Vol.2, No.4, 57-65 (2013) Modern Chemotherapy
Allogeneic and autologous stem cell transplantation
with busulfan, cyclophosphamide, and etoposide
conditioning therapy for relapsed/refractory
non-Hodgkin lymphoma
Neelima Vidula1*, Andrew M. Evens2*, Irene B. Helenowski3, Borko Jovanovic3,
Jane N. Winter4, Jayesh Mehta4, Seema Singhal4, Stephanie F. Williams4,
Olga Frankfurt4, Jessica K. Altman4, Joanne Monreal4, Leo I. Gordon4#
1Division of Hematology-Oncology, University of California, San Francisco, USA
2Division of Hematology-Oncology, The University of Massachusetts Medical School, Worcester, USA
3Department of Preventive Medicine, Northwestern University, Chicago, USA
4Division of Hematology-Oncology, Northwestern University, Chicago, USA;
#Corresponding Author: l-gordon@northwestern.edu
Received 10 September 2013; revised 15 October 2013; accepted 21 October 2013
Copyright © 2013 Neelima Vidula et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The optimal stem cell transplantation (SCT) con-
ditioning therapy for relapsed/refractory non-
Hodgkin lymphoma (NHL) is not clearly defined.
In a retrospective analysis, we examined 25 pa-
tients with “high risk” relapsed/refractory NHL
who received busulfan, cyclophosphamide, and
etoposide (Bu/Cy/VP16) conditioning with auto-
logous or allogeneic SCT. The majority of pa-
tients had aggressive histology and 52% had
primary refractory NHL. Furthermore, 48% of pa-
tient s had chem otherapy-re sist ant disease at the
time of SCT. Fifty-six percent of patients under-
went allogeneic SCT, while 44% had autologous
SCT. The median engraftment time for neutro-
phils and platelets was 13.5 and 14 days, re-
spectively. The 100-day treatment-related mor-
tality (TRM) was 16%, while the 2-year non-re-
lapse mortality (NRM) rate was also 16%. At a
median follow-up of 15 months, the estimated 2-
year disease-free survival (DFS) rate was 64%
(95% confidence inter val (CI): 36 % - 82%) and the
estimated 2-year overall survival (OS) was 69%
(9 5% CI: 40% - 86%). Furthermore, the 2- year dis-
ease-specific survival (DSS) rate was 73% (95%
CI: 40% - 90%). Using Cox proportional hazard
modeling, the International Prognostic Index at
time of relapse predicted DFS and OS. Altoge-
th er, Bu/Cy/VP16 was associated w ith ear ly TRM;
however, lat e toxicities (including NRM) w ere un-
common resulting in relatively good survival rates
in a high-risk relapsed/refractory NHL population.
Keywords: Stem Cell Transplantation; Busulfan;
Cyclophosphamide; Etoposide; Non-Hodgk in
Stem cell transplantation (SCT) is an effective thera-
peutic modality for patients with relapsed or refractory
non-Hodgkin lymphoma (NHL) [1-5]. The timing and
type of SCT (i.e., autologous or allogeneic) depends in
part on disease histology, disease status (i.e., relapsed vs.
refractory), patient physical condition, and disease-spe-
cific prognostic and other risk factors. A number of SCT
chemotherapy conditioning regimens have been studied
in relapsed/refractory NHL; however, the optimal condi-
tioning regimen is not clearly defined.
Busulfan, cyclophosphamide, and etoposide (Bu/Cy/
VP16) have been investigated as a SCT conditioning
regimen [6-12]. The outcomes of prior studies, however,
have been quite variable with 3-year progression-free
survival (PFS) rates ranging from 39% to 70% and
3-year overall survival (OS) rates ranging from 43% to
72% [8,10]. Furthermore, there are few Bu/Cy/VP16
studies that have been reported in the past 5 - 10 years as
supportive care treatments, and understanding of SCT
has improved over the past decade. Also, an improved
*Authors contributed equally.
Copyright © 2013 SciRes. OPEN A CCESS
N. Vidula et al. / Modern Chemotherapy 2 (2013) 57-65
understanding of the complications associated with Bu/
Cy/VP-16 is needed, especially as the early treatment-
related mortality (TRM) with this regimen may be as
high as 46% [13].
We analyzed the Northwestern experience with utili-
zing Bu/Cy/VP16 conditioning therapy for patients with
relapsed/refractory NHL. Notably, this conditioning regi-
men was reserved at our institution for patients with
high-risk disease (e.g., short initial remission, high IPI at
relapse, chemotherapy-resistant disease at SCT, etc.). We
examined detailed patient and disease characteristics,
patient outcomes, and analyzed potential prognostic fac-
tors that predicted survival with Bu/Cy/VP16 SCT.
