General AML

Azacitidine in combination with chemotherapy in pediatric AML patients– a phase I study

DNA hypermethylation has been found to be strongly associated with leukemogenesis, chemotherapy resistance in Acute Myeloid Leukemia (AML). Hypomethylating agents, azacitidine (AZA) and decitabine can be potent DNA methyltransferase inhibitors at lower dose and can effectively reduce drug resistance and leukemic cell count in vitro.

Based on this preclinical activity, Weili Sun from  City of Hope National Medical Center, Duarte, CA, and colleagues conducted a phase I study (NCT01861002), which evaluated the toxicity and preliminary efficacy of AZA with chemotherapy in pediatric patients with Relapsed/Refractory (R/R) leukemia. The evaluation of a methylation biomarker was also implemented. The results of the study were reported in a Letter to the Editor of  Blood on 16 January 2018.

In total, 14 R/R patients with either AML (n = 12), or Acute Lymphoblastic Leukemia (n = 2) were enrolled in this phase I study. Patients received AZA (75 mg/m2/day) for five days, followed by fludarabine (30 mg/m2/day and cytarabine 2 gm/m2/day) for another five days. Here, we report results for the AML cohort.

Key findings:
  • Safety
    • Febrile neutropenia and infection were the most common non-hematologic toxicities
    • No patients experienced dose limiting toxicity
  • Complete Response (CR)/ CR with incomplete count recovery (CRi) rate: 58% (7/12)
  • Four patients achieved Minimal Residual Disease negative status

In order to identify distinct methylation patterns in patients, comprehensive DNA methylation profiling was performed on baseline bone marrow samples from AML patients enrolled in this trial.

  • A single region at gene body of farnesyldiphosphate farnesyl-transferase 1 gene (FDFT1) was identified
  • FDFT1 was significantly different between responders and non-responders, P = 0.002

In order to confirm the prognostic significance of the DNA methylation region, FDFT1, the authors analyzed its impact in a separate data set from a phase II study (DACO202) of decitabine in combination with chemotherapy in children with newly diagnosed de novo AML. In this data set, patients were separated into two groups including patients in CR (n = 6) and patients who are deceased (n = 5).

  • At baseline, there was a significant difference observed in the methylation of the FDFT1 region between patients who achieved response vs those who previously died of AML, P = 0.0022

In summary, this is the  first  study to evaluate AZA in sequence with chemotherapy in pediatric AML. The findings of this study demonstrates that AZA in combination with intensive chemotherapy is tolerable and active in pediatric R/R AML patients. Although, regarding the small number of patients, further study is required.

An epigenetic biomarker, FDFT1, which correlated with clinical outcomes was identified. Based on the findings of this study and the limited number of patients enrolled, the authors noted that a prospective randomized phase II epigenetic priming study (NCT03164057) is currently underway. The phase II study aims to investigate the significance of the FDFT1 methylation region in 200 children with newly diagnosed AML.

  1. Weili al. A phase 1 study of azacitidine combined with chemotherapy in childhood leukemia: a report from TACL consortium. Blood. 2018 Jan 16. DOI: 10.1182/blood-2017-09-803809. [Epub ahead of print]
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