Effect of c-mpl ligands after total body irradiation, (TBI) with and without allogeneic hematopoietic stem cell transplantation: Low-dose TBI does not prevent sensitization

Richard A. Nash; Alessandra Takatu; Ziding Feng; Sherrill Slichter; Kraig Abrams; German Espino; M. John Gass; George E. Georges; Peter A. McSweeney; Howard M. Shulman; Rainer Storb

doi:10.1053/bbmt.2002.v8.pm12171482

Effect of c-mpl ligands after total body irradiation, (TBI) with and without allogeneic hematopoietic stem cell transplantation: Low-dose TBI does not prevent sensitization

Richard A. Nash^*, Alessandra Takatu, Ziding Feng, Sherrill Slichter, Kraig Abrams, German Espino, M. John Gass, George E. Georges, Peter A. McSweeney, Howard M. Shulman, Rainer Storb

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

4 Scopus citations

Abstract

This study investigates the potential role of the recombinant c-mpl ligands (recombinant human thrombopoietin [rhTPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rhMGDF]) on the recovery of platelet counts after TBI with and without allogeneic hematopoietic stem cell transplantation (HSCT) in an established canine model. Initially, 3 cohorts, each with 2 nonirradiated dogs, received increasing doses of rhTPO (5 μg/kg per day; 10 μg/kg per day; 20 μg/kg per day) for 7 days to determine the optimal dose. The dose of 10 μg/kg per day of rhATPO was selected for subsequent studies. Ten dogs then received either rhTPO or placebo for 28 days after 200 cGy TBI without HSCT. The rhTPO group had fewer days with platelet counts <20,000/μL (9.8 days versus 17.8 days, P < .05) and significantly increased granulocyte counts (n = 5) compared to the controls (n = 5). RhTPO-specific antibodies developed in 2 dogs, which caused a significant but transient decrease of the platelet counts. Retreatment of these sensitized dogs with rhTPO resulted in profound transient decreases in platelet counts. In the next study, 20 dogs received either PEG-rhMGDF or placebo for 21 days after 920 cGy TBI and allogeneic HSCT. The median time to platelet recovery (>20,000/μL) for the PEG-rhMGDF group (n = 10) was 14.0 days compared to 15.5 days for the control group (n = 10; log rank, P = .35). There were no significant differences in the total time to platelet counts <20,000/μL or in the time to recover neutrophil counts >500/μL. The effects of rhTPO on recovery of platelet and granulocyte counts after sublethal TBI were modest, and no effects of PEG-rhMGDF were observed on hematopoietic recovery after high-dose TBI and allogeneic HSCT. The significant effect that rhTPO-specific antibodies had on the platelet counts may limit the clinical role of recombinant c-mpl ligands unless sensitization can be prevented.

Original language	English (US)
Pages (from-to)	360-367
Number of pages	8
Journal	Biology of Blood and Marrow Transplantation
Volume	8
Issue number	7
DOIs	https://doi.org/10.1053/bbmt.2002.v8.pm12171482
State	Published - 2002

Funding

This work was supported in part by grant DK42716 from the National Institute of Diabetes, Digestive and Kidney Diseases, grant CA15704 from the National Cancer Institute, and grant HL03701 from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; Amgen, Thousand Oaks, CA; and ZymoGenetics, Seattle, WA. Support was also received from the Josef Steiner Kreb-sstiftung, Bern, Switzerland. The ELISA to monitor for the presence of rhTPO-specific antibodies was performed by Amgen. The RIA and the neutralizing antibody bioassay for PEG-rhMGDF was performed by Zymogenetics.

Keywords

Antibodies
Dogs
PEG-rhMGDF
Platelet recovery
Sensitization
Thrombopoietin
Total body irradiation
c-mpl ligand
rhTPO

ASJC Scopus subject areas

Hematology
Transplantation

Access to Document

10.1053/bbmt.2002.v8.pm12171482

Cite this

Nash, R. A., Takatu, A., Feng, Z., Slichter, S., Abrams, K., Espino, G., Gass, M. J., Georges, G. E., McSweeney, P. A., Shulman, H. M., & Storb, R. (2002). Effect of c-mpl ligands after total body irradiation, (TBI) with and without allogeneic hematopoietic stem cell transplantation: Low-dose TBI does not prevent sensitization. Biology of Blood and Marrow Transplantation, 8(7), 360-367. https://doi.org/10.1053/bbmt.2002.v8.pm12171482

