Mercaptopurine
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Mercaptopurine: From Acute Lymphoblastic Leukaemia to Myeloid Leukaemia
One-Sentence Summary
Mercaptopurine is a purine antimetabolite chemotherapy drug, originally approved in the EU (as Xaluprine) for acute lymphoblastic leukaemia (ALL) in adults, adolescents and children. The TxGNN model predicts it may be effective for myeloid leukaemia. The data compiled for this report list 15 clinical trials and 20 publications, but in most trials the contribution of mercaptopurine itself cannot be separated from the multi-drug regimens used.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute lymphoblastic leukaemia (ALL) in adults, adolescents and children |
| Predicted New Indication | Myeloid leukaemia |
| TxGNN Prediction Score | 99.94% |
| Evidence Level | L2 |
| EU Market Status | Cancelled only (no currently valid authorization) |
| Number of Authorizations | 1 (0 valid, 1 cancelled) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data for mercaptopurine are not available in the data compiled for this report. Mercaptopurine is known to be a purine antimetabolite. Its thioguanine nucleotide metabolites are incorporated into DNA and RNA and inhibit de novo purine synthesis. This is toxic to rapidly dividing cells, including leukaemic blasts.
ALL and myeloid leukaemia are both blood cancers of fast-dividing blasts, so a drug that disrupts nucleotide synthesis could plausibly act in both. In ALL, mercaptopurine plus methotrexate is a core maintenance backbone. In acute myeloid leukaemia (AML), the available evidence is mostly for mercaptopurine as part of multi-drug regimens or oral maintenance with methotrexate. There is little evidence that it works as a stand-alone treatment. How much mercaptopurine contributes in these studies remains uncertain.
Clinical Trial Evidence
The trials below are the most relevant of the 15 listed. For most of them, mercaptopurine’s role is not confirmed from the registry text.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00003934 | Phase 3 | Completed | 420 | Untreated acute promyelocytic leukaemia (APL): compares intermittent tretinoin versus tretinoin plus mercaptopurine and methotrexate as maintenance; mercaptopurine is named explicitly |
| NCT06199557 | Phase 1/2 | Recruiting | 48 | 6-Mercaptopurine plus valproic acid (or hydroxyurea plus valproic acid) in AML or high-risk MDS patients unfit for standard therapy; early phase, small |
| NCT05506332 | Phase 1 | Recruiting | 10 | Venetoclax plus 6-mercaptopurine in relapsed/refractory AML (ApoAML); very small |
| NCT00492856 | Phase 3 | Completed | 105 | SWOG S0521: maintenance versus observation in low/intermediate-risk APL; mercaptopurine role not confirmed |
| NCT02521493 | Phase 3 | Active, not recruiting | 280 | Risk-stratified therapy for AML in Down syndrome; mercaptopurine involvement not confirmed |
| NCT02688140 | Phase 3 | Completed | 133 | Arsenic trioxide plus ATRA and idarubicin versus the AIDA regimen in high-risk APL; mercaptopurine only possibly part of maintenance |
| NCT00482833 | Phase 3 | Completed | 276 | Arsenic trioxide plus ATRA versus AIDA in non-high-risk APL; mercaptopurine role not stated |
| NCT00866918 | Phase 3 | Completed | 106 | Risk-adapted therapy with arsenic trioxide in childhood APL; mercaptopurine role not stated |
| NCT00136084 | Phase 3 | Completed | 238 | Two cytarabine-dose regimens in newly diagnosed AML or myelodysplasia; mercaptopurine role not evident |
| NCT00551460 | Phase 2 | Completed | 78 | ATRA, arsenic trioxide and gemtuzumab in high-risk APL; mercaptopurine role not stated |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 26425037 | 2015 | Cohort | J Korean Med Sci | Oral maintenance with daily 6-MP plus weekly methotrexate in transplant-ineligible AML patients, given after first remission and consolidation |
| 27275453 | 2016 | Prospective pilot study | South Asian J Cancer | Metronomic oral 6-MP as a palliative option in elderly AML |
