Repeated Dosing Of Anti-KIR (IPH2101) As Maintenance Therapy In Ederly Patients With Acute Myeloid Leukemia

Inhibitory killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell–mediated killing of HLA class I-expressing tumors. Anti-KIR treatment resulted in long-term survival in SCID mice inoculated with autologous AML cells (Romagne et al. Blood 114: 2667, 2009). Lack of KIR-HLA class I interactions has been associated with a markedly reduced relapse risk and increased survival in patients with acute myeloid leukemia (AML) upon stem cell transplantation from KIR-mismatched haploidentical donors (Ruggeri et al. Blood 2007).

IPH2101 is a fully human monoclonal, hybridoma manufactured antibody (mAb) targeting the KIR2D receptors on NK cells. Results of a dose escalation phase 1 trial conducted in elderly patients with AML in complete remission (CR) indicated a satisfactory safety profile. The maximal tolerated dose was not reached at 3mg/kg. There was a clear correlation between drug exposure and KIR occupancy. Survival was consistent with a dose-related anti-leukemia effect (Vey et al. Blood 120: 4317, 2012. An extension of this phase 1 study was conducted in order to further assess the safety and efficacy of repeated monthly cycles of IPH2101 given at doses producing continuous KIR occupancy. The results of this extension are reported here.

This was an open-label, multicenter extension trial to the phase 1 dose-escalation study, conducted in 12 patients ≥ 60 years with an AML in CR. They were to receive up to 6 monthly cycles of IPH2101 at doses of 1 or 2 mg/kg administered as an IV infusion over one hour. Age £ 80, ineligibility for allogeneic cell transplantation, recovery from toxicities of prior chemotherapies and a time lapse ≤ 60 days since the last consolidation cycle were required.

Twelve patients were enrolled (median age 71 years; range: 64-75). All were in CR after a median of 3 consolidation cycles (range: 1-6). Seven patients received 6 cycles of IPH2101 and the others between 1 and 3 cycles. Premature discontinuation was due to relapse of AML in four patients and to an unrelated adverse event in one patient (worsening of heart failure).

Thirty one related adverse events (AEs) occurred in 83% of the patients. No grade 4 related AEs was reported. Four patients had transient grade 3 related AEs: lymphopenia (4) and amylase/lipase increased (1). Related AEs that were observed in more than one patient included lymphopenia (4), pruritus (3) and erythema/ rash (3). There was no suggestion of a dose effect for safety.

The first 6 patients received a dose of 1 mg/kg. At this dose level, full KIR2D occupancy (>95%) was not sustained during monthly cycles in 3/6 patients. Six additional patients received 2 mg/kg with continuous full KIR2D occupancy in all patients. After treatment discontinuation, full occupancy persisted for a median of 1 month (range: 1-3).

Median follow-up is 62 weeks at the time of this analysis, 5/12 patients were still alive including 1 in continuous CR All deaths were secondary to AML relapse.

Analyses are ongoing to document the impact of IPH2101 treatment on various hematological and immunological parameters in serum (cytokine levels) and in peripheral blood (minimal residual disease), distribution of lymphocytes subsets, as well as phenotypic and functional analysis of NK cells.

The safety of IPH2101 was confirmed in this extension cohort assessing repeated monthly cycles leading to full and sustained KIR occupancy for more than 6 months.

Vey:Innate Pharma: Honoraria; Bristol Myers Squibb: Honoraria. Andre:Innate-Pharma: Employment, Equity Ownership. Calmels:Innate-Pharma: Employment, Equity Ownership. Zerbib:Innate Pharma: Employment. Buffet:Innate-Pharma: Employment.