Madiha Iqbal, MD, MBBS, Mayo Clinic, Jacksonville, Florida, discusses calcineurin inhibitor free graft-versus-host-disease (GVHD) prophylaxis for patients undergoing matched-related and matched-unrelated donor allogeneic hematopoietic cell transplant.

Transcript

Dr Iqbal: Hi, thank you for having me. My name is Madiha Iqbal. I am an assistant professor and consultant here at the Mayo Clinic in Jacksonville, Florida. My clinical and research expertise is in bone marrow transplant and CAR T-cell therapy.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Iqbal: Today, I'll be talking about our study, which we recently presented at ASH (2021), titled "A Calcineurin Inhibitor Free GVHD Prophylaxis in Patients Undergoing Match-Related and Match-Unrelated Donor Transplantation."

Post-transplant cyclophosphamide has been a true innovation in the field of hematopoietic cell transplant in the last one decade. It has allowed haploidentical transplants, which previously had prohibitive rates of graft failure and GVHD to become routine.

Due to the increase in use of haploidentical-transplant and post-transplant cyclophosphamide, also come to know that this platform of post-transplant cyclophosphamide offers a lower rate GVHD overall. This has led to this preventive regimen, essentially to be explored in the setting of matched transplants, including what match-related and match-unrelated donor transplant.

BMT-CTN 1703, a prospective clinical trial, was evaluating post-transplant cyclophosphamide in combination with tacrolimus and MMF (mycophenolate mofetil) against the standard historical regimen of tacrolimus and methotrexate.

In reference to our study, post-transplant cyclophosphamide offers GVHD prevention, which is presumably better, although we await the results of the prospective trial, but the platform can be further improved in terms of both efficacy as well as safety. My senior investigator on this study, Dr. (Ernesto) Ayala actually conducted a phase 2 prospective clinical trial, which was a single center at Moffitt, where post-transplant cyclophosphamide in combination with sirolimus and MMF was explored in patients who were undergoing a haploidentical transplant.

This study met its primary endpoint of reduced (rate of) acute GVHD. That was the main idea. We decided to expand the same concept in our study to patients undergoing matched transplants. So post-transplant cyclophosphamide is combined with sirolimus, not a calcineurin inhibitor, to see how that performs in patients who are undergoing matched transplant.

OLN: Could you briefly describe the study and its findings?

Dr Iqbal: Our study was a single center study with data that was extracted from Mayo Clinic in Florida.

We have a total of around 116 patients, and that were divided into 2 groups. All of these patients received matched transplant for various hematologic conditions, and this included a match-related or match-unrelated donor transplant.

Around 30 (n = 29) patients receive post-transplant cyclophosphamide in combination with sirolimus and the remainder (n = 87) received tacrolimus and methotrexate. The choice of these prophylaxis regimens was really physician dependent. What they saw as a result of our study was that patients who receive post-transplant cyclophosphamide in combination with sirolimus had a lower rate of chronic GVHD as compared to those who received tracrolimus and methotrexate. That was the main finding from our study.

OLN: Were any of the outcomes particularly surprising?

Dr Iqbal: They were surprising and also not.

We do know that post-transplant cyclophosphamide has a lower rate of chronic GVHD, but what was specifically surprising about the findings of our study was this, that our patients had a much shorter median time of immune suppression withdrawal—more like 130 days (138 days) compared to more than 200 days (232 days) for patients who received tacrolimus and methotrexate.

What you're seeing is this, that patients were on immune suppression, post-transplant for a much shorter time period as compared to tacrolimus and methotrexate. In spite of that, they had a lower rate of chronic GVHD. The 2-year freedom from chronic GVHD was 75% for post-transplant cyclophosphamide/sirolimus versus (20% for) tac/methotrexate.

The other thing that was also interesting and rather surprising is that in this we did not in our study, all of our patients only received sirolimus, was the only post-transplant immune suppression. They did not receive mycophenolate mofetil, which is standard in, let's say in post-transplant cyclophosphamide tacrolimus regimens.

We essentially had one less immune suppressive agent that was given to the patients. So less immune suppression, shorter time being on immune suppression. In spite of that, we were able to detect a notable difference of chronic GVHD. Those were, I think the most exciting findings from our study.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Iqbal: As you can see from our practice over here, we have already been using this regimen, especially for our matched-transplantations as a result of our study indicate.

I think the efficacy of the regimen is one thing, but the advantage of the calcineurin inhibitor-free post-transplant or GDHD prophylaxis regimen, is really this, that this possibly leads to less toxicity. You do not have to deal with the renal toxicity, the hypermagnesemia, those kinds of things that you often have to deal with when you're dealing with a calcineurin inhibitor.

I think it's really easy to translate these two into clinical practice and really we would need more prospective data for it to become more standard but it's really, survival has been there for a long time and it's easy to get it retranslated into real world.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what will be your next steps?

Dr Iqbal: Our main goal is really to do the same study essentially in a prospective manner.

Like I said, Dr. Ayala who's my senior investigator on this study has done a phase 2 prospective, but for haploidentical, so same GVHD prophylaxis regimen.

Our goal is really to do post cyclophosphamide in combination with sirolimus in a prospective fashions, from match transplantation, including match-related, and match-unrelated. That's really our next goal.

OLN: Is there anything else pertaining to your research and findings that you would like to add?

Dr Iqbal: In conclusion, I'll just add that this regimen is well tolerated and efficacious, and we would like to have this regimen be explored in a prospective fashion to validate the results of our study.