We appreciate the thoughtful comments by Kharfan-Dabaja and colleagues on our study using the combination of tacrolimus and sirolimus as GVHD prophylaxis in sibling donor allogeneic hematopoietic cell transplantation (HCT). They point out important issues in our paper related to thrombotic microangiopathy (TMA).
With regard to the first comment on the definition of TMA, we realized that our manuscript overlooked the inclusion of another criterion we used, “elevated serum Cr > 1.5 times the pre-transplant baseline.” This error is being communicated to the ASH Editorial Office, and we appreciate Kharfan-Dabaja and colleagues for pointing it out. Thus our TMA definition in this study was very similar to that of the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN), although not entirely the same, partly due to a trial start date in late 2004 before the BMT-CTN guidelines became available. We agree that that the difference in the definition may explain the observed difference in TMA incidence between our center and Dana-Farber Cancer Institute (DFCI). But in our experience, TMA is not an infrequent event and treating physicians sometimes change their immunosuppressive medications even before the patients meet the full criteria for TMA. We have previously reported our experience in unrelated donor HCT using tacrolimus/sirolimus and mini-methotrexate as GVHD prophylaxis, in which we observed TMA in 28% of the patients1 using the same criteria as our current paper.2
We agree with their second comment that tacrolimus levels during the first 30 days were significantly higher in the Bu/Cy group, and therefore, the observed high incidence of TMA in the Bu/Cy group may be attributable to the tacrolimus levels rather than to the direct endothelial damage of Bu/Cy conditioning. The DFCI group reported an increased incidence of veno-occlusive disease (VOD), which shares with TMA a pathophysiology of endothelial damage, when the combination of tacrolimus/sirolimus was used in Bu/Cy conditioning.3 The authors recommend that sirolimus not be used in conjunction with myeloablative doses of busulfan until there is a greater understanding of the etiology of VOD associated with sirolimus and busulfan use. Echoing Kharfan-Dabaja and colleagues' comments, further work is needed to better define therapeutic levels for tacrolimus and sirolimus which may reduce the risk of TMA/VOD in tacrolimus/sirolimus GVHD prophylaxis.
Authorship
Acknowledgments: We thank our scientific writer/editor, Dr Sandra Thomas, who contributed to this response.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Ryotaro Nakamura, MD, City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA 91010; e-mail: rnakamura@coh.org.
