Guidelines for antineoplastic agent dosing in obese patients undergoing HSCT
What are the issues to be addressed?
Are the outcomes affected in obese patients
- Definition of levels of obesity
o -% Ideal body weight
o - BMI
- Outcomes in allos
o –Safety (TRM)
o –Efficacy (disease control)
- Outcomes in autos
o –Safety (TRM)
o –Efficacy (disease control)
How should antineoplastics and immunosuppressant’s be dosed in obese patients
- Agents assesssed
o Cytotoxics – alemtuzumab, cyclophosphamide, fludarabine, melphalan,
clofarabine, etoposide, cytarabine, pentostatin, carmustine, busulfan, thiotepa
o Immune modulators – atgam, thymoglobulin,
- Actual vs. adjusted body weight
o -formula
o -% adjustment
- Special populations – Elderly, pediatric,
Allogeneic- Reduced intensity vs ablative regimens
- Ablative
- Reduced Intensity
- Nonablative
Considerations
- Different dose limiting toxicities
Autologous stem cell transplant
o Cytotoxics – Cylophosphamide, melphalan, etoposide, cytarabine, carmustine,
busulfan, thiotepa
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Outcomes References
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2
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Wardley AM, Jaysoin GC, Swindell R, et al. Prospective evaluation of oral mucositis in
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Overview References
Articles:
Hanley MJ, Abernathy DR, Greenblatt DJ. Effect of Obesity on the Pharmacokinetics of
Drugs in Humans. Clin Pharmacother 2010;49(2):71-87
Langbrake C, Bernhardt F, Baehr M, et al. Drug dosing and monitoring in obese patients
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Alemtuzumab References
Articles:
Busulfan References
Articles:
Andersson BS, Madden T, Tran HT, et al. Acute safety and pharmacokinetics of
intravenous busulfan when used with oral busulfan and cyclosphosphamide as a
pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant
2000;6:548-54
Andersson BS, Kashyap A, Gian V, et al Conditioning Therapy with Intravenous
Busulfan and Cyclophosphamide (IV BuCy2) for Hematologic Malignancies Prior to
Allogeneic Stem Cell Transplantation: A Phase II Study. BBMT 2002;8:145-54
Beelen DW, Quabeck K, Graeven U, et al. Acute Toxicity and First Clinical results of
intensive postinduction therapy using a modified busulfan and Cyclophosphamide
regimen with autologous bone marrow rescue in first remission of acute myeloid
leukemia. Blood 1989;74(5):1507-16.
3
Bolinger AM, Zangwill AB, Slatry JL, et al. Target dose adjustment of busulfan in
pediatric patients undergoing bone marrow transplantation Bone Marrow transplant
2001;28:1013-8.
Booth BP, Rahman A, Dagher R, et al. Population Pharmcokinetic-Based Dosing of
Intravenous Busulfan in pediatric Patients J of Clin Pharmacol 2007;47:101-11.
Bornhouser M, Storer B, Slattery JT, et al Conditioning with fludarabine and targeted
busulfan for transplantation of allogeneic stem cells. Blood 2003;103:820-6
Browning B, Thormann K, Donaldson, A et al. Busulfan Dosing in Children with BMI
>85% Undergoing HSCT: A New Optimal Strategy. Biol Blood Marrow Transplant
2011;17:1383-8
Cogle CR, Moreb JS, Leather HL et al. Busulfan, Cyclophosphamide, and Etoposide as
Conditioning for Autologous Stem Cell Transplantation in Multiple Myeloma Am J
Hematology 2003;73:169-75
Costa LJ, Micalleff IN, Inwardo, DJ, et al. Effect of the dose per body weight of
conditioning chemotherapy on severity of mucositis and risk of relapse after autologous
haematopoietic stem cell transplantation in relapsed diffuse large B cell lymphoma. Br J
Haematol 2008;143:268-37.
De Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine:
clinical and pharmacokinetic results of a myeloablative reduced-toxicity conditioning
regimen for allogeneic stem cell transplantation in AML and MDS. Blood
2004;104:857-64
Gibbs JP, Gooley T, Corneau B, et al. The Impact of Obesity and Disease on Busulfan
Oral Clearance in Adults Blood 1999;93:4436-40
Grigg A, Harun MH, Szer J. Variability in determination of body weight used for dosing
busulphan and cyclophosphamide in adult patients: Results of an international survey.
