Arsenic Trioxide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Arsenic Trioxide
- Arsenic Trioxide: From Acute Promyelocytic Leukaemia to Unclassified Myelodysplastic Syndrome
Arsenic Trioxide: From Acute Promyelocytic Leukaemia to Unclassified Myelodysplastic Syndrome
One-Sentence Summary
Arsenic trioxide was originally used to treat acute promyelocytic leukaemia and related myeloid leukaemias. The TxGNN model's top-ranked prediction is unclassified myelodysplastic syndrome (99.93%), but no clinical trials or publications were found for this specific subtype. The closest, better-supported prediction is myelodysplastic syndrome (MDS) in general, with 20 clinical trials and 20 publications compiled for this report.
Note: The first-ranked prediction has no direct evidence. The sections below present it as requested, and the evidence for the broader MDS category is shown separately where it matters for the decision.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute promyelocytic leukaemia (also myelomonocytic leukaemia and AML with inv(16)/t(16;16)); the Singapore licence records contain no indication text |
| Predicted New Indication | Unclassified myelodysplastic syndrome |
| TxGNN Prediction Score | 99.93% |
| Evidence Level | L5 (for the top-ranked prediction); L2 for the broader MDS category |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Hold (top-ranked prediction); the broader MDS category is a research question |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, arsenic trioxide is a cytotoxic and differentiating agent. Its efficacy in acute promyelocytic leukaemia is well established, and mechanistically it may be applicable to myelodysplastic syndromes.
Published studies describe several effects that make this plausible. Arsenic trioxide induces apoptosis (including through NF-κB/FLIP and BCL2-family modulation), promotes cell differentiation, and has epigenetic and immunomodulatory effects. MDS is a clonal bone marrow disorder that often progresses to acute myeloid leukaemia, so it shares biology with the myeloid leukaemias for which the drug is used.
For the specific "unclassified" MDS subtype, however, nothing direct was found. The link is indirect, through the broader MDS category, and the high TxGNN score is a prediction only.
Clinical Trial Evidence
No clinical trials were found for unclassified myelodysplastic syndrome itself. The table below shows the most relevant trials for the broader MDS category (the sixth-ranked prediction), which is the closest indirect evidence.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00251511 | Phase 2 | Terminated | 60 | Arsenic trioxide plus thalidomide in low- to high-risk MDS; the largest MDS-specific phase 2 trial here |
| NCT00195104 | Phase 1/2 | Completed | 87 | Arsenic trioxide plus low-dose cytarabine in high-risk MDS and poor-prognosis AML |
| NCT02190695 | Phase 2 | Completed | 92 | Randomised: decitabine vs decitabine plus carboplatin vs decitabine plus arsenic in relapsed, refractory or elderly AML/MDS |
| NCT00093366 | Phase 1/2 | Completed | 32 | Arsenic trioxide plus etanercept in advanced MDS |
| NCT00274781 | Phase 2 | Completed | 30 | Arsenic trioxide plus gemtuzumab ozogamicin in advanced MDS |
| NCT00671697 | Phase 1 | Completed | 13 | Decitabine, arsenic trioxide and ascorbic acid in MDS and AML; safety and dosing data |
| NCT00621023 | Phase 2 | Completed | 7 | Pilot of decitabine, arsenic trioxide and ascorbic acid in MDS; safety focus |
| NCT06670222 | Phase 1 | Recruiting | 24 | Oral arsenic in low-risk MDS after failure of erythropoiesis-stimulating agents and luspatercept |
| NCT06778187 | Phase 2 | Recruiting | 30 | Oral arsenic trioxide with low-intensity therapy in TP53-mutated myeloid malignancies |
| NCT07737769 | Phase 1 | Not yet recruiting | 20 | TP53 reactivation with arsenic trioxide in allogeneic transplantation for AML/MDS |
Many of these trials were terminated early or enrolled very few patients. No Phase 3 trial has completed (NCT03377725, a Phase 3 trial of decitabine plus arsenic trioxide, was withdrawn with zero enrolment).
