Bendamustine supercharge plus brentuximab vedotin as early salvage therapy following failure to obtain complete metabolic remission after two cycles of adriamycin–bleomycin–vinblastine–dacarbazine for classic Hodgkin lymphoma in patients aged ≤ 60 years: Long-term efficacy results of a retrospective multicentre study

To the editor,

Treatment intensification with salvage therapy, high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) is the best course of action for patients ≤60 years with classic Hodgkin lymphoma (c-HL) failing to obtain complete metabolic remission (CMR) to adriamycin–bleomycin–vinblastine–dacarbazine (ABVD). However, its clinical impact in patients showing interim 2-deoxy-2[F-18] fluoro-D-glucose positron emission tomography (i-FDG-PET) positive scans after only two cycles remains to be confirmed.^{1, 2} In these patients with primary chemo-refractory illness, the prognosis is dismal with disease progression within 12 months from ASCT; the reported 2-year progression-free survival (PFS) reaches the rates of 28%–66% following conventional salvage regimens.^{1, 2} Thus, optimizing the results of salvage regimens before ASCT is still essential to provide the best chance of recovery for most patients with refractory c-HL.¹ The combination of bendamustine (B) at 90 mg/m² iv on days 1–2 and brentuximab vedotin (Bv) at 1.8 mg/kg iv on day 1 of a 21-day cycle has been investigated, and clinical trials with cohorts of refractory/relapsed patients showed a manageable toxicity profile and an overall response rate (ORR) of 80% (average CMR, 70%) following a median of four cycles.^3-5 Follow-up data tempered the expectations: pooled 2-year PFS rate of about 50%. Emerging in vitro data allowed the speculation that high-dose B, administered right after Bv, facilitated the anti-CD30–auristatin conjugates pharmacodynamics and thus targeted delivery of anticancer therapeutics.^6-8 Phase II and real-life studies in this setting presented convincing evidence that an increasing dosage of B held promising anticancer activity with no dose-limiting toxicity.^9-12 Thus, a compelling case is presented for using early treatment intensification with bendamustine supercharge (Bs) that maximizes the synergistic effects with Bv and raises the remission rates obtained with either drug in the pre-ASCT setting after failure of front-line ABVD. Therefore, we undertook a multicentre retrospective study involving large southern Italy tertiary centres with long-standing experience in HL cure: the Hematology Unit of the Federico II University, Oncology Unit of the Federico II University Medical School of Naples and Hematology Unit of the Antonio Cardarelli Hospital of National Importance in Naples, Italy.

We acquired consistent information about a selected population of patients aged ≥18 and ≤60 years with c-HL and positive FDG-PET scans following two courses of ABVD from 1 September 2013 to 1 September 2023 (view study design and inclusion criteria in the Data S1). The sequential combination (every 3 weeks) of Bv standard dose and Bs, named ‘Bv + Bs₂₁’ regimen, for four courses as early salvage treatment intensification (Bv + Bs₂₁ regimen and relative prophylaxis is shown in the Data S1 and in Figure S1) followed by HDT and ASCT was used as the routine first-line salvage regimen in the three hospital units for patients aged ≤60 years with c-HL and i-FDG-PET positivity.^{9, 12} The primary objective of the study was the 5-year PFS of Bv + Bs₂₁ regimen followed by HDT and ASCT in a selected population of high-risk c-HL adult patients who were primary refractory to ABVD, as timely identified by i-FDG-PET scans interpreted with the Deauville scale (DS) 5-point scoring system .¹³ Secondary end-points were overall survival (OS), end-of-treatment (EoT) response and toxicity following the fourth cycle of Bv + Bs₂₁,¹⁴ peripheral blood stem cell (PBSC) collection and bridge to transplant, and feasibility of the Bv + Bs₂₁ regimen (outcomes analysis in the Data S1). As routinely performed in the participating Institutions, all patients underwent PBSC collection after two Bv + Bs₂₁ courses. At any time beyond cycle 4, those who achieved at least a partial metabolic response (PMR) at FDG-PET scans according to the Lugano criteria proceeded to ASCT (Figure S1). Statistical analysis details are in the Data S1.

On initial review of the medical records or database of the three haematology units, 50 consecutive patients ≤60 years with c-HL and no response/stable disease or progression after two cycles of front-line ABVD were identified among 330 newly diagnosed c-HL patients (≥18 years aged) treated from 1 September 2013 to 1 September 2023; 8% were excluded due to other salvage regimens and/or insufficient information. The remaining 46 patients constituted the entire population included in the final assessment; a diagram in Figure 1 summarizes the flow of patients throughout the study. Patients' characteristics are detailed in Table 1. All patients had positive FDG-PET with DS scores of 4 (n = 12) or 5 (n = 34) and were scheduled to receive four courses of Bv + Bs₂₁ as 3-day outpatient iv infusions of 1.8 mg/kg Bv on day 1 and of B at a fixed dose of 120 mg/m²/day (days 2 and 3), and all received routine prophylaxis (Figure S1). Regarding Bv + Bs₂₁ regimen feasibility, all patients received more than 85% of the planned treatment: the median dose intensity was 100% (range: 88.6–102.4%) for Bv and 100% (range: 88.7%–102.4%) for B. After four cycles of Bv + Bs₂₁, all patients (n = 46) were assessable for disease response (Table S1). The ORR was 100% with 42 patients obtaining CMR (91%) and four obtaining PMR (9%). The full courses of the salvage regimen served as a bridge to ASCT in 42 patients (91%) while four patients (9%) did not proceed to ASCT due to patient preference (Figure 1). All patients had successful engraftment. During post-transplant follow-up, five patients relapsed; the four patients refusing the procedure were in CMR after Bv + Bs₂₁ but then 50% relapsed. Four patients died during post-salvage follow-up at a median time of 20 months (see Data S1). The 5-year PFS rate at a median follow-up of 60 months (range: 6–132 months) from Bv + Bs₂₁ administration for the overall population was 82% (95% confidence interval [C.I.], 0.91–0.65; Figure 2). With a median follow-up of 60 months (range: 6–132 months) from Bv + Bs₂₁ administration, the 5-year OS rate was 90% (95% C.I, 0.96–0.76) for the entire population analysed (Figure 2). The survival analysis was stratified according to the FDG-PET DS pre-salvage treatment score results and the analysis findings are reported in Figures S2 and S3 and in the Data S1. PBSC collection, in terms of percentage of success and amount of PBSC, was evaluated for all patients (n = 46). All patients underwent PBSC mobilization after two courses of Bv + Bs₂₁ (details in Table S1). Both mobilization and harvest were successful in all cases, with a median CD34+ cells/kg yield of 4.1 × 10⁶ (range: 1.9–5.1 × 10⁶).

