At ASH [American Society of Hematology annual meeting], there were lots of interesting new concepts. Hannah, what did you think was the most interesting new strategy to come out of ASH in terms of GVHD [graft versus host disease] prevention?

: I don’t know if you can go much farther than the big hit with the BMT CTN 1703 trial. That’s going to obviously be game-changing for everybody here, but there were some interesting new ideas. There were a lot of JAK inhibition combinations that came forward. Are you referring to acute or chronic?

: There were a lot of interesting preclinical data presented. You can’t talk about GVHD without mentioning T regulatory cells. There were data presented at SOHO [Society of Hematologic Oncology meeting], for example, with the Orca-T trials, with engineering the grafts to have a higher concentration of T-reg cells, seeing promising results from that. There were some preclinical data about the importance of specific T-reg cells in combination, as you mentioned, even the microbiome. T-reg cells have a key relationship with the microbiome that might be important. Also there were some data about infusing T regulatory cells in increasing concentrations and being able to treat GVHD that way as well, which I thought was very exciting.

Doris, anything that caught your eye that was particularly interesting in the GVHD prevention space?

: Definitely, the JAK inhibition showing to be safe without affecting engraftment, I thought it was very interesting with the itacitinib data in particular. It could be part of the armamentaria that we could use. We are interested in it for patients with MPN [myeloproliferative neoplasm], that’s something we could incorporate safely into our strategy. JAK inhibition could be used in that setting, and that was interesting for me.

Yi-Bin, what about regimens, or strategies that particularly target individual organs? We all know that the impact of GVHD is different depending on which organ is involved, with the GI [gastrointestinal] tract being probably the most important organ in terms of outcomes. Are there any particular strategies you’re interested in that maybe target individual organs?

: When you speak about acute GVHD, you’re mainly looking at 3 organs, the skin, liver, and the intestines. As all of us know because we take care of a lot of patients, the intestine or the GI tract is the most important. Lower GI acute GVHD causes the most morbidity and mortality for our patients. While we’ve made improvements in the prevention of severe acute GVHD, as evidenced by abstracts presented here already, those patients still hit home. Those are early patients who end up back in the hospital and they sort of demoralize the program. It remains an unmet need, prevention and specific treatment. In terms of organ-specific prevention, we had completed a couple of years ago a phase 3 study that was placebo-controlled randomizing patients to vedolizumab, which is anti–alpha-4 beta-7 monoclonal antibody that targets lymphocyte trafficking to the gut, in conjunction with standard tacrolimus and methotrexate in both myeloablative and reduced-intensity transplants. This is a study that randomized about 340 patients, and we hope to be able to share the results soon to see if there’s a benefit or not. That’s something that’s organ specific, and for the first time, it tries to separate acute GVHD into different organs. If you’re able to make a dent in intestinal GVHD, that’s a victory.

: I have an additional presentation, it’s a multicenter study. [Memorial] Sloan Kettering [Cancer Center] is very vested in the concept. We only presented the clinical trial design, and it’s the use of this ecobiotic capsule. It’s like an FMT [fecal microbiota transplantation] 2.0. It’s basically a beneficial bacteria that is made as a capsule so we know the amount of bacteria, the dosing. These patients are using it in the pretransplant and after-engraftment setting. In our clinical trial design, we’re looking to prove that it’s safe. The efficacy end point includes engraftment of the actual bacteria in the GI tract. One of the secondary end points is prevention of graft versus host disease.

: There are also the preemption trials. The MAGIC study is looking at itacitinib preemption, so it’s not by organ system, but it’s by risk of acute GVHD. It’s measuring high biomarkers or low biomarkers for acute GVHD risk, to be able to see if you can have a steroid-sparing alternative, using itacitinib. That’s not necessarily organ specific but….