Leuk Lymphoma 1997;25: 487-91.
Grochow LB, Krivit W, Whitley CB, et al. Busulfan Disposition in Children Blood
1990;75(8):1723-7
Hadjibabaie M, Tabeefar H, Alimohaddam K, et al. The relationship between body mass
index and outcomes in leukemic patients undergoing allogeneic hematopoietic stem cell
transplantation Clinical Transplantation 2012;26:149-55.
Hoffer E, Akria L, Tabak A, et al. A Simple Approximation for Busulfan Dose
Adjustment in Adult Patients Undergoing Bone Marrow Transplantation Ther Drug
Monit 2004;26:331-5
Kim JG, Sohn SK, Chase YS et al. Multicenter study of intravenous busulfan,
cyclophosphamide, and etoposide (i.v. Bu/Cy/E) as conditioning regimen for autologous
stem cell transplantation in patients with non-Hodgkin’s Lymnphoma Bone Marrow
Transplant 2007;40:919-24
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Markova M, Barker JN, Miller JS, et al. Fludarabine vs. cladribine plus busulfan and
low-dose TBI as reduced intensity conditioning for allogeneic hematopoietic stem cell
transplantation: a prospective trial Bone Marrow transplant 2007;39:193-9
McCune JS, Batchelder A, Deeg HJ, et al. Cyclophosphamide following Targeted Oral
Busulfan as Conditioning for Hematopoietic Cell Transplantation: Pharmacokinetics,
Liver Toxicity, and Mortality. Biol Blood Marrow transplant 2007;13:853-62.
Meloni G, Proia, A, Capria S, et al. Obesity and autologous stem cell transplantation in
acute myeloid leukemia Bone Marrow Transplant 2001;28:365-7
Nguyen L, Leger F, Lemon S, et al. Intravenous busulfan in adults prior to
haematopoietic stem cell transplantation a population based study. Cancer Chemother
Pharmacol 2006;57:191-8
Russel JA, Tran HT, Quinlan D, et al. Once daily intravenous busulfan given with
fludarabine as conditioning for allogeneic stem cell transplantation: study of
pharmacokinetics and early outcomes. Biol Blood Marrow Transplant 2002;8:468-76
Schiltmeyer B, Klingebiel T, Schwab M, et al Population pharmacokinetics of oral
busulfan in children Cancer Chemother Pharmacol 2003;52:209-16
Shaughnessy P, Alexander W, Tran H, et al. Phase I and Pharmacokinetic Study of
Once-Daily Dosing of Intravenously Administered Busulfan in the Setting of RedecedIntensity Preparative Regimen and Allogeneic Hematopoietic Stem Cell Transplantation
as Immunotherapy for Renal Cell Carcinoma Military Medicine 2006:171(2):161-5
Sucak GT, Suyani E, Baysal NA, et al. The role of body mass index and other body
composition parameters in early post-transplant complications in patients undergoing
allogeneic stem cell transplantation with busulfan-cyclophosphamide conditioning Int J
Hematol 2012;95:95-101
Takama H, Tanaka H, Nakashima D, et al. Population pharmacokinetics of intravenous
busulfan in patients undergoing hematopoietic stem cell transplantation Bone Marrow
Transplant 2006;37:345-51
Thomas ED, Sanders JE, Flournoy N et al Marrow Transplantation for patients with
acute lymphoblastic leukemia in remission. Blood 1979;54:468-76.
Trame M, Bergsstrand M, Mats O, et al Population Pharmacokinetics of Busulfan in
Children: Increased Evidence for Body Surface Area and Allometric Body Weight
Dosing of Busulfan in Children Clin Cancer Res 2011;17:6867-6877
Tutschka, PJ, Copelan EA, Klein JP. Bone marrow Transplantation for Leukemia
Following a New Busulfan and Cyclophosphamide Regimen Blood 1987;70(5):1382-8
Carboplatin References
5
Carmustine References
Articles:
Costa LJ, Micalleff IN, Inwardo, DJ, et al. Effect of the dose per body weight of
conditioning chemotherapy on severity of mucositis and risk of relapse after autologous
haematopoietic stem cell transplantation in relapsed diffuse large B cell lymphoma. Br J
Haematol 2008;143:268-37.
