Weight-based mycophenolate mofetil dosing predicts acute GVHD and relapse after allogeneic hematopoietic cell transplantation

Nelli Bejanyan; John Rogosheske; Qing Cao; Aleksandr Lazaryan; Shernan Holtan; Celalettin Ustun; Pamala Jacobson; Margaret MacMillan; Daniel J. Weisdorf; John Wagner; Mukta Arora; Claudio G. Brunstein

doi:10.1111/ejh.13537

Weight-based mycophenolate mofetil dosing predicts acute GVHD and relapse after allogeneic hematopoietic cell transplantation

Nelli Bejanyan, John Rogosheske, Qing Cao, Aleksandr Lazaryan, Shernan Holtan, Celalettin Ustun, Pamala Jacobson, Margaret MacMillan, Daniel J. Weisdorf, John Wagner, Mukta Arora, Claudio G. Brunstein

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVES: Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT.

METHODS: MMF was combined with cyclosporine (n = 599) or sirolimus (n = 81). We divided MMF dose/kg/day in quartiles.

RESULTS: The median time to grade II-IV acute GVHD was 32 days. The incidence of grade II-IV acute GVHD at day 30 was 30% in 1st (<29), 20% in 2nd (29-34), 16% in 3rd (35-41), and 19% in 4th (≥42) quartile (P < .01). Corresponding relapse incidence at 1 year was 16%, 25%, 27%, and 31%, respectively (P = .01). In multivariate analysis, as compared to 1st quartile, higher dose of weight-based MMF reduced grade II-IV acute GVHD (HR = 0.64 for 2nd, HR = 0.48 for 3rd, and HR = 0.55 for 4th quartile), but increased the risk of relapse (HR = 1.63 for 2nd, HR = 1.75 for 3rd, and HR = 2.31 for 4th quartile).

CONCLUSIONS: Weight-based MMF dose had no significant impact on engraftment, chronic GVHD, or survival. These data suggest that higher weight-based MMF dose reduces the risk of acute GVHD at the expense of increased relapse and supports conducting prospective studies to optimize MMF dosing after HCT.

Original language	English (US)
Pages (from-to)	205-212
Number of pages	8
Journal	European Journal of Haematology
Volume	106
Issue number	2
DOIs	https://doi.org/10.1111/ejh.13537
State	Published - Feb 2021

Bibliographical note

Funding Information:
This work was funded in part by National Institutes of Health, National Cancer Institute grant P01 CA65493 (CGB and JEW), and P30 CA77598 utilizing the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota (QC)

Publisher Copyright:
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords

GVHD
MMF
bone marrow transplantation
relapse
umbilical cord blood
Recurrence
Hematopoietic Stem Cell Transplantation/adverse effects
Body Weight
Prognosis
Humans
Middle Aged
Male
Transplantation, Homologous
Young Adult
Adult
Female
Mycophenolic Acid/administration & dosage
Severity of Illness Index
Acute Disease
Graft vs Host Disease/diagnosis
Immunosuppressive Agents/administration & dosage
Graft Survival
Adolescent
Aged
Transplantation Conditioning

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10.1111/ejh.13537

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Bejanyan, N., Rogosheske, J., Cao, Q., Lazaryan, A., Holtan, S., Ustun, C., Jacobson, P., MacMillan, M., Weisdorf, D. J., Wagner, J., Arora, M., & Brunstein, C. G. (2021). Weight-based mycophenolate mofetil dosing predicts acute GVHD and relapse after allogeneic hematopoietic cell transplantation. European Journal of Haematology, 106(2), 205-212. https://doi.org/10.1111/ejh.13537

Bejanyan, N, Rogosheske, J, Cao, Q, Lazaryan, A, Holtan, S, Ustun, C, Jacobson, P , MacMillan, M , Weisdorf, DJ , Wagner, J, Arora, M & Brunstein, CG 2021, 'Weight-based mycophenolate mofetil dosing predicts acute GVHD and relapse after allogeneic hematopoietic cell transplantation', European Journal of Haematology, vol. 106, no. 2, pp. 205-212. https://doi.org/10.1111/ejh.13537

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title = "Weight-based mycophenolate mofetil dosing predicts acute GVHD and relapse after allogeneic hematopoietic cell transplantation",

abstract = "OBJECTIVES: Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT.METHODS: MMF was combined with cyclosporine (n = 599) or sirolimus (n = 81). We divided MMF dose/kg/day in quartiles.RESULTS: The median time to grade II-IV acute GVHD was 32 days. The incidence of grade II-IV acute GVHD at day 30 was 30% in 1st (<29), 20% in 2nd (29-34), 16% in 3rd (35-41), and 19% in 4th (≥42) quartile (P < .01). Corresponding relapse incidence at 1 year was 16%, 25%, 27%, and 31%, respectively (P = .01). In multivariate analysis, as compared to 1st quartile, higher dose of weight-based MMF reduced grade II-IV acute GVHD (HR = 0.64 for 2nd, HR = 0.48 for 3rd, and HR = 0.55 for 4th quartile), but increased the risk of relapse (HR = 1.63 for 2nd, HR = 1.75 for 3rd, and HR = 2.31 for 4th quartile).CONCLUSIONS: Weight-based MMF dose had no significant impact on engraftment, chronic GVHD, or survival. These data suggest that higher weight-based MMF dose reduces the risk of acute GVHD at the expense of increased relapse and supports conducting prospective studies to optimize MMF dosing after HCT.",

