Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation

Roni Shouval; Nicholas R. Waters; Antonio L.C. Gomes; Corrado Zuanelli Brambilla; Teng Fei; Sean M. Devlin; Chi L. Nguyen; Kate A. Markey; Anqi Dai; John B. Slingerland; Annelie G. Clurman; Emily Fontana; Luigi A. Amoretti; Roberta J. Wright; Tobias M. Hohl; Ying Taur; Anthony D. Sung; Daniela Weber; Daigo Hashimoto; Takanori Teshima; Nelson J. Chao; Ernst Holler; Michael Scordo; Sergio A. Giralt; Miguel Angel Perales; Jonathan U. Peled; Marcel R.M. van den Brink

doi:10.1158/1078-0432.CCR-22-1254

Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation

Roni Shouval, Nicholas R. Waters, Antonio L.C. Gomes, Corrado Zuanelli Brambilla, Teng Fei, Sean M. Devlin, Chi L. Nguyen, Kate A. Markey, Anqi Dai, John B. Slingerland, Annelie G. Clurman, Emily Fontana, Luigi A. Amoretti, Roberta J. Wright, Tobias M. Hohl, Ying Taur, Anthony D. Sung, Daniela Weber, Daigo Hashimoto, Takanori TeshimaNelson J. Chao, Ernst Holler, Michael Scordo, Sergio A. Giralt, Miguel Angel Perales, Jonathan U. Peled, Marcel R.M. van den Brink

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Abstract

levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepacyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. Conclusions: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.

Purpose: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. Experimental Design: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in a-diversity. Results: We identified distinct patterns of microbiota injury that varied by conditioning regimen.

Original language	English
Pages (from-to)	165-173
Number of pages	9
Journal	Clinical Cancer Research
Volume	29
Issue number	1
DOIs	https://doi.org/10.1158/1078-0432.CCR-22-1254
State	Published - 4 Jan 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
©2022 American Association for Cancer Research.

Funding

This research was supported by NCI award numbers, R01-CA228358, R01-CA228308, P30 CA008748 MSK Cancer Center Support Grant/Core Grant and P01-CA023766; National Heart, Lung, and Blood Institute (NHLBI) award number R01-HL123340 and R01-HL147584; National Institute of Aging award number P01-AG052359; and Tri Institutional Stem Cell Initiative. Additional funding was received from The Lymphoma Foundation, The Susan and Peter Solomon Divisional Genomics Program, Cycle for Survival, and the Parker Institute for Cancer Immunotherapy. T.M. Hohl reports support from NIAID NIH Award R21AI156157. J.U. Peled reports funding from NHLBI NIH Award K08HL143189. K.A. Markey would like to acknowledge funding from the DKMS and American Society for Hematology, the Royal Australasian College of Physicians, The Haematology Society of Australia and New Zealand, and the American Australian Association. R. Shouval was supported by the American Society of Transplantation and Cellular Therapy New Investigator Award, the American Society of Hematology Fellow Scholar Award, a grant from the Long Island Sound Chapter, Swim Across America, the Robert Hirschhorn Award, and the Memorial Sloan Kettering Steven Greenberg Lymphoma Research Award.

Funders	Funder number
American Society for Hematology
Long Island Sound Chapter
National Institute on Aging	P01-AG052359
National Heart, Lung, and Blood Institute	R01-HL123340, R01-HL147584
National Cancer Institute	P01-CA023766, R01-CA228308, P30 CA008748, R01-CA228358
National Institute of Allergy and Infectious Diseases	K08HL143189, R21AI156157
American Society of Hematology
American Australian Association
Lymphoma Foundation
Parker Institute for Cancer Immunotherapy
American Society for Transplantation and Cellular Therapy
Swim Across America
Cycle for Survival
Royal Australasian College of Physicians
Haematology Society of Australia and New Zealand
DKMS Foundation

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10.1158/1078-0432.CCR-22-1254

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Shouval, R., Waters, N. R., Gomes, A. L. C., Brambilla, C. Z., Fei, T., Devlin, S. M., Nguyen, C. L., Markey, K. A., Dai, A., Slingerland, J. B., Clurman, A. G., Fontana, E., Amoretti, L. A., Wright, R. J., Hohl, T. M., Taur, Y., Sung, A. D., Weber, D., Hashimoto, D., ... van den Brink, M. R. M. (2023). Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation. Clinical Cancer Research, 29(1), 165-173. https://doi.org/10.1158/1078-0432.CCR-22-1254

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title = "Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation",

abstract = "levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepacyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. Conclusions: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.Purpose: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. Experimental Design: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in a-diversity. Results: We identified distinct patterns of microbiota injury that varied by conditioning regimen.",

author = "Roni Shouval and Waters, {Nicholas R.} and Gomes, {Antonio L.C.} and Brambilla, {Corrado Zuanelli} and Teng Fei and Devlin, {Sean M.} and Nguyen, {Chi L.} and Markey, {Kate A.} and Anqi Dai and Slingerland, {John B.} and Clurman, {Annelie G.} and Emily Fontana and Amoretti, {Luigi A.} and Wright, {Roberta J.} and Hohl, {Tobias M.} and Ying Taur and Sung, {Anthony D.} and Daniela Weber and Daigo Hashimoto and Takanori Teshima and Chao, {Nelson J.} and Ernst Holler and Michael Scordo and Giralt, {Sergio A.} and Perales, {Miguel Angel} and Peled, {Jonathan U.} and {van den Brink}, {Marcel R.M.}",

note = "Publisher Copyright: {\textcopyright}2022 American Association for Cancer Research.",

year = "2023",

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doi = "10.1158/1078-0432.CCR-22-1254",

language = "אנגלית",

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Shouval, R, Waters, NR, Gomes, ALC, Brambilla, CZ, Fei, T, Devlin, SM, Nguyen, CL, Markey, KA, Dai, A, Slingerland, JB, Clurman, AG, Fontana, E, Amoretti, LA, Wright, RJ, Hohl, TM, Taur, Y, Sung, AD, Weber, D, Hashimoto, D, Teshima, T, Chao, NJ, Holler, E, Scordo, M, Giralt, SA, Perales, MA, Peled, JU & van den Brink, MRM 2023, 'Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation', Clinical Cancer Research, vol. 29, no. 1, pp. 165-173. https://doi.org/10.1158/1078-0432.CCR-22-1254

TY - JOUR

T1 - Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation

AU - Shouval, Roni

AU - Waters, Nicholas R.

AU - Gomes, Antonio L.C.

AU - Brambilla, Corrado Zuanelli

AU - Fei, Teng

AU - Devlin, Sean M.

AU - Nguyen, Chi L.

AU - Markey, Kate A.

AU - Dai, Anqi

AU - Slingerland, John B.

AU - Clurman, Annelie G.

AU - Fontana, Emily

AU - Amoretti, Luigi A.

AU - Wright, Roberta J.

AU - Hohl, Tobias M.

AU - Taur, Ying

AU - Sung, Anthony D.

AU - Weber, Daniela

AU - Hashimoto, Daigo

AU - Teshima, Takanori

AU - Chao, Nelson J.

AU - Holler, Ernst

AU - Scordo, Michael

AU - Giralt, Sergio A.

AU - Perales, Miguel Angel

AU - Peled, Jonathan U.

AU - van den Brink, Marcel R.M.

PY - 2023/1/4

Y1 - 2023/1/4

N2 - levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepacyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. Conclusions: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.Purpose: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. Experimental Design: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in a-diversity. Results: We identified distinct patterns of microbiota injury that varied by conditioning regimen.

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Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation

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