Biol Blood Marrow Transplant xxx (2015) 1e4

Biology of Blood and

Marrow Transplantation
journal homepage: www.bbmt.org

Adjusting Cyclophosphamide Dose in Obese Patients

with Lymphoma Is Safe and Yields Favorable Outcomes
after Autologous Hematopoietic Cell Transplantation
Veronika Bachanova*,1, John Rogosheske 1, Ryan Shanley 1, Linda J. Burns 2, Sara M. Smith 1,
Daniel J. Weisdorf 1, Claudio G. Brunstein 1
1
2

Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota

National Marrow Donor Program, University of Minnesota, Minneapolis, Minnesota

Article history:
Received 13 July 2015
Accepted 9 October 2015
Key Words:
Cyclophosphamide
Obese
Lymphoma
Hematopoietic cell
transplantation

a b s t r a c t
No clear dosing guidelines exist for cyclophosphamide (Cy) dose adjustments in obese patients treated with
high-dose chemoradiotherapy followed by autologous hematopoietic cell transplantation (HCT). We prospectively compared the outcomes of high-dose Cy/total body irradiation (TBI) conditioning in 147 nonHodgkin lymphoma (NHL) patients in 3 weight groups: nonobese (<120% ideal body weight [IBW];
n 72), overweight (120% to 149% IBW; n 46), and obese (150% IBW; n 29). Nonobese and overweight
patients received Cy (120 mg/kg of total body weight, intravenously) and TBI (1320 cGy), whereas obese
patients (median body mass index, 36) received an adjusted Cy dose based on IBW plus 50% of the difference
between total body weight and IBW (AdjBW50). The median patient age was 57 years (range, 19 to 73). The
most common diagnoses were diffuse large B cell lymphoma (n 57) and mantle cell lymphoma (n 51).
Three-year overall survival was 61% (95% condence interval [CI], 48% to 72%) for nonobese patients, 68% (95%
CI, 52% to 82%) for overweight patients, and 80% (95% CI, 62% to 93%) for obese patients. Cumulative incidence
of relapse (48%, 43%, and 38%, respectively) and nonrelapse mortality (w4%) were similar in all groups.
Hemorrhagic cystitis and cardiac toxicity were rare events. Our data show that the AdjBW50 formula can be
safely and effectively used for Cy dose adjustments in obese patients treated for NHL with high-dose Cy/TBI
conditioning followed by autologous HCT.
2015 American Society for Blood and Marrow Transplantation.

INTRODUCTION
Cyclophosphamide (Cy) is a bifunctional alkylating cytotoxic agent commonly used as the backbone of hematopoietic cell transplantation (HCT) preparative regimens of varied
intensity. In addition to its antitumor activity against
hematologic malignancies, Cy contributes lympholytic and
immunosuppressive properties. Despite its wide use, limited
data exist on how to safely and effectively dose Cy in obese
patients. Optimally, the dose should provide equivalent
antitumor and tissue exposure as for a nonobese person;
however, altered pharmacokinetic parameters, including
drug distribution, exposure, and clearance in obese patients
compared to nonobese patients, add complexity to the
optimal dose calculation [1-3]. Routine Cy dosing is based on
Financial disclosure: See Acknowledgments on page 4.
* Correspondence and reprint requests: Veronika Bachanova, MD, PhD,
Blood and Marrow Transplant Program, University of Minnesota, Mayo Mail
Code 480; 420 Delaware Street SE, Minneapolis, MN 55455.
E-mail address: bach0173@umn.edu (V. Bachanova).

http://dx.doi.org/10.1016/j.bbmt.2015.10.012
1083-8791/ 2015 American Society for Blood and Marrow Transplantation.

