A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients

Hui-Jen Tsai, Shih Sheng Jiang, Wen-Chun Hung, Gautam Borthakur, Sheng-Fung Lin, Naveen Pemmaraju, Elias Jabbour, John S Bomalaski, Ya-Ping Chen, Hui-Hua Hsiao, Ming-Chung Wang, Ching-Yuan Kuo, Hung Chang, Su-Peng Yeh, Jorge Cortes, Li-Tzong Chen, Tsai-Yun Chen, Hui-Jen Tsai, Shih Sheng Jiang, Wen-Chun Hung, Gautam Borthakur, Sheng-Fung Lin, Naveen Pemmaraju, Elias Jabbour, John S Bomalaski, Ya-Ping Chen, Hui-Hua Hsiao, Ming-Chung Wang, Ching-Yuan Kuo, Hung Chang, Su-Peng Yeh, Jorge Cortes, Li-Tzong Chen, Tsai-Yun Chen

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://ichgcp.net/clinical-trials-registry/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.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Progression-free survival and overall survival of all intention-to-treat patients.
Figure 2
Figure 2
The mean circulating arginine and citrulline levels and the titers of anti-ADI-PEG20 antibodies in the intention-to treat patients during the ADI-PEG20 treatment.
Figure 3
Figure 3
The complete blood count (CBC) and bone marrow (BM) profiles of Case 1 and Case 2 during ADI-PEG20 treatment. (A) The dynamic CBC and BM changes in Case 1 after ADI-PEG20 treatment and the timing of packed red blood cell and platelet transfusion. (B) The dynamic CBC and BM changes in Case 2 after ADI-PEG20 treatment.
Figure 4
Figure 4
mRNA expression of associated genes in responders and non-responders before and after ADI-PEG20 treatment. (A) The relative mRNA expression levels of RHAG, ANK1, and NPM1 in the bone marrow mononuclear cells (BMMCs) of Case 1 and Case 2 at the indicated time points by QR-PCR. BMMC1B is the BMMCs of Case 1 before ADI-PEG20 treatment. BMMC1A is the BMMCs of Case 1 after ADI-PEG20 and in complete remission status. BMMC1R is the BMMCs of Case 1 collected at the time of relapse after ADI-PEG20 treatment. BMMC2B is the BMMCs of Case 2 before ADI-PEG20 treatment. BMMC2A is the BMMCs of Case 2 after ADI-PEG20 and in complete remission. The samples of BMMC1B and BMMC1R were compared with BMMC1A for analysis. The sample of BMMC2B was compared with BMMC1A for analysis. (B) The mRNA expression of c-MYC in AML cases responsive and non-responsive to ADI-PEG20. (left) Fold changes of mRNA expression of c-MYC in BMMC1B, and 1 R relative to BMMC1A and in BMMC 2B relative to BMMC2A. Case 1 and Case 2 were responders to ADI-PEG20. (right) Fold changes of mRNA expression of c-MYC in BMMC4A, 9 A, 10 A, 11 A, and 14 A relative to BMMC4B, 9B, 10B, 11B, and 14B, respectively. Cases 4, 9, 10, 11, and 14 were non-responders to ADI-PEG20. (Cases 4, 10, and 11were PD; Cases 9 and 14 were SD) “A” indicates after ADI-PEG20, “B” indicates before ADI-PEG20.

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