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”.

Abstract

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), https://clinicaltrials.gov/ct2/show/NCT01910012?term = 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.

References
  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.