Phase II study evaluating azacitidine plus nivolumab in relapsed/refractory acute myeloid leukemia

Researchers from The University of Texas MD Anderson Cancer Center, Houston, TX, USA, conducted a phase II study to evaluate the safety and efficacy of nivolumab in combination with azacitidine in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). The rationale for this trial was to assess the best response to azacitidine plus nivolumab at the end of three courses of combination therapy. The authors published their paper in a recent issue of Cancer Discovery.

Seventy patients with R/R AML (median age = 70 years; range, 22–90) were treated with azacitidine (75 mg/m² on days 1–7 IV or SC) plus nivolumab (3 mg/kg IV on day 1 and 14 every 4–6 weeks). The median number of azacitidine plus nivolumab cycles were three (range, 1–25).

Key findings:

Efficacy

• Median follow up: 13.3 months (range, 8.2–25.5)
• Overall response rate (ORR): 23/70 (33%)
  • Complete response (CR) rate: 4/70 (6%)
  • Complete remission with incomplete count recovery (CRi): 11/70 (16%)
  • Partial response (PR) rate: 1/70 (1%)
  • Seven patients had hematologic improvement (HI)
• With a median follow up of 21.4 months (95% CI, 14.8–not estimated), 57/70 (81%) patients have died
• Median overall survival (OS): 6.3 months
• Median event-free survival (EFS) among responders/stable disease (n = 29): 4.5 months
• Median duration of response (DOR) among responders (n = 23): 5.2 months
• Those patients who achieved a CR/CRi/PR/HI/SD (n = 29; 42%) had superior OS compared to non-responders (n = 41; 58%): 16.16 vs 4.1 months, respectively, P < 0.0001

Safety

• Four- and eight- week mortality rates were 3% and 11%, respectively
• Grade 2–4 immune related adverse events (irAEs) occurred in 16 (23%) patients: pneumonitis (n = 9), nephritis (n = 6), immune-related skin rash (n = 3), and transaminitis (n = 2)
• 13% of patients discontinued treatment with nivolumab due to grade 3/4 irAEs

Immune profiling of pre- and post-therapy bone marrow (BM) aspirates were evaluated using multicolour flow-cytometry and mass cytometry.

• Patients who achieved a response showed a higher frequency of pre-therapy BM CD3⁺ cells in comparison with non-responders: 32.5% vs 17.5%, P = 0.04
• Patients who responded to treatment had a higher frequency of pre-therapy PB CD3⁺ cells compared to non-responders: 45% vs 21.8%, P = 0.0058
• Responders had a higher frequency of CD4⁺Teff cells in the pre-therapy BMAs than non-responders: 15.6% vs 9.0%, P = 0.08
• Responding patients also had a higher frequency of CD8⁺ T cells in pre-therapy BMAs than those who did not achieve a response: 13.1% vs 6.9%, P = 0.09

In this study, azacitidine plus nivolumab yielded a hematologic response rate of 33% and a median OS of 6.3 months. However, immune-mediated toxicities may occur and should be adequately managed with prompt diagnosis followed by systemic steroids. The authors stated that there are other trials currently underway such as “a randomized phase III and a randomized phase II study of azacitidine with or without PD-1 inhibitor in frontline elderly AML (NCT03092674, NCT02775903) and a randomized trial of PD-1 inhibitor for the eradication of MRD in high-risk AML in remission (NCT02275533).”