Regarding treatment toxicity, the most common haematological adverse event reported was febrile neutropenia involving five patients (11%); CMV reactivation with viraemia was recorded in five patients successfully treated with valganciclovir pre-emptive therapy. Notably, due to the specific premedication (Figure S1) against acute toxicity during the iv administration of Bv + Bs₂₁, serious infusion-related reactions were reported only for three patients (6%) during the first cycle of administration (Table S2). Overall, a total of five patients (11%) temporarily discontinued therapy due to treatment-related adverse events. In particular, at least one Bv and/or Bs dose modification in terms of delays (n = 3) or reductions (n = 2) was recorded.

To the best of our knowledge, this is the first study to present long-term data of the clinical effectiveness of Bv + Bs₂₁ combination as a very early first salvage regimen in a selected population of relatively young and fit patients with high-risk HL (primary refractory to ABVD), considering as the primary end-point the 5-year PFS. In comparison with the standard scheme,^3-5 we have employed the increased B dose (120 mg/m²) adjusting the timing of administration (after Bv), as already reported.^{9, 12} The regimen was promptly employed in these patients with i-FDG-PET positive scans after only two cycles of ABVD characterized by very poor prognostic factors for primary refractory disease which strongly correlates with the response to salvage therapy and survival.¹⁵ Conventional salvage chemotherapy shows no significant differences regarding the outcome in the same subset of high-risk patients: PFS—40%–50% and OS—60%–70% at 5 years following ASCT.^16-18

Our survival results compare favourably with data reported from studies with similar treatment schemes in primary refractory/relapsed patients: 3-year OS and PFS of 92% and 60.3%, respectively, for La Casce et al.⁷ and 3-year OS and PFS of 88.1% and 67%, respectively, for Broccoli et al.¹⁹ (both studies with relatively short median follow-up). In our study, Bv + Bs₂₁ proved highly effective, resulting in significant rates of overall and complete response (100% ORR with CMR of 91%) and an overall 5-year PFS of 82% and OS of 90% with a median follow-up of 60 months was reported. Moreover, a substantial percentage of patients (91%) received ASCT after the Bv + Bs₂₁ regimen. This encouraging data were largely due to the sustained response and lack of disease progression during the pre-transplantation period. Thus, this salvage regimen has a twofold advantage: initially reducing tumour burden and subsequently prolonging the duration of metabolic response. Indeed, the regimen's safety profile was notable, but a comprehensive approach to primary prophylaxis with broad-spectrum supportive care and close clinical and laboratory monitoring, especially for CMV-DNA, is crucial.⁹ Bone marrow toxicity that could potentially compromise subsequent stem cell mobilization was minimal, and this was corroborated by successful mobilization and harvest procedures in all patients.

Our study has limitations that must be pointed out: the small sample size and retrospective design that limit the power in assessing adverse events, and lack of data regarding tissue biopsy repetition for patients with DS5 at i-FDG-PET. In addition, both Bv and B were used as off-label due to their very early employment (after only 2 ABVD cycles) in contrast with AIFA (Italian Agency of the drug) and EMA (European Medicine Agency) regulations.²⁰ Finally, other studies are needed to demonstrate leverage from therapy with Bv + Bs₂₁ in patients with R/R cHL and aged >60 years.

The potential benefits of Bv + Bs₂₁ followed by HDT and ASCT strategy, contrasting with the convention of delaying salvage therapy until disease progression/resistance to the full induction therapy, include improved long-term outcomes due to reduced resistance to salvage therapy and a potentially lower incidence of both early and late adverse events. In conclusion, this is a proof-of-concept study that needs further validation from large prospective phase II studies.

No funding was received for the study.

C. Giordano and M. Picardi designed the research; C. Giordano performed the research and wrote the paper; A. Vincenzi, L. De Fazio, M. Lamagna, R. Reina, A. Scarpa, A. Lombardi, E. Vigliar, G. Troncone, M. Mascolo, C. Mainolfi, V. Damiano, R. Bianco, F. Trastulli, F. Ronconi, and A. Salemme collected data; C. Giordano and N. Pugliese analysed data; F. Pane and M. Picardi performed the final revision of the manuscript.

Authors have no relevant financial conflicts of interest to declare.

All necessary approvals were obtained from our ethics committee, and the study was undertaken in accordance with the Declaration of Helsinki.

All necessary approvals were obtained from our ethics committee (approval protocol number: 92/2024) and ClinicalTrials.gov (number, NCT06295211).

All patients provided written informed consent for personal data analysis for research purposes.