Replacing transplant and chemo with CI-based therapy and ISRT maintains survival, reduces side effects in younger patients with classic Hodgkin lymphoma.
Among child, adolescent and young adult patients with low-risk relapsed classic Hodgkin lymphoma (cHL), replacing autologous transplant and high-dose chemotherapy with checkpoint inhibitor-based therapy and involved-site radiotherapy (ISRT) may maintain event-free survival (EFS) outcomes while reducing side effects, according to research published in JAMA Oncology.
In the journal article, first study author Dr. Stephen Daw and colleagues wrote: “This nonrandomized clinical trial found that for children, adolescents and young adults with low-risk, relapsed cHL, a transplant-free, risk-adapted, response-based approach with Opdivo [nivolumab] plus Adcetris [brentuximab vedotin] and ISRT offered high complete metabolic response [CMR] rates and high three-year EFS rate, with a safety profile consistent with that of each agent used.”
Progression-free survival (PFS): the amount of time a patient lives with a disease, like cancer, without it getting worse
Complete metabolic response (CMR): no detectable metabolic activity within a tumor, indicating that the cancer has completely responded to treatment and shows no signs of active disease on the scan.
Daw is a consultant pediatric and adolescent haemato-oncologist at University College London Hospitals in the United Kingdom.
Most children, adolescents and young adults with cHL achieve cure with first-line treatment; however, cases of relapsed/refractory disease require second-line systemic therapy followed by high-dose chemotherapy and autologous hematopoietic cell transplant. These approaches can carry an increased risk of late mortality, primarily due to secondary malignancies, organ failure and other long-term complications. Based on this unmet need, new strategies aim to maintain high survival rates while reducing toxicity.
For low-risk relapsed cHL, ISRT may offer an alternative, though standardized treatment remains undefined. With emerging therapies such as Opdivo and Adcetris, pediatric patients are achieving high complete remission rates. Radiotherapy is also being refined with smaller fields and conformal techniques to minimize toxic effects. Reducing overall radiation exposure may further lower long-term risks while maintaining disease control. Based on this data, investigators launched the phase 2 CheckMate 744 trial.
CheckMate 744 is a multicenter study assessing a risk-stratified, response-adapted Opdivo and Adcetris induction, with Adcetris plus Bendeka (bendamustine) intensification for suboptimal responders. In the standard-risk (R2) cohort (median follow-up, 20.9 months), 94% of patients achieved CMR prior to high-dose chemotherapy (HDCT)/autologous HCT consolidation and 59% did so after Opdivo and Adcetris alone.
The 12-month progression-free survival (PFS) rate was 91%; however, the median PFS was not reached. Investigators shared their report on findings from the low-risk (R1) cohort,
treated with an HDCT/autologous HCT–free approach using ISRT for consolidation in the journal article.
Eligible patients were enrolled at trial sites based on CheckMate 744 trial enrollment criteria, and no patients had prior exposure to checkpoint inhibitors or Adcetris. Patients 5 to 30 years of age were assigned to the R1 cohort by study sites. Notably, investigators explained that patients were defined as having low-risk disease if they had either stage 1A/2A disease at initial diagnosis and relapsed within three to 12 months (with three or fewer cycles of treatment and no radiotherapy [RT]) or at 12 months or later or stage 1B/2B/3B disease at initial diagnosis with more than 12 months to relapse.
Patients initially received four cycles of Opdivo and Adcetris induction; those who achieved CMR continued to two more cycles of Opdivo and Adcetris, followed by consolidation with ISRT. Patients who did not have CMR following induction then received intensification with Adcetris plus Bendeka.
Regarding treatment administration, study drugs were given open label in 21-day cycles at the trial site. Intravenous Opdivo was administered at 3 milligrams per kilogram (mg/kg) on day eight of cycle one and day one of each subsequent cycle; there was a maximum of six cycles. Intravenous Adcetris was given at 1.8 mg/kg on day one of each cycle. For intensification, patients received Adcetris on day one and Bendeka at 90 mg/m2 on days one and two of each cycle.
“The coprimary end points were CMR rate per blinded independent central review … at three years,” Daw and investigators wrote.
In the low-risk cohort of 28 patients, 64% were female and there was a median age of 17 years; the median follow-up was 31.9 months. CMR before ISRT was 93% and there was an objective response rate (ORR) of 100%, with 82% achieving CMR after four cycles of Opdivo plus Adcetris, with an ORR of 96.4%. Three-year EFS and PFS rates were 87% and 95%, respectively. Treatment-related side events occurred in 79% of patients, including seven with grade three or four events. Serious side effects led to treatment discontinuation in two patients.
“To our knowledge, the CheckMate 744 study, a collaboration between EuroNet, the Children’s Oncology Group and industry, is the first evaluation of risk-stratified, response-adapted retrieval therapy using novel agents in combination in pediatric relapsed/refractory cHL. ... Opdivo plus Adcetris demonstrated a high CMR rate and ORR. As expected for this lower-risk population, CMR rate and ORR per BICR after four cycles of induction with Opdivo plus Opdivo were slightly higher in the R1 cohort than the R2 cohort,” authors concluded.
Looking to the future, Daw and co-authors went say that “recent studies have shown high rates of local control with modern, risk-adapted RT-treatment volumes in patients with high-risk disease... supporting further investigation of this approach in future studies.”
"Transplant-Free Approach in Relapsed Hodgkin Lymphoma in Children, Adolescents, and Young Adults. A Nonrandomized Clinical Trial," by Stephen Daw, et al. JAMA Oncology.
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