Richard Maziarz, MD, highlights the fact that graft-vs-host disease (GVHD) is a T-cell disease and then outlines qualitative and quantitative mechanisms that are used to prophylactically target the alloreactive T-cell population. A calcineurin inhibitor combined with methotrexate is the currently accepted standard of care for GVHD prophylaxis. Panelists weigh in on the use of post-transplant cyclophosphamide (PTCy) for prevention of GVHD.
Corey Cutler, MD, PhD, FRCPC: How do we prevent it? Rich: do you want to walk us through some prophylaxis and talk about strategies there?
Richard Maziarz, MD: In the world of prophylaxis, there are a couple of basic tenets of transplant. First, the reason you want prophylaxis is if graft-vs-host is a T-cell disease, and T-cells will expand when they see antigen, over time you will have a greater burden of T-cells to control as we go through the stages of acute graft-vs-host disease [GVHD]where we have clinically significant disease. If we do try to intervene with corticosteroids and we have a steroid-resistant GVHD, we’re seeing a greater number of clonally reactive T-cells that have to be dealt with as opposed to what the goal of prophylaxis is: to treat the lowest number of alloreactive cells at a given time.
We also know that prophylaxis has 2 approaches. 1 is you can take the fact that you can use qualitative, or you can use quantitative effects to target the T-cell population. Going back to the 1980s, some of the first work done to try and create and expand the utilization of allogeneic transplant was on T-cell depletion. Whether its antibody complements or antibody conjugates; it was used to decrease the number of T-cells. We then found the emergence of calcineurin inhibitors. With the birth of cyclosporine, in effect, it created a qualitative defect in the T-cells. The T-cells are still there; they’re not being killed by the cyclosporine and they still can trigger through the T-cell receptor, they just can’t catalyze the events that lead to maturation and interleukin-2 secretion.
Our prophylaxis strategies are going to be based on: can we decrease the number of allocative cells or can we biologically affect them? Over the years, there have been many attempts that have tried to improve on guidelines. Across the world, there is a current a 2-drug approach. One is calcineurin inhibitor with methotrexate that creates a qualitative defect in the T-cells, and then methotrexate which is a quantitative elimination of alloreactive cells. We have seen evolutions, and we’ve seen where people try to substitute the toxic agent. We have seen 2-drug with mycophenolate mofetil or with corticosteroids alone; what we found is they were inferior to methotrexate. We have seen 3-drug prophylaxis regimens which have been shown that they can be effective, but don’t necessarily improve outcomes compared to our standard 2-drug regimen.
One of the big controversies that still faces us in prophylaxis is the role of ATG [anti-thymocyte globulin]. Again, that is a way to quantitatively decrease T-cells; it is the standard of care in Europe. In the United States, there are still studies from the IBMTR as well as a randomized study published by [Robert J.] Soiffer in JCO [Journal of Clinical Oncology], with a goal of decreasing chronic GVHD. However, it was associated with worse outcomes. We still have not solved that issue, but it still remains an approach. I think the baseline approaches are can we modify the GVHD risk by either decreasing the number of cells or changing the ability of the cells to respond.
Before I pass this on, I want to point out that there is a lot of attention recently at post-transplant cyclophosphamide. I think in effect, that’s just substituting a posttransplant drug for another; methotrexate kills cells, Cytoxan [cyclophosphamide] kills cells. What we’re doing is using a drug that will not affect the stem cell; it should be specifically targeting the alloreactive expanding T-cell population, and that’s when you use the posttransplant cyclophosphamide. In the world of antibody depletion, it’s also important to recognize that Ellen Vitetta with John Barrett 20 years ago did a similar approach, where they did ex vivo stimulation of donor peripheral blood stem cells with a recipient product, then treated with an anti-IL-2 receptor antibody coupled to an immunotoxin that would allow the depletion of an alloreactive cell prior to the infusion of cells. Again, there is a bit of graft engineering to take out the population.
