Treating patients with brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine with and without consolidative radiotherapy resulted in strong efficacy and encouraging tolerability in early-stage, unfavorable-risk Hodgkin lymphoma.
Pilot study data, published in the Journal of Clinical Oncology, suggested that the combination of brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, and dacarbazine (AVD) with and without consolidative radiotherapy induced significant clinical responses in patients with early-stage, unfavorable-risk Hodgkin lymphoma, and that the treatment was generally tolerable for patients.1
Overall, PET negativity rates were 87% at PET-2, 88% at PET-4, and 85% at the end of therapy. Moreover, the complete response (CR) rates at the end of therapy in cohorts 1 though 4 were 93%, 100%, 93%, and 97%, respectively, meeting the primary efficacy end points for cohorts 2 to 4.
At a median follow-up of 3.8 years (cohorts 1-4: 5,9, 4.5, 2.5, and 2.2, respectively), the overall 2-year progression-free survival (PFS) rate was 94% (95% CI, 89.7%-98.3%), and the overall survival (OS) rate at this time point was 99.1% (95% CI, 97.3%-1.0%).
When broken down by cohort, the 2-year PFS rates in cohorts 1 through 4 were 93.1% (95% CI, 83.9%-1.0%), 96.6% (95% CI, 89.9%-1.0%), 89.7% (95% CI, 78.5%-1.0%), and 96.6% (95% CI, 89.9%-1.0%), respectively. Moreover, the 4-year PFS rates in both cohorts 1 and 2 was 93.1%.
“This study represents among the best-reported outcomes to date for patients with bulky early-stage Hodgkin lymphoma,” Anita Kumar, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, wrote. “Given the limited number of patients per cohort and the nonrandomized design, the current pilot study was note designed to definitively compare the 4 treatment arms; however, the outcomes establish brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine [AVD] x 4 cycles as a highly active and well-tolerated regimen.”
The multicenter study comprised 4 cohorts. To be eligible for participation, patients needed to be aged 18 years to 60 years and have treatment-naïve, stage I/II, biopsy-proven, CD30-positive classical Hodgkin lymphoma.
In cohort 1, eligible candidates had to having unfavorable-risk factors like bulky mediastinal mass, an erythrocyte sedimentation rate of at least 50 mm/h or a rate of at least 30 mm/h in patients with B symptoms, extranodal involvement, over 2 lymph node sites, or infradiaphragmatic disease. In cohort 2, patients needed to meet the same disease bulk criteria; however, the definition was updated to reflect the Memorial Sloan Kettering (MSK) definition of maximal transverse or coronal diameter of the largest lymph node mass at any site greater than 7 cm on CT imaging. In cohorts 3 and 4, patients with early-stage Hodgkin lymphoma needed to have disease bulk per MSK criteria.
Across the cohorts, patients needed to have stage IIB disease with disease bulk and/or extranodal involvement.
Study participants were given brentuximab vedotin at 1.2 mg/kg, doxorubicin at 25 mg/m2, vinblastine at 6 mg/m2, and dacarbazine at 375 mg/m2 on days 1 and 15 of each 28-day cycle for 4 cycles.
Patients who had a PET-negative response following 4 cycles of brentuximab vedotin plus AVD and those with a PET-positive response with subsequent biopsy that was negative for disease were given 30-Gy involved-site radiotherapy (ISRT) in cohort 1, 20-Gy ISRT in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4.
Notably, in cohorts 2 and 3, either dose or field was reduced. In cohort 2, the dose was reduced to 20 Gy. In cohort 3, the field was reduced with consolidation-volume radiotherapy and the standard dose of 30 Gy was maintained.
The study enrolled 117 patients; 30 patients were enrolled to cohort 1 and cohort 2 through 4 comprised 29 patients each. Eighty-six percent of patients had MSK-defined disease bulk, 27% had traditionally-defined bulk, and 23% had advanced-stage disease per German Hodgkin Study Group criteria.
With the change in eligibility criteria, a greater proportion of patients had disease bulk per MSK criteria in cohorts 3 and 4, but more patients had traditional disease bulk in cohort 1 vs cohorts 2 through 4. Across the cohorts, 99% of patients had been given the 4 cycles of chemotherapy as planned and 94% of patients in cohorts 1 through 3 were administered planned consolidative radiation therapy.
Additional data demonstrated that 2 patients in cohort 1 had a positive PET-4 following brentuximab vedotin plus AVD for 4 cycles and biopsy-proven primary refractory disease. One patient in cohort 2 relapsed 34 months following the start of chemotherapy. Two patients in cohort 3 had a positive PET scan at end of therapy following completion of 30-Gy CVRT and biopsy-proven primary refractory disease; 1 patient relapsed 9 months following the start of treatment. Three patients in cohort 3 reported early treatment failures following CVRT. One patient in cohort 4 had a positive PET-4 and/or end-of-therapy PET, as well as biopsy-confirmed primary refractory disease.
Regarding safety, dose modifications like delays holds, or reductions were reported at a low rate. The most common reason for dose modification was because of the development of peripheral neuropathy, which resulted in a dose reduction of brentuximab vedotin, mostly from 1.2 mg/kg to 0.9 mg/kg.
Forty-four percent of patients experienced any-grade neutropenia and 8% had febrile neutropenia with the regimen. All participants received mandatory growth factor support. Fifty-four percent of patients experienced peripheral sensory neuropathy; however, most were low grade (95%) and resolved (76%) or improved to grade 1 (24%) by the last follow-up visit. Notably, no treatment-associated pulmonary toxicity was reported.
Forty-one serious adverse effects were reported in 21 patients and required hospitalization and these included fever and neutropenia, abdominal pain, and infection.
“The results of this pilot study of brentuximab vedotin plus AVD with and without consolidative radiotherapy for early-stage, unfavorable-risk Hodgkin lymphoma, including patients with disease bulk, demonstrate excellent efficacy across all 4 cohorts with an overall 2-year PFS of 94%,” the study authors concluded. “To our knowledge, this is the largest published study reporting outcomes associated with frontline brentuximab vedotin plus AVD in patients with bulky stage I or II classical Hodgkin lymphoma.”
Kumar A, Casulo C, Advani RH, et al. Brentuximab vedotin combined with chemotherapy in patients with newly diagnosed early-stage unfavorable-risk Hodgkin lymphoma. J Clin Oncol. 2021;39(20):2257-2265. doi:10.1200/JCO.21.00108