Mercaptopurine
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Mercaptopurine: From Acute Lymphoblastic Leukaemia to Myeloid Leukaemia
One-Sentence Summary
Mercaptopurine (6-MP) is a thiopurine antimetabolite whose established use is in acute lymphoblastic leukaemia (ALL) maintenance therapy. The TxGNN model predicts it may also be effective for Myeloid Leukaemia, with 29 clinical trials and 20 publications currently identified in this evidence pack supporting further evaluation — though most trials involve 6-MP as part of combination maintenance regimens (particularly for acute promyelocytic leukaemia) rather than as a standalone-tested agent for this indication.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute Lymphoblastic Leukaemia (established antileukaemic maintenance agent — no structured original-indication or ARTG data available in this pack; see note below) |
| Predicted New Indication | Myeloid Leukaemia |
| TxGNN Prediction Score | 99.94% |
| Evidence Level | L2 |
| Australia Market Status | Not marketed |
| Number of ARTG Entries | 0 |
| Recommended Decision | Proceed with Guardrails |
Note on data gaps: The original_indications and original_moa fields for this drug were empty in the source data (flagged as Data_Level gaps DG002, High severity). The original-indication statement above is derived from the extensive supporting clinical trial and literature evidence within this pack (6-MP as the backbone of ALL maintenance chemotherapy), not from a structured regulatory record.
Why is This Prediction Reasonable?
Detailed, structured mechanism-of-action data was not available for this drug (data gap DG002). Based on the supporting evidence in this pack, Mercaptopurine is a purine analogue (thiopurine) that inhibits DNA/RNA synthesis after intracellular conversion to thioguanine nucleotides, producing cytotoxicity in rapidly proliferating haematopoietic blasts. This mechanism underlies its long-standing, well-proven role in ALL maintenance therapy.
Myeloid and lymphoid leukaemias share the underlying feature of uncontrolled proliferation of immature haematopoietic precursors, which is the basis for cross-lineage applicability of antimetabolite chemotherapy. Notably, the evidence base already shows 6-MP being used within combination maintenance regimens for acute myeloid leukaemia — particularly acute promyelocytic leukaemia (APL), where it is combined with methotrexate and ATRA in multiple large Phase 3/4 trials (e.g. AIDA, PETHEMA LPA2005) — as well as in early-phase trials combining 6-MP with newer agents (venetoclax, valproic acid) for relapsed/refractory AML and unfit AML/high-risk MDS patients. This existing precedent of use in myeloid disease supports the biological plausibility of the TxGNN prediction, although 6-MP is rarely the primary investigational agent in these regimens.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT00408278 | Phase 4 | Completed | 300 | PETHEMA LPA2005: maintenance therapy with ATRA + low-dose chemotherapy (methotrexate + mercaptopurine) after risk-adapted induction/consolidation for newly diagnosed APL |
| NCT00180128 | Phase 4 | Unknown | 80 | AIDA2000 risk-adapted APL therapy; 2-year maintenance with 6-mercaptopurine, methotrexate and ATRA |
| NCT01064557 | N/A | Unknown | 1068 | AIDA protocol guideline for newly diagnosed APL, testing intermittent ATRA maintenance vs standard maintenance with methotrexate and 6-mercaptopurine |
| NCT00465933 | Phase 4 | Completed | N/A | AIDA regimen for APL in patients >70 years; ATRA maintenance plus methotrexate/mercaptopurine salvage therapy for relapse |
| 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 | ApoAML: venetoclax combined with 6-mercaptopurine (purine analogue) as an oral combination for relapsed/refractory AML |
| NCT00003934 | Phase 3 | Completed | 420 | Tretinoin + chemotherapy ± arsenic trioxide as consolidation for untreated APL, followed by maintenance with tretinoin alone vs tretinoin + mercaptopurine + methotrexate |
| NCT00136084 | Phase 3 | Completed | 238 | Comparison of two multi-agent chemotherapy regimens (different cytarabine dosing) for newly diagnosed AML/myelodysplasia (disease-level evidence; not mercaptopurine-specific) |
| NCT00866918 | Phase 3 | Completed | 106 | Risk-adapted arsenic trioxide consolidation for newly diagnosed childhood APL (6-MP not the primary study drug) |
