Mind the gap: anti–PD-1 salvage before autologous transplantation in classical Hodgkin lymphoma

In this issue of Haematologica, Tharmaseelan and colleagues report a multicenter European real-world analysis of programmed cell death protein 1 (PD-1) inhibitor-based salvage therapy for relapsed or refractory classical Hodgkin lymphoma, largely delivered with curative intent, frequently followed by consolidative transplantation.¹ Their experience reflects a rapidly evolving clinical reality: PD-1 blockade, once positioned primarily as later-line therapy, is now increasingly deployed earlier to deepen responses before high-dose therapy and autologous stem cell transplantation (HD-ASCT). However, a transplant-eligible second-line indication remains off-label in many jurisdictions, including the absence of European Medicines Agency (EMA) approval for intent-to-transplant use, a gap the authors explicitly highlight.

The real-world results validate phase II findings of efficacy while reflecting broader practice. In the reported cohort, 47 patients were treated across eight academic centers, with an overall response rate (ORR) and complete response (CR) rate of 90.9% and 47.7%, respectively. Higher CR rates were observed for anti-PD-1 plus chemotherapy (with 88.2% receiving P-GVD [pembrolizumab plus gemcitabine, vinorelbin, liposomal doxorubicin]) versus immune checkpoint inhibitor monotherapy approaches (61.3% vs. 10%).¹ While lower than the 86% to 95% CR rates reported in selected trials, these results likely reflect a broader case mix and pragmatic response assessment (Table 1).^1-4

Importantly, responses were frequently converted into durable disease control through consolidation: 91.5% of patients proceeded to transplant-based consolidation, most commonly HD-ASCT, and among evaluable patients after transplantation, 97% achieved a CR. Importantly, seven of eight patients in partial remission after pre-transplant immune checkpoint inhibitor monotherapy converted to a CR after transplant. The reported 1-year progression-free survival (PFS) of 83.9% and overall survival of 95.6% underscore that “imperfect” pre-transplant remission rates can still translate into excellent early outcomes when anti-PD-1-based salvage is integrated into an effective transplant pathway.¹

Why does this matter now? Because PD-1 blockade plus chemotherapy has repeatedly demonstrated the capacity to produce deep remissions quickly in patients for whom traditional platinum-based salvage delivered CR rates that were often only 40% to 50%. The pivotal P-GVD experience produced an ORR of 100% with a CR rate of 95% as second-line therapy, enabling most patients to proceed to ASCT.² Similarly, pembrolizumab plus ICE (ifosfamide, carboplatin, etoposide) yielded a CR rate of 86.5% and a 2-year PFS exceeding 85% in a multi-institutional phase II study.³ A response-adapted approach using nivolumab alone with selective intensification (nivolumab plus ICE) achieved an end-of-protocol ORR of 93% with a CR rate of 91%, with a 2-year PFS of 94% among those bridged directly to autologous transplantation.⁴ Collectively, these studies suggest that PD-1 blockade before autologous transplantation can deepen response and may improve long-term disease control compared to that achieved with chemotherapy alone. However, the field should not overlook the regulatory paradox that Tharmaseelan et al. bring into focus. Even as guidelines and practice have shifted toward checkpoint inhibitor-based salvage in transplant-eligible second-line settings, licensing frameworks still largely reflect the earlier era in which PD-1 antibodies were developed for later-line, post-transplant relapse or transplant-ineligible populations. Lack of an on-label indication complicates access, reimbursement, and uniform adoption, and it disincentivizes the randomized trials that would most cleanly define when immunotherapy should be paired with HD-ASCT, and when it might even safely replace it.^5-7