For those of us who don’t use the biomarkers in routine clinical practice, there was a nice abstract from the CIBMTR [Center for International Blood and Marrow Transplant Research] that looked at an integrated clinical risk score for the development of acute graft versus host disease, which incorporates what most of us think are common risk factors and known risk factors into the development of acute GVHD. It tends to overweigh the conditioning regimen, so we’ll see how this is going to function in a prospective fashion.

Videos

A look into the future of acute GvHD prevention and discussing the impact of targeting specific organs to help manage GvHD prevention. 

Future of Acute GvHD Prevention 

ASH [American Society of Hematology annual meeting] has come and gone. We all saw the results of the BMT CTN 1703 trial, the PROGRESS 3 trial. We now need to decide what we’re going to do. Yi-Bin, why don’t you briefly review what that trial was and tell us about the major results, and then we’ll go around the table and see how that’s going to change our practice.

: PROGRESS 3, also known as CTN 1703, is a phase 3 randomized trial in reduced-intensity transplantation. The eligible population were donors who were either fully matched, related or unrelated, or had a single antigen mismatch. Although, the vast majority of patients enrolled were recipients of fully matched transplants and used peripheral blood stem cells as the graft source. Again, these were all reduced-intensity conditioning regimens and had hematological malignancies as their diagnosis. The randomization was to figure out if a post-transplant cyclophosphamide [PTCy]-based GVHD [graft versus host disease] prophylaxis regimen was inferior or superior to what had been the standard for years, which was tacrolimus and methotrexate. This was a 1:1 randomization, and the primary end point was a composite event-free survival end point called GRFS, or graft versus host disease relapse-free survival, where the events were death, relapse of the underlying disease, severe grade 3 to 4 acute GVHD, or chronic GVHD requiring the initiation of systemic immunosuppression.

What we saw in the results was that patients treated with post-transplant cyclophosphamide had a significantly higher 1-year GRFS rate than those treated with traditional tacrolimus-methotrexate. The differences were driven mainly by less severe acute GVHD and less chronic GVHD requiring systemic treatment. Overall rates of nonrelapse mortality were similar. Overall rates of disease relapse were similar, and there weren’t any big differences in progression-free or overall survival. Based on those results, many in the community have suggested that post-transplant cyclophosphamide with tacrolimus and mycophenolate should become the standard of care in a reduced-intensity transplant setting when using a fully matched, related or unrelated donor.

Speak on behalf of your colleagues, Hannah. Tell us how the results of this trial are going to change medical practice at your center.

: The clearest decision point would be that for reduced intensity and fully matched donors, PTCy can be employed. Expanding that to myeloablative [cases] is not as clear. There are very few data supporting the myeloablative [setting]. For those, we’ll still lean toward probably tacrolimus and methotrexate versus a clinical trial. A clinical trial, if given the option, would be No. 1. Then, for haploidenticals, which we are increasingly doing, PTCy remains the gold standard. So I do think it will be adopted very quickly.

I agree. Now, why don’t you tell us about the myeloablative setting because the PROGRESS 2 trial, which involved a therapeutic arm that was based on the Memorial Sloan Kettering [Cancer Center] regimen, had very different results. Doris, you want to tell us about the standards in ablative transplant and whether PTCy is going to change care there?

: That’s a good question. In terms of those results, the primary end point of the study was chronic rapid disease-free survival [CRFS]. In that primary end point, the CD34-selected arm was inferior compared with standard of care and PTCy. Based on that, we are having conversations about what triggered an inferior CRFS in these patients, even though the rate of chronic rapid disease is significantly lower. Some of it has to do, looking into our data, with infection risk and immune reconstitution. At Sloan Kettering, we are introducing and using more widely, and we’ll probably extend more PTCy. We’re using it more comfortably in mismatched unrelated donors. In the matched setting, we are looking for strategies on how to customize ATG [antithymocyte globulin]. The CD34-selected [setting] does have a platform that includes ATG. We’re now doing ATG by PK [pharmacokinetics], and we think that could improve the risk of delayed immune reconstitution and infection. It’s still a platform that we haven’t abandoned. We think we can enhance that because…it’s a CNI [calcineurin inhibitor]-free regimen. It won’t be abandoned, I think there will be a TCD [T-cell depletion] 2.0.

