Methotrexate for Myeloproliferative Disorders

(TREATMORE Trial)

Overseen By Gabriela Bello

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Icahn School of Medicine at Mount Sinai

Must be taking: Ruxolitinib

Must not be taking: MTX

Disqualifiers: Cardiovascular disease, Invasive malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 48 weeks

54 Participants Needed

Trial Summary

What is the purpose of this trial?

Low-dose MTX is a widely used, inexpensive, and safe therapy used for decades and is well tolerated by patients with rheumatologic diseases. Recently, it was identified as a type 2 JAK inhibitor. If MTX proves to be safe and tolerable with a signal of clinical activity, this could have a significant benefit to patients with MPNs. Beyond the potential benefit of adding a type 2 JAK inhibitor to current therapy, this could signal the need to study MTX in MPNs further as a monotherapy. Discovering MTX as safe and clinically effective in MPNs could be profound on both a public health and global health scale for patients who are uninsured and cannot afford more expensive novel JAK inhibitors, or for those in countries where JAK inhibitors are not available. Accordingly, the research team deems it reasonable and prudent to assess the safety and efficacy of MTX in addition to current therapy for patients with MPN. The research team will evaluate patients for spleen responses, symptom responses, and cytologic responses. Correlative data will evaluate pharmacokinetic and disease modifying activity of MTX in MPNs to inform future clinical trials.

Will I have to stop taking my current medications?

The trial does not require you to stop your current medications. In fact, it allows you to continue certain therapies like aspirin, hydroxyurea, and ruxolitinib, as long as they have been stable for at least 12 weeks.

What data supports the effectiveness of the drug Methotrexate for treating myeloproliferative disorders?

Methotrexate is known to be effective in treating rheumatoid arthritis by improving the efficacy of other treatments and is well-tolerated, which suggests it might be beneficial for other conditions like myeloproliferative disorders. ^{1 2 3 4 5}

Is methotrexate generally safe for humans?

Methotrexate is generally considered safe for use in humans, especially in low doses for conditions like rheumatoid arthritis. However, serious side effects like pancytopenia (a decrease in blood cells) and rare cases of leukemia have been reported, often linked to interactions with other medications or specific health conditions. ^{4 6 7 8 9}

How is the drug methotrexate unique for treating myeloproliferative disorders?

Methotrexate is unique because it was originally discovered for treating childhood leukemia and is now a standard treatment for rheumatoid arthritis, showing its versatility in treating different conditions. Its use in myeloproliferative disorders may offer a novel approach, as there are no standard treatments specifically for these conditions. ^{3 4 10 11 12}

Research Team

John Mascarenhas

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

The TREATMORE trial is for patients with myeloproliferative disorders such as myelofibrosis, essential thrombocythemia, or polycythemia vera. Participants should be currently receiving therapy for their condition but are still looking for additional treatment options.

Inclusion Criteria

Must voluntarily sign ICF and be willing and able to adhere to the study visit schedule and all protocol requirements

I agree to use birth control during the study.

My myelofibrosis is classified from low to high-risk, or I have polycythemia vera or essential thrombocythemia of any risk level.

Exclusion Criteria

I haven't had any cancer except for skin, prostate, or cervical cancer in the last 3 years.

I have moderate or severe heart disease.

I have not had a heart attack or stroke in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive low-dose Methotrexate in addition to current therapy for Myeloproliferative Neoplasms

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Methotrexate

Trial Overview This study tests low-dose Methotrexate (MTX), a medication traditionally used in rheumatologic diseases and recently identified as a type 2 JAK inhibitor. The trial will assess its safety, tolerability, and effectiveness when added to current therapies in MPNs.

Participant Groups

Group I: Polycythemia vera (PV) Experimental Treatment 1 Intervention

18 patients with MF will be enrolled

Group II: Myelofibrosis (MF) Experimental Treatment 1 Intervention

18 patients with MF will be enrolled

Group III: Essential thrombocythemia (ET) Experimental Treatment 1 Intervention

18 patients with MF will be enrolled

Methotrexate is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Trexall for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in Canada as Mexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in European Union as Methotrexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis
• Crohn's disease
• Ulcerative colitis

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

Findings from Research

The combination of methotrexate (MTX) and anti-TNF agents significantly increases apoptosis in transmembrane TNF (tmTNF)-expressing cells compared to either treatment alone, suggesting a synergistic effect that may enhance treatment efficacy in rheumatoid arthritis.

