General AML

Ipilimumab for patients with relapse after allogeneic transplantation

The anti-CTLA-4 monoclonal antibody, ipilimumab, has been used to effectively improve overall survival in two phase III studies involving patients with advanced melanoma1. Following on from the success in melanoma, Davids M.S, from the Dana-Farber Cancer Institute et al., hypothesized that immune checkpoint blockade, established by targeting CTLA-4 with ipilimumab, may induce a graft-versus-tumor effect in patients with relapse after allogeneic HSCT and lead to a clinical response.2

Davids MS, et al., conducted a phase 1/1b multicenter, open-label, investigator-initiated study to determine the MTD, the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer (12 AML patients out of 28) after allogeneic hematopoietic stem-cell transplantation (HSCT). The results were published in N Engl J Med in July 2016.

The trial was conducted in accordance to the Declaration of Helsinki and ICH-GCP guidelines and was registered at ClinicalTrials.gov (NCT01822509).

The key findings were:

  • No objective response was seen at a dose of 3 mg/kg, whereas 10 mg/kg induced OR in 7 patients out of 22. The 5 CR were observed in patients with extra-medullary AML (4) and in one patient with MDS developing into AML. This patient remained in CR at 16 months.
  • Ipilimumab was active in patients with relapsed hematologic cancers after allogenic HSCT, but some patients experienced graft versus host disease (GVHD) (2 chronic GVHD of the liver and one case of grade II acute GVHD of the gut) or irAEs (grade 2 immune thrombocytopenia (1), grade 2 pneumonitis (1) and grade 3 colitis and pneumonitis grade 4 (1). This last patient died 42 days after receiving the initial dose of ipilimumab.

These data warrant the further investigation of the use of ipilimumab for patients with relapsed hematologic malignancies after transplantation, however, monitoring for immune-related adverse events is required.

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.).

References
  1. Postow M.A, et al. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol. 2015 Jun 10;33 (17): 1974–1982. DOI: 10.1200/JCO.2014.59.4358. [Epub 2015 Jan 20].
  2. Davids M.S, et al. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N Engl J Med. 2016 Jul 14;375 (2):143–153. DOI: 10.1056/NEJMoa1601202.