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title = "Effect of c-mpl ligands after total body irradiation, (TBI) with and without allogeneic hematopoietic stem cell transplantation: Low-dose TBI does not prevent sensitization",

abstract = "This study investigates the potential role of the recombinant c-mpl ligands (recombinant human thrombopoietin [rhTPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rhMGDF]) on the recovery of platelet counts after TBI with and without allogeneic hematopoietic stem cell transplantation (HSCT) in an established canine model. Initially, 3 cohorts, each with 2 nonirradiated dogs, received increasing doses of rhTPO (5 μg/kg per day; 10 μg/kg per day; 20 μg/kg per day) for 7 days to determine the optimal dose. The dose of 10 μg/kg per day of rhATPO was selected for subsequent studies. Ten dogs then received either rhTPO or placebo for 28 days after 200 cGy TBI without HSCT. The rhTPO group had fewer days with platelet counts <20,000/μL (9.8 days versus 17.8 days, P < .05) and significantly increased granulocyte counts (n = 5) compared to the controls (n = 5). RhTPO-specific antibodies developed in 2 dogs, which caused a significant but transient decrease of the platelet counts. Retreatment of these sensitized dogs with rhTPO resulted in profound transient decreases in platelet counts. In the next study, 20 dogs received either PEG-rhMGDF or placebo for 21 days after 920 cGy TBI and allogeneic HSCT. The median time to platelet recovery (>20,000/μL) for the PEG-rhMGDF group (n = 10) was 14.0 days compared to 15.5 days for the control group (n = 10; log rank, P = .35). There were no significant differences in the total time to platelet counts <20,000/μL or in the time to recover neutrophil counts >500/μL. The effects of rhTPO on recovery of platelet and granulocyte counts after sublethal TBI were modest, and no effects of PEG-rhMGDF were observed on hematopoietic recovery after high-dose TBI and allogeneic HSCT. The significant effect that rhTPO-specific antibodies had on the platelet counts may limit the clinical role of recombinant c-mpl ligands unless sensitization can be prevented.",

keywords = "Antibodies, Dogs, PEG-rhMGDF, Platelet recovery, Sensitization, Thrombopoietin, Total body irradiation, c-mpl ligand, rhTPO",

author = "Nash, {Richard A.} and Alessandra Takatu and Ziding Feng and Sherrill Slichter and Kraig Abrams and German Espino and Gass, {M. John} and Georges, {George E.} and McSweeney, {Peter A.} and Shulman, {Howard M.} and Rainer Storb",

note = "Funding Information: This work was supported in part by grant DK42716 from the National Institute of Diabetes, Digestive and Kidney Diseases, grant CA15704 from the National Cancer Institute, and grant HL03701 from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; Amgen, Thousand Oaks, CA; and ZymoGenetics, Seattle, WA. Support was also received from the Josef Steiner Kreb-sstiftung, Bern, Switzerland. The ELISA to monitor for the presence of rhTPO-specific antibodies was performed by Amgen. The RIA and the neutralizing antibody bioassay for PEG-rhMGDF was performed by Zymogenetics.",

year = "2002",

doi = "10.1053/bbmt.2002.v8.pm12171482",

language = "English (US)",

volume = "8",

pages = "360--367",

journal = "Biology of Blood and Marrow Transplantation",

issn = "1083-8791",

publisher = "Elsevier Inc.",

number = "7",

}

Nash, RA, Takatu, A, Feng, Z, Slichter, S, Abrams, K, Espino, G, Gass, MJ, Georges, GE, McSweeney, PA, Shulman, HM & Storb, R 2002, 'Effect of c-mpl ligands after total body irradiation, (TBI) with and without allogeneic hematopoietic stem cell transplantation: Low-dose TBI does not prevent sensitization', Biology of Blood and Marrow Transplantation, vol. 8, no. 7, pp. 360-367. https://doi.org/10.1053/bbmt.2002.v8.pm12171482

Effect of c-mpl ligands after total body irradiation, (TBI) with and without allogeneic hematopoietic stem cell transplantation: Low-dose TBI does not prevent sensitization. / Nash, Richard A.; Takatu, Alessandra; Feng, Ziding et al.
In: Biology of Blood and Marrow Transplantation, Vol. 8, No. 7, 2002, p. 360-367.

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

TY - JOUR

T1 - Effect of c-mpl ligands after total body irradiation, (TBI) with and without allogeneic hematopoietic stem cell transplantation

T2 - Low-dose TBI does not prevent sensitization

AU - Nash, Richard A.

AU - Takatu, Alessandra

AU - Feng, Ziding

AU - Slichter, Sherrill

AU - Abrams, Kraig

AU - Espino, German

AU - Gass, M. John

AU - Georges, George E.

AU - McSweeney, Peter A.

AU - Shulman, Howard M.