| NCT00962767 | Phase 3 | Completed | 168 | Gemtuzumab ozogamicin dosing vs 2-year ATRA + chemotherapy maintenance as post-consolidation treatment for intermediate/high-risk APL |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 10497848 | 1999 | RCT | International Journal of Hematology | JALSG-AML92: adding etoposide to daunorubicin/cytarabine/6-MP induction gave no additional benefit in adult AML |
| 9095207 | 1997 | Clinical trial | Cancer Investigation | High-dose IV 6-MP plus intermediate-dose cytarabine was feasible during first AML remission in children (14/17 achieved CR) |
| 26425037 | 2015 | Cohort | Journal of Korean Medical Science | Oral maintenance with 6-MP + methotrexate after consolidation improved leukaemia-free survival in transplant-ineligible AML patients |
| 8174198 | 1994 | RCT | Cancer Chemotherapy and Pharmacology | Nationwide randomised trial: daunorubicin vs aclarubicin combined with BHAC/6-MP/prednisolone in untreated AML (CR 63.7% vs 53.9%) |
| 8558199 | 1996 | RCT | Journal of Clinical Oncology | Randomised comparison of BHAC vs cytarabine (± ubenimex) in combination induction/consolidation for adult AML |
| 1793832 | 1991 | Clinical study | International Journal of Hematology | Intensive individualised induction with BHAC, daunorubicin and 6-MP achieved 71% complete remission in adult AML |
| 5220682 | 1966 | Case series | Minnesota Medicine | Early report of AML treated with 6-MP and cyclophosphamide |
| 4518586 | 1973 | Clinical study | Cancer | Treatment of adult AML with cytarabine in combination with 6-MP |
| 1059498 | 1975 | Clinical study | Cancer | Childhood AML treated with cytarabine, daunorubicin, prednisolone and mercaptopurine or thioguanine (78% initial remission rate) |
| 265178 | 1977 | Case series | Blood | Juvenile chronic myeloid leukaemia treated with sequential subcutaneous cytarabine and oral mercaptopurine (3 cases) |
Australia Market Information
Mercaptopurine is not currently registered on the Australian Register of Therapeutic Goods (ARTG) and has no marketed product in Australia (0 ARTG entries, market status: not marketed). Any use in Australia would require sourcing via an unapproved-medicine pathway (e.g. TGA Special Access Scheme or Authorised Prescriber pathway) and referencing overseas-approved Product Information, as no Australian PI exists for this drug.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (antimetabolite — thiopurine/purine analogue class) |
| Myelosuppression Risk | High — well documented across the literature evidence, particularly in TPMT- and NUDT15-deficient patients, where risk of severe neutropenia is markedly increased |
| Emetogenicity Classification | Low (consistent with the general antimetabolite/thiopurine class) |
| Monitoring Items | FBC with differential, liver function tests, renal function; TPMT and/or NUDT15 genotype or phenotype testing prior to initiation is strongly supported by the pharmacogenomic literature in this pack |
| Handling Protection | Standard cytotoxic drug handling and disposal precautions required |
Safety Considerations
No structured TGA/TFDA warnings, contraindications or drug-interaction data were available for this drug in the evidence pack (flagged as data gap DG001, Blocking severity — this currently prevents a formal safety pre-assessment). Please refer to an approved Product Information from a jurisdiction where Mercaptopurine is registered, and obtain specialist haematology/oncology input, before considering clinical use.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Multiple Phase 3/4 trials and mechanistic/clinical literature support 6-MP’s use within myeloid leukaemia (largely APL) maintenance regimens, and the TxGNN prediction score is very high (99.94%). However, the drug is unregistered in Australia and a Blocking-severity safety data gap (no TGA-equivalent warnings/contraindications) currently prevents formal safety sign-off.
To proceed, the following is needed:
- Product Information (warnings, contraindications) sourced from a jurisdiction where Mercaptopurine is TGA/TFDA-equivalent registered, to resolve the Blocking safety gap (DG001)
- Formal mechanism-of-action documentation (DG002)
- Confirmation of TPMT/NUDT15 testing availability and a monitoring protocol before any clinical use
- A defined access pathway (TGA Special Access Scheme or Authorised Prescriber) given the drug is not marketed in Australia
- Clarification of the specific myeloid leukaemia subtype(s) (the strongest evidence is for APL maintenance rather than AML generally)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.