Optimizing salvage therapy for Hodgkin lymphoma: progress and future challenges

ABSTRACT

Introduction

Despite clear advancements in the management of classical Hodgkin lymphoma (cHL) over the past decade including better risk stratification, the usage of 18F-flurodeoxyglucose positron emission tomography (FDG-PET)-guided approaches and incorporation of novel agents, approximately one-third of the patients will relapse. Important themes have been recently explored in the first salvage setting including the recognition of the positive prognostic value of a negative pre-autologous stem cell transplantation (ASCT) FDG-PET response and the incorporation of novel agents such as brentuximab vedotin (BV) and immune checkpoint inhibitors (CPIs) as salvage regimens to improve patient outcomes.

Areas covered

The evolving treatment paradigm in optimizing salvage therapy in relapsed refractory cHL (RR-cHL) is discussed, including a vision to the future. The methodology included a literature search on PubMed using keywords. Selected articles were screened and evaluated by the authors of this review.

Expert opinion

Achieving a complete remission by FDG-PET pre-ASCT is the most important prognostic factor in obtaining disease control and subsequent cure, and therefore should be a key goal of any salvage regimen. Although data from randomized controlled trials are currently lacking, retrospective evidence demonstrate superior event free survival with CPI-based regimens compared to conventional chemotherapy or BV-based therapy.

KEYWORDS:

• Hodgkin lymphoma
• salvage therapy
• novel agents
• brentuximab vedotin
• checkpoint inhibitors
• relapsed and refractory

Article highlights

• There is still an opportunity to further improve the outcomes for relapsed refractory Hodgkin lymphoma.

• At present, salvage therapy followed by autologous stem cell transplantation remains the standard of care for transplant eligible patients in first relapse, however no RCTs comparing salvage regimens are available to guide therapeutic decisions.

• More, recently, two important themes are paving the way in the first salvage setting with the intention to advance outcomes.

  1. It has become evident that pre-ASCT FDG-PET negativity is one of the strongest predictors of post-transplant outcomes.

  2. The incorporation of novel agent such as BV and CPIs to conventional salvage regimens or in combination pre-ASCT are being actively investigated and have demonstrated favorable ORR and CR rates. However, the addition of such agents to conventional chemotherapy has raised concern for increased hematologic toxicity and the possibility of uncommon immune-related adverse events.

• Retrospective evidence evaluating salvage regimens demonstrate superior event free survival with CPI-based regimens compared to conventional chemotherapy, BV and chemotherapy and BV monotherapy.

• The ongoing RCTs comparing BV-ESHAP versus ESHAP and pembolizumab + BV versus GDP are eagerly awaited.

• In the era of novel salvage regimens, the role for high dose chemotherapy and ASCT as well as BV maintenance is uncertain. The ongoing Part 2 of the pembrolizumab-GVD clinical trial and the BRESELIBET study (NCT04378647) may provide some clarity.

• Novel agents are increasingly being established in the frontline treatment of advanced stage cHL. The integration of novel agents both BV (currently stand of care in some countries) and CPIs (not yet established) to front-line treatment creates further uncertainty regarding the optimal salvage regimen and sequencing strategy of novel agents.

• Although limited by small patient numbers, re-treatment with BV and CPIs remains plausible in those patients who have had an objective response with prior exposure to such agents.

Declaration of interest

J Kuruvilla has received honoraria from AbbVie, Bristol Myers Squibb, Amgen, AstraZeneca, Beigene, Genmab Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, ad Seattle Genetics, and has a consultancy or advisory role with Lymphoma Canada (chair), AbbVie, Bristol Myers Squibb, Gilead/Kite, Merck, Roche, and Seattle Genetics, and has received research grants or funding from Canadian Cancer Society Research Institute (CCSRI), Canadian Institutes of Health Research (CIHR), Leukemia and Lymphoma Society Canada, Princess Margaret Cancer Foundation, Astra Zeneca, Kite, Merck, Novartis Janssen, and Roche, and is a member of the Data Safety Monitoring Board of Karyopharm. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.