Project description:Acute myeloid leukemia (AML) is a markedly heterogeneous hematological malignancy that is most commonly seen in elderly adults. The response to current therapies to AML is quite variable, and very few new drugs have been recently approved for use in AML. This review aims to discuss the issues with current trial design for AML therapies, including trial end points, patient enrollment, cost of drug discovery and patient heterogeneity. We also discuss the future directions in AML therapeutics, including intensification of conventional therapy and new drug delivery mechanisms; targeted agents, including epigenetic therapies, cell cycle regulators, hypomethylating agents and chimeric antigen receptor T-cell therapy; and detail of the possible agents that may be incorporated into the treatment of AML in the future.
Project description:Older patients with acute myeloid leukemia (AML) have worse rates of complete remission and shorter overall survival than younger patients. The epigenetic modifier CC-486 is an oral formulation of azacitidine with promising clinical activity in patients with AML in Phase I studies. The Phase III, randomized, double-blind, placebo-controlled QUAZAR AML Maintenance trial (CC-486-AML-001) examines CC-486 maintenance therapy (300 mg/day for 14 days of 28-day treatment cycles) for patients aged ≥55 years with AML in first complete remission. The primary end point is overall survival. Secondary end points include relapse-free survival, safety, health-related quality of life and healthcare resource utilization. This trial will investigate whether CC-486 maintenance can prolong remission and improve survival for older patients with AML.
Project description:Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza®), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra®), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra® in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities.
Project description:The DNA demethylating therapy with azacitidine (AZA) is a promising therapeutic strategy for elderly patients with acute myeloid leukemia (AML). AZA primarily inhibits DNA methylation, promotes cell differentiation and apoptosis in AML. However, as a cytosine nucleoside analog, AZA also has the potential to be incorporated into RNA molecules. To assess the impact of AZA on RNA m5C methylation during demethylating therapy, we conducted Nanopore direct-RNA sequencing on samples from three AML patients pre and after demethylating therapy, as well as on HL-60 cells pretreated with AZA. We performed an integrated analysis of the transcriptome and the m5C methylome, contrasting the states of complete remission with those of active disease (AML). Our results revealed an extensive demethylation effect at the RNA level attributable to AZA and found that mRNA m5C modification may play a pivotal role in the progression of AML. Additionally, S100P was identified as a biomarker with significant prognostic implications. We also conducted a conjoint analysis of the transcriptome and the m5C methylome of the full-length transcripts, uncovering several dysregulated mRNA isoforms. Collectively, our findings indicate that mRNA m5C methylation is implicated during AML progression, and AZA exhibits an overall suppressive effect on this process.
Project description:Background5-Azacitidine administered as a 7-day dosing regimen (7-0-0) is approved in high risk IPSS myelodysplastic syndrome (MDS) patients. Alternative regimens such as a 5-day (5-0-0) or 7-day with a weekend break (5-2-2) are commonly used. No randomized controlled trial has been done directly comparing all three dosing regimens. The objective of this study was to compare the efficacies of the 5-0-0, 5-2-2, and 7-0-0 regimens in MDS and AML.MethodsA systematic review was conducted using MEDLINE, EMBASE and CENTRAL. Eligible studies were randomized controlled trials (RCTs), observational prospective and retrospective studies. The primary clinical outcomes were Objective Response Rate (ORR) defined as the sum of complete response (CR), partial response (PR), and hematological improvement (HI) as defined by the IWG 2006 criteria. A meta-analysis of simple proportions was conducted using a random effects model with weights defined according to Laird and Mosteller. Comparisons between groups were not attempted due to the heterogeneity of study designs.ResultsThe only RCT directly comparing alternative azacitidine regimens showed no difference in ORR between the 5-0-0 and 5-2-2 regimens. All other RCTs compared a dosing regimen to conventional care. The pooled proportion of ORR was 44.8% with 95% CI (42.8%, 45.5%) for 7-0-0, 41.2% with 95% CI (39.2%, 41.9%) for 5-0-0, and 45.8% with 95% CI (42.6%, 46.4%) for 5-2-2.ConclusionsIndirect comparison of alternative azacitidine dosing regimens in MDS and AML shows a benefit for the 7-day regimen in attaining ORR. Additional RCTs are required to definitively address this comparison.
Project description:Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell-based disorders characterized by ineffective hematopoiesis, increased genomic instability and a tendency to progress toward acute myeloid leukemia (AML). MDS and AML cells present genetic and epigenetic abnormalities and, due to the heterogeneity of these molecular alterations, the current treatment options remain unsatisfactory. Hypomethylating agents (HMA), especially azacitidine, are the mainstay of treatment for high-risk MDS patients and HMA are used in treating elderly AML. The aim of this study was to investigate the potential role of the epigenetic reader bromodomain-containing protein-4 (BRD4) in MDS and AML patients. We identified the upregulation of the short variant BRD4 in MDS and AML patients, which was associated with a worse outcome of MDS. Furthermore, the inhibition of BRD4 in vitro with JQ1 or shRNA induced leukemia cell apoptosis, especially when combined to azacitidine, and triggered the activation of the DNA damage response pathway. JQ1 and AZD6738 (a specific ATR inhibitor) also synergized to induce apoptosis in leukemia cells. Our results indicate that the BRD4-dependent transcriptional program is a defective pathway in MDS and AML pathogenesis and its inhibition induces apoptosis of leukemia cells, which is enhanced in combination with HMA or an ATR inhibitor.
Project description:Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.