Arsenic Trioxide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Arsenic Trioxide
- Pharmacist Assessment Report
- Arsenic Trioxide: From Acute Promyelocytic Leukemia to Unclassified Myelodysplastic Syndrome
- One-Sentence Summary
- Quick Overview
- Why is This Prediction Reasonable?
- Clinical Trial Evidence
- Literature Evidence
- India Market Information
- Cytotoxicity
- Safety Considerations
- Conclusion and Next Steps
- Disclaimer
Arsenic Trioxide: From Acute Promyelocytic Leukemia to Unclassified Myelodysplastic Syndrome
One-Sentence Summary
Arsenic trioxide was originally used to treat acute promyelocytic leukemia (APL) and related myeloid leukemias. The TxGNN model predicts it may be effective for myelodysplastic syndrome (MDS), a closely related myeloid disorder. The data compiled for this report include 20 clinical trials and 20 publications for this indication, although most trials are small, early-phase, or terminated.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute promyelocytic leukemia (also myelomonocytic leukemia and AML with inv(16)/t(16;16)) |
| Predicted New Indication | Myelodysplastic syndrome (predicted_indications rank 6, the best-supported prediction; the top-scoring prediction, unclassified myelodysplastic syndrome, has no trials or literature) |
| TxGNN Prediction Score | 0.9991 (myelodysplastic syndrome); the top-ranked term, unclassified myelodysplastic syndrome, scores 0.9993 |
| Evidence Level | L5 |
| India Market Status | Listed in a compiled Indian medicine price dataset (3 of 3) – CDSCO approval status is not included in this data |
| Number of Listed Products | 3 (valid: 3) |
| Recommended Decision | Proceed with Guardrails |
Note on selection: The highest-scoring predictions (unclassified MDS, refractory cytopenia of childhood, congenital sideroblastic anemia) have no or only indirect supporting evidence. This report therefore focuses on the broader MDS entity, which has the strongest evidence among the predictions. Aplastic-type anemia (L3) and Ewing sarcoma (L3) are secondary research questions.
Why is This Prediction Reasonable?
Detailed mechanism-of-action data are not available in the compiled data. Based on the literature, arsenic trioxide induces apoptosis (through NF-κB/FLIP and BCL2-family modulation), promotes cell differentiation, and has epigenetic (demethylating) and anti-angiogenic effects. These actions are the basis for its established efficacy in APL.
APL and MDS are both clonal myeloid disorders of the bone marrow. MDS can progress to acute myeloid leukemia, and arsenic trioxide is already established in a related myeloid malignancy. This biological overlap supports the TxGNN prediction.
The clinical picture is mixed. Several Phase 1 and Phase 2 trials exist, including combinations with decitabine and ascorbic acid, thalidomide, cholecalciferol, etanercept, and low-dose cytarabine. However, response rates are modest (about 20% in one review), many trials were terminated, enrollments are small, and no Phase 3 trial specific to arsenic trioxide in MDS was identified.
Clinical Trial Evidence
Top 10 most relevant trials, selected from 20 linked trials:
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00251511 | Phase 2 | Terminated | 60 | Arsenic trioxide plus thalidomide in low- to high-risk MDS; largest MDS-specific arsenic trioxide trial |
| NCT00093366 | Phase 1/2 | Completed | 32 | Arsenic trioxide plus etanercept in advanced MDS |
| NCT00020969 | Phase 2 | Terminated | Not reported | Single-agent arsenic trioxide in MDS (multicenter) |
| NCT00195104 | Phase 1/2 | Completed | 87 | Arsenic trioxide with low-dose cytarabine in high-risk MDS and poor-prognosis AML |
| NCT02190695 | Phase 2 | Completed | 92 | Randomized: decitabine vs decitabine plus carboplatin vs decitabine plus arsenic in relapsed/refractory/elderly AML and MDS |
| NCT00621023 | Phase 2 | Completed | 7 | Pilot of decitabine, arsenic trioxide and ascorbic acid; safety focus |
| NCT00671697 | Phase 1 | Completed | 13 | Decitabine plus arsenic trioxide and ascorbic acid; safety and dose information |
| NCT00274781 | Phase 2 | Completed | 30 | Arsenic trioxide plus gemtuzumab ozogamicin in advanced MDS |
| NCT06670222 | Phase 1 | Recruiting | 24 | Oral arsenic in low-risk MDS failing ESAs and luspatercept |
| NCT06778187 | Phase 2 | Recruiting | 30 | Oral arsenic trioxide with ascorbic acid and low-intensity therapy in TP53-mutated myeloid malignancies |