You mentioned ATG, or antithymocyte globulin. It’s used very commonly in Canada, it’s used extensively in Europe. It’s not used as much in the United States outside of aplastic anemia. Why do you think it’s not used, and do you think there is a role for it in standard transplants in the United States?

: At Ohio State [University] it was eliminated a few years back and taken out completely. The concern for ATG is the risk of infections and viral infections. The upfront benefit with it…it’s advertised for acute GVHD, but the benefit comes with chronic GVHD. Now, what may be interesting to see over the course of time here is with less severe acute GVHD, are we going to be seeing as much chronic GVHD anyway? The use of ATG may become less over time with that adoption, with that culture shift.

It’s important to mention abatacept in this setting as we talk about GVHD prevention regimens. It is the only drug that’s approved in the prophylaxis setting. It was approved on the basis of the ABA2 trial, which was a combination of an open-label phase 2 study in mismatched unrelated donor transplant, where it had very promising data in comparison to a historical control. The data were less strong in [8/8 matched] transplantations in a truly prospective randomized trial. Do you use it at [Massachusetts General Hospital] for standard of care, either in the mismatched setting or in the matched unrelated setting?

: We don’t use it routinely. As you mentioned, the big difference seemed to be in the mismatched unrelated donor setting. For the last several years, our standard prophylaxis regimen for that donor source was post-transplant cyclophosphamide. We’ve had great success with that, as have others, as what’s been published, and so it’s difficult to stray. The other issue is the abatacept trials didn’t show any decrease in the incidence of significant chronic graft versus host disease. There are ongoing trials with a longer course of abatacept, which we’re participating in, in the mismatched unrelated donor setting and so forth, to try to figure that out. As the community shifts more toward the prevention of chronic GVHD as a priority, it would make testing other regimens more important.

That’s the ABA3 trial you’re referring to that’s ongoing, which randomizes to short versus long course abatacept. There was an interesting abstract presented by Leslie Kean, [MD, PhD,] looking at historical data from the CIBMTR [Center for International Blood and Marrow Transplant Research] in comparison to the prospective abatacept data. The abatacept data looked promising even against PTCy, but I don’t think any of us would take historically controlled data against a prospective cohort and call that definitive quite yet.

Experts review the Phase III BMT CTN 1703 trial and share how the results of this trial might impact their practice and discuss the role of ATG and abatacept in their practice

Clinical Implications of the Phase III BMT CTN 1703 Trial 

I’m going to go back to a point you made about trying to separate graft versus leukemia from graft versus host disease [GVHD]. We’ve traditionally used high-intensity conditioning regimens as a way of helping induce that graft versus tumor effect, or at least eradicating a tumor with high doses of chemotherapy and radiation. Doris, what are the major conditioning regimens you use at your center, particularly when you’re looking at myeloablation, or high intensity?

: We use a TBI [total body irradiation]-based regimen, BU-CY [busulfan and cyclophosphamide]. We could use a combination with BU-MEL-FLU [busulfan, melphalan, fludarabine]. As you know, there’s a national shortage of fludarabine, so we’re becoming more creative. Clofarabine is making an entrance in the armamentaria to use as part of our conditioning regimen options. For lymphoid malignancies like ALL [acute lymphocytic leukemia], it’s TBI-based, we’re leaning more into it, and for myeloid, a busulfan-based regimen is part of what we use.

Do you think there’s a difference in these myeloablative regimens? Does it matter, BU-CY [busulfan, cyclophosphamide], FLU-BU [fludarabine, busulfan], or BU-MEL [busulfan, melphalan]? Are there differences in toxicity? What do you use at your center?

