Gail Roboz, MD: TET mutations, again are going to be particularly controversial, which is why you picked it. I would probably- I don't think that there has been any demonstrated benefit for a hypomethylating agent for that particular patient with respect to overall survival so I would wait. I've been pleasantly surprised a number of times in patients who I've been absolutely sure would kind of declare themselves and yet two years later they're not declaring themselves and maybe we're going to have a better therapy by then or something different to offer so I would probably do what you're doing and sit tight and you will have an aha moment of when the patient really is going to start blasting off. I don't think you're protecting him particularly by starting early because then all the transplanters are going to tell you, is that, well, he still has low-risk disease, but now you gave him an HMA and made his counts worse. We'll take the extra step and toss that also to the others just quickly to get what would happen to the patients at each of your institutions? Rami, I'll start first with you.

Rami Komrokji, MD: We actually just published this week, looking at the article, what's the optimal timing of starting hypomethylating agents in higher-risk patients? What we did in that study, so it's retrospective, is we looked at patients that don't have profound cytopenia. Arbitrary defined for that purpose of the study, platelets about 15 or red blood cells transmute independence and see about [INAUDIBLE] We looked at the timing, 90 days plus or less and there was actually no difference in the outcome for those patients when we waited till they got profound cytopenia. I see sometimes patients, even with a blast of 15% that they have adequate hematopoiesis. I don't think that early initiation. I think your case is totally different in the sense of the age of the patient and the projected outcome over long time. If this patient was 75, I don't think we would be having that discussion. We would say let's observe, but somebody who's 47, even with the best risk certification, you are going to say this patient median survival is going to be 8.8 years, which is probably in somebody who's in his forties, not acceptable. The margin of benefits for this patient for transplant is going to be much, much more than somebody older. I'll tend to be on the more side of to pull the trigger early on in a transplant in somebody who's young. I agree with Gail, I don't know what's the benefit of the HMA alone if this patient is not going to transplant so I prefer to convince the transplanters to transplant rather than just do a champion AEs with no defined endpoint for me. I think at the earliest, more dropping the counts and stuff, this is the patients that we call them lower risk, but I would think of transplant for them upfront.

Gail Roboz, MD: Amy, you run up and down the hallways. Sometimes you put on your transplant coat and sometimes you leave your transplant coat and you put on your other coat, but do you agree with me that you could find a transplanter potentially even you? Even Azra's patient was turned away from transplant, I feel like I could find a transplanter for that patient in a minute if I wanted to. What do you think, will you transplant him or will you sit and wait a minute?

Amy DeZern, M.D., M.H.S.: I would wait a minute. I agree with you that you could find people that would, but I think the current transplant thinking, and these are generalizations though falls back on some really very reasonable data that there's a lot of Markov models in particular. Some of them are very elegant added to get know that look at large groups of patients with MDS by RIPSS and don't take into account some of the mutations or even the age. What seems to hold in all of these analyses is that there probably is a survival advantage when delaying transplant in very low and low-risk patients, but postponement beyond when they sort of hit intermediate risk is deleterious. My belief is that a proverbial softening of the marrow from azacytidine is important in these patients. Similar to Azra, I do proactively follow their counts. We see each other, we manage expectations. We have a donor chosen, but I try, I won't say I always hit it, but to hit a very sweet spot to start when things are just on the subtle decline, maybe on the way to intermediate the HMA and then roll into transplant three to four cycles after that even if the counts are not increased blast or anything like that.

Gail Roboz, MD: I can't help saying that every once in a while, one is forced to look at the natural history of the disease in a weird way, and COVID did that to us a lot. I will say that there were quite a number of patients. I won't say exactly the same as yours Azra, but comparable in that I was on the transplant bus and I was getting ready and then I said, oh, this is maybe we're all going to die. Nobody can visit you. You can't see your kids. We're going to wait and transplant. This is last March. I'm thinking we're waiting six weeks. Oops, COVID was longer than that. Now I'm a year later, oh my God, I didn't transplant you and everything is the same. That weirded me out, actually, in a lot of my MDS patients. I got to see the disease in a way because I was interrupted. I was prevented from doing what I was otherwise going to do and everything came out OK. Wait, I have another transplanter here. James definitely runs down that part of the hallway. Are you grabbing Azra's patient, getting him out of New York, and getting him done in Florida?

James Foran, MD: Well, they tend to come down to Florida anyway.

Gail Roboz, MD: If they don't want to wear a mask, they're going to Florida for sure.

James Foran, MD: The hardest thing to teach in hematology, and this is something we bring up as long as it's safe. Some patients can cope, some can't. Obviously, if someone's not coping, they're falling apart and they need to get on with it but you have to be patient. There's really no. If I can't find an advantage of exposing somebody to a risk, I don't put them through that risk. I would really drag my feet and try to teach them how to live with the disease and find life if I can. If the platelets are 50, 30, 20, you're moving forward. I don't know if there's a role phrase society or not. I'm not sure if I would do the exact same thing as Amy and soften their marrow, so to speak. I like the thought of doing that. I just don't know how to do it. Satay? I don't know. I would try to be patient and that's just even what Rami said at the beginning about watching and waiting higher-risk patients. If you don't have to treat right away and they're actually OK and their blood counts are OK, it's not a disservice so I would kind of drag my feet also.

Gail Roboz, MD: I do think one point that you brought up is so important just in thinking of the whole patient here, that if someone is actually- we say watch and wait is the same as watch and worry. If someone is literally going to be eaten alive, not being able to plan a vacation or to think because they're waiting for the other shoe to drop at every doctor visit. That's a horrible thing to put somebody through. I think patients possibly know themselves pretty well and might even say, you know what, I'm totally not like that. I'm not thinking about this disease until I come into your office. I'm fine with kicking the can versus others who will say, you've got to be kidding me. I'm going to walk into this office one day and you're going to say, OK, today's the day. I just think that was a really important point that you brought up to let's not forget the makeup of the patient who is now being told that, well, we're going to watch and wait and jump in.

Transcript edited for clarity.