Ipilimumab for Patients with Relapse after Allogeneic Transplantation

Abstract

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.)

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma

“…29,30 In addition, decreased Treg: CD4Tcon ratios may also predict an augmented GVT effect as observed in a trial of IPI for relapse after HSCT where there was a trend among clinical responders of lower Treg:CD4Tcon. 13 Notably, the immune profiling results also demonstrate severe and persistent depletion of PD1 1 T cells in patients exposed to prior PD-1 blockade, a finding that to our knowledge has not been published previously. Decreased PD-1 expression could contribute to the relative decrease in Treg cell populations, as the PD-1/PD-L1 pathway appears to be important in the conversion of type 1 T helper cells to Treg cells and maintenance of Treg populations.…”

“…10,11 Early clinical trials suggest that checkpoint blockade therapy with nivolumab or ipilimumab (IPI) as treatment of relapse after HSCT could be effective with a tolerable side-effect profile. 12,13 Understanding the impact of prior PD-1 blockade on both the safety and the efficacy of HSCT is critical to select candidates for PD-1 blockade among patients who may be future candidates for HSCT and to select appropriate treatment strategies for HSCT candidates who are responding to PD-1 blockade or who have relapsed after prior PD-1 blockade.…”

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…Along with this, first reports suggest that immune checkpoint blockade may also be efficient in case of relapse after allo-SCT [80,81].…”

Immunotherapy in Pediatric Acute Leukemia: A Novel Magic Bullet or an Illusory Hope?

“…It has been proved that the higher levels of soluble CTLA-4 and CD86 in B-ALL patients worsen the prognosis and should be considered as potential high-risk factors [20,21]. Inhibition of CTLA-4 by specific antibody ipilimumab was not yet investigated in acute leukemia in children, but there are ongoing clinical trials assessing its potential in small groups of adults with acute myeloid leukemia, relapsed after allo-HSCT showing promising regression of malignancy, but also immune-related adverse events connected with drug infusion [22][23][24].…”