General AML

ADI-PEG20 in R/R or poor-risk AML patients – a phase II study

Arginine, a semi-essential amino acid, is critical for a range of tumor metabolism and is required for the growth of Arginosuccinate Synthetase (ASS [an enzyme that limits the production of endogenous arginine in the urea cycle]) deficient cancers.  Deficiency of ASS have been shown to occur in 87% of Bone Marrow (BM) samples of Acute Myeloid Leukemia (AML) patients. Additionally, preclinical studies have demonstrated that pegylated form of Arginine Deiminase (ADI-PEG20 [converts arginine into citrulline]), can kill leukemic AML cells.1

Hui-Jen Tsai from the National Institute of Cancer Research, Taiwan, et al., conducted a prospective phase II study (NCT01910012), which evaluated the efficacy of ADI-PEG20 monotherapy in patients with Relapsed or Refractory (R/R) or poor-risk AML. The results of the study were published in Scientific Reports on 12th September 2017.2

Overall, 43 R/R or poor-risk AML patients (median age = 67.3 years) were enrolled in this study between October 2013 and October 2015 in Taiwan and United States. Patients were administered weekly intramuscular injections of ADI-PEG20 36 mg/m2 (4 weeks as one cycle).

The key results of the study were:
  • Intention to Treat (ITT) patients (n = 43)
    • Complete Remission (CR); 4.7%
    • Median Overall Survival (OS); 3.5 months
    • Median Progression Free Survival (PFS); 1.8 months
  • Evaluable patients (n = 21)
    • CR; 9.5% (2/21)
    • Stable Disease (SD); 33.3% (7/21)
    • Progressive Disease (PD); 57% (12/21)
    • Median Overall Survival (OS) and Progression Free Survival (PFS) were 1.8 months and 7.9 months respectively
    • Disease Control Rate (DCR); 42.9%
    • Response duration for the two patients in CR were 7.5 and 8.8 months
  • Most common treatment related Adverse Events (AEs) in ITT patients were grade 1–2 skin rash (9.3%), hyperuricemia (7%), grade 3–4 leukopenia (7%), neutropenic fever (4.7%) and anemia (4.7%)

In summary, “weekly ADI-PEG20 monotherapy resulted in a low response rate among patients with R/R or poor-risk AML with minimal toxicities”.

The authors concluded by suggesting that “further investigations are warranted to explore the biological mechanism of ADI-PEG20 in AML, the biological markers of response and potential combinations, including with cytarabine, for the treatment of AML”.


Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS-deficient cancers by depleting arginine. The efficacy of pegylated ADI (ADI-PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), = ADI-PEG20&rank = 12). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5%) and stable disease in 7 (33.3%), yielding a disease control rate (DCR) of 42.9%. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to ≤10 μM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI-PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20.

  1. Miraki-Moud F. et al. Arginine deprivation using pegylated arginine deiminase has activity against primary acute myeloid leukemia cells in vivo. Blood. 2015 Jun 25; 125(26): 4060–4068. DOI: 10.1182/blood-2014-10-608133. Epub 2015 Apr 20.
  2. Tsai H. J. et al. A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients. Sci Rep. 2017 Sep 12; 7(1): 11253. DOI: 10.1038/s41598-017-10542-4.