Methotrexate
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Methotrexate
- Methotrexate: From Acute Lymphoblastic Leukemia and Rheumatoid Arthritis to Pulmonary Blastoma
Methotrexate: From Acute Lymphoblastic Leukemia and Rheumatoid Arthritis to Pulmonary Blastoma
One-Sentence Summary
Methotrexate is an antifolate drug originally used for acute lymphoblastic leukemia, lymphomas, rheumatoid arthritis, psoriasis and cutaneous T-cell lymphoma. The TxGNN model's top-ranked prediction is pulmonary blastoma, but this prediction has no clinical trials and no publications behind it. The better-supported predicted directions are Hodgkin lymphoma (45 trials, 20 publications), small cell lung carcinoma (4 trials, 20 publications) and rhabdomyosarcoma (4 trials, 20 publications). Primary pulmonary lymphoma has 20 publications but no registered trials.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute lymphoblastic leukemia, non-Hodgkin lymphoma, mycosis fungoides, rheumatoid arthritis, psoriasis (the approved indication text in the Singapore licenses is blank; these come from the TxGNN knowledge graph) |
| Predicted New Indication | Pulmonary blastoma (rank 1) |
| TxGNN Prediction Score | 99.45% |
| Evidence Level | L5 (model prediction only) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 7 |
| Recommended Decision | Hold |
Other top predictions in the data compiled for this report:
| Rank | Predicted Indication | TxGNN Score | Evidence Level | Recommendation |
|---|---|---|---|---|
| 2 | Primary pulmonary lymphoma | 99.45% | L4 | Research Question |
| 3 | Small cell lung carcinoma | 99.43% | L4 | Hold |
| 4 | Well-differentiated fetal adenocarcinoma of the lung | 99.42% | L5 | Hold |
| 5 | Hodgkin lymphoma | 99.32% | L1 (field-level, see below) | Research Question |
| 6 | Rhabdomyosarcoma | 99.25% | L2 | Research Question |
| 7-8 | CLL/SLL (two molecular subtypes) | 99.23% | L5 | Hold |
| 9-10 | Parameningeal embryonal rhabdomyosarcoma; botryoid-type embryonal rhabdomyosarcoma of the vagina | 99.21%, 99.21% | L5 | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on general pharmacology, methotrexate is an antifolate that inhibits dihydrofolate reductase (DHFR). This suppresses purine and pyrimidine synthesis and therefore DNA synthesis in rapidly dividing cells. Its efficacy in lymphoid malignancies (acute lymphoblastic leukemia, non-Hodgkin lymphoma) is established, and at lower doses it also acts as an anti-inflammatory and immunomodulatory agent in rheumatoid arthritis and psoriasis.
For the top-ranked prediction, pulmonary blastoma, the link is only a general one: an antiproliferative drug acting on a proliferative lung malignancy. No study supports it. The predictions for lymphoid and sarcoma diseases (primary pulmonary lymphoma, Hodgkin lymphoma, rhabdomyosarcoma) are more plausible because methotrexate is already used in related cancers, and some historical studies exist. For small cell lung carcinoma, methotrexate was used in older combination regimens, but the data do not show a methotrexate-specific benefit.
Clinical Trial Evidence
The top-ranked prediction (pulmonary blastoma) has no registered trials. The trials below are from the better-supported predictions, so the tables show Hodgkin lymphoma and small cell lung carcinoma separately. Most trials were screened as adjacent evidence only.
Hodgkin lymphoma (rank 5): the 10 most relevant of 45 trials
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03206671 | Phase 3 | Active, not recruiting | 650 | NHL-BFM/NOPHO protocol testing rituximab in pediatric mature aggressive B-cell lymphoma; methotrexate-containing chemotherapy backbone, but the disease is NHL |
| NCT00012051 | Phase 3 | Completed | 340 | Randomized rituximab study with sequential chemotherapy and autologous transplant in relapsed B-cell NHL (HOVON 44) |
| NCT00005977 | Phase 3 | Completed | 83 | Dose intensification of methotrexate in advanced small non-cleaved cell NHL and B-cell ALL |
| NCT00928018 | Phase 3 | Completed | 139 | GVHD prophylaxis regimens (including methotrexate) after transplant for lymphoma; supportive care, not antilymphoma efficacy |
| NCT00002471 | Phase 2 | Completed | N/A | Intensive short-course combination chemotherapy in poor-risk lymphoma and recurrent NHL |
| NCT00290498 | Phase 2 | Completed | 67 | Rituximab-HCVAD alternating with rituximab-methotrexate-cytarabine vs R-CHOP in high-risk aggressive B-cell NHL |
| NCT00045539 | Phase 2 | Completed | N/A | Methotrexate plus thiotepa in newly diagnosed primary CNS lymphoma |
| NCT04514393 | Phase 2 | Unknown | 33 | Methotrexate, ibrutinib and temozolomide (MIT) in newly diagnosed primary CNS lymphoma |
| NCT01399372 | Phase 2 | Completed | 91 | Rituximab, methotrexate, procarbazine, vincristine and cytarabine with or without low-dose whole-brain radiotherapy in primary CNS lymphoma |
| NCT00574496 | Phase 2 | Completed | 25 | Salvage chemotherapy then allogeneic transplant in high-risk or relapsed Hodgkin lymphoma; methotrexate likely only GVHD prophylaxis |
The remaining Hodgkin-listed trials are mostly NHL protocols, transplant studies and GVHD prophylaxis studies. None is a Hodgkin-specific trial of methotrexate as the antilymphoma agent.