Yi-Bin Chen, MD: Rich, could I just ask; you bring up a point of the rise of posttransplant cyclophosphamide or PT-Cy. We here at Mass General [Massachusetts General Hospital] use that routinely as our standard for haploidentical or mismatch unrelated transplants. Does anybody else use it differently? Has it become the standard for perhaps all routine transplants at anybody’s center? Sophie, can I ask you?
Sophie Paczesny, MD, PhD: Yes, in our center it’s the standard for everything, including MRD [minimal residual testing]. This institution is a small center. Unless there is an exception, they do all post-Cy for all the patients for adults. In pediatrics, they continue to do less post-Cy than in others. However, yes; it is becoming standard.
Yi-Bin Chen, MD: What drove that decision?
Sophie Paczesny, MD, PhD: We had an MD that came from a center, I believe from Johns Hopkins, who used to use Cy [cyclophosphamide] post transplant, so now we are all doing Cy post transplant.
Yi-Bin Chen, MD: Yes. Other thoughts on that?
Corey Cutler, MD, PhD, FRCPC: It’s not our approach here at Dana Farber [Cancer Institute]. We use tacrolimus/methotrexate or a three-drug tacrolimus/sirolimus/methotrexate, particularly in reduced-intensity transplant as our standard. We’ve yet to see randomized data that suggests the posttransplant cyclophosphamide regimen is advantageous. There are things to think about with PT-Cy, such as excess rates of graft failure and early graft loss, higher rates of poor immunologic reconstitution, and viral problems. In our hands, we don’t see the advantage yet. Now certainly in our haploidentical program and in our mismatched unrelated donor program, where rates of GVHD are higher, we are using post-transplant cyclophosphamide as our standard. However, in situations where our rates are low to begin with, such as in fully matched-related and fully matched-unrelated donor transplants, we haven’t seen an advantage to moving to that regimen yet. The real great sort of touted advantage of that regimen, the reduction rates of chronic GVHD, I think really must be tempered as the field moves toward using peripheral blood with the post-transplant CY regimen.
Richard Maziarz, MD: I would just like to point out to your question is that the work has been developed as a measure of haploidentical transplantation instead of complex graft engineering that can be done to overcome the barriers of haploidentical transplant. I do think we are starting to see studies emerge that are going to test it as the standard of care. The BMT CTN [Blood and Marrow Transplant Clinical Trials Network] is currently running a reduced-intensity study comparing tacrolimus/methotrexate versus tacrolimus/post-transplant cyclophosphamide with MMF [mycophenolate mofetil]. There has also been a study comparing the posttransplant cyclophosphamide with cord blood transplantation, and in the myeloablative setting against a graft-engineered CD34 project; it’s being tested. I think now we know that in single-antigen mismatch, which in a way is a haploidentical graft, the CIBMTR [Center for International Blood and Marrow Transplant Research] will be sponsoring a multicenter study. We will be seeing the expansion of posttransplant cyclophosphamide, and the answer will come in the next several years.
Sophie Paczesny, MD, PhD: May I add something? MUSC is in South Carolina; it is a poor type of state, and I should say that cost goes into consideration, too. We cannot deny the cost of post CY is really low. Something that should be at least as good or even better is the patient of naïve T-cells, right…the cost is more prohibitive than CY post transplant, for instance. I think that is something that should be considered.
Yi-Bin Chen, MD: I agree with you, Sophie. Traditionally we chose a GVHD prevention regimen purely based on what donor we were using, right? That is how every institution had its standards. As we have become more sophisticated and have more options, where one is not definitively “better than another,” and they come with different pros and different cons, I think we are going to make these types of choices. If you are in a community or in a country whose resources cannot treat chronic graft-vs-host disease as well as other places, then you may choose to use a certain prevention regimen based on what you perceive to be that regimen’s own risks. Similarly, we may start choosing GVHD prevention regimens based on what we perceive to be the patient’s biggest competing risk; be it graft-vs-host disease versus relapse. I think we are moving into an age where it will just not be just about who the donor is, but these other considerations as well.
Transcript edited for clarity.