For patients with relapsed or refractory (R/R) classic Hodgkin lymphoma (cHL), the current standard of care in the salvage setting includes consolidation high-dose chemotherapy (HDCT) and autologous hematopoietic cell transplantation (AHCT). In a study published in JAMA Oncology, researchers found that pediatric and adolescent patients with early or late relapsed cHL who achieve a complete metabolic remission (CMR) on fludeoxyglucose-18 positron emission tomography (FDG-PET) imaging after two cycles of reinduction chemotherapy can go on to receive transplant-free chemoradiotherapy with excellent long-term outcomes.1
“The most important result of our study was that any pediatric or adolescent patient with early or late relapse of their cHL that achieved a CMR after two cycles of chemotherapy may safely de-escalate to a non-transplant salvage while maintaining an excellent five-year progression-free survival (PFS) of 89.7%,” said study author Stephen Daw, MD, of University College London Hospital in England. “In contrast, those patients with an inadequate FDG-PET response or primary progressive cHL, all of whom received intensified HDCT plus AHCT, achieved a relatively disappointing five-year PFS of 53.3%.”
cHL is not a common cancer in children but does occur in adolescents and has an excellent cure rate with first-line risk-adapted chemotherapy and radiotherapy regimens. However, about 10% to 15% of patients present with R/R disease. While HDCT plus AHCT is often considered the standard consolidation in adults, non-transplant chemoradiotherapy salvage has demonstrated efficacy in several pediatric studies.
“We knew from previous pediatric trials that not all patients with R/R cHL need HDCT and an autologous transplant to achieve a cure,” Dr. Daw said. Known important risk factors for patients with R/R disease are time to relapse and prior treatment burden, including the number of chemotherapy cycles and use of radiation in the first line, which can be used to select patients for non-transplant salvage, thereby avoiding toxicities of HDCT.
In the phase III EuroNet-PHL-R1 trial, Dr. Daw and colleagues addressed whether risk stratification and FDG-PET response assessment in R/R cHL could identify patients with low-risk disease for treatment de-escalation to salvage therapy without transplantation and patients with high-risk disease who do require HDCT and AHCT.
“We had not previously used FDG-PET response as an additional factor to guide decisions on the use of transplant or non-transplant salvage, yet FDG-PET response was universally used in the first-line setting. Including FDG-PET response to guide treatment intensity proved to be a very good decision,” Dr. Daw said.
One hundred and eighteen patients with R/R cHL across 13 countries in Europe were enrolled in the trial. The study included mostly older adolescents with a median age of 16.3 years. Fifty-eight (49.2%) of the patients were female, and the median follow-up was 67.5 months. Twenty-four patients had primary progression, and 94 had relapsed disease.
Patients were stratified up front into three relapse groups (RGs): patients with late relapse after two cycles in frontline (RG-1), those with primary progressive disease (RG-3), and any other relapse group (RG-2). The RG-1 group was not evaluated by FDG-PET, received radiotherapy, and was not eligible to receive intensified HDCT plus AHCT. In contrast, patients in the RG-3 group were considered to have high-risk disease, and as a result, they received HDCT plus AHCT and were not eligible for transplant-free salvage. In the RG-2 group, FDG-PET response was used to escalate or de-escalate salvage treatment between transplant and transplant-free consolidation.
All patients received two cycles each of IEP (ifosfamide, etoposide, and prednisolone) and ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) followed by consolidation with either radiotherapy alone in patients with low-risk disease or HDCT plus AHCT with or without radiotherapy in patients with high-risk disease. FDG-PET response was timed after one cycle each of IEP and ABVD for the RG-2 and RG-3 patient groups.
Fifty-nine patients (50%) were defined as having low-risk disease, and of these, 41 received chemotherapy and radiotherapy only. The other 18 patients received HDCT and AHCT off protocol, almost exclusively because they had already received radiotherapy in first-line treatment. Another 59 patients were defined as having high-risk disease and all received HDCT and AHCT.
The overall five-year PFS was 71.3%, and the overall survival (OS) was 82.7%. Among the transplant-free, low-risk disease group of 41 patients, the five-year PFS was 89.7%, and the OS was 97.4%. Of the 59 patients with high-risk disease who received HDCT plus AHCT, the five-year PFS was 53.3%, and the OS was 66.5%. Overall, 33 patients had second relapse or progressions, and 19 patients died. Of 19 deaths, 18 occurred in the HDCT plus AHCT group and one in the transplant-free group.
“[These results] challenge the current understanding that HDCT plus AHCT is superior to a non-transplant salvage approach,” Dr. Daw said.
“We have shown that a substantial proportion of patients with relapsed cHL do not need HDCT and AHCT intensification. As radiotherapy is used less in first line, it is an attractive consolidation in selected patients in second line,” Dr. Daw said.
“We recognize that because this was a trial in younger patients, the adult community may need to be convinced, as sometimes it’s seen that pediatric data have little relevance to adult patients, but our trial provides a starting point to support wider research in adult practice to develop more standardized risk- and response-based salvage approaches,” Dr. Daw added.
Simultaneously with the EuroNet-PHL-R1 study, findings from the low-risk cohort of the CheckMate 744 study were published in JAMA Oncology.2 The results of that study support non-transplant salvage but with reinduction of brentuximab vedotin and nivolumab instead of conventional chemotherapy with radiotherapy consolidation in place of HDCT plus AHCT.
“The outcomes with non-transplant salvage are similarly excellent. The data from these two trials are very exciting because they show non-transplant salvage is possible with excellent PFS using conventional chemotherapy or novel agent combinations. For patients, achieving potential cure without the toxicities of HDCT is clinically meaningful,” Dr. Daw said.
The risk- and response-adapted approach to salvage therapy in cHL is incorporated into the EuroNet guidelines,3 based on the results of these studies.
Any conflicts of interest declared by the authors can be found in the original article.
References
- 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 [published online ahead of print, 2025 Jan. 2]. JAMA Oncol. doi: 10.1001/jamaoncol.2024.5636.
- 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 [published online ahead of print, 2025 Jan. 2]. JAMA Oncol. doi: 10.1001/jamaoncol.2024.5627.
- Daw S, Hasenclever D, Mascarin M, et al. Risk and response adapted treatment guidelines for managing first relapsed and refractory classical Hodgkin lymphoma in children and young people. Recommendations from the EuroNet Pediatric Hodgkin Lymphoma Group. Hemasphere. 2020;4(1):e329.
