TY - JOUR
T1 - Mycophenolate Mofetil
T2 - A Friend or a Foe with Post-Transplantation Cyclophosphamide and Tacrolimus Prophylaxis in HLA-Matched Donors?
AU - Mehta, Rohtesh S.
AU - Saliba, Rima M.
AU - Hayase, Eiko
AU - Jenq, Robert R.
AU - Abraham, Susan
AU - Rashid, Asif
AU - Rondon, Gabriela
AU - Al-Atrash, Gheath
AU - Bashir, Qaiser
AU - Hosing, Chitra M.
AU - Kebriaei, Partow
AU - Khouri, Issa
AU - Marin, David
AU - Nieto, Yago
AU - Olson, Amanda
AU - Oran, Betul
AU - Popat, Uday R.
AU - Qazilbash, Muzaffar H.
AU - Ramdial, Jeremy
AU - Srour, Samer
AU - Champlin, Richard E.
AU - Rezvani, Katayoun
AU - Shpall, Elizabeth J.
AU - Alousi, Amin M.
N1 - Funding Information:
Financial disclosure: No relevant financial disclosure related to this study. Conflict of interest statement: R.S.M. has received research funding from CSLBehring, Kadmon, Incyte, and Syndax. The other authors have no conflicts of interest to report. Authorship statement: R.S.M. conceptualized the study design, collected the data, helped with the interpretation of data, and wrote the manuscript. R.M.S. designed and performed all statistical analysis, contributed to data interpretation, provided critical feedback, and wrote the statistical section of the manuscript. E.H. and R.J. conducted the stool microbiome analysis. S.A. and A.R. reviewed the biopsies for patients with gastrointestinal tract GVHD. G.R. provided clinical data. G.A. Q.B. C.M.H. P.K. I.K. D.M. Y.N. A.O. B.O. U.P. M.H.Q. J.R. S.S. R.E.C. K.R. E.J.S. enrolled patients in the study. A.A.A. reviewed the data, provided critical feedback, supervised the study, and enrolled patients. R.S.M. R.M.S. and G.R. had full access to the raw data. All authors approved the final manuscript. The corresponding author had the final responsibility to submit for publication. R.S.M. and R.M.S. contributed equally as co-first authors. Will individual participant data be available (including data dictionaries)? Yes, deidentified data can be shared, if approved by our Institutional Review Board. What data in particular will be shared? Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). What other documents will be available? Study protocol. When will data be available (start and end dates)? Beginning 9 months and ending 36 months following article publication. With whom? Investigators whose proposed use of the data has been approved by an independent review committee (“learned intermediary”) identified for this purpose and if approved by our institutional review board. For what types of analyses? For individual participant data meta-analysis. By what mechanism will data be made available? Proposals may be submitted up to 36 months following article publication. After 36 months the data will not be available. Financial disclosure: See Acknowledgments on page XXX.
Publisher Copyright:
© 2022 The American Society for Transplantation and Cellular Therapy
PY - 2022/8
Y1 - 2022/8
N2 - Adapted from the haploidentical hematopoietic stem cell transplantation (HCT) literature, post-transplantation cyclophosphamide (PTCy) is being used increasingly with HLA-matched donors, generally with a calcineurin inhibitor, such as tacrolimus (Tac), and with or without mycophenolate mofetil (MMF). Owing to its immunosuppressive and potentially antitumor and antimicrobial properties, MMF is an attractive drug; the benefit gained when it is used with PTCy/Tac remains unclear, however. To assess this, we compared PTCy/Tac (n = 242) and PTCy/Tac/MMF (n = 144) regimens in recipients of HLA-matched donor transplantation. In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.6 to 2.8; P < .001), and steroid-refractory/dependent aGVHD (HR, 4.8; 95% CI, 2.4 to 9.6; P < .001), yet a significantly lower risk of relapse (HR, .5; 95% CI, .3 to .9; P = .009) and better progression-free survival (PFS) (HR, .7; 95% CI, .5 to .9; P = .04). There were no differences in the risk of grade III-IV aGVHD, chronic graft-versus-host disease (cGVHD), nonrelapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days and an elevated risk of bacterial infection. In an exploratory stool microbiome analysis (n = 16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD. Our data suggest that the addition of MMF to PTCy/Tac for HLA-matched donor HCT does not provide any advantage for GVHD prevention. Further studies are needed to decipher this mechanism and understand its role with PTCy-based prophylaxis.
AB - Adapted from the haploidentical hematopoietic stem cell transplantation (HCT) literature, post-transplantation cyclophosphamide (PTCy) is being used increasingly with HLA-matched donors, generally with a calcineurin inhibitor, such as tacrolimus (Tac), and with or without mycophenolate mofetil (MMF). Owing to its immunosuppressive and potentially antitumor and antimicrobial properties, MMF is an attractive drug; the benefit gained when it is used with PTCy/Tac remains unclear, however. To assess this, we compared PTCy/Tac (n = 242) and PTCy/Tac/MMF (n = 144) regimens in recipients of HLA-matched donor transplantation. In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.6 to 2.8; P < .001), and steroid-refractory/dependent aGVHD (HR, 4.8; 95% CI, 2.4 to 9.6; P < .001), yet a significantly lower risk of relapse (HR, .5; 95% CI, .3 to .9; P = .009) and better progression-free survival (PFS) (HR, .7; 95% CI, .5 to .9; P = .04). There were no differences in the risk of grade III-IV aGVHD, chronic graft-versus-host disease (cGVHD), nonrelapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days and an elevated risk of bacterial infection. In an exploratory stool microbiome analysis (n = 16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD. Our data suggest that the addition of MMF to PTCy/Tac for HLA-matched donor HCT does not provide any advantage for GVHD prevention. Further studies are needed to decipher this mechanism and understand its role with PTCy-based prophylaxis.
KW - GVHD prophylaxis
KW - Matched sibling donor
KW - Matched unrelated donor
KW - MMF
KW - Post-transplantation cyclophosphamide
KW - PTCy
KW - Tacrolimus
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U2 - 10.1016/j.jtct.2022.05.039
DO - 10.1016/j.jtct.2022.05.039
M3 - Article
C2 - 35662592
AN - SCOPUS:85133283958
SN - 2666-6367
VL - 28
SP - 500.e1-500.e10
JO - Transplantation and Cellular Therapy
JF - Transplantation and Cellular Therapy
IS - 8
ER -