) (HR = 0.40, CI95: 0.22–0.72; p = 0.003; Fig. 4a), as well as those who had achieved a PMR (HR = 0.32, CI95: 0.17–0.61; p < 0.001; Supplementary Fig. 5). The limited number of death events in this post-FDA approval cohort did not effectively support formal evaluation of OS differences between treatment arms in these response-based subgroups, although a difference was observed in those who achieved a PMR prior to ASCT (HR = 0.16, CI95: 0.04–0.66; p = 0.008)
Fig. 4. Effect of BV maintenance on PFS in the subgroup of CMR stratified by FDA approval and AETHERA risk factors.
a Progression-free survival by BV maintenance in the subgroup of CMR-post-FDA approval era. PFS progression-free survival, BV brentuximab vedotin, ASCT autologous stem cell transplant, CMR complete metabolic response, HR hazard ratio, CI95 95% confidence interval. b Progression-free survival by BV maintenance in the subgroup of CMR with <3 AETHERA risk factors. Abbreviations: PFS progression-free survival, BV brentuximab vedotin, ASCT autologous stem cell transplant, CMR complete metabolic response, HR hazard ratio, CI95 95% confidence interval. c Progression-free survival by BV maintenance in the subgroup of CMR with 3 + AETHERA risk factors. PFS progression-free survival, BV brentuximab vedotin, ASCT autologous stem cell transplant, CMR complete metabolic response, HR hazard ratio, CI95 95% confidence interval.
Interaction between the number of AETHERA risk factors and the efficacy of BV maintenance
To assess whether the number of AETHERA risk factors affected the efficacy of BV maintenance within the subgroup of patients who achieved a CMR pre-ASCT, we analyzed interaction effects between BV maintenance and AETHERA risk factors within this subgroup. There were no significant interactions between receiving BV maintenance and an increasing number of AETHERA risk factors for CMR or for PMR patients (p = 0.41 and p = 0.12, respectively). However, in the subgroup of patients who were treated after ASCT in the post-FDA approval era, having 3 or more AETHERA risk factors was a significant effect modifier on PFS in patients who had achieved a CMR prior to ASCT (p = 0.008). In this subset of CMR patients with 3 or more AETHERA risk factors who were treated post-FDA approval, receipt of post-ASCT BV maintenance did not show significant differences in PFS. (HR = 0.84, CI95: 0.37–1.93; p = 0.68; Fig. 4b). However, we did observe a significant difference in PFS based on receipt of BV maintenance post-ASCT in those with fewer than 3 AETHERA risk factors and pre-ASCT CMR (HR = 0.15, CI95: 0.05–0.40; p < 0.001; Fig. 4c). Specifically, those CMR patients with <3 AETHERA risk factors treated in the post-FDA approval era who were treated with BV maintenance post-ASCT had significantly better PFS than those who did not, with 5-year PFS rates of 93.2% (CI95: 79.9–97.8) vs. 54.3% (CI95: 33.7–70.9), respectively. No significant interactions were observed with the number of AETHERA risk factors and maintenance therapy in those who achieved a PMR pre-ASCT. We have observed significant improvements in PFS between those who receive BV maintenance vs. those who do not, regardless of the number of AETHERA risk factors.
Discussion
In this multicenter real-world evidence (RWE) cohort, we observed that post-ASCT BV maintenance was associated with significantly higher PFS compared with no maintenance in patients with R/R cHL who are transplanted in PMR. In the subgroup of patients who were transplanted in CMR, BV maintenance was associated with a trend toward higher PFS that became statistically significant in the subgroup of patients treated in the post-FDA approval era. Receipt of BV maintenance was associated with superior OS in the entire population (p = 0.025). This is the first and largest RWE cohort to our knowledge to demonstrate differential effects of BV maintenance on PFS by pre-ASCT metabolic response using a more complex model utilizing propensity scores in weighted Cox regression models to account for potential confounding factors.
Subgroup analyses of the AETHERA trial showed that the benefit of post-ASCT BV maintenance is uncertain in patients who are transplanted CMR (pre-ASCT FDG negative) [10, 11]. Results of our study suggest the benefit of post-ASCT BV maintenance in these patients, specifically when we conducted this analysis in the subgroup of patients who were treated in the post-FDA approval era. Proportion of patients who received BV maintenance was substantially higher in post-FDA approval era, thereby leading to a more equitable distribution of patients between comparison groups and a more precise analysis. Furthermore, we observed that the efficacy of BV maintenance can be different based on the presence of high-risk features within the subgroup of CMR, specifically those treated in the more current timeframe of post-FDA approval. Patients who underwent ASCT in CMR and had 2 or fewer AETHERA risk features derived significant benefit from post-ASCT BV maintenance (p < 0.001), whereas those patients with 3 or more risk factors did not (p = 0.68). We also noted that patients who had achieved a PMR pre-ASCT significantly benefited from BV maintenance therapy regardless of the number of AETHERA risk factors they had. Thus, those who were transplanted in PMR as well as those transplanted in CMR with 2 or fewer AETHERA risk factors appear to be those who may benefit from post-ASCT BV maintenance. Conversely, the efficacy of BV maintenance in patients with 3 or more AETHERA risk factors who are transplanted in CMR is not as certain. This suggests that the adverse effect of AETHERA risk factors may not be able to fully compensated for by BV maintenance and may need more efficacious maintenance therapies such as PD1 inhibitors.
