Multicentre data show high response rates and 95% three-year overall survival in heavily pretreated children and adolescents treated outside clinical trials.
A nationwide French real-world study has provided compelling evidence supporting the use of immune checkpoint inhibitors in children, adolescents and young adults with primary refractory or relapsed classical Hodgkin lymphoma.
Classic Hodgkin lymphoma remains the most common lymphoma in the paediatric and young adult population.
While frontline multiagent chemotherapy and advances in radiotherapy have driven five-year overall survival rates above 95%, approximately 15% of patients experience primary refractory or relapsed disease.
For these patients, high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation has been the standard approach, however, relapse rates after transplant remain substantial and long-term toxicity is a significant concern.
In recent years, the therapeutic landscape of relapsed or refractory classical Hodgkin lymphoma has shifted with the introduction of immune checkpoint inhibitors targeting the programmed death-1 pathway.
Agents such as nivolumab and pembrolizumab have demonstrated high response rates and favourable safety profiles in adults, and early paediatric trials have shown similarly encouraging results.
The anti-CD30 antibody–drug conjugate brentuximab vedotin has also become an important component of salvage strategies, frequently used in combination with checkpoint blockade.
The French retrospective study evaluated 27 patients treated outside clinical trials across 11 French centres between August 2015 and May 2023. Results have been published in the British Journal of Haematology.
“A particularly noteworthy observation comes from our subset of primary refractory patients – those who had progressed after one or two lines of frontline therapy,” the researchers wrote.
“In this subgroup, where CPI were initiated early in the treatment course, no deaths occurred during follow-up, and the disease was effectively controlled in most cases.
“These findings suggest that early use of CPI in refractory patients may be beneficial and that such benefit extends beyond clinical trial populations to real-life practice.”
All patients were aged under 18 years at initial diagnosis and received at least one dose of nivolumab or pembrolizumab for relapsed or refractory disease.
The median age at checkpoint inhibitor initiation was 16 years, and 70% of patients had advanced-stage disease.
Nearly half had previously received brentuximab vedotin, 22% had undergone autologous transplantation, and a small number had received allogeneic transplantation, reflecting a heavily pretreated cohort often excluded from prospective trials.
Nivolumab was administered in 89% of cases, most commonly in combination with brentuximab vedotin. The overall metabolic response rate was 93%, with 63% achieving complete metabolic response.
Among patients assessed early, 83% demonstrated a metabolic response within four cycles, with a median time to response of 51 days. Importantly, complete metabolic response was associated with significantly improved progression-free survival compared with partial metabolic response.
At a median follow-up of 30 months, three-year progression-free survival was 48%, and three-year overall survival reached 95%.
Although progression-free survival was lower than rates reported in phase 2 trials, the researchers attributed this difference to broader real-world inclusion, including patients with prior autologous or allogeneic transplantation and those treated with checkpoint inhibitor monotherapy rather than combination regimens.
In the subgroup with primary refractory disease, who initiated checkpoint inhibition early in their salvage course, outcomes were particularly notable. The metabolic overall response rate was 86%, and no deaths occurred during follow-up.
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Many responding patients proceeded to consolidation with autologous or allogeneic transplantation and remained in durable remission, the researchers said.
These findings suggested that earlier integration of checkpoint blockade in refractory disease might confer meaningful long-term benefit.
Among relapsed patients, including those with secondary refractory disease, response rates reached 100%, with durable remissions observed in a substantial proportion following consolidation.
Even in patients who relapsed after prior transplantation, checkpoint inhibition demonstrated clinically meaningful activity, underscoring its value in highly vulnerable subgroups with limited therapeutic options.
Treatment-related toxicity was manageable. Adverse events were reported in 30% of patients, with grade 3 or higher events in four individuals. Immune-related events such as gastritis, duodenitis and hepatitis led to discontinuation in three cases. Secondary thyroiditis was observed in several patients.
The researchers noted that adverse events appeared more common in those receiving prolonged therapy, suggesting a possible association between treatment duration and immune-related toxicity.
“This remarkable efficacy of CPI raises an important question about the continuing role of allo-SCT for patients relapsing post-aHSCT,” the researchers wrote.
“Our findings, while promising, do not allow us to conclude that CPI therapy may serve as an alternative to allo-SCT in this setting.
“One possible effect of checkpoint inhibition, however, could be to postpone the realisation of allo-SCT, without necessarily providing cure, thereby allowing time for the emergence of novel therapies such as Chimeric Antigenic Receptor-T (CAR-T) cells.
They concluded that their study confirmed that CPI was highly effective and well-tolerated in CAYA patients with R/R cHL.
“CPI showed strong activity even in heavily pretreated patients, including those with prior stem cell transplants,” the researchers wrote.
“Early use of CPI in primary refractory cases was associated with excellent long-term outcomes.
“These findings support the earlier integration of CPI in the R/R treatment strategy for CAYA cHL, particularly given their favourable efficacy and tolerability, which may help reduce the overall treatment burden in R/R patients.”
