Brentuximab Vedotin-Chemo Boosts EFS in High-Risk Pediatric Hodgkin Lymphoma

CHICAGO — A combination of brentuximab vedotin (Adcetris) and chemotherapy was safe and effective in pediatric patients (up to age 21 years) with newly diagnosed high-risk Hodgkin lymphoma, a researcher reported here.

In the phase III study, a regimen of brentuximab vedotin (Bv) combined with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide chemotherapy (AVE-PC) was superior to a standard pediatric dose-intensive regimen of bleomycin-containing chemotherapy consisting of doxorubicin, bleomycin, and vincristine (ABVE-PC), resulting in a “remarkable” 59% risk reduction in event-free survival (EFS), according to Sharon M. Castellino, MD, MSc, of Emory University School of Medicine in Atlanta.

At a median follow-up of 42.1 months, children and adolescents treated with Bv-AVE-PC achieved a 3-year EFS rate of 92.1% versus 82.5% among patients treated with ABVE-PC (hazard ratio 0.41, 95% CI 0.25-0.67, P=0.0002) in an intent-to-treat analysis, she said in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting.

Furthermore, this EFS improvement was achieved without an increase in toxicity, and with fewer patients receiving involved site radiotherapy (ISRT) compared with previous pediatric trials for high-risk Hodgkin lymphoma, she noted.

“We conclude that Bv-AVE-PC presents a new standard for front-line therapy in pediatric high-risk Hodgkin lymphoma, including stage IIB with bulk,” Castellino said.

Bv is an “antibody-drug conjugate…comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E,” that is currently FDA approved for certain types of relapsed or refractory Hodgkin lymphoma and previously untreated peripheral T-cell lymphoma; it was recently tested in a phase III trial in advanced classical Hodgkin lymphoma, according to developers Takeda Pharmaceuticals and Seagen.

The current 4-year phase III Children’s Oncology Group trial (AHOD1331) included 587 patients. Patient and disease characteristics were balanced across study arms (median age 15.6 years; majority male and non-Hispanic white); histology was nodular sclerosing in 76.5%; and stage distribution was 20.6% IIB-bulk, 19.3% IIIB, 28.5% IVA, and 31.7% IVB.

Patients were randomized to 5 cycles of either ABVE-PC or Bv-AVE-PC given every 21 days. On either arm, an interim PET assessment was performed after 2 cycles and graded by central review on a Deauville 5-point scale. A slow responding lesion at that point was characterized by a score of 4 or 5. Consolidative RT was prescribed for slow responding lesions and to all large mediastinal adenopathy (LMA).

The investigators also reported that the median time to first event was 9.4 months for both arms, with the range differing by arm (3.6-57.8 for ABVE-PC and 1.3-25.8 for Bv-AVE-PC). Also, the predominant event was relapse, with rates of 17% following ABVE-PC versus 7% with Bv-AVE-PC. In addition, one second malignant neoplasm was observed in each arm: thyroid cancer at 57.8 months and acute myeloid leukemia at 20.3 months. And the 3-year overall survival was 98.5% for ABVE-PC and 99.3% for Bv-AVE-PC.

As for administering RT to pediatric patients, Castellino said that consolidative RT “was designed to reduce the number of high-risk patients overall who would have to receive radiation compared to historic trials, and to tailor the approach to involved site radiation and to minimize normal tissue volume exposure.” ISRT was prescribed at 21 Gy and limited to slow responding lesions and LMA, with a 9 Gy boost to slow responding lesions with residual avidity after the completion of 5 cycles.

Slightly more than half of patients in either group (52.7% with Bv-AVE-PC vs 55.7% with ABVE-PC) received RT, Castellino reported, noting that “This represents the lowest percentage of high-risk patients in a pediatric population to date who have received radiation as part of their regimen.”

EFS results by response at the interim PET assessment were “remarkable,” Castellino said. Specifically, in the standard ABVE-PC arm, interim PET-positive patients who had a slow responding lesion had a 3-year EFS of 68.3% compared with 85.7% in PET-negative patients. In contrast, the patients who received brentuximab vedotin had 3-year EFS rates >90% regardless of the interim response.

“This was a surprise, and makes us question going forward the role of interim response with a 5-point scale in brentuximab-containing regimens,” she said.

Key adverse events were as expected from a dose-intensive regimen, Castellino reported. Fever and neutropenia (grade ≥3) did not differ by arm (32.5% with ABVE-PC; 30.9% with Bv-AVE-PC), and neither did chemotherapy-induced peripheral neuropathy (CIPN), with about 19% of patients in either arm, respectively, experiencing CIPN.

ASCO discussant Alison J. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York City, agreed that brentuximab-based chemotherapy is now the standard in pediatric high-risk Hodgkin lymphoma. However, “there are many ongoing questions,” she said. “Some of them include whether or not we should be incorporating PD-1 blockade into the front-line setting.”

There is an ongoing SWOG phase III study comparing Bv plus doxorubicin, vinblastine, and dacarbazine (AVD) versus nivolumab (Opdivo) plus AVD for advanced Hodgkin lymphoma, Moskowitz noted. “The study includes patients [ages] 12 [years] and up, so it’s nice that it is also including some pediatric patients,” she said.