Brentuximab vedotin consolidation after autologous stem cell transplantation for Hodgkin lymphoma: A Fondazione Italiana Linfomi real‐life experience

Abstract The standard management for relapsed or refractory classical Hodgkin lymphoma (cHL) is salvage therapy followed by autologous stem cell transplantation (ASCT). This strategy allows almost 50% of patients to be cured. Post‐ASCT maintenance treatment with brentuximab vedotin (BV) confers improved progression‐free survival (PFS) to cHL patients at high risk of relapse. We investigated the outcome of 105 cHL patients receiving post‐ASCT BV maintenance in the real‐life setting of 23 Italian hematology centers. This population included naïve patients and those previously exposed to BV. Median follow‐up was 20 months. Patients presented a median of two lines of treatment pre‐ASCT, with 51% receiving BV. Twenty‐nine percent of patients had at least two high‐risk factors (refractory disease, complete response [CR] less than 12 months, extranodal disease at relapse), while 16% presented none. At PET‐CT, a Deauville score (DS) of 1–3 was reported in 75% and 78% of pre‐ and post‐ASCT evaluations, respectively. Grade 3–4 adverse events (AEs), mainly peripheral neuropathy, were observed in 16% of patients. Three‐year PFS and overall survival (OS) were 62% and 86%, respectively. According to BV exposure, 3‐year PFS and OS were 54% and 71%, respectively, for naïve and 77% and 96%, respectively, for previously exposed patients. Refractory disease (hazard ratio [HR] 4.46; p = 0.003) and post‐ASCT DS 4–5 (HR 3.14; p = 0.005) were the only two factors significantly associated with PFS reduction in multivariable analysis. Post‐ASCT BV maintenance is an effective, safe treatment option for cHL naïve patients and those previously exposed to BV.


| INTRODUCTION
Classical Hodgkin lymphoma (cHL) is a highly curable disease, with complete remission (CR) rates of 75%-90% after standard first line treatment. 1,2 However, for the non-negligible proportion of patients presenting relapsed or refractory disease, the best treatment option is salvage therapy, followed by consolidation with autologous hematopoietic stem cell transplantation (ASCT), 3 which cures almost 50% of these patients. 4,5 Several studies have analyzed the risk factors associated with poor outcomes in this setting, finding that primary refractory disease, CR duration of less than 12 months, and extranodal disease at relapse were related to reduced progression-free survival (PFS) rates. [6][7][8] More recently, the predictive role of positron emission tomography (PET)-computed tomography (CT) has been validated, with worse outcomes reported for patients presenting metabolically active disease before ASCT. 9 During past years, several attempts have been done to change standard strategy and improve the outcome for these patients, unsuccessfully. [10][11][12][13] Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody, initially approved for cHL patients with progressive disease after ASCT. A phase 2 trial found that, when used as a single agent, BV determined an overall response rate (ORR) and a CR rate of 75% and 34%, respectively. 14 In the randomized phase 3 AETHERA trial, cHL patients at high risk of progression or relapse after ASCT (at least one of the following criteria: primary refractory disease, CR < 12 months, extranodal disease at relapse) were randomized to receive either consolidation treatment with BV or placebo. BV consolidation treatment was associated with a significant reduction in the risk of progression compared to placebo, with 5-year PFS rates of 59% and 41%, respectively, leading to BV's approval in this setting. 15,16 There are only limited real-word data on the use of BV as post-ASCT consolidation treatment: the French AMAHRELIS study, presented at the 2020 American Society of Hematology (ASH) congress, and a MASSARO ET AL.
-33 recently published Turkish experience. 17,18 It must be underlined that the AETHERA trial excluded patients who had previously received BV. Based on the data emerging on BV efficacy in the salvage setting, both as a single agent and in combination with chemotherapy, an increasing number of patients now receive BV before ASCT. [19][20][21][22] However, an issue to be clarified concerns toxicity, and particularly peripheral neuropathy, which was observed in 67% of the patients in the AETHERA trial, leading to treatment discontinuation in 23% of cases. 15 We report here the results of a multicenter real-life retrospective study on 105 cHL patients treated with BV as consolidation after ASCT.

