The History of Methotrex...
Highlights
- The history of methotrexate began 75 years ago.
A short 🧵 on its history and pivotal moments, covering key trials to show realignment of #hematology #rheumatology, disciplines that belong to each other♥️
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- In the early 1940s, folic acid was isolated and found to cure some patients with megaloblastic anemia, not responding to vitamin B 12.
Also, patients with acute leukemia were treated with folic acid or folate conjugates (polyglutamated forms of folic acid)
👉proved ineffective:(
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- The subsequent demonstration by Heinle and Welch that a diet-induced deficiency of folic acid caused a decrease in the leukemia cell count, stimulated efforts, primarily by the Lederle group, to synthesize analogs of folic acid.
Overview of isolation and synthesis of folates👇
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- Era of chemotherapy:
-Aminopterin (4-aminopterolylglutamic acid),
proved to be a powerful antagonist, shown by Farber et al in a landmark paper, to produce remissions in children with acute lymphocytic leukemia (ALL)
-nitrogen mustard caused regressions in patients with lymphoma
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- Aminopterin interfered with proliferation of connective tissue. This led to a study in 1951 by Gubner et al. in several patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis👉rapid improvement in RA signs and symptoms 6/7 seven patients
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- In 1956, studies of leukemia-bearing mice showed that methotrexate, another folate analog, had a therapeutic index superior to that of´aminopterin; based on these studies, methotrexate supplanted
aminopterin in the clinic. (View Tweet)
- Lessons learnt early:
-drug resistance occurs rapidly if cure is not achieved (for most tumors within 4-6 months)👉treatment failure
-curable diseases with drugs: Hodgkin's, DLBCL, certain childhood solid tumors
-treatment with MTX not associated with long term
side effects
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- Other drugs were also found to be useful in the treatment of ALL, in particular 6-mercaptopurine (6MP), prednisone, and vincristine.
A very important study by the Acute Leukemia B cooperative group showed that 6MP-MTX was better than either drug used alone.
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- The next major advance (1971, 1978) that led to cures in 50% of the patients was the use of intrathecal methotrexate with adequate central nervous system (CNS) irradiation, for prophylaxis of sanctuary disease.
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- In 1972, Rex Hoffmeister, reported positive effects with intramuscular MTX (10-15 mg per week) in 29 patients with RA. 11/2929 patients had “major” clinical improvements and 14 had “moderate” improvements in RA activity. These patients underwent treatment for up to 25 months.
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- In 1983, a RCT crossover study of 35 patients with refractory RA was done.
Initial MTX dose: 7.5 mg per week with an increase at 6 weeks to 15 mg/w.
- 3 weeks after MTX initiation: >50% with >50% improved joint tenderness index
- 39% with improvement in the joint swelling index
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- The other pivotal study was an NIH-funded study network of 189 patients with active RA. Patients initially received MTX at 7.5 mg per week with dose escalation to 15 mg per week.
-32% had >50% decrease in the joint tenderness index
-21% with reduction in joint swelling index
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- Graft-versus-host disease:
In 1986, Storb and colleagues reported that the combination of MTX with cyclosporine A was superior to CSA alone in a series of prospective randomized phase 3 trials. This remains one of the most widely used regimen today as prophylaxis regimen in BMT.
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- If we go back in time 75 years and tell Dr Farber, that 21st-century medicine would utilize MTX more in rheumatology but also show the widespread use in oncology and hematology, he might scratch his head...that's a lovely thought, showing the beauty of medical research!
Fin.
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- Sources and references:
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