Radiol Oncol 2017; 51(1): 81-87. doi:10.1515/raon-2016-0040
81
research article
Long-term outcomes of high dose treatment 
and autologous stem cell transplantation in 
follicular and mantle cell lymphomas – a single 
centre experience
Lucka Boltezar1, Karlo Pintaric2, Jože Pretnar3, Maja Pohar Perme4,  
Barbara Jezersek Novakovic1 
1 Department of Medical Oncology, Institute of Oncology Ljubljana, Slovenia
2 Faculty of Medicine, University of Ljubljana, Slovenia
3 Department of Hematology, University Clinical Centre Ljubljana, Slovenia
4 Department of Biostatistics and Medical Informatics, University of Ljubljana, Slovenia
Radiol Oncol 2017; 51(1): 81-87.
Received 6 January 2016 
Accepted 24 May 2016
Correspondence to: Assoc. Prof. Barbara Jezeršek Novaković, M.D., Ph.D., Department of Medical Oncology, Institute of Oncology Ljubljana, 
Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 1 5879 631; Fax: +386 1 5879 305; E-mail: bjezersek@onko-i.si
Disclosure: No potential conflicts of interest were disclosed. 
Background. Advanced follicular lymphoma (FL) and mantle cell lymphoma (MCL) are incurable diseases with 
conventional treatment. The high dose treatment (HDT) with autologous stem cell transplantation (ASCT), however, 
offers a certain proportion of these patients the prospect of a prolonged disease-free and overall survival. The aim of 
this study was to investigate the event free survival (EFS) and overall survival (OS) in patients with FL and MCL treated 
with ASCT.
Patients and methods. Seventeen patients with FL and 29 patients with MCL were included, 15 of them were trans-
planted to consolidate the response to second line treatment and 24 to consolidate their first remission, respectively. 
All were conditioned with total body irradiation (TBI) and high dose cyclophosphamide between 2006 and 2014 and 
all were transplanted with peripheral blood stem cells.
Results. The estimated 5-year OS for FL was 87.8% (95% confidence interval [CI] 59.5%–96.8%) and for MCL 79.3% 
(95% CI 56.1%–91.1%), respectively. The estimated 5-year EFS for FL was 76.0% (95% CI 48.0%–90.3%) and for MCL 69.8% 
(95% CI 45.5%–84.8%), respectively. There were no secondary hematological malignancies observed in either group.
Conclusions. Based on above results, the ASCT with TBI is a good treatment option in terms of long-term survival for 
patients with follicular and mantle cell lymphoma demonstrating a relatively low rate of late toxicities and secondary 
malignancies.
Key words: follicular lymphoma; mantle cell lymphoma; autologous stem cell transplantation; overall survival; hema-
tological malignancies
Introduction
Follicular lymphoma (FL) is nowadays still an in-
curable disease using standard chemotherapy.1 
Even though it is very sensitive to chemo- and radi-
otherapy relapses remain the main treatment fail-
ure. Significant changes were made in the past two 
decades, a great gain was the addition of rituximab 
to the standard CHOP regimen (cyclophospha-
mide, doxorubicin, vincristine, and prednisone) 
to prolong progression-free survival (PFS).2,3 
Rituximab is now the golden standard in the first 
line treatment2, it also improves the overall sur-
vival (OS) in relapsed FL patients.4 In a Cochrane 
review in 2012, the authors demonstrated that high 
dose treatment (HDT) with autologous stem cell 
Radiol Oncol 2017; 51(1): 81-87.
