Cyclosporine, Interferon-γ , and Interleukin-2 Immunotherapy Is Tolerable and Induces Autoreactivity in Patients with Recurrent/Refractory Hodgkin Disease Undergoing Autologous Stem Cell Transplantation with BEAM: A COG Study.
Authors: Chen Allen , Hess Allan , Gardner Sharon , Trippett Tanya , de Alarcon Pedro , Guillerman Robert , Hogan Shirley , Mitchell Joy , Gamis Alan , Massey Vicki , Constine Louis S. , Villaluna Doojduen , Sposto Richard , Schwartz Cindy 
Published: October 2019

For patients with recurrent and refractory Hodgkin Disease (HD), the major risk after standard treatment with high-dose chemotherapy and autologous hematopoietic stem cell rescue (ASCR) is relapse. In the setting of allogeneic SCT, the graft-vs.-lymphoma effect is offset by high transplant-related mortality. The Children’s Oncology Group has therefore undertaken a study of immunotherapy to induce autologous graft-vs.-host disease (auto GVHD) in an effort to reduce the relapse rate without excessive morbidity and mortality. The objectives of part I of the study were to determine the toxicity and feasibility of inducing auto GVHD with cyclosporine, interferon-γ , and IL-2 after high-dose BEAM. Twenty-four patients with biopsy-confirmed recurrent/refractory HD were enrolled at 13 institutions. One patient was inevaluable because of a protocol violation. At initial diagnosis, 5 were stage IV, 8 stage III, 7 stage II, 1 stage I, and 3 unknown; 16 had B symptoms, and 15 had bulky disease. All patients had failed intensive multi-agent chemotherapy, and most had received prior radiation therapy. At relapse, 3 patients had B symptoms and 2 had bulky disease, and 8 had extranodal disease. All patients received full doses of the preparative regimen, with the expected reversible complications of febrile neutropenia, pancytopenia, nausea, vomiting, anorexia, mucositis, and electrolyte disturbances. In addition to fever, fatigue, and cytopenias, two patients developed pneumonitis after receiving immunotherapy, one of whom died of respiratory failure 6 wks after study entry. Of note, this patient received only 2 doses of IL-2 before developing pneumonitis. Bronchoalveolar lavage failed to demonstrate an etiology, but a culture obtained by open lung biopsy was positive for staphylococcus epidermidis. One patient developed a rash and one patient developed liver function abnormalities during the immunotherapy consistent with auto GVHD.

Toxicities Toxicity RT/BEAM/ASCR Immunotherapy n = 16 n = 15 Febrile neutropenia 11 (69%) 4 (27%) Nausea/vomiting/anorexia 10 (63%) 3 (20%) Mucositis 7 (44%) 2 (13%) Metabolic/lab 8 12 Pneumonitis 0 2 (13%) Fever 0 2 (13%) Fatigue 0 2 (13%) Hypotension 1 (6%) 0

Blood was requested at weekly intervals during immunotherapy administration to test for autoreactivity in mixed lymphocyte cultures and by cytokine assays with autologous stimulator cells. The sample submission rate was 90%. In 11 of 14 patients, there was significant in vitro lymphocyte autoreactivity. We conclude that this immunotherapy regimen is tolerable and induces autoreactivity in a sufficient proportion of patients to warrant proceeding with part II of the study. Part II will test the efficacy of immunotherapy by randomizing patients with chemosensitive recurrent/refractory HD to receive immunotherapy or not after BEAM and ASCR.