GUIDELINES FOR Dosing Antineoplastics In Obesity for HSCT Conditioning
Grading system for ranking recommendations in clinical guidelines:
(Kish MA. Guide to Development of Practice Guidelines. Clin Infectious Disease. 2001; 32: 851-4)
Strength of Recommendations
A
Good evidence to support a recommendation for use
B
Moderate evidence to support a recommendation for use
C
Poor evidence to support a recommendation
D
Moderate evidence to support a recommendation against use
E
Good evidence to support a recommendation against use
Quality of Evidence
Type I
Evidence from ≥ 1 properly randomized, controlled trial
Type II
Evidence from ≥ 1 well-designed clinical trial, without randomization; from cohort or
case-controlled analytic studies (preferably from > 1 center); from multiple time-series;
or from dramatic results from uncontrolled experiments
Type III
Evidence from opinions of respected authorities, based on clinical experience, descriptive
studies, or reports of expert committees
Table 1. Outcomes
Definitions
Outcomes in Obese
patients?
Allogeneic Outcomes?
Autologous outcomes?
Recommendation
Strength of
Recommendation
Quality of
Evidence
References
-BuFluATG(r) or BuFluECP in
peds on TBW with Bu dosed on
test dose PK. Note: lowest
dose/kg and lowest bu clearance in
obese thus requiring lower bu
doses. Dosing needed to be PK
based
-Bu (16)Cy(120) (TBW) –
Increased BMI had shorter time to
engraftment and no difference in
OS or LFS
CIBMTR AML
-7 regimens (ABW40) Note:
assessed on age adjusted BMI
(?validity) possible increase in
NRM in obese (NS diff)
-BEAM (melphalan dose used as
surrogate marker) (BSA based on
ABW25)Note: Obese patients had
less mucositis and shorter LOS.
No difference in relapse or
survival
-Busulfan 16 mg/kg PO plus
etoposide 60 mg/kg x 1(ABW25)
B
III
Browning
2011
B
III
Hadjibabaie
2011
B
III
Coglin
Dickson
1999
B
III(?)
Costa 2008
B
III
Navarro
2003
Note: decreased mucositis, peak
alk phos no survival difference
Definitions
TBW= total body weight
IBW=ideal body weight
ABW25 = IBW +
0.25(TBW-IBW)
ABW40 = IBW +
0.4(TBW-IBW)
Table 2 Individual agents
Agent
Alemtuzumab
Busulfan
Recommendation
IV Busulfan
3.2 mg/kg/dose (IBW)
0.8 mg/kg x 16 doses (IBW)
PO Busulfan
16 mg/kg (IBW)
Pediatrics
IV Busulfan
PO Busulfan
1-2 mg/kg x 16 doses (TBW)
Carmustine
Clofarabine
Cyclophosphamide
Cytarabine
Etoposide
Fludarabine
Melphalan
Pentostatin
Thiotepa
Antithymocyte globulin
Strength of
Recommendation
Quality of
Evidence
References
B
B
III
III
Russell 2002
Andersson 2000,
2002
B
III
Tutschka 1987
B
III
Grochow 1990
Andersson 2000,
2002
Tutschka 1987
Cy 120 mg/kg (IBW)
B
III
Cy 120 mg/kg (IBW)
B
III
MTD 2400 mg/m2 (800
mg/m2/day x 3 single agent
(DLT hepatitis)
50 mg/m2/day x 5 days(TBW)
BEAM (melphalan dose used as
surrogate marker) (BSA based
on ABW25)Note: Obese
patients had less mucositis and
shorter LOS. No difference in
relapse or survival 3.6 mg/kg
breakpoint
B
III
Wolff 1984
B
B
III
III
Russell 2002
Costa 2008
140-200 mg/m2 (BSA-ABW40
for > 60 kg). Notes: ? should
not be adjusted in obese,
mucositis endpoints, 3.4 mg/kg
breakpoint
B
III
Grazziutti 2006
– Equine
Antithymocyte globulin
- Rabbit
4.5 mg/kg over 3 days (TBW)
B
III
Russell 2002
References:
Outcomes
1.
ASCO Guideline Griggs 2012 – No HSCT specific info
2.
Allogeneic Outcomes
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.
Autologous Outcomes
Couglin TM, Kusnierz-glaz CR, Blume K, et al. Impact of admission body weight and chemotherapy
dose adjustment on the outcome of autologous bone marrow transplantation. Biol Blood Marrow
Transplant 1999;5:299-305
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.
Navarro WH Impact of obesity in the setting of high dose chemotherapy Bone Marrow Transplant
2003;31:961-6.
Individual Agents
Alemtuzumab
Busulfan
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
Grochow LB, Krivit W, Whitley CB, et al. Busulfan Disposition in Children Blood 1990;75(8):1723-7
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
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
Carmustine
Clofarabine
Cyclophosphamide
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
Tutschka, PJ, Copelan EA, Klein JP. Bone marrow Transplantation for Leukemia Following a New
Busulfan and Cyclophosphamide Regimen Blood 1987;70(5):1382-8
Cytarabine
Etoposide
References
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
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
Melphalan
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 melphalanbased autologous stem cell transplantation: Incidence, risk factors, and a severity predictive model.
Bone Marrow Transplant 2006;38:501-6
Pentostatin
Thiotepa
Antithymocyte globulin – Equine
Antithymocyte globulin - Rabbit