: Yes, definitely. We do follow a pretty traditional landscape of using fludarabine-busulfan regimens and then, titrating the AUC [area under the concentration time curve] of the busulfan for the degree of myeloablation. In the borderline reduced intensity, FLU-MEL 140 mg, and then lower intensity, FLU-MEL 100 mg. The pretty traditional [landscape] for AMLs [acute myelocytic leukemias] and MDSs [myelodysplastic syndromes]. But that difference between using busulfan versus melphalan comes up particularly for older patients, we’ll tend toward the melphalan. For patients who are at high risk of lung toxicity or liver toxicity, we then avoid busulfan. Generally, those are our preferences there.

Once we’ve cleared out the patient of their own marrow cells, we need to give them some stem cells back, and that’s the time when we have to prevent graft versus host disease. I’m going to give you 2 scenarios. I’m going to ask you pre-ASH [American Society of Hematology annual meeting] and post-ASH, what is the preferred or standard GVHD prevention regimen that you use at Massachusetts General Hospital in the pre-ASH setting?

: Do you want to specify donor, or disease?

Let’s talk about a standard scenario, a matched related or a matched unrelated donor transplant where you have the ability to give bone marrow.

: For the last couple of decades, the standard at Massachusetts General where I am, for a fully matched related, or unrelated donor, our standard graft versus host disease prevention platform is the combination of tacrolimus plus short course methotrexate after transplant. We use that for fully matched donors. For donors with any mismatch, be it a mismatched unrelated donor or a haploidentical donor, we would use a regimen that is built around high-dose post-transplant cyclophosphamide, or PTCy as we call it, in combination with tacrolimus and mycophenolate. Prior to ASH, that was our standard and has been for the last several years.

Hannah, is this any different at your center?

New York is a little different, tell us about it.

: In New York, [Memorial] Sloan Kettering [Cancer Center] has invested many years, decades, studying T-cells ex-vivo, CD34 selection, T-cell depletion, and that’s part of the armamentaria for reduction of graft versus host disease. For this particular approach, it’s a CNI [calcineurin inhibitor]-free regimen, so patients are not exposed to CNI.

: What’s the practice at Dana-Farber [Cancer Institute]?

The practice at our center is very similar to what you described, tacrolimus and methotrexate, 4 doses. In the mismatched setting, it’s either post-transplant cyclophosphamide, or abatacept.

: How do you use sirolimus in your regimen now?

We use sirolimus in our reduced-intensity transplants for the most part. We performed a randomized trial a number of years ago that suggested that outcomes might be a bit better. There are a number of centers that use sirolimus regularly, for example, [Fred] Hutch [Cancer Center], City of Hope, and the Moffitt Cancer Center are all regular users of sirolimus. Every now and then I will use sirolimus even in the myeloablative setting in someone who I don’t want to give methotrexate to, who I want to engraft a bit quicker, a day or two, or who has very high risk of getting bad mucositis.

A brief review of the different regimens used by experts for GvHD prevention at their institutions and discuss the importance of GvHD Prevention.

Regimens Used for GvHD Prevention 

 entitled, “Expert Perspectives on the Current State of Graft Versus Host Disease.” I’m Dr Corey Cutler, the medical director of the stem cell transplant program at the Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School. Joining me in this discussion are my colleagues, Dr Yi-Bin Chen from Massachusetts General Hospital, Dr Hannah Choe from Ohio State University, and Dr Doris Ponce from Memorial Sloan Kettering Cancer Center. I’m going to ask each of you to introduce yourselves.

 Thank you, Corey. My name is Yi-Bin Chen. I direct the transplant program at Massachusetts General Hospital in Boston.

 Hi, I’m Hannah Choe. I’m an assistant professor at Ohio State University in Columbus, and I’m the director of the GVHD program there.

: Thank you. My name is Doris Ponce. I’m an associate professor and I am the GVHD program director of adult BMT [bone marrow transplant] at Memorial Sloan Kettering.