2.1. Study Design
We performed a retrospective analysis of all relapsed/
refractory NHL patients who received stem cell trans-
plantation with Bu/Cy/VP16 conditioning chemotherapy
at the Northwestern University Robert H. Lurie Com-
prehensive Cancer Center from 3/2003 to 6/2011. This
study was approved by the Northwestern University In-
stitutional Review Board. Relapsed disease was defined
as disease that recurred following a response to initial
therapy (lasting >6 months), while refractory disease was
defined as disease that did not respond to therapy or re-
lapsed within 6 months of remission. Patients who had
received prior SCT were excluded from the analysis.
Detailed patient characteristics were collected including
patient age, gender, co-morbidities, baseline pulmonary
(diffusing capacity for carbon monoxide (DLCO) and
presence of obstructive or restrictive defects on pulmo-
nary function testing), liver (liver enzymes), and cardiac
function (ejection fraction and diastolic function on
echocardiographic evaluation), and performance status.
Furthermore, detailed disease characteristics at the time
of relapse prior to SCT were examined including disease
histology, chemotherapy sensitivity, number of extran-
odal sites, disease stage, number of prior chemotherapy
regimens, history of prior radiation, LDH immediately
before transplant after salvage therapy (pre-SCT LDH),
presence of bulk disease (>10 cm), International Prog-
nostic Index (IPI), and disease status at time of SCT.
2.2. Preparative Regimen
Busulfan was dosed at 3.2 mg/kg intravenous (IV)
daily for 4 days on days -8 to -5, etoposide was dosed at
20 - 40 mg/kg (most commonly 30 mg/kg) IV for one
day on day -4, and cyclophosphamide was dosed at 50
mg/kg IV daily for 2 days on days -3 and -2 (all based on
ideal body weight). Granulocyte colony stimulating fac-
tor (G-CSF), dosed at 5 µg/kg, was started on day 5 for
autologous SCTs. Dilantin seizure prophylaxis was given
with chemotherapy infusion and all patients received
ciprofloxacin for prophylaxis prior to conditioning thera-
py, and bactrim, acyclovir, and diflucan prophylaxis on
discharge after transplant. Patients who received allo-
geneic SCT received graft versus host disease (GVHD)
prophylaxis with a calcineurin inhibitor and metho-
2.3. Statistical Analysis
Engraftment time was defined as the time to an abso-
lute neutrophil count (ANC) > 500/µL for 3 consecutive
days and a platelet count > 20,000/µL post-SCT without
requiring a transfusion. Toxicity post transplant was
graded according to the National Cancer Institute Com-
mon Terminology Criteria (NCI CTC) scale. Early toxic-
ity was defined as adverse events occurring less than 100
days post-transplant, whereas late toxicity was defined as
adverse events occurring 100 days post-transplant. Al-
logeneic SCT patients were also evaluated for the pres-
ence of GVHD in the acute (<100 days) and chronic
(100 days) post-SCT period.
Overall survival (OS), disease-free survival (DFS),
and disease-specific survival (DSS) curves were con-
structed using the Kaplan-Meier method. OS was defined
as survival after transplant. DFS was defined as survival
in complete remission (complete clinical and radiogra-
phic resolution of tumor). DSS was defined as survival
from disease post SCT. Univariate proportional hazard
modeling was performed to determine which patient and
disease characteristics as described above might be asso-
ciated with survival outcomes. Logrank tests were used
to compare survival rates and the Wald chi-square test
was used to determine the significance of model coeffi-
cients from the Cox regression, which was in turn used to
determine the effect of various factors on survival. Fi-
sher’s exact test was used to examine the association
between toxicity outcomes and categorical patient and
disease characteristics, while the Wilcoxon rank-sum test
was used to examine the association between toxicity out-
comes and continuous patient and disease characteristics.
For all analyses, p < 0.05 was considered statistically
3.1. Patient Demographics
Twenty-five patients with relapsed or refractory NHL
underwent SCT with Bu/Cy/VP16 conditioning from 3/
2003 to 6/2011. The demographics of the study popula-
tion and the associated disease characteristics are sum-
marized in Table 1.
The majority of patients (76%) had aggressive NHL
histology. All patients had relapsed or refractory disease.
Copyright © 2013 SciRes. OPEN A CCESS
N. Vidula et al. / Modern Chemotherapy 2 (2013) 57-65 59
Furthermore, 52% of patients had primary refractory
lymphoma. The median number of prior regimens was 3.
In terms of disease status at time of SCT (i.e., response to
salvage therapy), 52% of patients had chemotherapy sen-
sitive disease (n = 11 complete remission and n = 2 par-
tial remission), while 48% had chemotherapy resistant
disease (n = 12 progressive disease).
