Risk-adapted chemoimmunotherapy using brentuximab vedotin and rituximab in children, adolescents, and young adults with newly diagnosed Hodgkin's lymphoma: a phase II, non-randomized controlled trial

Abstract

Background: Cure rates for Hodgkin's lymphoma are excellent, but excess short-term and long-term morbidities from treatment remain a concern. Immunotherapy targeting both tumor antigens and the immunosuppressive tumor microenvironment in children, adolescents, and young adults with Hodgkin's lymphoma may improve early response rates and eliminate toxic chemotherapy and radiation, thus minimizing toxicity. We conducted a phase II study to evaluate the safety and overall response rate of brentuximab vedotin and rituximab in combination with risk-adapted chemotherapy in children, adolescents, and young adults with newly diagnosed classic Hodgkin's lymphoma (cHL).

Methods: This is a prospective, phase II, non-randomized, risk-assigned study. Patients were treated and evaluated between 2012 and 2020. Eligible patients were aged ≥1 and ≤30 years old with advanced stage, intermediate-risk, and high-risk newly diagnosed cHL. Patients received four or six cycles of brentuximab vedotin (1.2 mg/kg), doxorubicin (25 mg/m2), vinblastine (6 mg/m2), dacarbazine (375 mg/m2), and rituximab (375 mg/m2). Early response was evaluated following two cycles of therapy. Involved field radiotherapy (IFRT) was restricted to high-risk patients with both bulky disease and slow response or those not in complete response at the end of chemoimmunotherapy.

Results: Thirty patients were enrolled, with a median age of 15 years (4-23). There were 18 intermediate-risk and 12 high-risk patients. Toxicities included grade III mucositis (3%), infusion reaction (3%), and peripheral neuropathy (6%). There was a 100% complete response rate on completion of chemoimmunotherapy. Eighteen patients (60%) achieved a rapid early response. Four patients (13%) required IFRT. The 5-year event-free and overall survival rates were 100%, with a median follow-up of 62 months (18-105).

Conclusions: Immunotherapy with brentuximab vedotin, rituximab, and risk-adapted chemotherapy is safe in children, adolescents, and young adults with newly diagnosed cHL. We have demonstrated 100% complete response and 100% event-free and overall survival rates at a median 5-year follow-up, with a significant reduction in use of more toxic chemotherapy and IFRT. A larger cohort is required to confirm these preliminary findings.

Trial registration number: NCT02398240.

Keywords: Drug Therapy, Combination; Hematologic Neoplasms; Immunotherapy; Pediatrics.

Conflict of interest statement

Competing interests: MSC reports research grants from Pediatric Cancer Research Foundation, Pediatric Cancer Foundation, and St Baldrick’s Foundation; is on the speaker bureau for Jazz Pharmaceuticals, Sanofi, Servier, Amgen, and Sobi; and has participated on the Data and Safety Monitoring Board or Advisory Board for Bristol Myers Squibb, Pfizer, Kite, and Instil. All other authors report no conflict of interest.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Immunohistochemistry in a classic Hodgkin’s lymphoma. (A) A patient demonstrating CD30 positivity on the surface of Reed-Sternberg cells (B) and CD20 (C) staining weakly positive on a few large cells, with strong positivity on the surrounding reactive and regulatory B cells.

Figure 2

Treatment schema for intermediate-risk and high-risk patients with cHL. Bv-AVD-R, brentuximab vedotin, doxorubicin, vinblastine, dacarbazine, rituximab; cHL, classic Hodgkin’s lymphoma; CR, complete response; Ifos, ifosfamide; RER, rapid early responder; SER, slow early responder; Vino, vinorelbine; XRT, radiation therapy; ds, disease.

Figure 3

FDG-PET imaging showing early response following two cycles of Bv-AVD-R in a patient with stage IV, high-risk, classic Hodgkin’s lymphoma. AVD-R, doxorubicin, vinblastine, dacarbazine, rituximab; Bv, brentuximab vedotin; FDG-PET, fluorodeoxyglucose-positron emission tomography.

Figure 4

Mean±SEM IgG (A), absolute CD19 (B) and absolute CD3 (C) levels at a median of 18 months of follow-up.

Figure 5

Probability of event-free and overall survival by the product limit method of Kaplan-Meier.