AU - Storb, Rainer

N1 - Funding Information: This work was supported in part by grant DK42716 from the National Institute of Diabetes, Digestive and Kidney Diseases, grant CA15704 from the National Cancer Institute, and grant HL03701 from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; Amgen, Thousand Oaks, CA; and ZymoGenetics, Seattle, WA. Support was also received from the Josef Steiner Kreb-sstiftung, Bern, Switzerland. The ELISA to monitor for the presence of rhTPO-specific antibodies was performed by Amgen. The RIA and the neutralizing antibody bioassay for PEG-rhMGDF was performed by Zymogenetics.

PY - 2002

Y1 - 2002

N2 - This study investigates the potential role of the recombinant c-mpl ligands (recombinant human thrombopoietin [rhTPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rhMGDF]) on the recovery of platelet counts after TBI with and without allogeneic hematopoietic stem cell transplantation (HSCT) in an established canine model. Initially, 3 cohorts, each with 2 nonirradiated dogs, received increasing doses of rhTPO (5 μg/kg per day; 10 μg/kg per day; 20 μg/kg per day) for 7 days to determine the optimal dose. The dose of 10 μg/kg per day of rhATPO was selected for subsequent studies. Ten dogs then received either rhTPO or placebo for 28 days after 200 cGy TBI without HSCT. The rhTPO group had fewer days with platelet counts <20,000/μL (9.8 days versus 17.8 days, P < .05) and significantly increased granulocyte counts (n = 5) compared to the controls (n = 5). RhTPO-specific antibodies developed in 2 dogs, which caused a significant but transient decrease of the platelet counts. Retreatment of these sensitized dogs with rhTPO resulted in profound transient decreases in platelet counts. In the next study, 20 dogs received either PEG-rhMGDF or placebo for 21 days after 920 cGy TBI and allogeneic HSCT. The median time to platelet recovery (>20,000/μL) for the PEG-rhMGDF group (n = 10) was 14.0 days compared to 15.5 days for the control group (n = 10; log rank, P = .35). There were no significant differences in the total time to platelet counts <20,000/μL or in the time to recover neutrophil counts >500/μL. The effects of rhTPO on recovery of platelet and granulocyte counts after sublethal TBI were modest, and no effects of PEG-rhMGDF were observed on hematopoietic recovery after high-dose TBI and allogeneic HSCT. The significant effect that rhTPO-specific antibodies had on the platelet counts may limit the clinical role of recombinant c-mpl ligands unless sensitization can be prevented.

AB - This study investigates the potential role of the recombinant c-mpl ligands (recombinant human thrombopoietin [rhTPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rhMGDF]) on the recovery of platelet counts after TBI with and without allogeneic hematopoietic stem cell transplantation (HSCT) in an established canine model. Initially, 3 cohorts, each with 2 nonirradiated dogs, received increasing doses of rhTPO (5 μg/kg per day; 10 μg/kg per day; 20 μg/kg per day) for 7 days to determine the optimal dose. The dose of 10 μg/kg per day of rhATPO was selected for subsequent studies. Ten dogs then received either rhTPO or placebo for 28 days after 200 cGy TBI without HSCT. The rhTPO group had fewer days with platelet counts <20,000/μL (9.8 days versus 17.8 days, P < .05) and significantly increased granulocyte counts (n = 5) compared to the controls (n = 5). RhTPO-specific antibodies developed in 2 dogs, which caused a significant but transient decrease of the platelet counts. Retreatment of these sensitized dogs with rhTPO resulted in profound transient decreases in platelet counts. In the next study, 20 dogs received either PEG-rhMGDF or placebo for 21 days after 920 cGy TBI and allogeneic HSCT. The median time to platelet recovery (>20,000/μL) for the PEG-rhMGDF group (n = 10) was 14.0 days compared to 15.5 days for the control group (n = 10; log rank, P = .35). There were no significant differences in the total time to platelet counts <20,000/μL or in the time to recover neutrophil counts >500/μL. The effects of rhTPO on recovery of platelet and granulocyte counts after sublethal TBI were modest, and no effects of PEG-rhMGDF were observed on hematopoietic recovery after high-dose TBI and allogeneic HSCT. The significant effect that rhTPO-specific antibodies had on the platelet counts may limit the clinical role of recombinant c-mpl ligands unless sensitization can be prevented.

KW - Antibodies

KW - Dogs

KW - PEG-rhMGDF

KW - Platelet recovery

KW - Sensitization

KW - Thrombopoietin

KW - Total body irradiation

KW - c-mpl ligand

KW - rhTPO

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Effect of c-mpl ligands after total body irradiation, (TBI) with and without allogeneic hematopoietic stem cell transplantation: Low-dose TBI does not prevent sensitization

Abstract

Funding

Keywords

ASJC Scopus subject areas

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