total body weight (BW) in nonobese individuals for whom

total BW, ideal body weight (IBW), and lean BW are similar.
Although obese patients have more adipose tissue, they also
have more lean BW, blood volume, bone mass, and cardiac
output compared with nonobese individuals [4,5]. Dosing
based on IBW does not account for these differences, which
could lead to substantial underdosing. Dosing based on total
body weight could lead to excess drug exposure and higher
risks of dose-dependent toxicities, including sinusoidal
obstructive syndrome, cardiac toxicity, and hemorrhagic
cystitis [6]. Consequently, there is a widely used habit of
reducing Cy doses in obese to minimize these toxicities.
These practices, however, may compromise the survival of
patients with curable malignancies. The curative potential of
high-dose chemotherapy for relapsed or high-risk lymphoma provide a strong rationale for the careful and judicious assessment to appropriately adjust Cy dosing.
Guidelines from the American Society of Clinical Oncology
recommend using full weightebased dosing for conventional

V. Bachanova et al. / Biol Blood Marrow Transplant xxx (2015) 1e4

chemotherapy, but no recommendations were made for

high-dose chemotherapy [7]. Practice guidelines from
American Society of Blood and Marrow Transplantation
recently highlighted insufcient evidence to make conclusive recommendations for high-dose chemotherapy dosing
in obese patients [8].
We developed a standard approach to Cy dosing in which
obese patients received adjusted Cy dose calculated by
combining IBW plus 50% of the difference between total and
IBW (adjusted Cy dose formula; AdjBW50) for individuals
above 150% of IBW, whereas others (with BW < 150% IBW)
received full dose of Cy based on actual BW. We report the
safety and efcacy of Cy in combination with total body
irradiation (TBI) followed by autologous HCT in patients with
non-Hodgkin lymphoma (NHL). Outcomes were compared
among 3 weight groups: nonobese, overweight, and obese.
PATIENTS AND METHODS
Study Population
Using prospectively collected data from the University of Minnesota
Blood and Marrow Transplantation Database, we analyzed 147 adults 
18 years old with NHL who underwent autologous HCT using high-dose
Cy/TBI conditioning between 2003 and 2012.
Denitions, Study Endpoints, and Statistical Analysis
All patient received Cy (60 mg/kg i.v.  2 days) plus TBI (1320 cGy)
conditioning followed by autologous hematopoietic cell infusion. We used
standard supportive care, as previously described [9]. Patients were divided
into 3 groups according to body weight: controls (<120% IBW), overweight
(120% to 149% IBW), and obese (150% IBW). Patients with total BW < 150%
of IBW were dosed using actual body weight. In obese patients, total Cy
was calculated using an adjusted body weight (AdjBW50) formula:
IBW .5(actual body weightIBW). Disease status was evaluated by positron emission tomography/computerized tomography (CT) before

transplantation and at day 100 and by CT every 3 months for 1 year and at 18
and 24 months thereafter using standard staging criteria for NHL [10].
The primary objective was to compare overall survival (OS), cumulative
incidence of relapse, and nonrelapse mortality (NRM) while adjusting for
patient, disease, and transplantation-related characteristics. We also evaluated cumulative incidences of neutrophil and platelet engraftment and
incidences of specic toxicities related to high-dose Cy, including hemorrhagic cystitis and cardiac toxicity. Infection density was calculated as the
number of infectious episodes divided by the number of patient days at risk
multiplied by 1000 and compared using Fishers exact test.
OS was evaluated using standard survival methods, including KaplanMeier estimations and Cox regression [11-13]. The cumulative incidence
function with Fine and Gray regression were used for other outcomes to
accommodate competing risks [14,15]. Relapse was considered a competing
risk for NRM, and death was considered a competing risk for relapse and
engraftment. Multivariable regression models were limited by event
numbers adjusting for 2 factors in addition to weight group. Because of their
previously established association with outcomes, lymphoma type (diffuse
large B cell lymphoma, mantle cell lymphoma, and others) and complete
remission (CR) status at HCT were prespecied. Age and gender were
associated with weight, and a separate model was t with these 2 factors,
which showed similar effects to weight on all outcomes. Incidence of cardiac
toxicity was compared using Fishers exact test.