3.2. Engraftment, Toxicity, and Transplant
Related Mortality (TRM)
The median engraftment time for neutrophils and
platelets were 13.5 and 14 days, respectively. In terms of
SCT-related toxicity, 92% patients experienced grade 3
or 4 hematologic toxicity. The most common grade 3 or
4 non-hematologic toxicities were neutropenic fever
(92%), infection (68%), pneumonitis (28%), intubation
(16%), and altered mental status/stroke (12%) in the
early post-transplant period (Table 2). In the late post-
transplant period, 44% of patients experienced pneu-
monitis (Tabl e 2). The most common grade 1 - 2 toxici-
ties in the early post-transplant period were elevated liver
enzymes (72%) and mucositis (64%) followed by renal
failure (8%), hypersensitivity reaction (8%), and throm-
boembolism (4%).
In the initial post-transplant period (i.e., <100 days), 4
of 25 patients died from hypoxemic respiratory failure (3)
and sepsis (1) yielding a TRM of 16%. Two of these pa-
tients had allogeneic SCT (diffuse large B-cell lympho-
ma (DLBCL) and acute lymphoblastic lymphoma), while
the other two had received autologous SCT (both DLBCL)
yielding TRM rates of 14% and 18% for allogeneic and
autologous patients, respectively.
Among patients who received allogeneic SCT, 11/14
(79%) experienced acute GVHD, with skin and liver
involvement being the most frequent organs involved.
After 100 days post-SCT, 6/11 (55%) patients experienc-
ed chronic GVHD most commonly affecting the skin. Not-
ably, there were no non-relapse deaths that occurred after
100 days post-SCT in either the autologous or allogeneic
population; thus, the 2-year NRM for all patients was
16% with all of these deaths occurring <100 days.
3.3. Survival
The median follow-up time for all patients was 15
months (range: 2 - 96 months). The 1-year and 2-year
DFS rates for all patients (Figure 1) were 73% (95%
confidence interval (CI): 64% - 87%) and 64% (95% CI:
36% - 82%), respectively, while the 1-year and 2-year
OS rates were 79% (95% CI: 57-91%) and 69% (95% CI:
40% - 86%), respectively (Figure 1). Of note, only 2 of
25 (8%) patients died due to NHL. This resulted in a
2-year disease-specific survival (DSS) for all patients of
012 24 36 48 60 72 84 96
Time in Months
Percent Survival
Figure 1. Overall Survival (OS), Disease Specific Survival
(DSS) and Disease Free Survival (DFS). The 1 year rate of OS
was 79% (95% CI: 57% - 91%) and the 2 year rate of OS was
69% (95% CI: 40% - 86%). The 1 year rate of DSS was 83%
(95% CI: 56 - 94%) and the 2 year rate of DSS was 73% (95%
CI: 40% - 90%). The 1 year rate of DFS was 73% (95% CI:
64% - 87%) and the 2 year rate of DFS was 64% (95% CI: 36%
- 82%).
73% (95% CI: 40% - 90%) (Figure 1). For allogeneic
patients, OS was 86% at 1 year and 75% at 2 years,
whereas for autologous patients, OS was 72% at 1 year
(OS could not be calculated at 2 years due to the follow-
up period).
3.4. Prognostic Factors
Proportional hazard modeling of multiple patient cha-
racteristics and disease factors were examined for all
patients to identify potential factors that predicted sur-
vival using a univariate analysis (Table 3). We identified
that elevated pre-SCT LDH (hazard ratio (HR) 8.1, 95%
CI: 1.4 - 45.2, p = 0.02) and IPI at time of relapse prior
to SCT (HR 3.0, 95% CI 1.1 - 7.9, p = 0.03) portend-
ed inferior DFS, while increasing age (HR 1.1, 95% CI:
1.0 - 1.1, p = 0.06), chemotherapy-resistant disease (HR
7.73, 95% CI: 0.93 - 64.5, p = 0.07), and performance
status prior to SCT (HR 6.5, 95% CI: 0.8 - 53.8, p =
0.08) were of borderline significance. Elevated pre-SCT
LDH (HR 15.0, 95% CI: 1.6 - 138.1, p = 0.02) and IPI
(HR 4.4, 95% CI: 1.5 - 13.1, p = 0.008) also predict-
ed inferior OS, while worse performance status (HR
3.74, 95% CI: 0.99 - 14.0, p = 0.05), age (HR 1.1, 95%
CI 1.0 - 1.2, p = 0.06), and chemotherapy-resistant dis-
ease (HR 6.54, 95% CI: 0.76 - 56.3, p = 0.09) were bor-
Fisher’s exact test and Wilcoxon rank sum test ana-
lysis were performed to examine patient and disease cha-
racteristics that correlated with late toxicity. The strong-
est predictors of post-SCT late toxicity were pre-tran-
splant LDH (p = 0.057) and IPI (p = 0.11). Finally, late
toxicity was more likely to be associated with aggressive
NHL disease histology (61%) compared with low grade
(31%) or mixed histologies (8%).
