Nivolumab for Relapsed or Residual Haematological Malignancies after Allogeneic Haematopoietic Stem Cell Transplantation (NIVALLO)

Aim: To evaluate the safety and efficacy of nivolumab for the treatment of relapsed or residual haematological malignancies after allogeneic stem cell transplantation (alloSCT).

Background: Relapse of haematological malignancies following alloSCT is a major cause of post-transplant mortality. Interaction between programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibits T-cell alloreactivity and contributes to immune escape. Nivolumab inhibits PD-1 signalling and augments T-cell cytotoxicity. The safety and efficacy of nivolumab post-alloSCT has not been evaluated in a clinical trial.

Method: In this investigator-initiated phase IIa clinical trial, patients with relapsed or persistent haematological malignancies following alloSCT receive nivolumab 3mg/kg for up to 48 weeks. Patients with current graft-versus-host disease (GVHD) or prior grade ≥2 acute GVHD or chronic GVHD are excluded.

Results: Six participants have received at least one dose of nivolumab at this interim assessment. Primary haematological malignancies relapsing post-alloSCT included Hodgkin lymphoma (HL, 2 patients), acute myeloid leukaemia (AML, 2), transformed chronic lymphocytic leukaemia (tCLL, 1) and mantle cell lymphoma (MCL, 1). The median time from alloSCT to first dose of nivolumab was 25.5 months. Two participants developed grade 3 acute GVHD at 6 days and 13 days following the first dose of nivolumab. Complete or partial responses were observed in 3 participants (50%). Two participants with HL achieved complete responses. One participant with MCL had a complete nodal response with small volume persistent bone marrow disease. One participant with monosomal karyotype AML achieved initial blast reduction (23% to 13%) however subsequently developed progressive AML. T-cell phenotyping at first AML relapse (prior to nivolumab) demonstrated a high proportion of CD8+ T cells that expressed PD-1 and T-cell immunoglobulin and mucin domain 3 (TIM-3) consistent with T-cell exhaustion. Following treatment with nivolumab there was an increase in TNFα production by CD8+ T-cells at day 7 post nivolumab, demonstrating augmentation of T-cell activity. Despite continued nivolumab treatment TNFα production subsequently declined and correlated with loss of clinical response. TIM-3 expression was further upregulated at post-nivolumab progression suggesting this inhibitory checkpoint receptor may have contributed to nivolumab resistance.

Conclusion: Nivolumab treatment after alloSCT results in potent immune stimulation with a high rate of clinical responses, albeit with a risk of GVHD. Acquired resistance to nivolumab may develop via upregulation of alternative inhibitory checkpoints.