Successful allogenic hematopoietic stem cell transplantation is dependent on continuous research efforts that are focused on understanding the mechanisms that cause transplant failure, namely graft-vs-host disease (GVHD) and disease relapse. In an ideal transplant scenario, GVHD - the term given when transplant donor cells attack non-cancerous cells of the donor recipient – and disease relapse would not occur. To achieve this goal, consistent efforts have been undertaken to identify improved treatment strategies. Conditioning regimens are one such strategy that combine multiple therapies given to the transplant recipient to prevent transplant rejection. Thymoglobulin, a common immunosuppressive conditioning treatment can be linked to mixed-chimerism, a state whereby donor and recipient host cells are present together post transplantation which although linked to graft failure in some instances can become a stable state for some recipients. Recently, with a goal of improving outcomes for transplant recipients, Drs. Albert Yeh and H. Joachim Deeg, members of Fred Hutch’s Clinical Research Division, interrogated long-term follow up data from patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who underwent transplant procedures. Their work, recently published in Bone Marrow Transplantation, examined clinical trials that provided conditioning treatment combinations of chemotherapeutic drugs busulfan and fludarabine, in addition to thymoglobulin. This study revealed that patients treated with all three agents had reduced rates of GVHD compared to a control group of patients treated, notably, without thymoglobulin. Further, in a subset of patients treated with thymoglobulin and who exhibited mixed chimerism, long-term relapse-free survival was observed.
The authors analyzed data from clinical trials that had been undertaken between 2004 and 2006. Patients with AML and MDS had been enrolled and treated with the aforementioned therapies, busulfan, fludarabine and thymoglobulin, and 15 years’ worth of follow up clinical data was available. As a comparison, the authors also assessed clinical data from trials that did not include thymoglobulin as part of the treatment regimens, rather busulfan and cyclophosphamide. Overall, transplant engraftment was successful across the different groups, and interestingly, the presence of stable mixed chimerism was observed in some patients who were treated with a busulfan, fludarabine and thymoglobulin regimen. The authors then examined incidence and effects of GVHD in their patient populations, noting that there were reduced incidences of acute GVHD in the patients who had been treated with thymoglobulin, compared to those who did not receive it. Remarkably, in a small number of patients who had mixed-chimerism for at least a year and received a combination of busulfan, fludarabine and thymoglobulin, chronic GVHD did not occur. Excitingly, the authors next observed reduced incidence of disease relapse and increased overall survival rates in the busulfan, fludarabine and thymoglobulin treated patients. Importantly, the mixed-chimerism noted above was not strongly associated with an increased risk of disease relapse. Although this finding requires confirmation in future controlled studies, the reporting of stable mixed-chimerism without increased incidence of disease relapse is promising for this patient population. Additionally, the authors assessed non-relapse mortality within the busulfan, fludarabine and thymoglobulin patient groups, and increased non-relapse mortality in patients who received a higher dose of fludarabine (250 mg/m2 vs. 120 mg/m2) was noted.
Lastly, as immunosuppressive treatments can interfere with immune function in transplant recipients, the authors assessed levels of virus reactivation, specifically cytomegalovirus and Epstein-Barr viruses, two viral flare-ups that are common in immunocompromised patients. Higher percentages of virus reactivation for both viruses occurred in the busulfan, fludarabine and thymoglobulin treated patients when compared to the control populations, thus, although virus associated diseases did not occur when intervention treatments were applied, the authors’ findings highlight the potential of an increased risk of viral reactivation in patients treated with thymoglobulin as part of their conditioning regimens.
Summing up the results of these notable long-term clinical findings, Dr. Yeh explained how “our study provides evidence that mixed-chimerism can be compatible with long-term (up to 15 years) relapse-free survival using a thymoglobulin based conditioning regimen.” Next steps for the authors are focused on better understanding the mixed-chimerism identified in the present work “why some patients are able to remain disease-free with mixed-chimerism while others relapse remains an unresolved question – how this state of mutual tolerance occurs should be further explored,” outlined Dr. Yeh.
This work was supported by funding from the National Institutes of Health, the American Society of Hematology Research, and The Miklos Kohary and Natalia Zimonyi Kohary Endowed Chair.
UW/Fred Hutch Cancer Consortium members Paul J. Martin, Kris Doney, Mary E. D. Flowers, Mohamed L. Sorror, Fredrick R. Appelbaum, Ted Gooley and H. Joachim Deeg contributed to this work.
Yeh AC, O'Donnell PV, Schoch G, Martin PJ, McFarland C, McCune JS, Cooper JP, Doney K, Flowers MED, Sorror ML, Appelbaum FR, Storer BE, Gooley T, Deeg HJ. Long-term survival with mixed chimerism in patients with AML and MDS transplanted after conditioning with targeted busulfan, fludarabine, and thymoglobulin. Bone Marrow Transplant. 2021 Nov 5. doi: 10.1038/s41409-021-01518-0. Epub ahead of print. PMID: 34741096.