Copyright © 2013 SciRes. OPEN A CCESS
N. Vidula et al. / Modern Chemotherapy 2 (2013) 57-65
Copyright © 2013 SciRes. OPEN A CCESS
Table 1. Patient demographics and disease characteristics.
Criteria Description
Median: 49 Age
Range: 27 - 71
Male: 16/25 (64%) Sex
Female: 9/25 (36%)
Low grade (5 FL and 1 MZL 6/25 (24%)
Aggressive (9 DLBCL, 3 MCL, 2 transformed DLBCL), 1 Richter’s transformation
(i.e., CLL to DLBCL), 1 precursor B-cell ALL): 16/25 (64%)
Mixed histology (i.e., 2 NHL and HL and 1 DLBCL and FL): 3/25 (12%)
Median: 2 Extra-nodal sites
Range: 0 - 7
Median: 4
Range: 2 - 4
Stage 2: 3/25 (12%)
Stage 3: 7/25 (28%)
Disease stage
Stage 4: 15/25 (60%)
Primary refractory: 13/25 (52%) Disease status*
Relapsed disease: 12/25 (48%)
Median: 4 months Remission period prior to SCT (for those patients in remission)
Range: 2 - 12 months
Median: 1 Performance Status
Range: 0 - 2
Normal: 16/25 (64%)
1 - 3 times normal: 8/25 (32%)
LDH immediately prior to SCT (pre-SCT LDH)
3 times normal: 1/25 (4%)
0:1/25 (4%)
1: 2/25 (8%)
2: 13/25 (52%)
3: 6/25 (24%)
4: 3/25 (12%)
Median: 2
Median: 3 Prior regimens
Range: 1 - 7
Yes: 4/25 (16%) Prior radiation
No: 21/25 (84%)
Yes: 4/25 (16%) Bulky adenopathy
No: 21/25 (84%)
N. Vidula et al. / Modern Chemotherapy 2 (2013) 57-65 61
Yes: 22/25 (88%)
No: 3/25 (12%)
Number of patients with various comorbidities:
Cardiac disease: 2/25 (8%)
Diabetes: 4/25 (16%)
Hyperlipidemia: 3/25 (12%)
Hypertension: 10/25 (40%)
Prior cancer: 6/25 (24%)
Pulmonary disease: 5/25 (20%)
Psychiatric: 8/25 (32%)
Renal disease: 4/25 (16%)
Thromboembolism: 3/25 (12%)
Other including rheumatologic/neurologic disease: 12/25 (48%)
Normal: 12/25 (48%) Baseline pulmonary status
Decreased DLCO or obstructive/restrictive defect: 13/25 (52%)
Normal: 19/25 (76%) Baseline liver function
Elevated liver function tests: 6/25 (24%)
Normal: 13/25 (52%) Baseline cardiac function
Depressed EF (<50%) or diastolic dysfunction: 12/25 (48%)
Sensitive: 13/25 (52%) Disease/chemotherapy sensitivity (at time of SCT)
Resistant: 12/25 (48%)
Type of SCT Allogeneic: 14/25 (56%)
Autologous: 11/25 (44%)
Abbreviations: FL, follicular lymphoma; MZL, marginal zone lymphoma; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; NHL,
Non-Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; ALL, acute lymphoblastic leukemia; HL, Hodgkin lymphoma; IPI, International Prognostic
Index; DLCO, diffusing capacity for carbon monoxide; EF, ejection fraction; SCT, stem cell transplant. *Primary refractory disease indicates no remission to
prior therapy or remission duration < 6 months.
Table 2. Early and late SCT-related grade 3 and 4 toxicities.
Toxicity Early* Late*
Neutropenic fever 23/25 (92%) None
Infection 17/25 (68%) 3/18 (17%)
Pneumonitis 7/25 (28%) 8/18 (44%)
Intubation 4/25 (16%) None
Altered mental status or stroke3/25 (12%) 1/18 (5.6%)
Renal failure 2/25 (8%) None
Cardiac complication 2/25 (8%) None
*Early indicates 1 - 99 days post-SCT, while late indicates 100 days post-
Stem cell transplantation has become a treatment op-
tion for NHL patients including those with relapsed/ re-
fractory disease, low, intermediate or high grade NHL,
and aggressive NHL [1-6,9-10,12,14-19]. For relapsed/
refractory NHL, Bu/Cy/VP-16 has been investigated as a
conditioning regimen. We retrospectively analyzed the
efficacy and toxicity of this regimen at the Northwestern
University Robert H. Lurie Comprehensive Cancer Cen-
ter for patients with “high risk” relapsed or refractory
Results of our study support data from prior studies
suggesting that Bu/Cy/VP-16 is an effective conditioning
regimen prior to SCT in patients with relapsed/refractory
NHL. We noted a 2-year OS rate of 69% and 2-year DFS
rate of 64% in a relatively high risk NHL patient popula-
tion. These data are similar to results obtained by Kim et
al. [10] who estimated the 3-year OS and PFS for re-
lapsed/refractory or high-risk NHL patients transplanted
with Bu/Cy/VP-16 to be 72% and 70%, respectively,
with 61% of patients in complete remission and 39% of
patients in partial remission prior to transplant. Escalon
et al. [8] noted a 3-year OS of 43% and progression-free
survival of 39%, with 60% of patients in complete
Copyright © 2013 SciRes. OPEN A CCESS
N. Vidula et al. / Modern Chemotherapy 2 (2013) 57-65
Table 3. Proportional hazard modeling of prognostic factors affecting survival.
