ABSTRACT
BACKGROUND: First-line treatment in patients with acute myeloid leukemia (AML) unfit for intensive therapy is the combination of a hypomethylating agent (HMA) with venetoclax (VEN). However, retrospective data confirming the benefits of this regimen outside of clinical trials have shown conflicting results. METHODS: We performed a multicenter retrospective analysis of outcomes with first-line HMA-VEN versus HMA in AML patients unfit for intensive chemotherapy. RESULTS: A total of 213 patients were included from three German hospitals (125 HMA-VEN, 88 HMA). Median overall survival in the HMA-VEN cohort was 7.9 months (95% confidence interval [CI], 5.1-14.7) versus 4.9 months (3.1-7.1) with HMA. After 1 year, 42% (95% CI, 33-54) and 19% (12-30) of patients were alive, respectively (hazard ratio [HR] for death, 0.64; 95% CI, 0.46-0.88). After adjusting for clinical and molecular baseline characteristics, treatment with HMA-VEN remained significantly associated with both prolonged survival (HR, 0.48; 95% CI, 0.29-0.77) and time to next treatment (HR, 0.63; 95% CI, 0.47-0.85). Patients who achieved recovery of peripheral blood counts had a favorable prognosis (HR for death, 0.52; 95% CI, 0.33-0.84). DISCUSSION: These data align with findings from the pivotal VIALE-A trial and support the use of HMA-VEN in patients unfit for intensive therapy.
ABSTRACT
The addition of midostaurin to standard chemotherapy has improved survival in patients with FLT3-mutated AML. However, the impact of midostaurin and other FLT3 inhibitors (FLT3i) on cardiovascular adverse events (CAEs) has not been studied in patients who underwent allogeneic hematopoietic stem cell transplantation in a real-world setting. We reviewed 132 patients with AML who were treated with intensive induction therapy and consecutive allogeneic stem cell transplantation at our institution (42 FLT3-mutated AML and 90 with FLT3 wildtype). We identified treatment with midostaurin and/or FLT3i as an independent risk factor for CAEs not resulting in higher non-relapse mortality (NRM) or impaired overall survival (OS). Hence, close monitoring for CAEs is warranted for these patients.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/drug therapy , Mutation , Staurosporine/adverse effects , Protein Kinase Inhibitors/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
Recent efforts reclassified B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) into more refined subtypes. Nevertheless, outcomes of relapsed BCP-ALL remain unsatisfactory, particularly in adult patients where the molecular basis of relapse is still poorly understood. To elucidate the evolution of relapse in BCP-ALL, we established a comprehensive multi-omics dataset including DNA-sequencing, RNA-sequencing, DNA methylation array and proteome MASS-spec data from matched diagnosis and relapse samples of BCP-ALL patients (n = 50) including the subtypes DUX4, Ph-like and two aneuploid subtypes. Relapse-specific alterations were enriched for chromatin modifiers, nucleotide and steroid metabolism including the novel candidates FPGS, AGBL and ZNF483. The proteome expression analysis unraveled deregulation of metabolic pathways at relapse including the key proteins G6PD, TKT, GPI and PGD. Moreover, we identified a novel relapse-specific gene signature specific for DUX4 BCP-ALL patients highlighting chemotaxis and cytokine environment as a possible driver event at relapse. This study presents novel insights at distinct molecular levels of relapsed BCP-ALL based on a comprehensive multi-omics integrated data set including a valuable proteomics data set. The relapse specific aberrations reveal metabolic signatures on genomic and proteomic levels in BCP-ALL relapse. Furthermore, the chemokine expression signature in DUX4 relapse underscores the distinct status of DUX4-fusion BCP-ALL.
