Reducing the Burden of Chemoradiotherapy with the Combination of Brentuximab Vedotin and Rituximab with Reduced Toxicity Chemotherapy in Children, Adolescents and Young Adults with Newly Diagnosed Hodgkin Lymphoma
Authors: Hochberg Jessica C. , Basso Jaclyn , Klejmont Liana , Harrison Lauren , Flower Allyson M. , Gardenswartz Aliza , Shi Qiuhu , Gerard Perry , Islam Humayan , Cairo Mitchell S 
Published: February 2020

Background: Cure rates for newly diagnosed Hodgkin Lymphoma remain high through the combined use of chemoradiotherapy. (Hochberg/Cairo Cancer Journal 2018) However, this has resulted in significant adverse physical and psychosocial function that significantly impacts the quality of life among survivors, including cardiotoxicity, neurocognitive deficits, poor quality of life, and secondary malignancies. Pediatric cancer survivor studies have shown significant increases adverse health events following therapy throughout adulthood. Major risk factors for late effects include significant exposure to radiation, anthracyclines, cyclophosphamide, etoposide and bleomycin. (Bhakta et al Lancet 2017, Oeffinger et al NEJM 2006, Gibson et al Lancet Oncol 2018) Immunotherapy targeting the Reed Sternberg cell and tumor microenvironment, including regulatory B-cells, has potential to reduce the burden of traditional treatment. Brentuximab Vedotin, an anti-CD30 antibody-drug conjugate, and Rituximab, a chimeric anti-CD20 monoclonal antibody, have both shown efficacy in relapsed Hodgkin Lymphoma and Brentuximab has gained FDA approval in up front adult HL in combination with standard chemotherapy. (Younes et al JCO 2012, Younes et al Blood 2012, Connors et al NEJM 2018) We hypothesized that the addition of Brentuximab vedotin (Bv) and Rituximab (R) combined with risk adapted chemotherapy will be well tolerated and effective in children, adolescents and young adults with all stages of newly diagnosed Hodgkin lymphoma and will allow for the elimination of more toxic chemotherapies as well as need for radiation.
Objectives: To evaluate the safety, tolerability and overall response rate of Brentuximab vedotin and Rituximab in combination with risk adapted chemotherapy in children, adolescents and young adults with newly diagnosed Hodgkin Lymphoma.
Methods: Eligible patients 1-30 yrs with all stages of newly diagnosed classical Hodgkin Lymphoma. Patients were risk assigned as either Low (Stage IA, IIA, no bulk), Intermediate (Stage IA bulk/E, IB, IIA bulk, IIB or IIIA) and High Risk (Stage IB bulk/E, II bulk, IIIA bulk, IIIB, IV). Low risk patients were given 3 cycles of Brentuximab vedotin (1.2mg/kg) with Doxorubicin (25mg/m2), Vincristine (1.5mg/m2), Prednisone and Dacarbazine (375mg/m2) on Days 1 and 15. Intermediate and High Risk patients received 4 or 6 cycles of Brentuximab vedotin, Doxorubicin, Vinblastine, Dacarbazine and Rituximab (375mg/m2) on Days 1,2 and 15, 16. (Figure 1) Early response was measured by PET/CT scan. Slow responders, defined by lack of a complete metabolic response or &lt;80% size reduction, received an additional 2 cycles of Bv-AVD-R for Intermediate Risk or Ifosfamide/Vinorelbine for High Risk. Involved Field RT was restricted to only patients with bulk disease with SER and those not in a CR at the end of therapy. Humoral and cellular immunity was measured upon completion of therapy.
Results: Total enrolled = 33 patients. Median age = 15yr (range 4-23yr). Total 12 males, 21 females. Risk Assignment = 4 low, 17 intermediate, 12 high. Toxicity = 1 episode of Gr III mucositis, 1 episode of Gr III infusion reaction to Brentuximab vedotin, 2 episode Gr III peripheral neuropathy. All 33 patients achieved a complete response for a CR = 100%. Eighteen patients (58%) achieved a rapid early response. Four patients (only 12%) have required radiation therapy to date due to the presentation of bulky disease with a slow early response. Each of these patients was in CR prior to the start of radiation therapy. At a median follow-up of 18 months, the mean±SEM IgG level, CD19 and CD3 levels were 1097±63, 325±105, and 1273±290, respectively, all within normal range. Furthermore, none of the patients developed agammaglobulinemia or required hospitalization for systemic infection during or following treatment. The EFS and OS is 100% with a mean follow up time of 1320 days (= 44 months, range 3-80). (Figure 2)
Conclusions: The addition of Brentuximab vedotin and Rituximab to combination risk adapted chemotherapy (without cyclophosphamide, etoposide or bleomycin) for newly diagnosed Hodgkin Lymphoma appears to be safe in children, adolescents and young adults. Our results show significant promise with a CR rate of 100%, 58% rapid early response and significant reduction in the use of toxic chemotherapy and radiation. The EFS/OS to date is 100% with a median follow up time of greater than 3.5 years.

Disclosures
Cairo: Osuka: Research Funding; Miltenyi: Other: MTA; Jazz Pharmaceuticals: Other: Advisory Board, Research Funding, Speakers Bureau.