Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma

Abstract

Background: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear.

Methods: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed.

Results: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group.

Conclusions: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

Figure 1.. Event-free Survival and Relapse.

Event-free survival was defined as the time to disease progression, relapse, a second malignant neoplasm, or death. Patients in the brentuximab vedotin group received brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide, and those in the standard-care group received the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide. The hazard ratio for event or death was calculated with the use of a Cox proportional-hazards model. Tick marks indicate censored data. In Panel B, the inset shows the same data on an enlarged y axis.

Figure 2.. Subgroup Analysis of Event-free Survival.

Race and ethnic group were reported by the investigator on the basis of documentation in the electronic health record. B symptoms were defined as weight loss, night sweats, and fever. Bulk tumor was defined as large mediastinal adenopathy (transverse tumor diameter more than one third the thoracic diameter at the dome of the diaphragm on a 1.83-meter posterior–anterior upright chest radiograph) or extramediastinal bulk (a continuous aggregate of nodal tissue outside the mediastinum that measured >6 cm in the transverse dimension on axial CT or the longest dimension on coronal or sagittal reformatted CT).

Figure 3.. Event-free Survival According to Results on Interim Positron-Emission Tomographic (PET) Assessment.

In a post hoc analysis involving patients with slow-responding lesions according to the interim PET assessment, 3-year event-free survival was 90.7% in the brentuximab vedotin group, as compared with 68.3% in the standard-care group (hazard ratio for event or death, 0.28; 95% CI, 0.10 to 0.76). Among patients with rapid-responding lesions, 3-year event-free survival was 92.3% in the brentuximab vedotin group and 85.7% in the standard-care group (hazard ratio, 0.48; 95% CI, 0.27 to 0.84).