Boltezar L et al. / Stem cell transplantation in follicular and mantle cell lymphomas82
transplantation (ASCT) improves the progression-
free survival in comparison with chemotherapy or 
immuno-chemotherapy in previously untreated 
patients with FL, but does not prolong the OS.5 
There is also evidence that HDT with ASCT brings 
benefits to patients with relapsed FL.5,6 A consen-
sus was made in 2013 by the European Group for 
Blood and Marrow Transplant stating that the SCT 
is appropriate in patients with first chemo-sensi-
tive relapse to consolidate remission, especially in 
patients with a short response after immuno-chem-
otherapy or with high-risk follicular lymphoma 
international prognostic index (FLIPI). They also 
pointed out that the HDT with ASCT is appropriate 
in second or subsequent chemo-sensitive relapses.1
Allogeneic transplantation and autologous 
transplantation are both possible. A higher relapse 
rate was observed in autologous SCT, whereas no 
significant difference in the disease-free survival or 
OS was found.7,8 Allogeneic SCT showed a lower 
risk for disease recurrence9,10, and that also ap-
plies for the reduced intensity conditioning SCT.8 
However, higher treatment-related mortality after 
allogeneic SCT than after autologous was objecti-
fied. One of the factors which contributed signifi-
cantly to the higher treatment-related mortality 
was the total body irradiation (TBI).9
The mantle cell lymphoma (MCL) is also an in-
curable disease and successful treatment is still a 
challenge. In the past few years, many induction 
regimens were tested for their efficacy.11-14 Since 
2013, we use in our centre the alternation of ritux-
imab-CHOP (R-CHOP) regimen with R-high dose 
cytarabine-based regimen for younger patients, as 
it was shown that it gives a better OS and a higher 
proportion of partial remission (PR) to complete 
remission (CR) conversions than other regimens.15 
Nevertheless, the HDT and ASCT remain an attrac-
tive option for those with chemo-sensitive disease 
regardless of the induction regimen applied.12,14-16 
In relapsed or refractory disease, long-term dis-
ease-free intervals have not been established, the 
reduced intensity conditioning transplantation is 
here an option.16 Secondary hematological malig-
nancies after the SCT remain an important issue 
with an estimated 5 year risk of 3.8%17, although 
some authors report of minimum hematological 
malignancies or none at all.15 The allogeneic SCT 
offers a lower relapse rate but a higher non-re-
lapse mortality resulting in OS similar to ASCT.18 
However, it was also shown by Romera et al. that 
intensive chemotherapy with R-hyper-CVAD (cy-
clophosphamide, vincristine, doxorubicin, and 
dexamethasone) alternating with R-high dose 
methotrexate-cytarabine is also a suitable treat-
ment option for treatment of MCL without ASCT.19
The aim of this study was to investigate the 
event free survival (EFS) and OS in patients with 
FL and MCL treated with ASCT. 
Patients and methods
The study population includes 17 patients with FL 
and 29 patients with MCL who underwent ASCT 
after HDT conditioning with TBI (fractionated 6 x 
200 cGy during three days’ period) and high dose 
cyclophosphamide (2 x 60 mg/kg) between 2006 
and 2014 and whose conventional treatment and 
the TBI were performed at the Institute of Oncology 
Ljubljana and the transplantation procedure at the 
University Clinical Centre Ljubljana, Department 
of Hematology. The study was conducted accord-
ing to the Helsinki Declaration, all patients were 
aged 18 or above and patient’s informed consent 
was obtained.
According to national guidelines, FL patients 
were transplanted in their second remission and 
only three patients with adverse prognostic fac-
tors were consolidated for their first remission. 
Conversely, MCL patients were transplanted al-
ready in their first remission and exceptionally on-
ly five patients (with low risk international prog-
nostic index for MCL [MIPI]) were consolidated 
for their second or later remission. All patients in-
cluded in the study were transplanted with stem 
cells collected from peripheral blood. All patients 
were also treated with maintenance rituximab post 
ASCT concordant with the latest studies20,21 and 
were treated with rituximab containing regimens 
in their induction treatments. Twenty-six MCL pa-
tients received R-CHOP regimen as their first in-
duction treatment and 3 patients received R-CHOP 
as the second line treatment. In the FL group, only 
10 patients started with R-CHOP as the first line in-
duction treatment and 7 patients received R-CHOP 
after failure of first line treatment without rituxi-
mab.
The disease status prior to ASCT was evalu-
ated according to revised Cheson’s criteria.22 The 
OS was measured from the time of HDT/ASCT to 
death from any cause. The EFS was measured from 
the time of HDT/ASCT to progression, recurrence 
of the disease, or death from any cause. The non-
relapse mortality was defined as death from any 
cause without progression or relapse of lympho-
ma. The EFS and OS were calculated according to 
the Kaplan-Meier method and differences between 
Radiol Oncol 2017; 51(1): 81-87.
Boltezar L et al. / Stem cell transplantation in follicular and mantle cell lymphomas 83
subgroups were analyzed by the log-rank test and 
by the Cox proportional hazards model. The non-
relapse mortality was estimated using the cumula-
tive incidence function. The program used was R 
Statistical software (R for Windows, version R-3.1.2, 
University of Auckland) and GraphPad Prism pro-
gramme (version 3.02, GraphPad Software, USA).
The survival outcomes of three patients with 
histologically confirmed transformation of FL into 
the diffuse large B-cell lymphoma at the time of 
HDT/ASCT were analyzed separately.