Small cell lung carcinoma (rank 3): all 4 trials, none in SCLC
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03520842 | Phase 2 | Completed | 22 | Regorafenib plus oral methotrexate in KRAS-mutated NSCLC; the only anticancer methotrexate combination, but in NSCLC |
| NCT05663866 | Phase 2 | Active, not recruiting | 68 | Methotrexate, dexamethasone or montelukast to prevent amivantamab infusion reactions; supportive care |
| NCT04356222 | Phase 4 | Unknown | 30 | Durvalumab with intrathecal chemotherapy in NSCLC leptomeningeal metastasis; methotrexate involvement not confirmed |
| NCT04356118 | Phase 4 | Unknown | 30 | Recombinant human endostatin in NSCLC leptomeningeal metastasis; methotrexate involvement not confirmed |
Rhabdomyosarcoma (rank 6): four trials were listed, but none is a rhabdomyosarcoma efficacy trial of methotrexate. NCT00357084 (Phase 2, n=53, methotrexate with glucocorticoids) concerns graft-versus-host disease treatment, and the others are transplant or brain tumor studies.
Literature Evidence
Primary pulmonary lymphoma (rank 2): 20 publications, mostly indirect
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 30842385 | 2019 | Cohort | Rinsho Ketsueki | High-dose methotrexate plus rituximab in six patients with primary CNS lymphoma; indirect for the lung |
| 12860951 | 2003 | Phase 2 | J Clin Oncol | EORTC chemotherapy-alone study in primary CNS lymphoma patients over 60 |
| 15747120 | 2005 | Clinical study | Ann Hematol | Modified ProMACE-MOPP with moderate-dose methotrexate in 32 primary CNS lymphoma patients |
| 38720609 | 2024 | Case report | Kyobu Geka | Primary pulmonary DLBCL arising from methotrexate-associated lymphoproliferative disorder (a safety signal) |
| 32590768 | 2020 | Case report | Medicine | Two cases of primary pulmonary NK/T-cell lymphoma plus literature review |
Small cell lung carcinoma (rank 3): no methotrexate-specific benefit shown
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 24282143 | 2013 | Cochrane review | Cochrane Database Syst Rev | Chemotherapy vs best supportive care in extensive SCLC |
| 2983855 | 1985 | Clinical study | Cancer | Adding methotrexate to VAC plus radiation in 50 patients; methotrexate did not improve the complete response rate |
| 2551355 | 1989 | Randomized | Acta Oncol | Two-drug vs four-drug chemotherapy with or without prophylactic cranial irradiation |
| 2982882 | 1985 | Randomized | J Cancer Res Clin Oncol | Vincristine, methotrexate and cyclophosphamide with or without immunotherapy in 79 patients |
| 6284535 | 1981 | Review | Eur J Respir Dis | Methotrexate listed among the commonly used SCLC agents |
| 32152484 | 2020 | Review | Nat Rev Clin Oncol | Folate receptor α as an anticancer target, alongside antifolates such as methotrexate |
Hodgkin lymphoma (rank 5)
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 14635074 | 2003 | Clinical study | Cancer | Vinblastine, bleomycin and methotrexate (VBM) plus irradiation in early-stage favorable Hodgkin lymphoma |
| 21592816 | 2012 | Review | Crit Rev Oncol Hematol | VBM plus radiotherapy: 94-100% complete remission and 75-95% 5-year progression-free survival in nine small trials, with early pulmonary toxicity |
| 15659500 | 2005 | Phase 3 RCT | J Clin Oncol | Intermediate-dose methotrexate and high-dose cytarabine in advanced pediatric large-cell lymphoma (not Hodgkin) |
| 7653488 | 1995 | Retrospective | Am J Med | Hematologic malignancies and methotrexate use in rheumatoid arthritis (safety signal) |
| 35848760 | 2022 | Cohort | Am J Surg Pathol | 9p24.1 alteration and PD-L1 in methotrexate-associated Hodgkin lymphoma (safety signal) |
Rhabdomyosarcoma (rank 6)
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 9329466 | 1997 | Phase 2 | J Pediatr Hematol Oncol | High-dose methotrexate in untreated children and adolescents with high-risk unresectable or metastatic rhabdomyosarcoma |
| 36614297 | 2023 | Retrospective cohort | Int J Mol Sci | BOMP-EPI (includes methotrexate) in 10 adults with relapsed or metastatic rhabdomyosarcoma |
| 22156656 | 2011 | Pilot | Oncotarget | Pediatric metronomic 4-drug regimen |
| 15529318 | 2005 | Cohort | Head Neck | Treatment strategies for parameningeal rhabdomyosarcoma in 90 patients |
Pulmonary blastoma and the other L5 entries (fetal adenocarcinoma of the lung, CLL/SLL subtypes, vaginal botryoid rhabdomyosarcoma) have no related literature in the data compiled for this report.