We did not have data regarding the emergence of peripheral neuropathy and BV dose interruptions related to it. Indeed, peripheral neuropathy and other toxicities of prolonged BV administration have been shown to compromise quality of life and frequently result in dose reductions or interruption [17–20]. However, real-world studies assessing the effects of BV dose reductions and interruptions on long-term PFS and OS suggest that outcomes are not affected by BV dose interruptions and reductions [18].
We observed that approximately 40% of patients with pre-ASCT CMR and 3 or more risk factors, or patients with pre-ASCT PMR, relapse and/or die at 5 years despite BV maintenance. These high-risk patients are at substantial risk of relapse even after BV maintenance and require investigational strategies to improve outcomes. These results are also relevant during shifting treatment paradigms for R/R cHL. PD1 inhibitor-based salvage regimens prior to ASCT have demonstrated PFS ranging from 80–90% in phase 2 trials and retrospective cohorts, improving upon platinum-based chemotherapy and BV-based regimens [14, 15, 21–24]. However, long-term outcomes of patients with high-risk features (3 + AETHERA risk factors) treated with PD1 inhibitor-based regimens have not been well characterized to date in large real-world cohorts. Post-ASCT maintenance with PD1 inhibitors with or without BV has shown post-ASCT PFS of 80–94% in R/R cHL patients. This may be a useful strategy in high-risk subgroups identified in this study, but larger trials and longer follow-up are required [25, 26]. As PD1 inhibitors move to the frontline setting, patients who progress on PD1 inhibitors are likely to be treated with BV-based salvage and maintenance strategies [24]. High-risk groups identified in this study may require novel strategies to improve outcomes in the era of changing treatment paradigms.
In contrast to the AETHERA trial, we observed that BV maintenance was associated with improved OS in our study. This is the first and largest study to our knowledge to demonstrate an OS benefit with BV maintenance in a real-world population. These results should be interpreted with caution, given the retrospective nature of this study, potential for selection bias, and increasing use of PD1 inhibitors following the approval of BV maintenance. Indeed, prior studies have demonstrated improved OS for R/R cHL after ASCT with increasing incorporation of novel agents, particularly PD1 inhibitors, in treatment paradigms [27–29].
Limitations of our study include the lack of data on BV dose and schedule, the lack of central review for PET response, and the exclusion of patients receiving PD1 inhibitor-based salvage regimens prior to ASCT. Although this is a very large cohort of R/R cHL patients, the subgroup of patients with PMR was too small to robustly analyze interactions between BV maintenance and AETHERA risk factors. Despite these limitations, our study identifies patient subgroups who are more likely to benefit from BV maintenance and may inform clinical practice and shared decision making with R/R cHL patients after ASCT.
Conclusion
In this large international cohort of patients with R/R cHL, post-ASCT BV maintenance was associated with improved PFS and OS in the entire population. In subgroup analyses, BV maintenance was associated with improved PFS for patients with pre-ASCT PMR. Within the subgroup of pre-ASCT CMR, the efficacy of BV maintenance was demonstrable in the post-FDA approval era and in patients with fewer than 3 AETHERA risk features. BV maintenance after ASCT remains an important therapy for high-risk R/R cHL patients.
Supplementary information
Author contributions
SD: Concept and design of the study, Data collection, data analysis, manuscript writing. SG: Statistical analyses, LDP: Statistical analyses, MAS: Data collection, manuscript writing. VB: Data collection, manuscript writing, AEM: Data collection, manuscript writing, GG: Data collection, manuscript writing; BK: Data collection, manuscript writing ; KD: Data collection, manuscript writing ; JA: Data collection, manuscript writing ; VPK: Data collection, manuscript writing; CC: Data collection, manuscript writing; BF: Data collection, manuscript writing; NS: Data collection, manuscript writing; HH: Data collection, manuscript writing; RS: Data collection, manuscript writing; UI: Data collection, manuscript writing; EIH: Data collection, manuscript writing; HS: Data collection, manuscript writing ; NWJ: Data collection, manuscript writing; DJ: Data collection, manuscript writing; KAB: Data collection, manuscript writing; CD: Data collection, manuscript writing; SI: Data collection, manuscript writing; KCR: Data collection, manuscript writing; FB: Data collection, manuscript writing; YC: Data collection, manuscript writing; RA: Data collection, manuscript writing; HM: Data collection, manuscript writing; AS: Data collection, manuscript writing; JM: Data collection, manuscript writing; VP: Concept and design of the study, Data collection, data analysis, manuscript writing; INM: Concept and design of the study, Data collection, data analysis, manuscript writing.
