Arsenic Trioxide
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Arsenic Trioxide: From Acute Promyelocytic Leukemia to Myelodysplastic Syndrome
One-Sentence Summary
Arsenic trioxide (DB01169) is an established antineoplastic arsenical, with acute promyelocytic leukemia (APL) as its well-documented original indication in the clinical trial evidence reviewed here. Of 10 TxGNN-predicted new indications in this candidate pack, myelodysplastic syndrome (MDS) carries by far the strongest supporting evidence, with 23 clinical trials (including one Phase 2/3 trial enrolling 2,000 patients) and 23 publications, including a 2023 systematic review/meta-analysis. The remaining 9 predicted indications (including several rare MDS-spectrum and sarcoma subtypes) currently have weak-to-no direct evidence and are held pending further data.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute Promyelocytic Leukemia (APL) — inferred from trial descriptions in this evidence pack (e.g., NCT01404949: "an approved medicine for APL"); not separately documented in German licensing data, as the drug is currently unmarketed |
| Predicted New Indication | Myelodysplastic Syndrome (MDS) |
| TxGNN Prediction Score | 99.91% |
| Evidence Level | L2 |
| Germany Market Status | ✗ Not marketed (未上市) |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails |
Note: This is a multi-indication candidate pack. See "All Predicted Indications" below for the other 9 candidates, most of which remain at Hold due to insufficient evidence.
All Predicted Indications (Overview)
| Rank | Disease | TxGNN Score | Evidence Level | Decision Stage | Recommendation |
|---|---|---|---|---|---|
| 1 | Unclassified myelodysplastic syndrome | 99.93% | L5 | S0 | Hold |
| 2 | Refractory cytopenia of childhood | 99.93% | L4 | S0 | Hold |
| 3 | Severe congenital hypochromic anemia with ringed sideroblasts | 99.93% | L5 | S0 | Hold |
| 4 | Aregenerative anemia (aplastic anemia) | 99.92% | L3 | S1 | Research Question |
| 5 | Partial deletion of long arm of chromosome 5 (5q- syndrome) | 99.92% | L5 | S0 | Hold |
| 6 | Myelodysplastic syndrome | 99.91% | L2 | S2 | Proceed with Guardrails |
| 7 | Ewing sarcoma | 99.89% | L3 | S1 | Research Question |
| 8 | Dermatofibrosarcoma protuberans | 99.77% | L5 | S0 | Hold |
| 9 | Liposarcoma | 99.75% | L5 | S0 | Hold |
| 10 | Ovarian myxoid liposarcoma | 99.70% | L5 | S0 | Hold |
The rest of this report focuses on Myelodysplastic Syndrome (rank 6), the only candidate with sufficient evidence to move past S0/S1.
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available (flagged as a data gap in DrugBank). Based on the evidence assembled in this pack, arsenic trioxide's mechanistic activity — ROS-dependent apoptosis induction, NF-κB pathway inhibition, and modulation of BCL2-family anti-apoptotic proteins — is described consistently across the MDS-related preclinical and mechanistic literature (e.g., PMID 16105982, 22964015).
Both APL and MDS are clonal hematopoietic disorders originating from abnormal myeloid progenitor populations, and MDS can itself progress to acute myeloid leukemia. This shared clonal biology is the theoretical basis for repurposing: arsenic trioxide's established ability to eliminate an abnormal malignant clone (PML-RARA+ cells in APL) is mechanistically plausible for eliminating dysplastic clones in MDS. The evidence pack also documents an additional, distinct rationale — ATO's regulation of the Treg/Th17 immune axis and IFN-γ/IL-17/TGF-β1 cytokine balance — supporting activity in immune-mediated marrow failure states more broadly (relevant to the aplastic anemia and childhood cytopenia candidates ranked 2 and 4).
Clinically, this mechanistic plausibility is reinforced by an extensive and long-running clinical trial program (1997–2025) specifically testing arsenic trioxide, alone or combined with hypomethylating agents (decitabine, azacitidine), in MDS populations — including one large completed Phase 2/3 program (n=2,000) and a completed Phase 2 randomized comparison against decitabine-based regimens (n=92).