Prognostic Factors HR 95% CI P HR 95% CI P
Allogeneic vs. autologous 0.52 0.09 - 3.11 0.47 0.66 0.13 - 3.36 0.62
III vs. II 0.3 0.02 - 4.92 0.4 0.3 0.02 - 4.96 0.4
IV vs. II 0.64 0.07 - 5.97 0.69 0.75 0.09 - 6.69 0.8
III/IV vs. II 0.52 0.06 - 4.67 0.56 0.6 0.07 - 5.20 0.65
Chemotherapy-resistant disease 6.54 0.76 - 56.3 0.09 7.73 0.93 - 64.5 0.07
IPI (continuous) 4.39 1.48 - 13.1 0.008 3.01 1.15 - 7.92 0.03
Bulky disease 0.97 0.11 - 8.34 0.98 0.77 0.09 - 6.45 0.81
Age (continuous) 1.07 1.00 - 1.15 0.06 1.06 1.00 - 1.13 0.06
Male vs. Female
1.08 0.20 - 5.92 0.93 1.3 0.25 - 6.72 0.75
Number of extra nodal sites >3 2.47 0.45 - 13.57 0.3 2.03 0.39 - 10.51 0.4
Number of prior regimens >3 0.51 0.09 - 2.84 0.45 0.41 0.08 - 2.13 0.29
Performance status 2 - 4 3.74 0.99 - 14.0 0.05 6.5 0.8 - 53.8 0.08
Baseline liver function* 1.55 0.28 - 8.62 0.62 2.29 0.50 - 10.34 0.29
Baseline cardiac function* 0.55 0.10 - 2.99 0.49 0.47 0.09 - 2.41 0.36
Baseline pulmonary function* 1.42 0.28 - 7.24 0.67 1.05 0.23 - 4.79 0.95
1 - 3 normal 15.03 1.64 - 138.08 0.02 8.05 1.44 - 45.18 0.02
>3 normal 114.45 4.00 - 3277.54 0.01 69.22 3.23 - 1480.45 0.01
Abbreviations: OS, overall survival; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval; P, p-value; IPI, International Prognostic Index;
Pre-SCT LDH, LDH immediately prior to transplant. *Analysis involved comparing abnormal versus normal status.
remission/complete remission unconfirmed and 30% of
patients with partial remission prior to transplant, while
Copelan et al. [7] noted a 3-year progression free sur-
vival of 47%, with 41% of patients in sensitive-first re-
The majority of our patients in the current series had
aggressive disease, which was noted by Copelan et al . [7]
to be an adverse prognostic factor. Weaver et al. [20]
showed that disease stage may be an important determi-
nant of survival outcomes. While disease stage alone did
not have a statistically significant impact on survival
outcomes in our study, it was factored into the calculated
IPI, which we identified as a predictive factor for sur-
vival. In addition, several studies have shown that dis-
ease status at time of SCT is a critical factor that predicts
survival [21,22]. Stiff et al. [22] found that the 3-year OS
and PFS of patients with chemotherapy-resistant disease
was statistically inferior (p = 0.009) at 29% and 22%, re-
spectively, in comparison with chemo-sensitive disease
patients whose 3-year OS and PFS were 55% and 42%,
respectively. Gulati et al. [21] found that the DFS of pa-
tients who were in complete remission prior to transplant
was 80% in comparison with 11% for those patients who
had progressive disease. Nearly 50% of patients in our
series had chemotherapy-resistant disease at time of SCT.
Despite these high-risk features of patients herein, Bu/
Cy/VP-16 appeared to mitigate this adverse prognostic
Our study was limited by sample size and follow-up.
Other investigators have estimated the 4 - 5 years survival
of patients with NHL to be approximately 50% [6,15,23],
although Zhang et al. [24] noted a 5-year survival rate of
64%, so further longitudinal analysis of our population is
needed to determine whether the pre-transplant charac-
teristics we have identified (lower baseline IPI and nor-
mal pre-transplant LDH) continue to confer a survival
advantage in the long-term. This will be critical not only
for observation of potential disease relapse, but also re-
Copyright © 2013 SciRes. OPEN A CCESS
N. Vidula et al. / Modern Chemotherapy 2 (2013) 57-65 63
garding the development of late effects, in particular the
second malignancies/leukemia.
