Chapter 06: The First Systematic Studies of Chemotherapy for Leukemia
In this chapter, Dr. Freireich talks about the first study of chemotherapy for treating leukemia, developing new treatments for childhood leukemia, and combination chemotherapy.
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History of Science, Technology, and Medicine | Oncology | Oral History
Emil J Freireich, MD
The second person was a guy named Abraham Goldin. Abe Goldin had been working in the NIH, in one of the basic science labs, and he was interested in how drugs affect mice with these transplanted tumors. Abe Goldin showed that if you gave methotrexate at the maximum tolerated dose every week to mice, the mice lived longer than if you give it every day. Now, the way methotrexate was given to children was by mouth, 2 mg a day, in pill form. Dr. Frei and I had a series of meetings with these 2 guys, and we came up with the idea that there's something worth investigating in man. If it's better in a mouse, and this is a model of human leukemia, maybe it would work in a man. We said, "Let's have a study where we randomize children to receive methotrexate daily or once a week."
We had to do some pilot studies to get the maximum tolerated dose in man. The thing that came out of the infectious disease literature that was exciting was that if you wanted to cure a disease, you always did better with 2 drugs than with one, provided they had a different mechanism action. We said, "Well, this is okay, but what if we also gave them 6-MP at the same time?" When this was reviewed by the committees, they gave us hell. "If you give 2 drugs at the same time, think of what you're doing wrong. I mean, when the children fail," and they all failed on 6-MP, "you didn't have methotrexate. So that's wrong. You're using up all your treatments. It's terrible to do. And they're adding that toxicity."
It took us a long time to get this program, but we got it approved. We called it Protocol 1. It was the first systematic study of chemotherapy of leukemia in man. Hypothesis: Is the combination better than single agents? And does the schedule of methotrexate affect outcome? Well, we didn't hit a home run. We got the same response rate. But we were impressed by one thing: the response rate in both arms was higher than had ever been reported with the single agents. We said, "There may be something to this combination chemotherapy, but we don't have concurrent controls. There have never been quantitative studies, so we can't be sure." We published this in Blood. The editorial said, "It's nice for these young guys to keep trying."
Then we came up with Protocol 2. Dr. Law had made an important observation. He was interested in the mechanisms of resistance. If you give a subcurative dose of methotrexate to a mouse and you transplant over several generations, you end up with an L1210 cell line where when you give methotrexate, nothing happens; they're completely resistant. If you did it with 6-MP, the same thing happened, and the same thing happened in man. Everybody who responded became resistant; the disease came back. So there was a mechanism of resistance. So we said, "Well, look, Dr. Law said if he took mice that had 6-MP-resistant leukemia and treated them with methotrexate, the methotrexate worked better than in mice that were not 6-MP-resistant." We now understand the biochemistry. This is what they call collateral sensitivity. When you have 6-MP, the mechanism of resistance, deleting an enzyme which is involved in the salvage pathway, methotrexate involved the de novo pathway. When you're resistant to the salvage pathway, you're enormously sensitive to interfering with the de novo pathway. We know the biochemistry now, but back then we didn't know anything about it. This was just experimental evidence. We went to man, and we did Protocol 2.
What was Protocol 2? This was really exciting. We randomized children to receive 6-MP, methotrexate, or the combination. Now we can test the hypothesis that the combination is better, with good, objective, quantitative prospective data. And since this was both drugs, and you're using them both up, it's obvious that we have to study the effect of the sequence. We had 6-MP followed by MTX, and the reverse—MTX followed by 6-MP. How do you think that came out? The combination of 6-MP and MTX won over the sequence. There was no collateral sensitivity. The response rate as initial therapy here was the same as after prior treatment. The combination was better across the board. Now we were onto something—combination chemotherapy. That's what led to the cure of leukemia and Hodgkin's disease. Everything in chemotherapy is now combinations, and it's all because of this resistance problem.
Freireich, Emil J. M.D. and Brunet, Lesley W., "Chapter 06: The First Systematic Studies of Chemotherapy for Leukemia" (2001). Interview Chapters. 154.