| 38828002 | 2024 | Cohort | Ther Adv Hematol | Intensive chemotherapy with dual induction and ALL-like consolidation for childhood AML in China |
| 32459546 | 2020 | Retrospective analysis | Pediatr Hematol Oncol | Outcomes of juvenile myelomonocytic leukaemia after sequential cytarabine and 6-MP |
| 31283407 | 2019 | Phase III randomized study | J Clin Oncol | Interfant-06 protocol in infant ALL; tested myeloid-style versus lymphoid-style consolidation |
| 3513537 | 1986 | Clinical studies | Am J Clin Oncol | Hydroxyurea plus 6-MP in chronic granulocytic leukaemia (92 patients); an old study in a related myeloid disease |
| 8383541 | 1993 | Case series and literature review | Ann Hematol | Chemotherapy for minimally differentiated AML (M0): five cases and a review |
| 2676034 | 1989 | Review | Blood Rev | Purine metabolism as a target for leukaemia chemotherapy; covers 6-MP and 6-thioguanine as purine analogues |
| 33183436 | 2021 | Review | J Nanosci Nanotechnol | 6-MP nanomedicine in leukaemia; addresses poor solubility and toxicity |
| 34442422 | 2021 | Review | J Pers Med | NUDT15 polymorphisms in thiopurine treatment; relevant to bone marrow suppression risk |
EU Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| EMEA/H/C/002022 (status: cancelled) | Xaluprine (previously Mercaptopurine Nova Laboratories) | Not specified | Treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (thiopurine antimetabolite) |
| Myelosuppression Risk | High. Myelosuppression is expected and is the basis of dose adjustment in maintenance therapy. Neutropenia is linked to TPMT/NUDT15 variants |
| Emetogenicity Classification | Low (oral agent) |
| Monitoring Items | Full blood count with differential, liver function (hepatotoxicity is linked to methylated metabolites), renal function; TPMT/NUDT15 genotyping before treatment |
| Handling Protection | Follow cytotoxic drug handling regulations. Please refer to the SmPC warnings and precautions |
Safety Considerations
- Disease associations flagged in the knowledge graph (not label text): The TxGNN knowledge graph links mercaptopurine with contraindication edges to kidney disease, liver disease, pancreatitis, gallbladder disease, thrombocytopenia, neutropenia, leukopenia, agranulocytosis, anaemia, hyperbilirubinaemia (including Gilbert syndrome), cholestasis and hepatosplenic T-cell lymphoma. These come from a research database and must be checked against the official SmPC.
- Drug Interactions: 296 interactions are recorded. Those with a known severity grade include the following.
- Moderate: mesalazine, balsalazide, olsalazine, sulfasalazine and naltrexone.
- Minor: levofloxacin.
- Many others have an unspecified severity.
- The literature also describes allopurinol altering mercaptopurine metabolite levels, so co-prescription needs review.
For label warnings and contraindications, please refer to the SmPC.
Conclusion and Next Steps
Decision: Hold
Rationale: The evidence for myeloid leukaemia is moderate (L2) but indirect. Most trials are multi-agent regimens in which mercaptopurine’s contribution is unclear, and the AML-specific literature consists of small cohorts, pilot studies and older reports. The only registered studies that name mercaptopurine directly are one APL maintenance trial and two small early-phase studies. The listed EU product is also cancelled. By contrast, the predictions for ALL and precursor lymphoblastic lymphoma/leukaemia are L1 and are effectively the existing approved indication.
To proceed, the following is needed:
- Mechanism-of-action data from DrugBank to support the mechanistic link analysis.
- The SmPC safety information (warnings and contraindications), which is currently missing and blocks safety screening.
- Trial data that isolate mercaptopurine’s contribution in AML or APL, for example the results and arm details of NCT00003934 and the ongoing NCT06199557.
- A prospective or randomized comparison of mercaptopurine-based maintenance in AML.
- Confirmation of current EU product availability.
- A TPMT/NUDT15 genotyping, blood count, liver monitoring and drug interaction plan.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.