Clofarabine References
Articles:
Cyclophosphamide References
Articles:
Andersson BS, Madden T, Tran HT, et al. Acute safety and pharmacokinetics of
intravenous busulfan when used with oral busulfan and cyclosphosphamide as a
pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant
2000;6:548-54
Andersson BS, Kashyap A, Gian V, et al Conditioning Therapy with Intravenous
Busulfan and Cyclophosphamide (IV BuCy2) for Hematologic Malignancies Prior to
Allogeneic Stem Cell Transplantation: A Phase II Study. BBMT 2002;8:145-54
Beelen DW, Quabeck K, Graeven U, et al. Acute Toxicity and First Clinical results of
intensive postinduction therapy using a modified busulfan and Cyclophosphamide
regimen with autologous bone marrow rescue in first remission of acute myeloid
leukemia. Blood 1989;74(5):1507-16.
Grigg A, Harun MH, Szer J. Variability in determination of body weight used for dosing
busulphan and cyclophosphamide in adult patients: Results of an international survey.
Leuk Lymphoma 1997;25:487-91.
Hadjibabaie M, Tabeefar H, Alimohaddam K, et al. The relationship between body mass
index and outcomes in leukemic patients undergoing allogeneic hematopoietic stem cell
transplantation Clinical Transplantation 2012;26:149-55.
Meloni G, Proia, A, Capria S, et al. Obesity and autologous stem cell transplantation in
acute myeloid leukemia Bone Marrow Transplant 2001;28:365-7
Tutschka, PJ, Copelan EA, Klein JP. Bone marrow Transplantation for Leukemia
Following a New Busulfan and Cyclophosphamide Regimen Blood 1987;70(5):1382-8
Thomas ED, Sanders JE, Flournoy N et al Marrow Transplantation for patients with
acute lymphoblastic leukemia in remission. Blood 1979;54:468-76.
Cytarabine References
Articles:
6
Costa LJ, Micalleff IN, Inwardo, DJ, et al. Effect of the dose per body weight of
conditioning chemotherapy on severity of mucositis and risk of relapse after autologous
haematopoietic stem cell transplantation in relapsed diffuse large B cell lymphoma. Br J
Haematol 2008;143:268-37.
Etoposide References
Articles:
Costa LJ, Micalleff IN, Inwardo, DJ, et al. Effect of the dose per body weight of
conditioning chemotherapy on severity of mucositis and risk of relapse after autologous
haematopoietic stem cell transplantation in relapsed diffuse large B cell lymphoma. Br J
Haematol 2008;143:268-37.
Wolff SN, Johnson DH, Hainsworth JD, et al. High-dose VP-16-213 Monotherapy for
refractory germinal malignancies: A phase II study. J Clin Oncol 1984;2(4):271-4.
Fludarabine References
Articles:
Quinlan D, et al. Once daily intravenous busulfan given with fludarabine as conditioning
for allogeneic stem cell transplantation: study of pharmacokinetics and early outcomes.
Biol Blood Marrow Transplant 2002;8:468-76
Melphalan References
Articles:
Costa LJ, Micalleff IN, Inwardo, DJ, et al. Effect of the dose per body weight of
conditioning chemotherapy on severity of mucositis and risk of relapse after autologous
haematopoietic stem cell transplantation in relapsed diffuse large B cell lymphoma. Br J
Haematol 2008;143:268-37.
Grazziutti ML, Dong L, Micelli MH et al. Oral mucositis in myeloma patients
undergoing melphalan-based autologous stem cell transplantation: Incidence, risk factors,
and a severity predictive model. Bone Marrow Transplant 2006;38:501-6
Pentostatin References
Articles:
Thiotepa References
Articles:
Atgam References
Articles:
Thymoglobulin References
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Articles:
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