BACKGROUND: Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect. METHODS: We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit. RESULTS: A total of 28 patients were enrolled. Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood. CONCLUSIONS: Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT, although immune-mediated toxic effects and GVHD occurred. Durable responses were observed in association with several histologic subtypes of these cancers, including extramedullary acute myeloid leukemia. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01822509.).
BACKGROUND: Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect. METHODS: We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit. RESULTS: A total of 28 patients were enrolled. Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood. CONCLUSIONS: Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT, although immune-mediated toxic effects and GVHD occurred. Durable responses were observed in association with several histologic subtypes of these cancers, including extramedullary acute myeloid leukemia. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01822509.).
Authors: Edwin P Alyea; Haesook T Kim; Vincent Ho; Corey Cutler; John Gribben; Daniel J DeAngelo; Stephanie J Lee; Sarah Windawi; Jerome Ritz; Richard M Stone; Joseph H Antin; Robert J Soiffer Journal: Blood Date: 2004-09-30 Impact factor: 22.113
Authors: Pavan Bachireddy; Ursula Hainz; Michael Rooney; Olga Pozdnyakova; Julie Aldridge; Wandi Zhang; Xiaoyun Liao; F Stephen Hodi; Karyn O'Connell; W Nicholas Haining; Natalie R Goldstein; Christine M Canning; Robert J Soiffer; Jerome Ritz; Nir Hacohen; Edwin P Alyea; Haesook T Kim; Catherine J Wu Journal: Blood Date: 2013-12-19 Impact factor: 22.113
Authors: Yoshinobu Koguchi; Helena M Hoen; Shelly A Bambina; Michael D Rynning; Richard K Fuerstenberg; Brendan D Curti; Walter J Urba; Christina Milburn; Frances Rena Bahjat; Alan J Korman; Keith S Bahjat Journal: Cancer Res Date: 2015-12-01 Impact factor: 12.701
Authors: Jedd D Wolchok; Bart Neyns; Gerald Linette; Sylvie Negrier; Jose Lutzky; Luc Thomas; William Waterfield; Dirk Schadendorf; Michael Smylie; Troy Guthrie; Jean-Jacques Grob; Jason Chesney; Kevin Chin; Kun Chen; Axel Hoos; Steven J O'Day; Celeste Lebbé Journal: Lancet Oncol Date: 2009-12-08 Impact factor: 41.316
Authors: Bruce R Blazar; Beatriz M Carreno; Angela Panoskaltsis-Mortari; Laura Carter; Yoshiko Iwai; Hideo Yagita; Hiroyuki Nishimura; Patricia A Taylor Journal: J Immunol Date: 2003-08-01 Impact factor: 5.422
Authors: David A Sallman; Amy F McLemore; Amy L Aldrich; Rami S Komrokji; Kathy L McGraw; Abhishek Dhawan; Susan Geyer; Hsin-An Hou; Erika A Eksioglu; Amy Sullivan; Sarah Warren; Kyle J MacBeth; Manja Meggendorfer; Torsten Haferlach; Steffen Boettcher; Benjamin L Ebert; Najla H Al Ali; Jeffrey E Lancet; John L Cleveland; Eric Padron; Alan F List Journal: Blood Date: 2020-12-10 Impact factor: 22.113
Authors: Christina S Baik; Eric H Rubin; Patrick M Forde; Janice M Mehnert; Deborah Collyar; Marcus O Butler; Erica L Dixon; Laura Q M Chow Journal: Clin Cancer Res Date: 2017-09-01 Impact factor: 12.531