Is Less More? Rethinking Salvage Therapy in Pediatric Hodgkin Lymphoma

The standard of care for relapsed and refractory classic Hodgkin lymphoma (cHL) has been trending toward a less aggressive protocol in the past decade. The improvement of first-line therapies is attributed to immunotherapeutic discoveries that have been effective in treating cHL.

However, for about 15% to 20% of patients with cHL who fail treatment, the combination of high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT)—is an effective, albeit toxic salvage therapy. It has been associated with cardiac issues, development of secondary cancers and other chronic health conditions, fueling research efforts to identify other salvage strategies for cHL.

Now, mounting evidence, including findings from three prospective clinical trials, reveal that nontransplant options are an effective second-line treatment for low-risk cHL patients—precluding the need for HDC/ASCT.

The data are, by all accounts, encouraging. However, patient selection is key, according to experts like Rabi Hanna, MD, Chair of Hematology and Medical Oncology, at Cleveland Clinic Children’s. He calls the evidence “practice changing” while adding a note of caution about extrapolating the data to intermediate or high-risk groups. He outlines the significance of these studies and other considerations in an editorial published in JAMA Oncology.

Significant contributions to the literature

“These studies provide ample evidence to support a transplant-free salvage therapy for certain low-risk cHL patients. However, it’s important to point out that each study differs in its design, relapse risk criteria and treatment approach,” asserts Dr. Hanna.

The Checkmate 744 Study. This phase 2 nonrandomized clinical trial in children and young adults with low-risk relapsed cHL evaluated a novel immunotherapy combination of brentuximab vedotin and nivolumab, offering a nontransplant alternative for many patients.

The study, reported by Daw et al,¹ found a three-year event-free survival (EFS) of 86.9% and three-year progression-free survival (PFS) of 95%. Limitations include a relatively short median follow-up of 31.9 months, leaving some unanswered questions about later-occurring toxicity and possible secondary cancers. Similarly, the inclusion of those receiving radiation raises some concerns about the regimen’s true morbidity-reducing effects.

EuroNet-PHL-R1. A phase 3, nonrandomized trial, reported by Daw et al,²evaluated fludeoxyglucose-18 (FDG) positron emission tomography (PET) response-guided salvage. In a cohort of 118 patients, 59 were in the low-risk group, and 41 of these patients received nontransplant salvage with a five-year PFS of 89.7% (95% CI, 80.7%-99.8%) and overall survival (OS) of 97.4% (95% CI, 92.6%-100%), comparable to that of the transplant cohort. The findings suggest a nontransplant strategy may be achievable for certain patients.

Limitations include the study’s reliance on FDG-PET, which could be an issue in widespread clinical settings. Additionally, the long-term assessment of radiation therapy is not addressed.

Children’s Oncology Group AHOD0431 trial. With a follow-up period of eight years, this nonrandomized trial, reported by Hoppe et al,³ edges out the others with respect to longer-term observation. However, the low-risk relapse sample is relatively smaller, with only 20 patients. Each patient in this cohort received retrieval chemotherapy with two cycles of IV (ifosfamide, vinblastine) and DECA (dexamethasone, etoposide, cisplatin, cytarabine), respectively, followed by involved-field radiation therapy at 21 Gy.

The five-year and eight-year EFS were 80.5% and 76.3%, respectively. The eight-year OS was 100%. Notably, no secondary cancers developed during this follow-up period, which Dr. Hanna describes as “reassuring.”

Takeaways and considerations

In addition to omitting the HDC/ASCT protocol for salvage therapy, Dr. Hanna offers the following takeaways and considerations from the trials:

• Transplant can be avoided, even with different regimens: In low-risk relapsed cHL, salvage therapy without HDC/ASCT can be achieved with different regimens—and particularly with the immunotherapy combination Bv + nivolumab.
• Questions remain about secondary cancers associated with the long-term effects of radiation therapy. Radiation therapy was used for every patient in the trials, although the cumulative doses were different. Time will tell whether longer-term treatment-related complications, like secondary neoplasms, will develop in these patients. These are more likely to occur after 10 years of post-treatment observation.
• More harmonization work is needed to determine the criteria for FDG-PET standards to improve clinical decision-making. For example, a Deauville score ≤3 is used to define complete metabolic remission for patients receiving the front-line therapy for the newly diagnosed cHL in all recent clinical trials in a pediatric and young adult population with cHL. In contrast, Daw et al¹ used a more conservative scoring to guide the treatment approach (Deauville score 1-2). Dr. Hanna elaborates on this point, writing in the report, “This is particularly important for patients who are receiving the checkpoint inhibitor-based retrieval strategies, when intratumoral inflammatory changes may result in increased metabolic activity, thereby creating diagnostic uncertainty.”

References

1. Daw S, Cole PD, Hoppe BS, et al. Transplant-Free Approach in Relapsed Hodgkin Lymphoma in Children, Adolescents, and Young Adults: A Nonrandomized Clinical Trial. JAMA Oncol. Published online January 02, 2025. doi:10.1001/jamaoncol.2024.5627
2. Daw S, Claviez A, Kurch L, et al. Transplant and Nontransplant Salvage Therapy in Pediatric Relapsed or Refractory Hodgkin Lymphoma: The EuroNet-PHL-R1 Phase 3 Nonrandomized Clinical Trial. JAMA Oncol. Published online January 02, 2025. doi:10.1001/jamaoncol.2024.5636
3. Hoppe BS, Milgrom SA, Renfro LA, et al. Transplant-Free Salvage Therapy for Low-Risk Relapsed Pediatric Hodgkin Lymphoma: A Nonrandomized Clinical Trial. JAMA Oncol. Published online January 02, 2025. doi:10.1001/jamaoncol.2024.5648
4. Berz AM, Dromain C, Vietti-Violi N, Boughdad S, Duran R. Tumor response assessment on imaging following immunotherapy. Front Oncol. 2023 Mar 07;13:1175321