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00454480 | Phase 2/3 | Completed | 2000 | Large treatment-development program for older AML/high-risk MDS patients; most direct large-scale evidence base |
| NCT02190695 | Phase 2 | Completed | 92 | Randomized comparison of decitabine vs. decitabine+carboplatin vs. decitabine+arsenic trioxide in relapsed/refractory/elderly AML and MDS |
| NCT00195104 | Phase 1/2 | Completed | 87 | ATO combined with low-dose cytosine arabinoside in high-risk MDS and poor-prognosis AML |
| NCT00003885 | Phase 2 | Unknown | 60 | ATO monotherapy in relapsed/refractory acute leukemia, CML blast crisis, and MDS |
| NCT00251511 | Phase 2 | Terminated | 60 | Trisenox plus thalidomide across low- to high-risk MDS (IPSS-defined) |
| NCT00803530 | Phase 2 | Terminated | 55 | Multicenter trial of ATO plus ascorbic acid in MDS |
| NCT00093366 | Phase 1/2 | Completed | 32 | ATO combined with etanercept in advanced-stage MDS |
| NCT06778187 | Phase 2 | Recruiting | 30 | Oral arsenic trioxide (Arsenol®)-based low-intensity therapy in TP53-mutated MDS/AML/CMML |
| NCT00274781 | Phase 2 | Completed | 30 | ATO combined with gemtuzumab ozogamicin in advanced MDS |
| NCT00621023 | Phase 2 | Completed | 7 | Pilot study of decitabine, ATO, and ascorbic acid combination safety in MDS |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37908176 | 2023 | Review/Meta-analysis | Hematology (Amsterdam) | Systematic review and component network meta-analysis of ATO-containing regimens for MDS efficacy and adverse events |
| 40167011 | 2025 | Cohort | Hematology (Amsterdam) | Retrospective study of decitabine + ATO efficacy/safety in elderly high-risk MDS |
| 20425329 | 2006 | Clinical Study | Curr Hematol Malig Rep | Review of ATO as MDS therapy via proapoptotic, antiproliferative, antiangiogenic mechanisms |
| 15610661 | 2005 | Clinical Study | Curr Hematol Rep | Earlier review of ATO's role and mechanism in MDS treatment |
| 18282365 | 2007 | Review | Clin Lymphoma Myeloma | New clinical data on ATO in leukemias and MDS |
| 14633782 | 2003 | Review | Hematology ASH Educ Program | Overview of MDS pathophysiology and treatment landscape |
| 20956016 | 2011 | Clinical Study | Leukemia Research | Phase 1/2 study of ATO + low-dose cytarabine in intermediate-2/high-risk MDS (49 patients, CR 17%) |
| 17920679 | 2008 | Clinical Study | Leukemia Research | ATO + thalidomide + retinoic acid combination in higher-risk MDS |
| 31775455 | 2019 | Clinical Study | Zhonghua Nei Ke Za Zhi | Retrospective safety/efficacy of low-dose subcutaneous decitabine + ATO in intermediate/high-risk MDS (11 patients) |
| 16651644 | 2006 | Commentary/Review | J Clin Oncol | Critical appraisal of whether IV arsenic trioxide is a useful MDS therapy |
Germany Market Information
Currently not marketed in Germany. No authorization records are available in this evidence pack (total_licenses = 0).
Cytotoxicity
This drug is classified as antineoplastic (established cytotoxic/apoptosis-inducing arsenical; original clinical use documented in this pack is APL).
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic — arsenical apoptosis-inducing agent |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert warnings and precautions |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
Please refer to the package insert for safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails (for Myelodysplastic Syndrome specifically)
Rationale: Among the 10 predicted indications, MDS is the only one supported by L2-level evidence — a large completed Phase 2/3 program (n=2,000), a completed randomized Phase 2 comparison (n=92), a 2023 systematic review/meta-analysis, and a decades-long, mechanistically coherent clinical trial program combining ATO with hypomethylating agents. The remaining 9 candidates (including aplastic anemia and Ewing sarcoma, both flagged as "Research Question") lack sufficient direct evidence and remain at Hold.
To proceed, the following is needed:
- Official package insert (TFDA/EMA) warnings, contraindications, and DDI data — currently a Blocking data gap (DG001)
- Formal MOA documentation via DrugBank query — currently a High-severity data gap (DG002)
- Since the drug is unmarketed in Germany, confirm formulation/route availability before any regional development plan
- For aplastic anemia and Ewing sarcoma (Research Question stage), commission targeted preclinical/clinical validation before advancing further
- No near-term action recommended for the remaining 7 low-evidence (L4–L5) candidates
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.