Soheil Meshinchi, MD, PhD, a Pediatric Oncologist at Fred Hutchinson Cancer Research Center talks about Mylotarg, a treatment option for patients with acute myeloid leukemia or AML.
Interview conducted by Ivanhoe Broadcast News in November 2017.
I know you’ve been involved with Mylotarg for a long time and it has an interesting history as a drug, if you could go through that?
Dr. Meshinchi: Mylotarg is the first immunotherapy that was used in treating cancer. It was developed ty Irv Bernstein at the Hutch to target a protein called CD33. This was based on his discovery that this protein was expressed on the leukemia cells in most acute myeloid leukemia (AML). He cloned CD33 gene and developed an antibody that targeted this protein. In working with a pharmaceutical company he was able to attach this antibody to a very potent toxin and generate the first immunotherapy. This combination of an antibody and a drug is referred to an antibody drug conjugate (ADC). The way that the mylotarg works is that antibody seeks out the leukemic cells that express CD33, recognizes and binds to the CD33 protein. As a result of this binding, the antibody with the attached drug get pulled into the cell, the toxin is released and kills the cell from inside. This is really the first targeted therapy that allowed us to deliver a potent chemotherapy to the source of the cancer; to the leukemia cells. Generally, with regular chemotherapy, we give to it to everyone, hoping that some would respond; about ten to thirty percent of the patients may not respond to chemotherapy but will endure large number of toxic side effects such as hair loss, bad mouth sores, infections and even death. With a targeted therapy such as mylotarg we were able to deliver the chemotherapy just to the leukemic cells that express CD33, thus we were able to really avoid a lot of these side effects. for the first time, we were able to deliver chemotherapy in a targeted fashion.
Mylotarg went away for a while, and you were one of the ones that brought it back. Why when everybody is inventing new things you went back into the closet and pulled an old one out? What made you think it was going to work?
Dr. Meshinchi: As we learned more about AML, we realized that we might be able to deliver mylotarg more effectively and to patients that would most benefit from this drug. The reason mylotarg went away was because of the fact that when they gave it to all patients regardless of CD33 expression, they saw really large toxicities. This means that the number of patients who received Mylotarg had higher rates of side effects and death compared to those who did not receive mylotarg. And that’s the reason that it was pulled. We have learned a lot more about how best to use mylotarg since then. The reason it came back is that with additional studies, we noticed that there was an effectiveness signal and learned about how we can more accurately target mylotarg to patients that are more likely to respond. We also learned that mylotarg can be given at lower doses if it is combined with chemotherapy, thus decreasing side effects. So the question was can you identify patients who most benefit from Mylotarg and treat those and leave out the patients who have no response to it; thus eliminating a concern for all the toxicity. This is where the precision medicine comes in; really being able to match a drug with a target that has a high degree of certainty for predicting who is going to respond and who is not going to respond. And that’s exactly what happened in the last five to ten years; we were able to better study AML, study Mylotarg, and identify specific genetic variants that can predict who would respond to Mylotarg before you deliver the first dose.
So you’re looking for the antibody expression, is that what you are looking for, or something different from that?
Dr. Meshinchi: It’s actually a combination. The antibodies and the protein expression is part of it. What we actually showed, this goes back almost five years ago, is that the expression of these proteins on the cell surface really makes a big difference. Those that have a high expression they benefit most by it. What was most compelling was discovery of genetic variation in CD33 gene (called a polymorphism) that predicts response to mylotarg. This discovery was made by a colleague, Dr. Jatinder Lamba, in University of Florida. Now we are able to test for a single genetic change that can predict with a significant degree of certainty who would respond to Mylotarg.
So what you’re doing then is you’re sequencing DNA before you admit people, is it still a study or where are we?
Dr. Meshinchi: It’s still being studied in other protocols to make sure that what we have discovered and reported on can be extrapolated to everyone. The component of this analysis is that we sequence the CD33 gene and we can identify a genetic variant that can predict whether the site that Mylotarg binds to is present or not. Whether patients express the part of the protein that antibody binds to is critical to mylotarg action. If the antibody binding site is not expressed, then there’s no place for Mylotarg to bind to; thus, there’s no affect. So Mylotarg just floats around and just causes toxicity without any benefit for the leukemia.
What kind of difference have you noticed in the people who do respond to the drug?
Dr. Meshinchi: Going back to when we treated everyone with mylotarg, the impact of Mylotarg was quite modest. You have to look very carefully to see maybe five to ten percent improvement in survival. And most studies showed very little survival if any. When you identify patients based on the genetic variant, we see nearly 35% to forty percent improvement in patients that have that what we call responsive variant. In contrast, those without that variant, have absolutely no benefit from Mylotarg. So the half of the patients that expressed this responsive genotype, have a substantial benefit that the other half doesn’t. Once you identify the patients who do benefit, you can include Mylotarg as part of a therapy and the rest of the patients they can go on to get something else. So you’re sparing them all the toxicities that Mylotarg can have.
How do you deliver it, what’s the treatment protocol?
Dr. Meshinchi: The Mylotarg is an infusion. It’s something that you give via IV and it’s usually given over a very short period of time. It’s most effective when it’s given in combination with other chemotherapy, some other conventional chemotherapies that we give. Actually the best time to give it is after all the leukemic cells that are floating have already gone away. You give a conventional chemotherapy; you deplete all tha circulating leukemia in the blood so they’re not there to soak up all the Mylotarg. Then you give a small dose of the Mylotarg where it attacks the remaining leukemic cells that are in the bone marrow and eliminate them. That’s the most effective way of giving mylotarg; to first deplete the circulating leukemia and then give Mylotarg in a small dose.
How soon until everybody who would be potentially a beneficiary of this is able to take part?
Dr. Meshinchi: The genetic test to determine who is responsive and who is not responsive is available right now. It’s a very easy test; we recently created a streamlined version that can be done in a matter of four hours. So it can be done very quickly before a patient sees even the first dose of any chemotherapy, it can easily be done before chemotherapy is delivered. This is really the ultimate in precision medicine where you are able to predict who is going to respond before exposing them to chemo.
So if someone in Houston has a high expression of this then what? Do they need to come here?
Dr. Meshinchi: No. They can send their sample to be tested. Specimens can be sent with overnight delivery and they can have the test results back within 24 hours, so that’s easily done. Also, we are always happy to shar our assay with other labs to offer locally. Since Mylotarg is now approved so you don’t necessary need to enter a study to get the drug; you can actually deliver it anywhere. Theoretically one can get the test done and determine whether a patient would be responsive to Mylotarg and get the Mylotarg. In my opinion all cancer treatments are best done in a context of a clinical trial that you can learn as much as you can from patients to be able to develop better therapies for the next trial. So Mylotarg is being included in a number of current trials.
Not by itself, always in combination?
Dr. Meshinchi: It’s always done best in combination, yes.
What haven’t I asked you about; the return of Mylotarg or the future?
Dr. Meshinchi: The initial removal of Mylotarg from market was remarkable for a drug that’s showed such huge promise. However, despite early promise, in one trial that treated all patients with high dose mylotarg, a subset of those who received mylotarg had high rate of toxicity that led to deaths in those who received mylotarg, forcing early closing of the trial and removing of the drug from market. However, with better understanding of appropriate dosing and ability to identify “responsive patients” before starting treatment, we can deliver this drug with high precision, increasing drug efficacy with minimal toxicity. The critical message is that knowledge of the disease is critical to better treatments and more we know about AML the better we can treat it, and the deeper understanding of the genetic makeup of AML will help design better targeted therapies.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Soheil Meshinchi, MD, PhD
Jonathan Rabinowitz
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