Blockade of immune checkpoints is emerging as new form of anticancer therapy. We studied the expression of PD-L1, PD-L2, PD-1 and CTLA4 mRNA expression in CD34+ cells from MDS, CMML and AML patients (N=124). Aberrant up-regulation (≥2 fold) was observed in 34%, 14%, 15% and 8% of the patients respectively. Increased expression of these 4 genes was also observed in PBMNC (N=61). The relative expression of PD-L1 from PBMNC was significantly higher in MDS (p=0.018) and CMML (p=0.0128) compared to AML. By immunohistochemical (IHC) analysis, PD-L1 protein expression was observed in MDS CD34+ cells, whereas stroma/non-blast cellular compartment was positive for PD-1. In a cohort of patients treated with epigenetic therapy, PD-L1, PD-L2, PD-1 and CTLA4 expression was upregulated. Patients resistant to therapy had relative higher increments in gene expression compared to patients that achieved response. Treatment of leukemia cells with decitabine resulted in a dose dependent up-regulation of above genes. Exposure to decitabine resulted in partial demethylation of PD-1 in leukemia cell lines and human samples. This study suggests PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to HMAs. Blockade of this pathway can be a potential therapy in MDS and AML.
Background:
Preclinical models showed that blocking PD-1/PD-L1 pathways enhanced anti-leukemic responses. Azacitidine up-regulates PD-1 and interferon-gamma signaling.
Methods:
In this single arm trial, patients with relapsed/refractory (R/R) AML were treated with azacitidine 75mg/m2 Days 1–7 intravenously or subcutaneously with nivolumab 3mg/kg intravenously on Day 1 and 14, every 4–6 weeks.
Findings:
Seventy patients were treated. The median age was 70 years (range, 22–90). The median number of prior therapies received was 2 (range, 1–7). The overall response rate (ORR) was 33% including 15 (22%) complete remission (CR)/complete remission with insufficient recovery of counts (CRi), 1 partial response, and 7 patients with hematologic improvement (HI) maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in HMA-naïve (n=25) and HMA pre-treated (n=45) patients, respectively. Grade 3–4 immune related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow-cytometry. CTLA-4 was significantly up-regulated on CD4+Teff in non-responders after 2 and 4 doses of nivolumab.
Interpretation:
Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and Salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection.
Trial Registration ID:
Clinicaltrials.gov identifier: NCT02397720
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