Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels

Jakub Tolar; H. Joachim Deeg; Sally Arai; Mitchell Horwitz; Joseph H. Antin; John M. McCarty; Roberta H. Adams; Marian Ewell; Eric S. Leifer; Iris D. Gersten; Shelly L. Carter; Mary M. Horowitz; Ryotaro Nakamura; Michael A. Pulsipher; Nancy L. DiFronzo; Dennis L. Confer; Mary Eapen; Paolo Anderlini

doi:10.1016/j.bbmt.2012.04.014

Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels

Jakub Tolar, H. Joachim Deeg, Sally Arai, Mitchell Horwitz, Joseph H. Antin, John M. McCarty, Roberta H. Adams, Marian Ewell, Eric S. Leifer, Iris D. Gersten, Shelly L. Carter, Mary M. Horowitz, Ryotaro Nakamura, Michael A. Pulsipher, Nancy L. DiFronzo, Dennis L. Confer, Mary Eapen, Paolo Anderlini

Hematology/Oncology

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

37 Scopus citations

Abstract

Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m²), and antithymocyte globulin was associated with excessive organ toxicity.

Original language	English (US)
Pages (from-to)	1007-1011
Number of pages	5
Journal	Biology of Blood and Marrow Transplantation
Volume	18
Issue number	7
DOIs	https://doi.org/10.1016/j.bbmt.2012.04.014
State	Published - Jul 2012

Keywords

Antithymocyte globulin
Bone marrow transplantation
Matched unrelated donor
Stem cell transplantation

ASJC Scopus subject areas

Hematology
Transplantation

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Tolar, J., Deeg, H. J., Arai, S., Horwitz, M., Antin, J. H., McCarty, J. M., Adams, R. H., Ewell, M., Leifer, E. S., Gersten, I. D., Carter, S. L., Horowitz, M. M., Nakamura, R., Pulsipher, M. A., DiFronzo, N. L., Confer, D. L., Eapen, M., & Anderlini, P. (2012). Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels. Biology of Blood and Marrow Transplantation, 18(7), 1007-1011. https://doi.org/10.1016/j.bbmt.2012.04.014

Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels. / Tolar, Jakub; Deeg, H. Joachim; Arai, Sally et al.
In: Biology of Blood and Marrow Transplantation, Vol. 18, No. 7, 07.2012, p. 1007-1011.

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

Tolar, J, Deeg, HJ, Arai, S, Horwitz, M, Antin, JH, McCarty, JM, Adams, RH, Ewell, M, Leifer, ES, Gersten, ID, Carter, SL, Horowitz, MM, Nakamura, R, Pulsipher, MA, DiFronzo, NL, Confer, DL, Eapen, M & Anderlini, P 2012, 'Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels', Biology of Blood and Marrow Transplantation, vol. 18, no. 7, pp. 1007-1011. https://doi.org/10.1016/j.bbmt.2012.04.014

Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty JM et al. Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels. Biology of Blood and Marrow Transplantation. 2012 Jul;18(7):1007-1011. doi: 10.1016/j.bbmt.2012.04.014

Tolar, Jakub ; Deeg, H. Joachim ; Arai, Sally et al. / Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia : Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels. In: Biology of Blood and Marrow Transplantation. 2012 ; Vol. 18, No. 7. pp. 1007-1011.

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title = "Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels",

abstract = "Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m2), and antithymocyte globulin was associated with excessive organ toxicity.",

keywords = "Antithymocyte globulin, Bone marrow transplantation, Matched unrelated donor, Stem cell transplantation",

author = "Jakub Tolar and Deeg, {H. Joachim} and Sally Arai and Mitchell Horwitz and Antin, {Joseph H.} and McCarty, {John M.} and Adams, {Roberta H.} and Marian Ewell and Leifer, {Eric S.} and Gersten, {Iris D.} and Carter, {Shelly L.} and Horowitz, {Mary M.} and Ryotaro Nakamura and Pulsipher, {Michael A.} and DiFronzo, {Nancy L.} and Confer, {Dennis L.} and Mary Eapen and Paolo Anderlini",

note = "Funding Information: We thank Juan Wu and Yanli Wang for help with manuscript preparation, Erica Sanchez for secretarial assistance, and the clinical investigators who entered and managed the patients in this study. The BMT CTN is supported in part by Grant EQ1 U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute . ",

year = "2012",

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doi = "10.1016/j.bbmt.2012.04.014",

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T2 - Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels

AU - Tolar, Jakub

AU - Deeg, H. Joachim

AU - Arai, Sally

AU - Horwitz, Mitchell

AU - Antin, Joseph H.

AU - McCarty, John M.

AU - Adams, Roberta H.

AU - Ewell, Marian

AU - Leifer, Eric S.

AU - Gersten, Iris D.

AU - Carter, Shelly L.

AU - Horowitz, Mary M.

AU - Nakamura, Ryotaro

AU - Pulsipher, Michael A.

AU - DiFronzo, Nancy L.

AU - Confer, Dennis L.

AU - Eapen, Mary

AU - Anderlini, Paolo

N1 - Funding Information: We thank Juan Wu and Yanli Wang for help with manuscript preparation, Erica Sanchez for secretarial assistance, and the clinical investigators who entered and managed the patients in this study. The BMT CTN is supported in part by Grant EQ1 U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute .

PY - 2012/7

Y1 - 2012/7

N2 - Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m2), and antithymocyte globulin was associated with excessive organ toxicity.

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Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels

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