Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: A Meta-Analysis

Abstract

BackgroundExperience with immune checkpoint inhibitors (ICIs) in the treatment of acute myeloid leukemia (AML) is still limited and based on early clinical trials, with no reported randomized clinical data. In this study, we reviewed the available evidence on the use of ICIs, either in monotherapy or in combination with other treatments, in different AML settings, including newly diagnosed AML, relapsed or refractory (R/R) AML and maintenance treatment after allogeneic-HSCT (allo-HSCT).Materials and MethodsA systematic literature review was conducted using PubMed electronic database as primary source to identify the studies involving immune checkpoint inhibitors in first-line and R/R AML. We recorded Overall Response (ORR), Complete Response (CR) and Complete Response with incomplete count recovery (CRi) rates, overall survival (OS) and immune-related adverse events ≥ grade 3 (irAEs). Hereafter, we analyzed the overall profile of these ICIs by performing a meta-analysis of the reported outcomes.ResultsA total of 13 studies were identified where ICI was used in patients with AML. ORR across these studies was 42% (IC95%, 31% - 54%) and CR/CRi was 33% (IC95%, 22%-45%). Efficacy was also assessed considering the AML setting (first-line vs. relapsed/refractory) and results pointed to higher response rates in first-line, compared to R/R. Mean overall survival was 8.9 months [median 8 months, (IC95%, 3.9 - 15.5)]. Differences between first line and R/R settings were observed, since average overall survival in first line was 12.0 months, duplicating the OS in R/R which was 7.3 months. Additionally, the most specific adverse events (AEs) of these therapies are immune-related adverse events (irAEs), derived from their inflammatory effects. Grade ≥3 irAEs rate was low and similar among studies [12% (95%CI 8% - 16%)].ConclusionICIs in combination with intensive chemotherapy, hypomethylating agents or other targeted therapies are gaining interest in the management of hematological malignancies such as AML. However, results obtained from clinical trials are modest and limited by both, the type of design and the clinical trial phase. Hopefully, the prospective study of these therapies in late-stage development could help to identify patients who may benefit from ICI therapy.

Checkpoint Inhibitors in Acute Myeloid Leukemia

“…The advent of checkpoint inhibitors in solid cancer has led to relevant improvement, mostly in tumors with limited therapeutic options. In AML, despite solid biological bases, the results appear less remarkable; a recent metaanalysis on ICIs in AML confirms the modest results reported by trials [219]. As expected, ORR, CR and OS were better in the first-line setting than in relapsed patients, but it must be underlined that virtually all studies employed ICIs in association with different conventional therapies, and the actual role of ICIs is not evaluable.…”

Phase II trial of hypomethylating agent combined with nivolumab for acute myeloid leukaemia relapse after allogeneic haematopoietic cell transplantation—Immune signature correlates with response

“…[31][32][33][34][35] A recent metaanalysis reported an overall response rate (ORR) of 58% (95% CI: 33-81) as a first-line treatment and an ORR of 33% (95% CI: 27-39) in relapsed/refractory (r/r) disease. 36 Apart from these trials outside of allo-HCT, several reports have provided a rationale for administering anti-PD-1 antibodies in the post-allo-HCT setting. 37 High frequency of PD-1 hi TIM-3 + T cells with signs of exhaustion was strongly associated with AML relapse post-allo-HCT.…”

“…Several studies tested the safety and efficacy of anti‐PD‐1 antibodies in combination with other agents in patients with AML outside the allo‐HCT setting 31–35 . A recent meta‐analysis reported an overall response rate (ORR) of 58% (95% CI: 33–81) as a first‐line treatment and an ORR of 33% (95% CI: 27–39) in relapsed/refractory (r/r) disease 36 . Apart from these trials outside of allo‐HCT, several reports have provided a rationale for administering anti‐PD‐1 antibodies in the post‐allo‐HCT setting 37 .…”

Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value

“…In contrast to their successful use in solid cancers, monoclonal antibodies targeting ICRs have yielded limited therapeutic efficacy in acute myeloid leukemia (AML) [ 4 ]. One could speculate that additional, nonredundant ICRs, specifically expressed in transformed leukemia cells and/or in AML-infiltrating immune cells, may represent better targets in this disease [ 5 ].…”