That replacement question is no longer theoretical. If anti-PD-1-based salvage can generate deep remissions, do all patients treated in this way still require HD-ASCT? The current real-world analysis cannot answer this because transplantation was integral to the observed outcomes and only a minority did not proceed to consolidation.¹ Yet the question is increasingly important given both shortterm and delayed toxicities of HD-ASCT. However, transplant-related inflammatory complications after recent anti-PD-1 exposure remain a concern. Following pembrolizumab-based salvage therapy prior to ASCT, phase II studies reported high rates of engraftment syndrome (e.g., 68% with P-GVD, and 1 fatal case among 42 patients treated with pembrolizumab-ICE), and larger lymphoma cohorts similarly showed substantially higher engraftment syndrome rates in patients with prior anti-PD-1 exposure compared with those who had not received prior PD-1 therapy.^2.3 In the series assessed by Tharmaseelan et al., severe immune-related adverse events were uncommon (10.6%), pneumonitis was reported in 4.3%, and engraftment syndrome occurred in 4.6% of transplanted patients. These rates are reassuring, but vigilance regarding inflammatory syndromes remains essential whenever PD-1 blockade precedes stem cell reinfusion.

Table 1.Summary of PD- 1 inhibitor-based second-line salvage regimens in relapsed or refractory classical Hodgkin lymphoma.

An alternative strategy that can reduce chemotherapy exposure is the combination of brentuximab vedotin (BV) with PD-1 blockade. BV plus nivolumab as first salvage achieved an ORR of 85% and a CR rate of 67%, with an estimated 3-year PFS of 77%, and particularly favorable outcomes among patients who proceeded directly to ASCT.⁸ While chemotherapy-free regimens may be appealing for selected patients with cumulative toxicity concerns, neuropathy, cost, and the possibility of slightly lower CR rates than anti-PD-1 plus multi-agent chemotherapy remain practical tradeoffs.⁸ The optimal approach is therefore not universal and should be guided by prior exposure, disease burden, clinical urgency, organ reserve, and the intended consolidative plan as well as shared decision-making with the patient (Figure 1). A key next step is randomized confirmation that adding PD-1 blockade to second-line chemotherapy improves response depth and clinically meaningful endpoints. The phase III ORIENT-21 trial (sintilimab plus ICE vs. placebo plus ICE) reported significantly higher complete remission rates with anti-PD-1 plus ICE (about 61% vs. 32%), with a favorable PFS trend.⁹ It is notable, however, that ASCT was not built into the ORIENT-21 strategy, which means the trial informs the benefit of immune checkpoint blockade but does not resolve the transplant versus no-transplant question.⁹

Figure 1.Pragmatic pathway for anti-PD-1-based salvage therapy with transplant intent in relapsed/refractory classical Hodgkin lymphoma. The algorithm highlights regimen selection (anti-PD-1 plus chemotherapy vs. anti-PD-1 plus brentuximab vedotin vs. anti-PD-1 monotherapy when chemotherapy is not feasible), response-adapted consolidation, and strategies after autologous stem cell transplantation. Side annotations summarize key efficacy signals, regulatory and safety considerations. PD-1. programmed cell death protein-1; r/r: relapsed/refractory; pembro: pembrolizumab; GVD: gemcitabine, vinorelbin, liposomal doxorubicin; ICE: ifosfamide, carboplatin, etoposide; nivo: nivolumab; BV: brentuximab vedotin; PET: positron emission tomography; CT: computed tomography; ctDNA: circulating tumor DNA; CR: complete response; PR: partial remission; PD: progressive disease; HD-ASCT: high-dose therapy with autologous stem cell transplantation.

In sum, Tharmaseelan and colleagues provide timely real-world confirmation that anti-PD-1-based salvage can be delivered at scale, can bridge most transplant-eligible patients to HD-ASCT, and can yield excellent early survival outcomes, despite lower response rates than in tightly controlled trials. The challenge now is to close the evidence-practice gap with randomized studies that define the best anti-PD-1-based regimen, establish the safest transplant timing, and identify the subset of patients for whom cure can be maintained with less toxicity, potentially even without HD-ASCT. Until then, anti-PD-1-based salvage before transplant represents both a transformative advance and a call for precision in how we deploy it.

Footnotes

• Received February 19, 2026
• Accepted February 26, 2026

Correspondence

D. Noerenberg daniel.noerenberg@charite.de

Disclosures

No conflicts of interest to disclose.