Funding
Research activities for the Czech Republic data is supported by the following grant: AZV NU22-03-00182 and MH CZ – DRO (FNOL, 00098892).
Data availability
For data related to this study, contact Micallef.Ivana@Mayo.edu.
Competing interests
SHD: Onclive: Honoraria; CurioScience: Honoraria; Merck: Research Funding; Beigene: Research Funding, Incyte: Research Funding. All funding except CurioScience was made to the institution. MAS: Gilead/Kite: Consultancy; ADC Therapeutics: Membership on an entity’s Board of Directors or advisory committees. VB: Citius: Research Funding; Incyte: Research Funding. AME: Incyte: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. BK: Genentech: Consultancy; Roche: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Lilly: Consultancy; Novartis: Consultancy; Kite: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy; Merck: Consultancy; ADCT: Consultancy. KD: BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Kite-Gilead: Research Funding; Hoffman La-Roche: Research Funding; Genmab: Research Funding. VPK: Ipsen: Research Funding. Ansell: Affimed: Membership on an entity’s Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; SeaGen: Research Funding; Takeda: Research Funding. HS: Incyte, Epizyme, Seattle Genetics, Loxo Oncology, Acerta: Research Funding; AbbVie, Seattle Genetics: Consultancy. Wagner-Johnston: Beigene: Consultancy; Merck: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding. Nowakowski: AbbVie Inc.: Consultancy; MorphoSys AG: Consultancy, Research Funding; TG Therapeutics Inc: Consultancy; ADC Therapeutics: Consultancy; Bantam Pharmaceutical, LLC: Consultancy; Segen: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; F. Hoffmann-La-Roche Limited: Consultancy; Constellation Pharmaceuticals: Consultancy; Kymera Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; MEI Pharma: Consultancy; Fate Therapeutics: Consultancy; Genentech: Consultancy; Blueprint Medicines Corporation: Consultancy; Celgene Corporation: Consultancy, Research Funding; Debiopharm: Consultancy; Daiichi Sankyo: Consultancy; Zai Laboratory: Consultancy; Ryvu Therapeutics: Consultancy; Selvita Inc: Consultancy; Curis: Consultancy, Research Funding; Incyte Corporation: Consultancy. HM: Eli Lilly: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees. DJ: Affimed, Daiichi Sankyo: Membership on an entity’s Board of Directors or advisory committees; AstraZeneca, ATARA Biotherapeutics, Debio Pharma, LOXO Pharmaceuticals, MEI Pharma, Regeneron Pharmaceuticals, Inc., Seagen, Trillium Pharmaceuticals: Research Funding. KAB: BMS: Research Funding; Seattle Genetics: Research Funding. CD: FATE Therapeutics: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Millenium: Research Funding; Merck: Consultancy, Research Funding; Gilead: Current equity holder in publicly-traded company, Research Funding; Genmab: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity’s Board of Directors or advisory committees; Incyte: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; I MAB: Consultancy, Current equity holder in private company; NYU Grossman School of Medicine/Perlmutter Cancer Center at NYU Langone Health: Current Employment; OverT Therapeutics: Current equity holder in private company; AbbVie: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding. VP: AbbVie: Consultancy; Eli Lilly: Consultancy; Novartis: Consultancy; Swixx: Consultancy, Speakers Bureau. RHA: Seattle Genetics: Research Funding; Cyteir: Research Funding; Regeneron: Research Funding; Autolus: Honoraria, Other: DSMB/Advisory Boards; Gilead: Research Funding; Merck: Other: Steering committee, DSMB/Advisory Boards, Research Funding; ADCT: Honoraria, Other: DSMB/Advisory Boards; BeiGene: Honoraria, Other: DSMB/Advisory Boards, Research Funding; Roche/Genentech: Honoraria, Other: Steering committee, DSMB/Advisory Boards, Research Funding.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Vit Prochazka, Ivana N. Micallef.
Supplementary information
The online version contains supplementary material available at https://doi.org/10.1038/s41408-026-01523-w.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
For data related to this study, contact Micallef.Ivana@Mayo.edu.