RESULTS
Patients, Disease, and Transplantation Characteristics
We examined 147 patients with NHL (Table 1). The most
common histologies were diffuse large B cell lymphoma
(n 57) and mantle cell lymphoma (n 51). Patient age
ranged from 19 to 73 years with median of 57 years.
There was a median of 12 months from diagnosis to
transplantation. Eighty-nine percent received lgrastimmobilized peripheral blood stem cell grafts; others received
peripheral blood stem cells and bone marrow grafts. The
median CD34 dose was 5.5  106 CD34 cells/kg, with the

Table 1
Characteristics by Weight of Patients Who Underwent Autologous HCT for NHL between 2003 and 2012
Characteristic

<120% IBW

120% to 149% IBW

150% IBW

Total

No.
Age, median, yr
Age, 19-49
Age, 50-59
Age, 60-73
Male
BMI, median (range)
Weight, median (range), kg
Lymphoma subtype
Diffused large cell NHL
Mantle cell lymphoma
Follicular lymphoma
T cell NHL
Other NHL
Disease status at HCT
CR
Relapse lymphoma/PIF sensitive
Resistant
KPS
KPS 70-80
KPS 90-100
Graft source
Marrow
Peripheral blood cells
CMV serostatus
Recipient negative
Recipient positive
Yr of transplantation
2003-2007
2008-2012
Mo from diagnosis to transplantation, median (range)
CD34, mean (SD), 106/kg
TNC, mean (SD), 108/kg

72
56
24
22
26
53
25
77

46
58
9
20
17
32
29
90

29
60
4
11
14
13
36
102

147
57
37
53
57
98
27
84

26
26
6
4
10

(100%)
(33%)
(31%)
(36%)
(74%)
(19-28)
(48-97)
(36%)
(36%)
(9%)
(6%)
(15%)

20
12
4
2
8

(100%)
(20%)
(43%)
(37%)
(70%)
(24-34)
(58-123)
(43%)
(26%)
(9%)
(4%)
(18%)

11
13
4
1

(100%)
(14%)
(38%)
(48%)
(45%)
(30-55)
(75-177)
(38%)
(45%)
(14%)
(3%)

57
51
14
7
14

(100%)
(25%)
(36%)
(39%)
(67%)
(19-55)
(48-177)
(39%)
(35%)
(8%)
(5%)
(8%)

42 (58%)
28 (39%)
2 (3%)

32 (70%)
14 (30%)
0 (0%)

19 (66%)
9 (31%)
1 (3%)

93 (63%)
51 (35%)
3 (2%)

4 (6%)
67 (93%)

6 (13%)
37 (80%)

2 (7%)
25 (86%)

12 (8%)
129 (88%)

9 (13%)
63 (88%)

3 (7%)
43 (93%)

4 (14%)
25 (86%)

16 (11%)
131 (89%)

32 (44%)
40 (56%)

19 (41%)
27 (59%)

11 (38%)
18 (62%)

62 (42%)
85 (58%)

27
45
11
5.1
11.8

(38%)
(63%)
(4-160)
(4.4)
(6.6)

14
32
16
5.7
11.7

(30%)
(70%)
(5-147)
(4.0)
(7.0)

11
18
12
6.1
9.0

(38%)
(62%)
(6-79)
(7.5)
(4.9)

52
95
12
5.5
11.2

(35%)
(65%)
(4-160)
(5.0)
(6.5)

BMI indicates body mass index; PIF, primary induction failure; KPS, Karnofsky performance status; CMV, cytomegalovirus; TNC, total nucleated cells.

