Post-Transplantation Cyclophosphamide Plus Sirolimus Associated With Lower Risk of Chronic GVHD

In an interview with Oncology Learning Network, Madiha Iqbal, MD, MBBS, Assistant Professor and Consultant, Mayo Clinic, Jacksonville, Florida, spoke on the findings and significance of a study on post-transplantation cyclophosphamide plus sirolimus and how it is associated with a lower risk of chronic GVHD when compared against the traditional prophylaxis of calcineurin inhibitor and methotrexate.

What existing data led you and your co-investigators to conduct this research?

Today I'll be talking about our study, which we recently presented at ASH 2021, titled "A Calcineurin Inhibitor Free Graft Versus Host Disease 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. It has allowed haploidentical transplants, which previously had prohibitive rates of graft failure and GVHD, to become routine.

With the increased use of haploidentical-transplant and post-transplant cyclophosphamide, we have observed a lower rate of GVHD when compared with the standard GVHD prophylaxis of tacrolimus and methotrexate. This has led to exploring post-transplant cyclophosphamide as a GVHD prophylaxis regimen in the setting of matched transplants, including match-related and match-unrelated donor transplant.

BMT-CTN 1703 is a prospective clinical trial that is currently comparing post-transplant cyclophosphamide in combination with tacrolimus and mycophenolate mofetil (MMF) against the standard regimen of tacrolimus and methotrexate for GVHD prophylaxis in matched-related and match-unrelated donor transplant.

In reference to our study, we know that post-transplant cyclophosphamide offers a presumably better rate of GVHD prevention, although we await the results of the prospective trial. The combination of post-transplant cyclophosphamide with sirolimus as a calcineurin inhibitor-free GVHD prophylaxis has shown promising results.

The senior investigator on this study, Dr. Ernesto Ayala, conducted a phase 2 single center prospective clinical trial, where post-transplant cyclophosphamide was combined with sirolimus and MMF in patients who were undergoing a haploidentical transplant. This study met its primary endpoint of a decreased rate of acute GVHD.

We decided to expand the same concept in our study to patients undergoing matched transplants. In our study post-transplant cyclophosphamide is combined with sirolimus without MMF, and compared it with the standard GVHD prophylaxis of tacrolimus and methotrexate.

Could you briefly describe the study and its findings?

Our study was a single center study with data from Mayo Clinic in Florida. We reported on a total of 116 patients that were divided into 2 groups. All patients received a matched donor transplant for various hematological conditions.

Twenty-nine patients received post-transplant cyclophosphamide in combination with sirolimus, and 87 received tacrolimus and methotrexate. The selection of these GVHD prophylaxis regimens was physician dependent. The results of our study indicated that patients who receive post-transplant cyclophosphamide in combination with sirolimus had a lower rate of chronic GVHD as compared to those who received tacrolimus and methotrexate. This was the main finding from our study.

Were any of the outcomes particularly surprising?

We know that post-transplant cyclophosphamide has a lower rate of chronic GVHD, but what was specifically surprising about the findings of our study was that patients who received post-transplant cyclophosphamide combined with sirolimus had a significantly shorter median time of immune suppression withdrawal—at 138 days compared to 232 days for patients who received tacrolimus and methotrexate.

In spite of a significantly shorter time for immune suppression withdrawal, we observed a lower rate of chronic GVHD in patients that received posttransplant cyclophosphamide in combination with sirolimus. The 2-year freedom from chronic GVHD was 75% for post-transplant cyclophosphamide and sirolimus versus 20% for tacrolimus and methotrexate.

The other finding that was also interesting in our study was that patients received sirolimus alone. They did not receive MMF, which is standard in post-transplant cyclophosphamide and tacrolimus or calcineurin inhibitor regimens.

We essentially had 1 less immune suppressive agent that was given to the patients. So, with less immune suppression and shorter time on immune suppression. we were able to detect a notable difference in the rates chronic GVHD between these 2 regimens.

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

As you can see from our practice, we have been using this regimen for patients undergoing matched-donor transplant.

Post-transplant cyclophosphamide in combination with sirolimus is an effective regimen to prevent GVHD based on the results of our study. Additionally, the advantage of a calcineurin inhibitor-free GVHD prophylaxis regimen is  possibly less toxicity. This includes less risk for renal toxicity, and hypomagnesemia; side effects that are typically common with a calcineurin inhibitor.

The results of our study can be easily translated into clinical practice, but we would need more prospective data for it to become more standard.

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

Our main goal is to assess the safety and efficacy of post-transplant cyclophosphamide in combination with sirolimus in patients undergoing matched door transplants in a prospective clinical trial.

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

In conclusion, this regimen is well tolerated and the data indicates that this regimen is effective in preventing GVHD. We would like to have this regimen investigated in a prospective clinical trial  to validate the results of our study.