Brentuximab Vedotin Combined With Chemotherapy in Patients With Newly Diagnosed Early-Stage, Unfavorable-Risk Hodgkin Lymphoma

Abstract

PURPOSE To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma. METHODS In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4–negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4. RESULTS Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering–defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible. CONCLUSION BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4–negative patients.

Current Situation of Proton Therapy for Hodgkin Lymphoma: From Expectations to Evidence

“…Reduced radiation fields to residual sites only was evaluated in the HD15 study of the German Hodgkin Study Group for advanced HL [64]. Similarly, for early-stage HL, investigators at Memorial Sloan Kettering Cancer Center suggested that reduced fields might be sufficient for areas of remaining masses that were PET-positive following chemotherapy (residual site RT, RSRT), particularly in patients with bulky mediastinal disease: this concept was tested in newly diagnosed HL patients with bulky stage HL (IIA/BX) after four cycles of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (BV-AVD) [65]. Most patients were PETor biopsy-negative after chemotherapy and were randomized to four cohorts: 25 patients to 30 Gy ISRT (cohort 1), 28 patients to 20 Gy ISRT (cohort 2), 29 patients to 30 Gy RSRT (cohort 3) and 24 patients to no further treatment (cohort 4).…”

Development and Implementation of Proton Therapy for Hodgkin Lymphoma: Challenges and Perspectives

“…Currently, ISRT and INRT usually consider as target volumes all the initially involved sites, whether or not these sites have responded to chemotherapy. Limiting radiation fields to the residual sites only (residual site radiation therapy, RSRT) has been evaluated for advanced-stage HL in the HD15 study [47] and, more recently, for early-stage HL, by investigators from the Memorial Sloan Kettering Cancer Center: Kumar et al evaluated an RSRT strategy for bulky HL patients (IIA/BX) following 4 cycles of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (BV-AVD) [12]. After initial chemotherapy, patients who were considered negative, according to PET imaging or biopsy, were randomized assigned to 4 different treatment groups: 30 Gy ISRT (cohort 1), 20 Gy ISRT (cohort 2), 30 Gy RSRT (cohort 3), or no further treatment (cohort 4).…”

“…Kumar et al [48] found that four cycles of BV-AVD and 30 Gy involved-site radiotherapy yielded a 93.3% 1 year-for unfavorable early-stage HL. A subsequent multicenter study on 117 patients [12] similarly evaluating four BV-AVD cycles for unfavorable early-stage HL including bulky disease demonstrated comparable 2-year PFS with or without consolidative involved-site radiation therapy (93% and 97% respectively) and consequently proposed elimination of consolidative irradiation after complete metabolic response with this chemotherapy regimen. Metzger et al [49] demonstrated that replacing vincristine with BV in frontline pediatric OEPA or COPDac protocols could spare consolidative radiotherapy for 35% of the children.…”

“…Prioritization methods for patient selection are subject to debate, considering the current particle beam therapy facility shortage and the societal and operational cost of proton therapy compared with lower-cost classic radiotherapy [11]. Further, management of HL has recently been rapidly changing with the evaluation of new, highly therapeutic systemic drugs (such as brentuximab vedotin and anti-CD30 car-T cells [12,13]). The purpose of this review is to identify and discuss controversies and challenges for the larger implementation of this promising technique in the near future.…”

Hodgkin Lymphoma: Recent Progress in Overall Management

“…An alternative approach to the standard treatment of early-stage HL has been recently proposed by Kumar et al (84) One-hundred-seventeen patients with early-stage unfavorable HL were enrolled, with the following risk factors: 86% with Memorial Sloan Kettering-defined disease bulk (maximum diameter > 7 cm. ), 27% traditional bulk (>10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites.…”