V. Bachanova et al. / Biol Blood Marrow Transplant xxx (2015) 1e4

highest cell dose infused in obese patients (6.1  106/kg)

compared with that in overweight (5.7  106/kg) and in
nonobese (5.1  106/kg).
The obese group contained more female patients (55%)
compared with the overweight (30%) and nonobese (26%)
groups. Only 12 (8%) patients had impaired performance
status (Karnofsky performance status  80%). Before transplantation, two-thirds were in CR as evaluated by positron
emission tomography/CT scan, and there were no signicant
differences in remission status or other disease and transplantation characteristics in the 3 weight groups (Table 1).
Patients underwent transplantation between 2003 and 2012
with a median follow up of 3 years (range, 1 to 10).
Transplantation Outcomes
Survival at 3 years was 61% (95% condence interval [CI],
48% to 72) for nonobese, 68% (95% CI, 52% to 82) for overweight, and 80% (95% CI, 62% to 93) for obese groups
(Figure 1A). The cumulative incidences of relapse at 3 years
were similar in all 3 groups: 48% (95% CI, 37% to 59%), 43%
(95% CI, 27% to 59%), and 38% (95% CI, 18% to 58%), respectively (Figure 1B). NRM at 1 year was low in all 3 groups: 4%,
4%, and 3%, respectively. In multivariable regression analysis,
male gender (hazard ratio [HR], 2.42; 95% CI, 1.18 to 5.00;
P .02) and no CR before transplantation (HR, 2.73; 95% CI,
1.51 to 4.9; P < .01) increased overall mortality. Disease status
before transplantation (not CR) was associated with 1.9-fold
increased risk of relapse (HR, 1.89; 95% CI, 1.13 to 3.18; P .02)
but weight did not affect OS (overweight HR, .70; 95% CI, .35
to 1.37 and obese .41; 95% CI, .16 to 1.07) or relapse incidence
(overweight HR, .92; 95% CI, .47 to 1.80; obese HR, .75; 95%
CI, .35 to 1.644) (Table 2).

Figure 1. (A) Cumulative incidence of relapse by weight groups and (B)

Kaplan-Meier estimate of OS by weight groups.

The median time to neutrophil recovery was 10 days

(range, 8 to 16) for all weight groups, with 1 patient
who received a suboptimal graft (weight 76 kg; CD34
dose, .94  106 cells/kg) failing to engraft. Platelet recovery
(>20,000/mL) occurred at a median day 19 (range, 9 to
105). Time to platelet recovery did not differ among 3 weight
groups.
Ten patients had cardiovascular complications after
transplantation, including 5 with congestive heart failure
(2 overweight, 2 obese, and 1 nonobese) and 6 experienced
at least 1 episode of atrial brillation/utter (3 obese, 2
overweight and, 1 nonobese). All patients had acceptable left
ventricular ejection fraction before transplantation (above
45%). Two nonobese patients had prior cardiac history,
including pericarditis and paroxysmal atrial brillation.
Hemorrhagic cystitis occurred in 5 patients: overweight
(n 3), obese (n 1), and nonobese (n 1). No patients
developed sinusoidal obstructive syndrome or > grade 1 oral
mucositis. In the rst 100 days after transplantation, few
patients developed bacteremia. Infection densities were not
increased in the obese group and rates were 2.3 infections/
1000 patient days in the nonobese group, 3.0 infections/1000
patient days in the overweight group, and .4 infections/1000
patient days in the obese group (overall P value .03). Sixteen
patients developed secondary malignancies after transplantation at a median of 2.5 years after HCT (range, .3 to
10 years); 2 patients died from secondary myelodysplastic
syndrome. Obesity did not increased risk of secondary malignancies (data not shown).
DISCUSSION
We report the outcomes of patients with NHL treated
with high-dose Cy/TBI conditioning followed by autologous
stem cell rescue and the effect of Cy dosing in those in
overweight or obese subjects. The Cy/TBI regimen using
AdjBW50 Cy dosing for obese patients conferred similar
relapse and survival rates compared with nonadjusted Cy
dosing for overweight patients and nonobese; Cy dosing
(adjusted or not) was safe without an increase in short-term
organ toxicity or late complications. With this dosing
approach, the patient weight did not affect relapse or OS.
The prevalence of obesity and overweight in the US
exceeds 70% [16], and such data are needed to guide decisionmaking of the preferred Cy dose in patients who are above
their IBW. Others have suggested that severe obesity is a poor
prognostic factor for hematopoietic transplantation [17], yet
this and another recent study using appropriate dose adjustments failed to show increased risk of serious complications for the severely obese treated with autologous HCT [18].
There are signicant differences between our study and other
reports. Lau et al. adjusted all agents in a chemotherapy-only
regimen using busulfan, Cy, and etoposide on the basis of
AdjBW25, in which 25% difference between TBW and IBW
was used for patients above IBW. In contrast, we adhered to
preserve maximum dose intensity of high-dose chemoradiotherapy and restricted the use of AdjBW50 formula only
to patients above 150% IBW and treated all other patients
with actual weightebased Cy dosing as recommended by
American Society of Clinical Oncology and American Society
for Blood and Marrow Transplantation [7,8]. Importantly, the
AdjBW50-adjusted Cy dose for those with the highest body
mass index (over 30) delivers an adequate antitumor dose
effect and yields similar efcacy and safety compared with
those for nonobese and overweight patients receiving standard, unadjusted Cy dosing. Notably, these ndings do not