The early TRM with Bu/Cy/VP-16 in our study was
16%. This overall result compares favorably with the
46% TRM noted by Vaughan et al. [13]. The majority of
patients in our series with TRM died due to sepsis and/or
hypoxemic respiratory failure, which has been described
[8,23]. Mucositis also occurred frequently in the early
post-transplant period, which has been noted by other
authors [7-9,25]. Hepatic toxicity was commonly seen in
the initial pre-transplant period, which was also noted by
Kim et al. [10] and Copelan et al. [7]. However, veno-
occlusive disease was rare in our population (n = 1); al-
though more cases have been noted in the literature [10,
13]. This may be due to intravenous administration of
etoposide as opposed to oral dosing, as suggested by
Kayshap et al. [26].
Pneumonitis was a common late toxicity, which has
previously been described with this regimen [9,27].
Crilley et al. [28] noted significant pulmonary toxicity
with this regimen in patients who had received prior ra-
diation, but Spitzer et al. [29] found no difference in
pulmonary toxicity between patients receiving total body
irradiation and busulfan in combination with etoposide;
the pulmonary toxicity noted in our population may
therefore be a consequence of busulfan [30]. Given the
prevalence of this toxicity, alternative regimens may be
considered in those patients with poor baseline pulmo-
nary function, given the risk of long-term disabling pul-
monary consequences. Nevertheless, despite these tox-
icities, there were no late non-relapse fatal events noted
(i.e. >100 days). Additionally, there were no secondary
malignancies or myelodysplasia seen in contrast with
Vaughan et al. [13]. This may be due in part to our fol-
low-up time period, and further longitudinal study of our
patient population is needed.
Altogether, we conclude that Bu/Cy/VP-16 may serve
as an effective conditioning regimen for patients with
relapsed/refractory NHL. This includes patients with
chemotherapy-resistant NHL, including active disease at
time of SCT. However, additional analysis and continued
refinement of this conditioning regimen are warranted in
order to decrease the transplant-related mortality associ-
ated with this therapy.
The authors would like to acknowledge the Northwestern University
Feinberg School of Medicine and the Robert H. Lurie Comprehensive
Cancer Center.
[1] Haioun, C., Lepage, E., Gisselbrecht, C., Salles, G., Coif-
fier, B., Brice, P., et al. (2000) Survival benefit of high-
dose therapy in poor-risk aggressive non-Hodgkin’s lym-
phoma: Final analysis of the prospective LNH87-2 pro-
tocol—a groupe d’Etude des lymphomes de l’Adulte stu-
dy. Journal of Clinical Oncology, 18, 3025-3030.
[2] Milpied, N., Deconinck, E., Gaillard, F., Delwail, V.,
Foussard, C., Berthou, C., et al. (2004) Initial treatment
of aggressive lymphoma with high-dose chemotherapy
and autologous stem-cell support. New England Journal
of Medici ne, 350, 1287-1295.
[3] Pettengell, R., Radford, J.A., Morgenstern, G.R., Scarffe,
J.H., Harris, M., Woll, P.J., et al. (1996) Survival benefit
from high-dose therapy with autologous blood progeni-
tor-cell transplantation in poor-prognosis non-Hodgkin’s
lymphoma. Journal of Clinical Oncology, 14, 586-592.
[4] Philip, T., Guglielmi, C., Hagenbeek, A., Somers, R., Van
der Lelie, H., Bron, D., et al. (1995) Autologous bone
marrow transplantation as compared with salvage chemo-
therapy in relapses of chemotherapy-sensitive non-Hodg-
kin’s lymphoma. New England Journal of Medicine, 333,
[5] Vose, J.M., Armitage, J.O., Bierman, P.J., Weisenburger,
D.D., Hutchins, M., Dowling, M.D., et al. (1989) Salvage
therapy for relapsed or refractory non-Hodgkin’s lympho-
ma utilizing autologous bone marrow transplantation. The
American Journal of Medicine, 87, 285-288.
[6] Aggarwal, C., Gupta, S., Vaughan, W.P., Saylors, G.B.,
Salzman, D.E., Katz, R.O., et al. (2006) Improved out-
comes in intermediate- and high-risk aggressive non-
Hodgkin lymphoma after autologous hematopoietic stem
cell transplantation substituting intravenous for oral bus-
ulfan in a busulfan, cyclophosphamide, and etoposide
preparative regimen. Biology of Blood and Marrow Tran-
splantation, 12, 770-777.
