Efficacy and safety of nivolumab-based therapy in children with relapse of hematologic malignancies after allogenic HSCT
Patients with posttransplant acute leukemia relapse are hardly curable and the outcome is extremely poor. The effectiveness of standard chemotherapy and donor lymphocyte infusions is limited. A possible alternative to standard chemotherapy and DLI is use of PD-1 inhibitors, which may potentiate the allogeneic immune response in order to harness graft-versus-leukemia effect.
We analyzed retrospectively 8 patients, age 3 to 14 years, who had received therapy with PD-1-inhibitor after HSCT. The cohort included 6 patients with acute myeloid leukemia, 1 pt with acute lymphoblastic leukemia and 1 pt with hepatosplenic gamma/delta T cell lymphoma. At the moment of HSCT 5 patients had an advanced stage of their disease, 2 were in complete remission and 1 had positive minimal residual disease. All patients received allo-HSCT (5 patients from haploidentical donors, 3 patients from HLA-identical siblings). At day +30 after HSCT all patients were in clinical and molecular remission, 50% of the patients developed grade 1-2 acute GVHD with skin and GI impairment. The average time to relapse was 180 (97-420) days. Bone marrow relapse was detected in 6 patients while 2 patients had molecular relapse. All patients received 1 injection of nivolumab at a dose of 3 mg/kg. One patient with AML received the injection of nivolumab already being in the remission after second HSCT because of high risk of relapse.
Adverse events were registered in 6 (75%) patients. Two patients developed immune meningoencephalitis, 1 pt had grade 4 immune-mediated liver toxicity, 2 pt had grade 3 skin GVHD flare and immune fever was registered in 4 pts. Four patients required prolonged systemic immunosuppressive therapy to control immune-mediated adverse effects. No mortality related to checkpoint-inhibitor toxicity was registered. One patient developed progressive liver disease. Bone marrow aspiration was done to evaluate efficiency of therapy after the first injection of nivolumab. Seven patients were evaluable for response. Six of 7 patients did not respond to therapy. Average time to disease progression was 21 days. Stable remission was achieved in 1 patient with ALL who received injection of nivolumab being in the full-blown relapse after HSCT. One year and 3 months later this patient remains in clinical and molecular remission, although immune-mediated liver damage progressed to end-stage liver disease and patient received a successful liver transplantation. Patient with AML received the injection of nivolumab already being in the remission and 22 months after therapy remains in clinical and molecular remission.
Our limited experience suggests that use of PD-1 inhibitors after allo-HSCT is associated with significant toxicity. Further prospective study is required to establish the safety and efficiency of this approach.
PD-1 inhibitors, allo-HSCT, relapse, ALL, AML.