Literature Evidence
No publications were found for unclassified myelodysplastic syndrome itself. The table below shows the most relevant publications for the broader MDS category.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37908176 | 2023 | Systematic review / network meta-analysis | Hematology | Evaluates the efficacy and adverse events of arsenic-containing regimens in MDS; trials are small with conflicting conclusions |
| 20956016 | 2011 | Phase I/II study | Leuk Res | Arsenic trioxide plus low-dose cytarabine in 49 untreated higher-risk MDS patients; complete remission in 17%; 8% mortality within 4 weeks |
| 17920679 | 2008 | Clinical trial | Leuk Res | Arsenic trioxide, thalidomide and retinoic acid in higher-risk MDS |
| 22964015 | 2012 | Ex-vivo cohort | J Hematol Oncol | Arsenic trioxide with ascorbic acid affects BCL2-family genes in MDS marrow; the drug is effective in about 20% of MDS patients |
| 16105982 | 2005 | Preclinical | Blood | NF-κB and FLIP involvement in arsenic trioxide-induced apoptosis in MDS |
| 38816179 | 2024 | Preclinical | Immunopharmacol Immunotoxicol | Compares immunological changes after realgar and arsenic trioxide in a mouse MDS model |
| 20425329 | 2006 | Review | Curr Hematol Malig Rep | Arsenic trioxide acts through pro-apoptotic, antiproliferative and anti-angiogenic mechanisms in MDS |
| 12886236 | 2003 | Review | Leukemia | Opportunities for arsenic trioxide in MDS |
| 18282365 | 2007 | Review | Clin Lymphoma Myeloma | Updates on arsenic trioxide in leukaemias and MDS |
| 27665715 | 2016 | Preclinical | Mol Med Rep | Arsenic trioxide and triptolide synergistically induce apoptosis in an MDS cell line |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16961P | Arsenic Trioxide-AFT Concentrated Solution for Injection for Infusion 10mg/10ml | Injection, solution, concentrate | Not stated in the available records |
| SIN16634P | Asadin Injection 1mg/ml | Injection | Not stated in the available records |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Cytotoxic antineoplastic (arsenic-based differentiating and pro-apoptotic 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; given the cardiac and metabolic concerns below, ECG (QT interval), electrolytes (potassium, magnesium), and liver and renal function are expected to be relevant |
| Handling Protection | Follow local cytotoxic drug handling regulations |
Safety Considerations
- Contraindications / conditions of concern (from drug-disease relationship data, not package insert text): long QT syndrome (including the familial form), torsades de pointes, atrioventricular block, kidney disease, liver disease, gallbladder disease, potassium deficiency, and pyoureter.
- Drug Interactions: 100 interactions were identified. Major interactions include:
- Drugs that prolong the QT interval: cisapride, clarithromycin, dolasetron, granisetron and levofloxacin.
- Amphotericin B and its lipid, cholesteryl sulfate and liposomal formulations.
- Hydrocortisone.
- Moderate interactions include famotidine, loperamide and several laxatives (bisacodyl, castor oil, glycerin, lactitol, lactulose, magnesium citrate and magnesium hydroxide). Metronidazole is a minor interaction.
Package insert warnings and contraindications could not be retrieved for this report. Please refer to the package insert for the full safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The top-ranked prediction, unclassified myelodysplastic syndrome, rests only on the TxGNN score, with no trials or publications for this specific subtype (Evidence Level L5). The broader MDS category has more support (L2), but its trials are mostly small or terminated, response rates were modest, and no Phase 3 RCT establishes benefit. It is better handled as a research question than as a go decision.
To proceed, the following is needed:
- Subtype-specific data for unclassified MDS, or a decision to evaluate the broader MDS category instead
- Results from the ongoing and planned trials (NCT06670222, NCT06778187, NCT07737769)
- Package insert warnings and contraindications from the HSA, since the safety screening cannot be completed without them
- Mechanism of action data
- A cardiac and electrolyte monitoring plan (QT prolongation risk and interacting drugs)
- Singapore-approved indication text, which is missing from both licences
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.