keywords = "GVHD, MMF, bone marrow transplantation, relapse, umbilical cord blood, Recurrence, Hematopoietic Stem Cell Transplantation/adverse effects, Body Weight, Prognosis, Humans, Middle Aged, Male, Transplantation, Homologous, Young Adult, Adult, Female, Mycophenolic Acid/administration & dosage, Severity of Illness Index, Acute Disease, Graft vs Host Disease/diagnosis, Immunosuppressive Agents/administration & dosage, Graft Survival, Adolescent, Aged, Transplantation Conditioning",

author = "Nelli Bejanyan and John Rogosheske and Qing Cao and Aleksandr Lazaryan and Shernan Holtan and Celalettin Ustun and Pamala Jacobson and Margaret MacMillan and Weisdorf, {Daniel J.} and John Wagner and Mukta Arora and Brunstein, {Claudio G.}",

note = "Funding Information: This work was funded in part by National Institutes of Health, National Cancer Institute grant P01 CA65493 (CGB and JEW), and P30 CA77598 utilizing the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota (QC) Publisher Copyright: {\textcopyright} 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd",

year = "2021",

month = feb,

doi = "10.1111/ejh.13537",

language = "English (US)",

volume = "106",

pages = "205--212",

journal = "European Journal of Haematology",

issn = "0902-4441",

publisher = "Wiley-Blackwell",

number = "2",

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TY - JOUR

T1 - Weight-based mycophenolate mofetil dosing predicts acute GVHD and relapse after allogeneic hematopoietic cell transplantation

AU - Bejanyan, Nelli

AU - Rogosheske, John

AU - Cao, Qing

AU - Lazaryan, Aleksandr

AU - Holtan, Shernan

AU - Ustun, Celalettin

AU - Jacobson, Pamala

AU - MacMillan, Margaret

AU - Weisdorf, Daniel J.

AU - Wagner, John

AU - Arora, Mukta

AU - Brunstein, Claudio G.

N1 - Funding Information: This work was funded in part by National Institutes of Health, National Cancer Institute grant P01 CA65493 (CGB and JEW), and P30 CA77598 utilizing the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota (QC) Publisher Copyright: © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

PY - 2021/2

Y1 - 2021/2

N2 - OBJECTIVES: Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT.METHODS: MMF was combined with cyclosporine (n = 599) or sirolimus (n = 81). We divided MMF dose/kg/day in quartiles.RESULTS: The median time to grade II-IV acute GVHD was 32 days. The incidence of grade II-IV acute GVHD at day 30 was 30% in 1st (<29), 20% in 2nd (29-34), 16% in 3rd (35-41), and 19% in 4th (≥42) quartile (P < .01). Corresponding relapse incidence at 1 year was 16%, 25%, 27%, and 31%, respectively (P = .01). In multivariate analysis, as compared to 1st quartile, higher dose of weight-based MMF reduced grade II-IV acute GVHD (HR = 0.64 for 2nd, HR = 0.48 for 3rd, and HR = 0.55 for 4th quartile), but increased the risk of relapse (HR = 1.63 for 2nd, HR = 1.75 for 3rd, and HR = 2.31 for 4th quartile).CONCLUSIONS: Weight-based MMF dose had no significant impact on engraftment, chronic GVHD, or survival. These data suggest that higher weight-based MMF dose reduces the risk of acute GVHD at the expense of increased relapse and supports conducting prospective studies to optimize MMF dosing after HCT.

AB - OBJECTIVES: Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT.METHODS: MMF was combined with cyclosporine (n = 599) or sirolimus (n = 81). We divided MMF dose/kg/day in quartiles.RESULTS: The median time to grade II-IV acute GVHD was 32 days. The incidence of grade II-IV acute GVHD at day 30 was 30% in 1st (<29), 20% in 2nd (29-34), 16% in 3rd (35-41), and 19% in 4th (≥42) quartile (P < .01). Corresponding relapse incidence at 1 year was 16%, 25%, 27%, and 31%, respectively (P = .01). In multivariate analysis, as compared to 1st quartile, higher dose of weight-based MMF reduced grade II-IV acute GVHD (HR = 0.64 for 2nd, HR = 0.48 for 3rd, and HR = 0.55 for 4th quartile), but increased the risk of relapse (HR = 1.63 for 2nd, HR = 1.75 for 3rd, and HR = 2.31 for 4th quartile).CONCLUSIONS: Weight-based MMF dose had no significant impact on engraftment, chronic GVHD, or survival. These data suggest that higher weight-based MMF dose reduces the risk of acute GVHD at the expense of increased relapse and supports conducting prospective studies to optimize MMF dosing after HCT.

KW - GVHD

KW - MMF

KW - bone marrow transplantation

KW - relapse

KW - umbilical cord blood

KW - Recurrence

KW - Hematopoietic Stem Cell Transplantation/adverse effects

KW - Body Weight

KW - Prognosis

KW - Humans

KW - Middle Aged

KW - Male

KW - Transplantation, Homologous

KW - Young Adult

KW - Adult

KW - Female

KW - Mycophenolic Acid/administration & dosage

KW - Severity of Illness Index

KW - Acute Disease

KW - Graft vs Host Disease/diagnosis

KW - Immunosuppressive Agents/administration & dosage

KW - Graft Survival

KW - Adolescent

KW - Aged

KW - Transplantation Conditioning

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U2 - 10.1111/ejh.13537

DO - 10.1111/ejh.13537

M3 - Article

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JO - European Journal of Haematology

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Weight-based mycophenolate mofetil dosing predicts acute GVHD and relapse after allogeneic hematopoietic cell transplantation

Abstract

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