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16395P | Methotrexate Orion Tablets 2.5 mg | Tablet | Not listed in the data |
| SIN00260P | Methotrexate Tablet 2.5 mg | Tablet | Not listed in the data |
| SIN16737P | Merex 2.5-Methotrexate Tablets USP 2.5 mg | Tablet | Not listed in the data |
| SIN00758P | DBL Methotrexate Injection BP 50 mg/2 ml (without preservative) | Injection | Not listed in the data |
| SIN12414P | Emthexate 2.5 Tablet 2.5 mg | Tablet | Not listed in the data |
Two further licenses are valid: SIN00242P (DBL Methotrexate Injection BP 1 g/10 ml) and SIN17136P (Methotrexate Remedica film-coated tablet 2.5 mg). All 7 are single-ingredient products, and none is cancelled. Both oral and injectable routes are available.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (antimetabolite, antifolate) |
| Myelosuppression Risk | High at antineoplastic doses; the knowledge graph links leukopenia, thrombocytopenia and anemia as contraindicated conditions |
| Emetogenicity Classification | Low to moderate, depending on dose; higher at high-dose regimens |
| Monitoring Items | CBC with differential, liver and renal function; high-dose use requires methotrexate level monitoring |
| Handling Protection | Follow cytotoxic drug handling regulations |
Please also refer to the package insert warnings and precautions.
Safety Considerations
- Contraindicated conditions (from the knowledge graph, not label text): liver failure and liver disease, kidney disease, gallbladder disease, thrombocytopenia, leukopenia, anemia (including macrocytic anemia), peptic or gastric ulcer disease, ulcerative colitis and inflammatory bowel disease, stomatitis, interstitial lung disease, pulmonary fibrosis (including postinflammatory), substance abuse/dependence, immune system disease, and pyoureter.
- Drug interactions: 100 interactions were found. The ones listed include Major interactions with rabeprazole, amoxicillin and acetylsalicylic acid. Moderate interactions include corticosteroids (hydrocortisone, dexamethasone, betamethasone, triamcinolone, budesonide), tetracyclines (doxycycline, tetracycline), clarithromycin, amphotericin B, mesalazine, balsalazide, pioglitazone, acarbose, bupropion and chenodeoxycholic acid. Potassium citrate is Minor.
- Methotrexate-associated lymphoproliferative disorders: several case reports and cohort studies describe lymphoma-like disease arising in patients treated with methotrexate (mostly for rheumatoid arthritis). This matters when interpreting the lymphoma literature.
Please refer to the package insert for the official warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The top-ranked prediction, pulmonary blastoma, rests on the model score alone (L5), with no trials or publications. Among the other predictions, Hodgkin lymphoma carries a nominal L1 grade only because methotrexate is mature in the lymphoma field. Its Phase 3 trials are in B-cell NHL or GVHD prophylaxis, not Hodgkin-specific. Rhabdomyosarcoma (L2) has only a historical Phase 2 study, and small cell lung carcinoma has no methotrexate-specific benefit. Primary pulmonary lymphoma and the VBM regimen in early-stage Hodgkin lymphoma are the most credible directions for further research, but none is ready to proceed.
To proceed, the following is needed:
- Package insert warnings and contraindications from the Singapore regulator (a blocking data gap), and the approved indication text for each license
- Mechanism of action data
- For primary pulmonary lymphoma and Hodgkin lymphoma: a focused review of methotrexate-containing regimens (including VBM and high-dose methotrexate) against current standard therapy
- For rhabdomyosarcoma: confirmation of whether NCT00357084 concerns this disease, and a comparison with current standard regimens
- Route compatibility and similarity-to-original analyses, which are still pending
- A safety plan covering hepatic, renal, pulmonary and hematologic toxicity, and the interaction risks above
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.