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Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia

ABSTRACT: Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia

PROVIDER: PRJNA800756 | ENA |

REPOSITORIES: ENA

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Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia

Project description:Background: The powerful ‘graft versus leukemia’ effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease. Methods: We report here the results of 17 H-0026 (PD- AML, NCT02996474), an investigator sponsored, single- institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML). Results: In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor β sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune- related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment. Conclusion: Addition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.

2022-01-26 | GSE195471 | GEO

Phase II Study of Immune Checkpoint Blockade with Pembrolizumab after High Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Project description:To address the role of immune dysregulation in AML, we conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg IV on day 14 to examine whether programmed death-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to two years. Among thirty-seven patients enrolled, the overall response rate, composite complete remission rate (CRc; primary endpoint), and median overall survival (OS) were 46%, 38% and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS 13.2 and 11.3 months, respectively). Grade >3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T-cells in the bone marrow prior to treatment and a non-significant increase in baseline T-cell diversity.

2021-09-09 | GSE183415 | GEO

Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia.

Project description: Not available

| S-EPMC8753450 | biostudies-literature

Phase II Study of Immune Checkpoint Blockade with Pembrolizumab after High Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Project description:Phase II Study of Immune Checkpoint Blockade with Pembrolizumab after High Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

| PRJNA760534 | ENA

Pembrolizumab in Treating Patients With Relapsed or Refractory Stage IB-IVB Mycosis Fungoides or Sezary Syndrome

Project description:Pembrolizumab in Treating Patients With Relapsed or Refractory Stage IB-IVB Mycosis Fungoides or Sezary Syndrome

| PRJNA842141 | ENA

Pembrolizumab in Treating Patients With Relapsed or Refractory Stage IB-IVB Mycosis Fungoides or Sezary Syndrome

Project description:Pembrolizumab in Treating Patients With Relapsed or Refractory Stage IB-IVB Mycosis Fungoides or Sezary Syndrome

| PRJNA842142 | ENA

DNA methylation of Relapsed/Refractory AML

Project description:Genome wide DNA methylation profiling of blood and bone marrow of Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia. The Illumina Infinium EPIC Human DNA methylation Beadchip was used to obtain DNA methylation profiles across over 860,000 CpGs.

2023-12-31 | GSE225239 | GEO

Spliceosome mutations are associated with clinical response in a Phase 1b/2 study of the PLK1 inhibitor onvansertib in combination with decitabine in relapsed or refractory acute myeloid leukemia.

Project description:Background: PLK1 is overexpressed in acute myeloid leukemia (AML). A Phase 1b trial of the PLK1 inhibitor onvansertib (ONV) combined with decitabine (DAC) demonstrated initial safety and efficacy in patients with relapsed/refractory (R/R) AML. The current study aimed to identify molecular predictors of response to ONV + DAC in R/R AML patients. Patients and methods: A total of 44 R/R AML patients were treated with ONV+DAC and considered evaluable for efficacy. Bone marrow (BM) samples were collected at baseline for genomic and transcriptomic analysis (n=32). A 10 gene expression-signature, predictive of response to ONV + DAC, was derived from the leading-edge genes of gene set enrichment analyses (GSEA). The gene signature was evaluated in independent datasets and used to identify associated mutated genes. Results: 20% of the patients achieved complete remission, with or without hematologic count recovery (CR/CRi) and 32% exhibited a ≥50% reduction in bone marrow blasts. Patients who responded to treatment had elevated mitochondrial function and OXPHOS. The gene signature was not associated with response to DAC alone in an independent dataset. By applying the signature to the BeatAML cohort (n=399), we identified a positive association between predicted ONV + DAC response and mutations in splicing factors (SF). In the Phase 1b/2 trial, patients with SF mutations (SRSF2, SF3B1) had a higher CR/CRi rate (50%) compared to those without SF mutations (9%). Conclusion: PLK1 inhibition with ONV in combination with DAC could be a potential therapy in R/R AML patients, particularly those with high OXPHOS gene expression and SF mutations.

2023-09-11 | GSE239678 | GEO

Genomic profiling of relapsed and refractory childhood cancers

Project description:Genomic profiling of relapsed and refractory childhood cancers

| PRJNA661354 | ENA

Genomic profiling of relapsed and refractory childhood cancers

Project description:Genomic profiling of relapsed and refractory childhood cancers

| PRJNA661355 | ENA