“This Phase II trial investigated the addition of nivolumab, a fully human IgG4 anti-PD-1 monoclonal antibody, to induction therapy with idarubicin and cytarabine as a strategy to improve remission duration, eradicate minimal residual disease, and enhance the activity of cytotoxic T cells,” said Ravandi. “We designed this study to evaluate the feasibility, safety, and activity of this combination for these disorders.”
Nivolumab is an immunotherapy approved for other cancers that frees immune system T cells to attack cancer by blocking activation of the inhibitory protein PD-1 on the T cell surface. As a single leukemia treatment, nivolumab has had low activity against AML.
Eligible patients ages 18 to 60 years with treatment-naïve AML or high-risk MDS were enrolled. Patients older than 60 years deemed fit to receive intensive chemotherapy were also eligible. Exclusion criteria included previous therapy for AML other than temporary measures such as apheresis or hydroxyurea, or one dose of cytarabine of two grams or less for control of hyperleukocytosis.
Previous therapy for MDS was allowed. Patients with active or suspected autoimmune disease were excluded as were pregnant or lactating women, as well as patients with any uncontrolled clinically significant illness or infection.
“The median relapse-free survival and median overall survival of responders was 18.54 months,” said Ravandi. “Overall, 34 patients achieved a response and 19 of them proceeded to an allogeneic stem cell transplant; grade 3-4 graft-versus-host disease was observed in five patients.”
The primary endpoint, assessed in all patients, was event-free survival, defined as the time between initiation of therapy and removal from the study for treatment failure, relapse or death. At median follow-up of 17.25 months, median event-free survival had not been reached. Secondary endpoints were relapse-free survival and overall survival.
While the current standard of care leads to remission in almost 80% of patients younger than 60 years. Ravandi says a new strategy is needed since only 30 to 50% of these patients achieve long-term, disease-free survival.
“The addition of nivolumab may improve outcomes by decreasing risk of relapse, and patients with exhausted immune phenotype in bone marrow T cells may be less likely to respond to induction, and may benefit from such immune modulation,” said Ravandi. “This preliminary study suggests the feasibility of this treatment approach and future larger randomized trials are needed to establish the efficacy of this approach.”
The study was funded by the National Institutes of Health (CA016672 and CA100632), and Bristol Myers Squibb. Ravandi has received honoraria from Bristol-Myers.