Azacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group

Abstract

We recently published a clinically-meaningful improvement in median overall survival (OS) for patients with acute myeloid leukaemia (AML), >30% bone marrow (BM) blasts and white blood cell (WBC) count ≤15 G/L, treated with front-line azacitidine versus conventional care regimens within a phase 3 clinical trial (AZA-AML-001; NCT01074047; registered: February 2010). As results obtained in clinical trials are facing increased pressure to be confirmed by real-world data, we aimed to test whether data obtained in the AZA-AML-001 trial accurately represent observations made in routine clinical practice by analysing additional AML patients treated with azacitidine front-line within the Austrian Azacitidine Registry (AAR; NCT01595295; registered: May 2012) and directly comparing patient-level data of both cohorts. We assessed the efficacy of front-line azacitidine in a total of 407 patients with newly-diagnosed AML. Firstly, we compared data from AML patients with WBC ≤ 15 G/L and >30% BM blasts included within the AZA-AML-001 trial treated with azacitidine (“AML-001” cohort; n = 214) with AAR patients meeting the same inclusion criteria (“AAR (001-like)” cohort; n = 95). The current analysis thus represents a new sub-analysis of the AML-001 trial, which is directly compared with a new sub-analysis of the AAR. Baseline characteristics, azacitidine application, response rates and OS were comparable between all patient cohorts within the trial or registry setting. Median OS was 9.9 versus 10.8 months (p = 0.616) for “AML-001” versus “AAR (001-like)” cohorts, respectively. Secondly, we pooled data from both cohorts (n = 309) and assessed the outcome. Median OS of the pooled cohorts was 10.3 (95% confidence interval: 8.7, 12.6) months, and the one-year survival rate was 45.8%. Thirdly, we compared data from AAR patients meeting AZA-AML-001 trial inclusion criteria (n = 95) versus all AAR patients with World Health Organization (WHO)-defined AML (“AAR (WHO-AML)” cohort; n = 193). Within the registry population, median OS for AAR patients meeting trial inclusion criteria versus all WHO-AML patients was 10.8 versus 11.8 months (p = 0.599), respectively. We thus tested and confirmed the efficacy of azacitidine as a front-line agent in patients with AML, >30% BM blasts and WBC ≤ 15 G/L in a routine clinical practice setting. We further show that the efficacy of azacitidine does not appear to be limited to AML patients who meet stringent clinical trial inclusion criteria, but instead appears efficacious as front-line treatment in all patients with WHO-AML.

Increased Expression of Micro-RNA-23a Mediates Chemoresistance to Cytarabine in Acute Myeloid Leukemia

“…In more detail, high miR-23a expression might help to select patients, in whom a suboptimal response to AraC-based therapies has to be expected. This knowledge would be particularly relevant for older patients, where the use of high-dose induction therapy is still a matter of debate, and where alternative low-intensity regimens, such as low-dose AraC and hypomethylating agents, exist [4,[43][44][45]. Such use of miR-23a as a biomarker is further fueled by the fact that miRNAs were successfully established as biomarkers previously and that they offer several advantages over conventional gene mRNAs [32,46].…”

Vitamin C in combination with inhibition of mutant IDH1 synergistically activates TET enzymes and epigenetically modulates gene silencing in colon cancer cells

“…For these tumours, IDH mutations have become a target for novel therapeutic approaches including the use of hypomethylating agentsi.e., DNMT inhibitors or enhancers of TET enzyme activityand inhibitors of mutant IDH enzymes [36,37]. Although the hypomethylating agents like decitabine or 5-azacytidine were originally developed as cytostatic agents for leukaemia chemotherapy, their epigenetic properties have since been revealed to play an important role in their anti-cancer activity [38][39][40][41][42]. A multitude of new compounds for the treatment of tumours bearing mutated IDH1 and IDH2 are presently in clinical trials [25].…”

Low‐dose azacitidine for relapse prevention after allogeneic hematopoietic cell transplantation in children with myeloid malignancies

“…The ideal relapse prevention approach would incorporate an agent not used in upfront therapy, with minimal toxicity that can be initiated as early as possible following alloHCT, in order to bridge the gap between leukemic control provided by the conditioning regimen and the immunologic GVL effect which can take time to emerge. Demethylating agents such as azacitidine are an excellent choice for this purpose given low toxicity profiles and track records of achieving improved remission in adult AML/MDS patients as either a monotherapy or in combination with other antileukemic agents …”

“…Demethylating agents such as azacitidine are an excellent choice for this purpose given low toxicity profiles and track records of achieving improved remission in adult AML/MDS patients as either a monotherapy or in combination with other antileukemic agents. [8][9][10] DNA methylation results in downregulation of tumor suppressor genes and alterations in protein expression that contribute to tumor growth, relapse risk, and treatment resistance. 11 In addition, demethylating agents exert immunomodulatory effects, including upregulation of leukemia-specific antigens and activation of cytotoxic T cells that can mediate GVL.…”