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The 2022 Tandem Meetings | Predicting immune reconstitution following alloHSCT

Jaap Jan Boelens, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, NY, talks on improving immune reconstitution following allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been shown that immune reconstitution is a key predictor of outcomes after alloHSCT. Several studies have demonstrated that conditioning regimens are critical in achieving adequate immune reconstitution. In addition, pharmacokinetic-pharmacodynamic (PKPD) analyses have shown that overexposure to anti-thymocyte globulin (ATG) and fludarabine has a significant impact on immune reconstitution, and individualizing ATG dosing results in improved predictable immune reconstitution, which leads to reduced non-relapse mortality (NRM) and better overall survival (OS). This interview took place at the Transplantation & Cellular Therapy (TCT) Meetings of ASTCT™ and CIBMTR® 2022 in Salt Lake City, Utah.

Transcript (edited for clarity)

Thanks for that question. I think that’s a very interesting one and really one to my heart because I think, and that’s not only what I think, but that’s also shown the immune reconstitution is the main driver of the outcomes after transplant. What my lab and others have shown, if you have a, let’s say, timely and robust immune reconstitution, you can prevent viral reactivations, non-relapse mortality...

Thanks for that question. I think that’s a very interesting one and really one to my heart because I think, and that’s not only what I think, but that’s also shown the immune reconstitution is the main driver of the outcomes after transplant. What my lab and others have shown, if you have a, let’s say, timely and robust immune reconstitution, you can prevent viral reactivations, non-relapse mortality. And so the main messages I always have is that CD4, and that’s what we have found and others, is the main predictor of these outcomes, in particularly non-relapse mortality, so that’s the ultimate endpoint. Before that, you have the viral reactivations, but also for instance, getting, let’s say, control over graft-versus-host disease. If you develop graft-versus-host disease, and that’s what we have shown in a big analysis between Memorial Sloan and Princess Maxima last year, if you develop graft-versus-host in the context of adequate immune reconstitution, you are ultimately good. Yes, you may have a bumpy time because you have developed acute graft-versus-host disease, but you are able to get control over your acute graft-versus-host disease.

What we have learned from pharmacokinetic and dynamic analyses is that the clue is into the conditioning regimen. Most of these less patients who have a hampered or a delayed immune reconstitution have an overexposure of agents that are given in the conditioning regimen prior to allotransplant. So examples are ATG-fludarabine, and we have shown that an overexposure in pediatrics and in adults population in a T-replete setting and T-cell depletion setting that overexposure influences the CD4 reconstitution. We also have shown in a prospective clinical trial, if you individualize the ATG because we have found in population PK analysis that weight and the absolute lymphocyte count prior to the first infusion of ATG are the main predictors of the clearance of this ATG. If you can individualize the ATG based on weight, as well as on the absolute lymphocyte count, you can get to a better predictable ATG exposure after transplant. Better predictable ATG exposure after transplant results in a better predictable immune reconstitution. In the prospective clinical trial, which was recently let’s say published in The Lancet, we have shown that it works. This was in a pediatric population. If you individualize the ATG dosing, it will result in better immune reconstitution and subsequently in a lower non-relapse mortality resulting in a better overall survival.

A similar clinical trial we have open at MSK and this enrolls pediatric and adult patients up to 70 years who will undergo a T-cell depletion BMT, and the preliminary results look very encouraging and aligned with what we have seen in this PARACHUTE clinical trial, which was recently let’s say published. Immune reconstitution is really crucial, and with the PKPD analysis we have done with ATG and I’m now focusing on ATG, but we have shown similar results in fludarabine, by using these PK models, individualizing the dosing of these agents prior to transplants will result in a better predictable immune reconstitution after and subsequently in a better survival.

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