The enhanced apoptosis is primarily mediated through reverse signal transduction rather than complement-dependent or antibody-dependent cytotoxicity, indicating that MTX and anti-TNF agents may activate independent intracellular pathways to improve clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate Enhances Apoptosis of Transmembrane TNF-Expressing Cells Treated With Anti-TNF Agents. Wang, Q., Oryoji, D., Mitoma, H., et al.[2021]

In a systematic review of 19 trials involving 2,025 patients with rheumatoid arthritis, methotrexate (MTX) monotherapy showed no significant advantage over MTX combined with non-biologic DMARDs in terms of efficacy or toxicity, with similar withdrawal rates due to lack of efficacy or adverse effects.

While MTX combination therapy did lead to significant reductions in pain and improvements in physical function for patients who had inadequate responses to MTX, the overall evidence suggests that combining MTX with other DMARDs does not provide a clear benefit compared to using MTX alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis. Katchamart, W., Trudeau, J., Phumethum, V., et al.[2022]

A patient with rheumatoid arthritis experienced life-threatening pancytopenia due to low-dose methotrexate (MTX) toxicity, which was worsened by the use of probenecid.

This case highlights the importance of recognizing clinically significant drug interactions, as they can lead to serious hematologic toxicity from low-dose MTX, which is becoming more common in rheumatologic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe pancytopenia in a patient taking low dose methotrexate and probenecid. Basin, KS., Escalante, A., Beardmore, TD.[2013]

This report adds two new cases of leukemia in patients with rheumatoid arthritis who were treated with low-dose methotrexate, bringing the total to three known cases.

The relationship between methotrexate treatment and the development of leukemia in these patients is still unclear, indicating a need for further investigation into the safety of this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temporal association between the use of methotrexate and development of leukemia in 2 patients with rheumatoid arthritis. Dubin Kerr, L., Troy, K., Isola, L.[2013]

Methotrexate (MTX) is the most commonly used drug in combination therapies for rheumatoid arthritis, showing the best results when paired with leflunomide, cyclosporine, or in a triple combination with sulphasalazine and hydroxychloroquine.

Combining MTX with biologics, especially TNF inhibitors, abatacept, rituximab, or tocilizumab, enhances treatment efficacy and helps prevent disease progression, with safety profiles similar to individual medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Combination therapy using methotrexate with DMARDs or biologics--current status]. Krüger, K.[2021]

Four patients with rheumatoid arthritis developed acute myeloid leukemia (AML) while on low-dose weekly methotrexate therapy, but this was not linked to the drug as they had no prior exposure to known leukemogenic agents.

The characteristics of AML in these patients differed from typical therapy-related leukemias, suggesting that the occurrence of AML may be coincidental rather than caused by methotrexate treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myeloid leukemia in the setting of low dose weekly methotrexate therapy for rheumatoid arthritis. Kolte, B., Baer, AN., Sait, SN., et al.[2019]

Low doses of methotrexate do not lead to more adverse effects compared to conventional anti-rheumatic drugs, indicating its safety profile in this context.

However, serious complications like pancytopenia can occur, often triggered by interactions with other medications or conditions that increase cell formation, highlighting the need for careful monitoring and the use of leukovorin when bone marrow suppression is suspected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pancytopenia during low-dosage methotrexate treatment in patients with rheumatoid arthritis]. Nygaard, H.[2013]

This case report describes an 83-year-old woman with rheumatoid arthritis who developed acute myeloid leukemia after 33 months of treatment with methotrexate, suggesting a potential link between the medication and the development of this cancer.