[7] Copelan, E.A., Penza, S.L., Pohlman, B., Avalos, B.R.,
Goormastic, M., Andresen, S.W., et al. (2000) Autotrans-
plantation following busulfan, etoposide and cyclophos-
phamide in patients with non-Hodgkin’s lymphoma. Bone
Marr ow Transplant, 25, 1243-1248.
[8] Escalón, M.P., Stefanovic, A., Venkatraman, A., Pereira,
D., Santos, E.S., Goodman, M., et al. (2009) Autologous
transplantation for relapsed non-Hodgkin’s lymphoma
using intravenous busulfan and cyclophosphamide as
conditioning regimen: A single center experience. Bone
Marr ow Transplant, 44, 89-96.
[9] Hänel, M., Kröger, N., Sonnenberg, S., Bornhäuser, M.,
Krüger, W., Kroschinsky, F., et al. (2002) Busulfan,
cyclophosphamide, and etoposide as high dose condition-
ing regimen in patients with malignant lymphoma. Annals
of Hematology, 81, 96-102.
[10] Kim, J.G
., Sohn, S.K., Chae, Y.S., Yang, D.H., Lee, J.J.,
Kim, H.J., et al. (2007) Multicenter study of intravenous
Copyright © 2013 SciRes. OPEN A CCESS
N. Vidula et al. / Modern Chemotherapy 2 (2013) 57-65
busulfan, cyclophosphamide, and etoposide (i.v. Bu/Cy/E)
as conditioning regimen for autologous stem cell trans-
plantation in patients with non-Hodgkin’s lymphoma.
Bone Marrow Transplant, 40, 919-924.
[11] Kim, J.E., Lee, D.H., Yoo, C., Kim, S., Kim, S.W., Lee,
J.S., et al. (2011) BEAM or BuCyE high-dose chemo-
therapy followed by autologous stem cell transplantation
in non-Hodgkin’s lymphoma patients: A single center
comparative analysis of efficacy and toxicity. Leukemia
Research, 35, 183-187.
[12] Kröger, N., Hoffknecht, M., Dreger, P., Krüger, W., Zeller,
W., Krüll, A., et al. (1998) Long-term disease-free survi-
val of patients with advanced mantle-cell lymphoma fol-
lowing high-dose chemotherapy. Bone Marrow Trans-
plant, 21, 55-57. http://dx.doi.org/10.1038/sj.bmt.1701033
[13] Vaughan, W.P., Dennisone, J.D., Reed, E.C., Klassen, L.,
McGuire, T.R., Sanger, W.G., et al. (1991) Improved re-
sults of allogeneic bone marrow transplantation for ad-
vanced hematologic malignancy using busulfan, cyclo-
phosphamide and etoposide as cytoreductive and immu-
nosuppressive therapy. Bone Marrow Transplant, 8, 489-
495. PMid:1790429.
[14] Bolwell, B., Kalaycio, M., Andresen, S., Goormastic, M.,
McBee, M., Kuczkowski, E., et al. (2000) Autologous
peripheral blood progenitor cell transplantation for trans-
formed diffuse large-cell lymphoma. Clinical Lymphoma,
1, 226-233. http://dx.doi.org/10.3816/CLM.2000.n.019
[15] Kröger, N, Hoffknecht, M., Dreger, P., Krüger, W., Zeller,
W., Krüll, A., et al. (1998) Long-term disease-free sur-
vival of patients with advanced mantle-cell lymphoma
following high-dose chemotherapy. Bone Marrow Trans-
plant, 21, 55-57.
[16] Philip, T., Armitage, J.O., Spitzer, G., Chauvin, F., Jagan-
nath, S., Cahn, J., et al. (1987) High-dose therapy and
autologous bone marrow transplantation after failure of
conventional chemotherapy in adults with intermediate-
grade or high-grade non-Hodgkin’s lymphoma. New Eng-
land Journal of Medicine, 316, 1493-1498.
[17] Schouten, H.C., Colombat, P., Verdonck, L.F., Gorin,
N.C., Björkstrand, B., Taghipour, G., et al. (1994) Autolo-
gous bone marrow transplantation for low-grade non-
Hodgkin’s lymphoma: The European Bone Marrow Tran-
splant Group experience. EBMT Working Party for Lym-
phoma. Annals of Oncology, 5, 147-149.
[18] Sweetenham, J.W., Proctor, S.J., Blaise, D., De Laurenzi,
A., Pearce, R., Taghipour, G., et al. (1994) High-dose
therapy and autologous bone marrow transplantation in
first complete remission for adult patients with high-
grade non-Hodgkin’s lymphoma: The EBMT experience.