A Phase 3 trial of decitabine plus arsenic trioxide (NCT03377725) was withdrawn with zero enrollment.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37908176 | 2023 | Systematic review / network meta-analysis | Hematology | Evaluates efficacy and adverse events of arsenic-containing regimens in MDS; notes small samples and conflicting trial conclusions |
| 20956016 | 2011 | Phase I/II study | Leuk Res | Arsenic trioxide plus low-dose cytarabine in 49 patients with intermediate-2/high-risk MDS; complete remission in 17%, 4-week mortality 8% |
| 17920679 | 2008 | Clinical study | Leuk Res | Arsenic trioxide, thalidomide and retinoic acid combination in higher-risk MDS |
| 18282365 | 2007 | Review | Clin Lymphoma Myeloma | Activity of arsenic trioxide in leukemias and MDS |
| 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 |
| 38816179 | 2024 | Preclinical | Immunopharmacol Immunotoxicol | Compares immunological changes with realgar and arsenic trioxide in a murine MDS model |
| 41398777 | 2025 | Preclinical | Medicine | Triptolide plus arsenic trioxide induces MDS cell apoptosis via NF-κB inhibition |
| 27665715 | 2016 | Preclinical | Mol Med Rep | Synergistic apoptosis with triptolide in the SKM-1 MDS cell line |
| 20471733 | 2010 | Review | Blood Rev | Arsenic trioxide as an old drug rediscovered, from APL to other malignancies including MDS |
India Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| Registration No. 2440 | Arsenox 10mg Injection (Intas Pharmaceuticals Ltd) | Vial of 10 ml injection | Not specified in the compiled data |
| Registration No. 9023 | Arsitri 10mg Injection (Neon Laboratories Ltd) | Vial of 10 ml injection | Not specified in the compiled data |
| Registration No. 8883 | Arsikem 10mg Injection (Alkem Laboratories Ltd) | Vial of 1 injection | Not specified in the compiled data |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic / antineoplastic (arsenical; induces apoptosis and differentiation) |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | ECG (QTc interval), serum electrolytes (potassium, magnesium), CBC, liver and renal function |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Safety Considerations
- Contraindication-related conditions (from the TxGNN model (deep learning), not label text; these may reflect similarities the model learned between related diseases, not biological evidence): long QT syndrome (including familial), torsades de pointes, atrioventricular block, potassium deficiency, kidney disease, liver disease, gallbladder disease, and pyoureter.
- Drug Interactions: 332 interactions were identified. Major interactions include:
- QT-prolonging agents: cisapride, clarithromycin, dolasetron, granisetron, levofloxacin
- Hydrocortisone
- Amphotericin B (conventional, lipid complex, cholesteryl sulfate, and liposomal forms)
Moderate interactions include famotidine, loperamide, and several laxatives and osmotic agents (bisacodyl, castor oil, glycerin, lactitol, lactulose, magnesium citrate, magnesium hydroxide). Metronidazole is a minor interaction.
- Cardiac risk: QT prolongation requires monitoring, supported by the associations above and the large interaction burden.
Please refer to the package insert for full warnings and contraindications.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Myelodysplastic syndrome has multiple completed Phase 1 and Phase 2 trials and a 2023 systematic review, with a plausible mechanism shared with APL. However, response rates are modest, several trials were terminated, enrollments are small, and no Phase 3 evidence exists. Other predicted indications (unclassified MDS, childhood refractory cytopenia, congenital sideroblastic anemia, del(5q), dermatofibrosarcoma protuberans, liposarcoma, ovarian myxoid liposarcoma) are prediction-only and should be held.
To proceed, the following is needed:
- Package insert warnings and contraindications for the Indian-marketed products (currently unavailable, and a blocking gap for safety screening)
- Detailed mechanism-of-action data from DrugBank
- Approved indication text for the Indian registrations
- Review of the 2023 meta-analysis to identify the best-performing combination regimens and the patient subgroups (e.g., TP53-mutated, low-risk after ESA failure) most likely to benefit
- A cardiac safety plan (baseline and serial ECG, electrolyte correction, and a review of concomitant QT-prolonging drugs)
- Consideration of a randomized trial, since no Phase 3 evidence exists
- Secondary research questions: refractory aplastic anemia (L3; small single-arm studies, one terminated for non-response) and Ewing sarcoma (L3; mainly preclinical)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.