The rarity of similar cases raises questions about methotrexate's safety profile, indicating that it may either have a protective effect against malignancy or is not widely recognized as a risk factor by healthcare providers, highlighting the need for more comprehensive reporting of such cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute leukemia after low dose methotrexate therapy in a patient with rheumatoid arthritis. Pointud, P., Prudat, M., Peron, JM.[2013]

Methotrexate (MTX) is the preferred treatment for rheumatoid arthritis due to its favorable safety profile and cost-effectiveness, with an optimal starting dose of 15 mg/week that can be increased to 25-30 mg/week based on patient tolerance.

While oral MTX is commonly used, subcutaneous administration may offer better efficacy and patient compliance, as it has been associated with fewer disease exacerbations and improved quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate in rheumatoid arthritis: optimizing therapy among different formulations. Current and emerging paradigms. Cipriani, P., Ruscitti, P., Carubbi, F., et al.[2018]

In a study of 35,640 rheumatoid arthritis patients, those who continued with oral methotrexate (MTX) had the lowest average healthcare costs ($47,464) over five years compared to those who switched to subcutaneous MTX ($59,058) or added biologic therapies ($175,391 to $212,595).

Switching to subcutaneous MTX before biologic therapy not only delayed the use of more expensive treatments but also resulted in lower overall costs, suggesting that optimizing MTX use can be a cost-effective strategy for managing rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing Healthcare Costs Associated with Oral and Subcutaneous Methotrexate or Biologic Therapy for Rheumatoid Arthritis in the United States. Lee, J., Pelkey, R., Gubitosa, J., et al.[2022]

Methotrexate (MTX) was originally developed for childhood leukemia but has become the standard treatment for rheumatoid arthritis (RA) and other related rheumatological diseases, showcasing its versatility and effectiveness.

The use of low-dose methotrexate (LD-MTX) in rheumatology is based on careful observations from the 1940s and 1950s, distinguishing it from high-dose methotrexate (HD-MTX) used for cancer treatment, which highlights its targeted application in managing autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Landmark papers on the discovery of methotrexate for the treatment of rheumatoid arthritis and other systemic inflammatory rheumatic diseases: a fascinating story. Malaviya, AN.[2017]

Severe pancytopenia, a serious blood condition, can occur in patients undergoing low-dose methotrexate (MTX) therapy for rheumatoid arthritis, as demonstrated in two case reports involving patients with renal impairment.

The risk of developing pancytopenia is heightened in individuals with kidney issues, and this adverse effect can arise at any point during MTX treatment, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe pancytopenia associated with low-dose methotrexate therapy for rheumatoid arthritis. Calvo-Romero, JM.[2017]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Methotrexate Enhances Apoptosis of Transmembrane TNF-Expressing Cells Treated With Anti-TNF Agents. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis. [2022]

3. Canada pubmed.ncbi.nlm.nih.gov

Severe pancytopenia in a patient taking low dose methotrexate and probenecid. [2013]

4. Canada pubmed.ncbi.nlm.nih.gov

Temporal association between the use of methotrexate and development of leukemia in 2 patients with rheumatoid arthritis. [2013]

5. Germany pubmed.ncbi.nlm.nih.gov

[Combination therapy using methotrexate with DMARDs or biologics--current status]. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Acute myeloid leukemia in the setting of low dose weekly methotrexate therapy for rheumatoid arthritis. [2019]

7. Norway pubmed.ncbi.nlm.nih.gov

[Pancytopenia during low-dosage methotrexate treatment in patients with rheumatoid arthritis]. [2013]

8. Canada pubmed.ncbi.nlm.nih.gov

Acute leukemia after low dose methotrexate therapy in a patient with rheumatoid arthritis. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Methotrexate in rheumatoid arthritis: optimizing therapy among different formulations. Current and emerging paradigms. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Comparing Healthcare Costs Associated with Oral and Subcutaneous Methotrexate or Biologic Therapy for Rheumatoid Arthritis in the United States. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Landmark papers on the discovery of methotrexate for the treatment of rheumatoid arthritis and other systemic inflammatory rheumatic diseases: a fascinating story. [2017]

12. United States pubmed.ncbi.nlm.nih.gov

Severe pancytopenia associated with low-dose methotrexate therapy for rheumatoid arthritis. [2017]