Lymphoma Working Party of the European Group for
Bone Marrow Transplantation. Annals of Oncology, 5,
[19] Takvorian, T., Canellos, G.P., Ritz, J., Freedman, A.S.,
Anderson, K.C., Mauch, P., et al. (1987) Prolonged dis-
ease-free survival after autologous bone marrow trans-
plantation in patients with non-Hodgkin’s lymphoma with
a poor prognosis. New England Journal of Medicine, 316,
[20] Weaver, C.H., Petersen, F.B., Appelbaum, F.R., Bensinger,
W.I., Press, O., Martin, P., et al. (1994) High-dose frac-
tionated total body irradiation, etoposide, and cyclophos-
phamide followed by autologous stem cell support in pa-
tients with malignant lymphoma. Journal of Clinical On-
cology, 12, 2559-2566. PMid:7989929.
[21] Gulati, S., Yahalom, J., Acaba, L., Reich, L., Motzer, R.,
Crown, J., et al. (1992) Treatment of patients with relaps-
ed and resistant non-Hodgkin’s lymphoma using total
body irradiation, etoposide, and cyclophosphamide and
autologous bone marrow transplantation. Journal of Cli-
nical Oncology, 10, 936-941.
[22] Stiff, P.J., Dahlberg, S., Forman, S.J., McCall, A.R., Horn-
ing, S.J., Nademanee, A.P., et al. (1998) Autologous bone
marrow transplantation for patients with relapsed or re-
fractory diffuse aggressive non-Hodgkin’s lymphoma:
Value of augmented preparative regimens—A Southwest
Oncology Group trial. Journal of Clinical Oncology, 16,
[23] Santos, E.C., Sessions, J., Hutcherson, D., Flowers, C.,
Langston, A. and Waller EK. (2007) Long-term outcome
of Hodgkin disease patients following high-dose busulfan,
etoposide, cyclophosphamide, and autologous stem cell
transplantation—A similar experience. Biology of Blood
and Marrow Transplantation, 13, 746-747.
[24] Zhang, H., Graiser, M., Hutcherson, D.A., Olufemi Dada,
M., McMillan, S., Zahir, A., et al. (2012) Pharmacoki-
netic-directed high dose busulfan combined with cyclo-
phosphamide and etoposide results in predictable drug
levels and durable long term survival in lymphoma pa-
tients undergoing autologous stem cell transplantation.
Biology of Blood and Marrow Transplant, 18, 1287-1294.
[25] Ritchie, D.S., Szer, J., Roberts, A.W., Shuttleworth, P. and
Grigg, A.P. (2002) A phase I dose-escalation study of eto-
poside continuous infusion added to busulphan/cyclo-
phosphamide as conditioning prior to autologous or al-
logeneic stem cell transplantation. Bone Marrow Trans-
plantation, 30, 645-650.
[26] Kashyap, A., Wingard, J., Cagnoni, P., Roy, J., Tarantolo,
S., Hu, W., et al. (2002) Intravenous versus oral busulfan
as part of a busulfan/cyclophosphamide preparative regi-
men for allogeneic hematopoietic stem cell transplanta-
tion: Decreased incidence of hepatic venoocclusive dis-
ease (HVOD), HVOD-related mortality, and overall 100-
day mortality. Biology of Blood and Marrow Transplan-
tation, 8, 493-500.
[27] Wadehra, N., Farag, S., Bolwell, B., Elder, P., Penza, S.,
Kalaycio, M., et al. (2006) Long-term outcome of Hodg-
kin disease patients following high-dose busulfan, eto-
poside, cyclophosphamide, and autologous stem cell
transplantation. Biology of Blood and Marrow Transplan-
Copyright © 2013 SciRes. OPEN A CCESS
N. Vidula et al. / Modern Chemotherapy 2 (2013) 57-65
Copyright © 2013 SciRes. OPEN A CCESS
tation, 12, 1343-1349.
[28] Crilley, P., Topolsky, D., Styler, M.J., Bernstein, E., Res-
nick K, Mullaney, R., et al. (1995) Extramedullary toxic-
ity of a conditioning regimen containing busulphan,
cyclophosphamide and etoposide in 84 patients undergo-
ing autologous and allogenic bone marrow transplantation.
Bone Marrow Transplantation, 15. 361-365.
[29] Spitzer, T.R., Cottler-Fox, M., Torrisi, J., Cahill, R.,
Greenspan, A., Lynch, M., et al. (1989) Escalating doses
of etoposide with cyclophosphamide and fractionated to-
tal body irradiation or busulfan as conditioning for bone
marrow transplantation. Bone Marrow Transplantation, 4,
559-565. PMid:2676044.
[30] Kalaycio, M., Pohlman, B., Kuczkowski, E., Rybicki, L.,
Andresen, S., Sobecks, R., et al. (2006) High-dose busul-
fan and the risk of pulmonary mortality after autologous
stem cell transplant. Clinical Transplantation, 20, 783-
787. http://dx.doi.org/10.1111/j.1399-0012.2006.00581.x