| MATERIALS AND METHODS
This was a multicenter retrospective study by the Fondazione Italiana Linfomi (FIL) on patients with relapsed or refractory cHL treated with BV in 23 Italian centers between April 2011 and August 2020. Patients were eligible if they had received at least two cycles of BV after ASCT, regardless of prior lines of treatment. The following data were collected at diagnosis and relapse by the treating physician from hospital records: age, sex, prognostic scores (EORTC score for limited-stage disease, IPS for advanced-stage disease), B symptoms (fever, night sweats, and weight loss of more than 10% of body mass in the previous 6 months), Ann Arbor stage and risk factors for poor PFS (refractory disease, CR < 12 months, extranodal disease at relapse), and total number of lines of treatment prior to ASCT. Data on disease response from PET-CT or CT alone were collected after each line of treatment, and both before and after ASCT. For BV consolidation treatment, we collected the following data: the number of cycles administered, any dose reduction, and any adverse event (AE) causing premature interruption or discontinuation when applicable, including allergic reactions, infections, peripheral neuropathy, liver toxicity, and fatigue. Data concerning the type of treatment for relapse after ASCT were recorded, even when the patient proceeded to allogeneic SCT (allo-SCT). Patient follow-up was censored at the most recent hospital visit or death. The data were locked and analyzed in September 2020.
As per approved treatment label in Italy, BV had to be administered at 1.8 mg/kg once every 3 weeks for up to 16 doses.
The primary aim of this study was to determine the PFS taking as reference data reported in the AETHERA trial, using data from the placebo arm of that study to assess the benefit deriving from BV consolidation strategy.
The primary study endpoint was PFS, which was calculated from the initiation of BV after ASCT to the time of relapse, disease progression, or death, whichever occurred first. The secondary endpoints were OS, overall response (OR) and CR, AE rates. OS was calculated from the initiation of BV after ASCT according to validated criteria. 23 Response rates were defined by the treating physician based on either PET-CT or standard CT. AE grades are reported according to the Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0. We recorded the therapeutic approach to peripheral neuropathy and the AE grade after the specific treatment.
Continuous covariates are summarized with the median and range, categorical covariates as absolute value and percent proportions. PFS and OS were calculated using the Kaplan-Meier method. A Cox proportional hazards model was used to estimate the HR and its confidence interval at 95% (95% CI). Univariable and multivariable analyses were carried out by means of Cox proportional hazards regression. All tests were two-sided.

| RESULTS
We included 105 patients in this retrospective analysis, with a median follow-up time of 20 months (range 2-108). Baseline features are summarized in Table 1 Characteristics of BV consolidation are listed in Table 2. Among the grade 3-4 AEs leading to treatment interruption, we recorded eight peripheral neuropathies (PN), four infections, two infusion reactions, and one liver toxicity (Table 3). Median time to discontinuation was 7 months.   we recorded a higher number of conversions to CR during BV consolidation therapy in BV naïve patients (9/15; 60%) than in those already exposed to BV before ASCT (3/7; 43%). Among the whole population receiving maintenance, the median time to best response was 4 months.  (Table 6).

| DISCUSSION
The use of BV as post-ASCT consolidation treatment has been validated in the 2015 AETHERA trial, which reported its advantage in terms of PFS compared to the placebo arm.
In our series, after a median follow-up of 20 months, we recorded an estimated 3-year PFS of 62%, which we consider comparable to the 2-and 5-year PFS rate of 63% and 59%, respectively, reported in the first and in the extended follow-up publications of the AETHERA trial. 15,16 Whether consolidation with BV confers an OS advantage still remains a matter of debate. The first AETHERA publication did not show any differences in OS between the two arms, while its recent update did not analyze the data due to the lack of sufficient events to be able to draw any significant conclusions.
We report an estimated 3-year OS of 86%, which appears to be similar to the survival curves from the AETHERA trial and which confirms the excellent result achieved with the available salvage therapies in HL.
It is important to underline that, differently from the AETHERA trial, our study included 16% of patients who did not present any high-risk feature. Nevertheless, our population presented a high frequency of poor prognostic features: 54% had received at least two prior lines of salvage therapy before ASCT and 29% had at least two pre-ASCT high-risk features.
Overall, 54% of patients completed the 16 cycles of BV treatment, which is in line with previous reports. It is important to note that almost one third of patients discontinued treatment due to physician decision or to proceed to further consolidation with allo-SCT. Currently, given the greater access to checkpoint inhibitors and a broader knowledge of how to manage drug-specific toxicities, it -37 is reasonable to believe that the entire consolidation program could be carried out in a higher proportion of patients.
Of note, we also included 54 patients who received BV before ASCT, mostly due to an incomplete response after salvage therapy that would have limited the success rate of ASCT consolidation. Our study did not permit an assessment of the efficacy of BV pre-ASCT but was able to investigate the toxicity and efficacy of BV pre-ASCT compared to that of standard post-ASCT BV consolidation.
Based on our results, administrating BV pre-ASCT was not associated with any change in the efficacy of standard BV consolidation.
Moreover, the safety profile of standard BV consolidation was not affected by prior exposure to the same drug.
Regarding toxicity, we chose to describe non-hematological events, specifically peripheral neurologic events and their evolution, because of a specific interest in PN associated with BV use. Abbreviations: ASCT, autologous stem cell transplantation; BV, brentuximab vedotin; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

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In conclusion, BV treatment as post-ASCT consolidation represents an effective, safe option for HL patients even in the real-life setting. The treatment also seems to be effective in patients already exposed to the drug before ASCT, a condition frequently seen in clinical practice. Further data are needed to evaluate whether the treatment confers an advantage in terms of OS, especially considering new available post-ASCT treatment.

Open Access Funding provided by Universita degli Studi di Modena e
Reggio Emilia within the CRUI-CARE Agreement.

DATA AVAILABILTY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1002/hon.2939.