Welcome, all of you. Let’s get started on our first topic. Today, we’re going to be talking about a number of discussion topics relevant to graft versus host disease [GVHD]. We’re going to start by talking in general about GVHD and why it occurs. What are the settings we’re seeing it in? Why don’t you give us a little bit of a background, Yi-Bin, on why we get graft versus host disease, and what diseases we’re treating at the time of inducing GVHD?

: These days, the vast majority of our patients have an underlying diagnosis of a hematological malignancy, and that’s why they’re referred to undergo hematopoietic cell transplantation. There is a minority who have nonmalignant diseases, but the vast majority have a hematological malignancy. Even though the chemotherapy or the radiation we give in the week before transplant has some disease-modifying effect, most of us believe that the reason a hematopoietic cell transplant is potent and potentially curative for the majority of these patients is something called the graft versus malignancy effect. This is an immunologically driven effect where the donor cells are able to eradicate any residual malignancy that is left behind. The issue with that, or the tax for that, is that sometimes the donor cells not only attack the patient’s malignancy, but they also attack the patient’s normal body. That gives rise to this complication called, graft versus host disease.

Hannah, are there any specific risk factors that make a patient more or less prone to developing graft versus host disease?

: The biggest one would be the degree of HLA match. When we try to identify donors for stem cell transplantation, we use HLA matching to identify patients who are more similar genetically as a donor versus recipient. When there’s more of a mismatch with that HLA degree, then there’s more of a likelihood of identifying the recipient as foreign, and there’s more of a divide between the graft, or a bigger jump between graft versus the host. That directly puts the patient at risk of developing graft versus host disease. Other risk factors include age. Increased age does preclude higher risk for graft versus host disease, and sex mismatch as well. Essentially, any more degree of a [mismatch] increases the risk for GVHD.

Doris, what about some of the other risk factors that perhaps we can modify as the transplant clinician, things like the donor source, or conditioning agents? Do any of those factors influence the rate of graft versus host disease?

: Yes, certainly. Donor source is important. We are learning about increasing mismatch in related donors as part of our platform and learning how can we use alternative donor transplantation to make transplants safer, so donor selection is important. Also, we’re learning about how old the donor should be and what would be ideal if we have a younger donor versus an older donor, and if that could increase your risk of graft versus host disease as well as if it is related or unrelated. Another thing we could consider is how intensely we want to put our patients into conditioning. Higher conditioning is associated with more tissue injury, and that can translate into more immune reactivation and eventually, graft versus host disease. Those will be additional factors.

Is it a static fixed rate of GVHD? Are there things you can do, Yi-Bin, to try to modulate that risk? How do you prioritize these factors when deciding on GVHD risk for your individual patient?

: This is a difficult question because a lot of us feel like we are in more control than we actually are. There are some patients where you have more of an appetite for graft versus host disease, perhaps, because they have a higher biological risk disease where you feel like you need to encourage this graft versus malignancy more. The traditional teaching has always been, we cannot separate graft versus host disease from graft versus malignancy, though that may be changing. Along the way, as you treat your patient, we all feel like we have some semblance of control in how we manage the immunosuppression, what levels we run certain medications at, and how well the patient is in terms of nourishment and nutritional status. One of the most popular risk factors of interest right now is the microbiome. The microbiome refers to the diversity of bacteria in one’s gut. Many associative studies have suggested that a nondiverse microbiome, or a narrow diversity microbiome, called dysbiosis, is associated with an increased risk of graft versus host disease. Whether there’s a cause-and-effect relationship, we need to figure that out, or if it’s just a marker of a patient at risk. There is plenty of research to see if we can modify the microbiome diversity and perhaps, modify the risk of graft versus host disease.

Expert oncologists define graft vs host disease (GvHD) and discuss which risk factors might increase a patient’s risk of developing GvHD.  

Doris M. Ponce, MD

Articles

Future of Acute GvHD Prevention

Clinical Implications of the Phase III BMT CTN 1703 Trial

Regimens Used for GvHD Prevention

An Overview of Graft vs Host Disease (GvHD)