V. Bachanova et al. / Biol Blood Marrow Transplant xxx (2015) 1e4

Table 2
Multivariable Analysis of the Effect of Weight on OS and Relapse
Factor

BMI

Weight Used for Cy Dose

Relapse HR (95% CI)

Control 120% IBW)

Overweight 121-149 IBW
Obese 150 IBW

72
46
29

25 (19-28)
29 (24-42)
36 (30-55)

TBW
TBW
IBW .5 (TBWIBW)

1.00
.92 (.47-1.80)
.75 (.35-1.64)

P Value

Overall Mortality HR (95% CI)

P Value

.80
.48

1.00
.70 (.35-1.37)
.41 (.16-1.07)

.29
.07

TBW indicates total body weight.

Models include disease status and lymphoma subtype.

address if this approach has any advantage over other

methods of dosing Cy.
Between 54% and 67% patients with NHL survived beyond
3 years after autologous HCT, and weight did not signicantly
inuence NRM or OS. It is possible that adjusting Cy dose
protected patients from increased toxicity, yet the heterogeneity in subjects and transplantation procedures likely
contribute to differences among published reports [17,19].
The current results only apply to Cy/TBI conditioning but
might also be appropriate for other high-dose regimens.
Despite lymphoma subtype heterogeneity, Cy dosing was
prospectively calculated whereas conditioning, supportive
care, management, and evaluation were standardized and
performed consistently in this cohort with the expected
prognostic effect of disease status on risks of relapse [20,21].
Our results demonstrate that autologous HCT can be safely
applied to all eligible patients with relapsed lymphoma,
regardless of body mass index. We report that the Cy dose
adjusted using the AdjBW50 formula does not reduce the
efcacy nor contribute to the risks of Cy/TBI autologous HCT.
ACKNOWLEDGMENTS
Research reported in this publication was supported by
the National Center for Advancing Translational Sciences of
the National Institutes of Health Award Number
UL1TR000114 (V.B.). The content is solely the responsibility
of the authors and does not necessarily represent the ofcial
views of the National Institutes of Health. This work was
also supported in part by NIH P30 CA77598 utilizing the
Biostatistics and informatics core, Masonic Cancer Center,
University of Minnesota shared resource.
Financial disclosure: Authors have no nancial disclosures
to report.
Conict of interest statement: The authors declare no
competing nancial interests.
Authorship statement: V.B., J.R., and C.B. conceived and
designed the study. V.B., R.S. C.B., S.M.S., and D.W. performed
data analysis and interpreted the data. V.B., J.R. R.S. L.B., D.W.,
and C.B. wrote the manuscript. V.B., J.R. R.S. L.B., S.M.S., D.W.,
and C.B. provided nal approval of the manuscript.
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