Mercaptopurine
| Evidence Level: L3 | Predicted Indications: 8 |
Table of Contents
Mercaptopurine: Myeloid leukemia
One-Sentence Summary
Mercaptopurine is a purine antimetabolite (thiopurine) used in the treatment of leukaemia. The TxGNN model predicts it may be relevant to myeloid leukemia, supported by 15 registered clinical trials and 20 publications. Most of this evidence comes from multi-agent regimens, so the contribution of mercaptopurine itself is hard to isolate, and the evidence level is L3.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Myeloid leukemia |
| TxGNN Prediction Score | 0.9994 |
| Evidence Level | L3 |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. From the literature, mercaptopurine is a purine antimetabolite. Its thioguanine nucleotide (TGN) metabolites are incorporated into DNA and RNA and inhibit de novo purine synthesis, so it acts against rapidly dividing leukaemic cells. This mechanism is not specific to lymphoid cells, which makes activity in myeloid disease biologically plausible.
In myeloid leukaemia, mercaptopurine appears mainly as a component of multi-agent regimens, such as oral 6-mercaptopurine plus methotrexate maintenance in acute myeloid leukaemia (AML) and maintenance in acute promyelocytic leukaemia (APL). Because of this, its independent contribution is difficult to separate. The cohort and pilot studies available (PMID 26425037, 27275453) are non-randomised, and no randomised trial tests mercaptopurine itself in myeloid leukaemia.
Clinical Trial Evidence
Many of the registered trials below are multi-agent protocols in which mercaptopurine’s role is not confirmed from the title or summary.
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT00003934 | Phase 3 | Completed | 420 | APL: tretinoin plus chemotherapy with or without arsenic trioxide, then maintenance with tretinoin versus tretinoin plus mercaptopurine and methotrexate |
| NCT06199557 | Phase 1/2 | Recruiting | 48 | Hydroxyurea + valproic acid, or 6-mercaptopurine + valproic acid, in AML or high-risk MDS patients unfit for standard therapy |
| NCT05506332 | Phase 1 | Recruiting | 10 | Venetoclax with 6-mercaptopurine in relapsed/refractory AML (ApoAML) |
| NCT00492856 | Phase 3 | Completed | 105 | S0521: maintenance versus observation in low/intermediate-risk APL; mercaptopurine’s role not confirmed |
| NCT00002701 | Phase 3 | Unknown | 750 | APL: ATRA with idarubicin and intensive consolidation, then randomised maintenance by minimal residual disease; specific arms need confirmation |
| NCT02688140 | Phase 3 | Completed | 133 | High-risk APL: arsenic trioxide + ATRA + idarubicin versus AIDA; mercaptopurine not the focus |
| NCT02521493 | Phase 3 | Active, not recruiting | 280 | Risk-stratified AML therapy in Down syndrome; mercaptopurine’s role unclear |
| NCT00136084 | Phase 3 | Completed | 238 | Two multi-agent regimens with different cytarabine doses in AML/myelodysplasia |
| NCT00866918 | Phase 3 | Completed | 106 | Risk-adapted treatment of childhood APL using arsenic trioxide in consolidation |
| NCT00482833 | Phase 3 | Completed | 276 | Arsenic trioxide + ATRA versus AIDA in non-high-risk APL |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 26425037 | 2015 | Cohort | Journal of Korean Medical Science | Oral maintenance with daily 6-mercaptopurine and weekly methotrexate in transplant-ineligible AML patients after first remission |
| 27275453 | 2016 | Prospective pilot study | South Asian Journal of Cancer | Metronomic oral 6-mercaptopurine in elderly AML |
| 38828002 | 2024 | Cohort | Therapeutic Advances in Hematology | Intensive chemotherapy with dual induction and ALL-like consolidation for childhood AML in China |
| 32459546 | 2020 | Retrospective series | Pediatric Hematology and Oncology | Outcomes in juvenile myelomonocytic leukaemia after sequential cytarabine and 6-mercaptopurine |
| 22715121 | 2012 | Cohort (Phase 2) | Blood | ATRA, idarubicin and intravenous arsenic trioxide as initial therapy in APL (APML4) |
| 12057059 | 2000 | Review | Current Treatment Options in Oncology | Treatment of APL, with ATRA as the essential component of induction |
| 33183436 | 2021 | Review | Journal of Nanoscience and Nanotechnology | 6-MP nanomedicine formulations to overcome poor solubility and toxicity in leukaemia |
| 2676034 | 1989 | Review | Blood Reviews | Purine metabolism as a target for leukaemia chemotherapy, including 6-mercaptopurine |
| 34442422 | 2021 | Review | Journal of Personalized Medicine | NUDT15 polymorphisms and thiopurine toxicity, including bone marrow suppression |
| 8383541 | 1993 | Case series | Annals of Hematology | Chemotherapy for minimally differentiated AML (five cases and literature review) |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 10214N | Allmercap | Oral suspension containing mercaptopurine monohydrate 20 mg per mL, 100 mL | Not available in the compiled data |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (purine antimetabolite, thiopurine) |
| Myelosuppression Risk | High; bone marrow suppression is a recognised adverse effect of thiopurines, and NUDT15 and TPMT variants increase the risk |
| Emetogenicity Classification | Low |
| Monitoring Items | Full blood count with differential, liver function, renal function; consider TPMT/NUDT15 genotyping |
| Handling Protection | Follow cytotoxic drug handling procedures |
Safety Considerations
- Conditions listed as contraindications or cautions in the reference data compiled for this report: kidney disease, liver disease, pancreatitis, gallbladder disease, cholestasis (including benign recurrent and familial intrahepatic forms), hyperbilirubinaemia (including hereditary forms and Gilbert syndrome), thrombocytopenia, neutropenia, leukopenia, agranulocytosis, anaemia (including macrocytic anaemia), pyoureter, and hepatosplenic T-cell lymphoma. These are not taken from TGA label text.
- Drug interactions: 100 interactions were recorded. Moderate-level interactions include mesalazine, balsalazide, olsalazine, sulfasalazine and naltrexone. Levofloxacin is rated minor. Other recorded interactions, such as with prednisone, omeprazole, metformin and vancomycin, have no severity rating.
Please refer to the TGA-approved Product Information (PI) for authoritative warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The evidence for myeloid leukaemia is limited to non-randomised studies (a cohort study and a prospective pilot study of oral 6-mercaptopurine maintenance in AML) and multi-agent protocols in which mercaptopurine’s role is unclear. No randomised trial tests mercaptopurine itself, so the evidence level is L3. The TxGNN score is high (0.9994) but is not evidence of efficacy.
To proceed, the following is needed:
- Review of the protocol arms of the multi-agent trials (especially NCT00003934, NCT00492856, NCT00002701) to confirm mercaptopurine’s role
- Results from the ongoing mercaptopurine trials in AML (NCT06199557, NCT05506332)
- Mechanism of action data and safety information from the TGA-approved Product Information
- A thiopurine safety plan covering TPMT/NUDT15 testing and blood count monitoring
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.