MPN Workshop of the Carolinas 2025 | Conditioning regimen optimization in stem cell transplantation for MPNs

Typically MPN patients are older when they undergo transplant and generally worldwide what is used is reduced intensity regimens. This consists of fludarabine and busulfan or fludarabine and melphalan. And the biggest challenge is about a third of the patients or even half of the patients relapse and about a third of them die of treatment-related complications. So over long term, we are curing about a third of the patients. And naturally, that’s not optimal. We need to do better. And there are two components of the equation here. 

So one is, the reason we do want to do transplant is to eradicate the disease, reduce relapse rate. And the challenge that we face with conditioning regimen is, yes, it does that job, but then it increases treatment-related or regimen-related toxicity and death from the regimen. So if you give too little conditioning intensity, you get higher relapse rate. If you give too much of conditioning, then you get higher non-relapse mortality. And really the challenge is identifying a regimen that is very high, that has very high intensity, but has lower relapse rate or myeloablative regimen that has lower relapse rate. And that is what we have been doing for last 20 years in a sequential fashion.

So what we have done over the last two decades, we started with the lowest dose of regimen and the best tolerated regimen fludarabine and busulfan. And we saw high relapse rate with fludarabine-busulfan reduced intensity regimen. So we said, why not intensify the regimen? So the first step we took was use pharmacokinetic guidance. So we would give a dose of busulfan, do the pharmacokinetics and give busulfan after pharmacokinetics. And with this, we were able to deliver about 80% of the myeloablative dose. And we saw reduction in relapse rate with this higher dose. But at the same time, the non-relapse mortality did not go up. 

So the next step was how do you further increase the intensity to fully myeloablative in older patients? So what we did was we used a simple concept whereby instead of giving busulfan over a four-day period, we gave it over a three-week period. So we would start on day minus 20, give a dose of busulfan, give another dose on day minus 13, and then give a block of fludarabine and busulfan. With this particular adaptation, we were able to intensify the regimen, were able to give myeloablative regimen to older patients. And naturally, this led to significant reduction in relapse. 

Now, the next step was to further reduce non-relapse mortality, which in most of this situation is because of graft-versus-host disease. We added post-transplant cyclophosphamide. And with that, we were able to reduce non-relapse mortality to less than 10%. So relapse less than 10%, non-relapse mortality less than 10% with this regimen.

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