Results 
Patients’ characteristics and disease 
status prior to ASCT
Patients’ characteristics are shown in Table 1. In 
the FL group, there was a slight male predomi-
nance. Median age at diagnosis of lymphoma was 
46 years. Thirteen patients had FL grade I/II and 
4 patients had FL grade IIIa. None of the patients 
had FL grade IIIb. Four of them were considered as 
low risk patients (0–1 points) according to FLIPI, 
9 were in the intermediate group (2 points) and 4 
of them in the high risk group (3–5 points). Three 
patients (17.6%) were transplanted to consolidate 
their first remission, 14 (82.4%) were transplanted 
as a consolidation after treatment for their first re-
lapse. Five (29.4%) of them were in CR before trans-
plantation, 12 (70.6%) of them had PR. In the MCL 
group, there were 23 males and 6 females. Median 
age at diagnosis was 54 years. There were 10 pleo-
morphic/blastoid variants of MCL in the study 
population. Twenty-four patients had MIPI below 
5.7 (low risk group), 4 patients between 5.7 and 6.2 
(intermediate risk group) and one patient was in 
the high risk group (MIPI above 6.2). Twenty-four 
patients (82.7%) were transplanted in their first 
remission, 3 patients (10.3%) were transplanted to 
consolidate their second remission and 2 patients 
(6.9%) for later than second remission. Thirteen 
(44.8%) of them had CR before transplantation and 
16 (55.2%) of them had PR. 
Overall and event free survival
The estimated 5-year OS for FL was 87.8% (95% 
confidence interval [CI] 59.5%–96.8%) and the 
median OS has not been reached yet with a me-
dian follow-up time of 57.5 months (range 15–102 
months) (Figure 1A). The FLIPI score did not influ-
ence the OS (p = 0.365, data not shown) and also 
the disease status had no significant impact on the 
OS (p = 0.570, hazard ratio (HR) 2.188, 95% CI HR 
0.120–47.29). 
The estimated 5-year OS for MCL was 79.3% 
(95% CI 56.1%–91.1%), and the median OS has not 
been reached yet with a median follow-up time 
of 31.5 months (range 2.5 months–95.5 months) 
(Figure 1B). The MIPI index had no impact on OS 
(p = 0.776, data not shown) and the same is true for 
TABLE 1. Patients’ characteristics 
Follicular lymphoma group
N = 17
Mantle cell lymphoma group
N = 29
Sex (F/M) 7 (41.2%) / 10 (58.8%) 6 (20.7%) / 23 (79. 3%)
Age at diagnosis in years, median 46 (range 29–62) 54 (range 38–65)
FL grade
I/II
IIIa
13 (76.5%)
4 (23.5%) /
Pleomorphic/blastoid MCL / 10 (34.5%)
Distribution according to FLIPI or MIPI
low risk/intermediate/high risk 4 (23.5%) / 9 (52.9%) / 4 (23.5%) 24 (82.8%) / 4 (13.8%) / 1 (3.4%)
HDT/ASCT
After first line treatment*
After second line treatment or later*
3 (17.6%)
14 (82.4%)
24 (82.7%)
5 (17.2%)
Disease status prior HDT/ASCT
CR
PR 5 (29.4%)12 (70.6%)
13 (44.8%)
16 (55.2%)
Documented rituximab treatment before HDT/
ASCT 17 (100%) 29 (100%)
* according to national guidelines; CR = complete remission; F = female; FL = follicular lymphoma; FLIPI = follicular lymphoma international prognostic index; HDT/ASCT = high 
dose treatment/autologous stem cell transplantation; M = male; MCL = mantle cell lymphoma; MIPI = international prognostic index for mantle cell lymphoma; N = number; PR 
= partial remission
Radiol Oncol 2017; 51(1): 81-87.
Boltezar L et al. / Stem cell transplantation in follicular and mantle cell lymphomas84
the CR or PR status prior to transplantation (p = 
0.668, HR 0.679, 95% CI HR 0.117–3.952).
The estimated 5-year EFS for FL was 76.0% (95% 
CI 48.0%–90.3%) and is shown in Figure 2A. The 
FLIPI score did not influence the EFS (p = 0.124, 
data not shown) and also the disease status (CR or 
PR) prior to ASCT did not (p = 0.851, HR 0.806, 95% 
CI HR 0.0936–7.056). 
The estimated 5-year EFS for MCL was 69.8% 
(95% CI 45.5%–84.8%) and is shown in Figure 2B. 
The MIPI index had no impact on the EFS (p = 
0.486, data not shown) and the same holds true for 
the CR or PR status prior to transplantation (p = 
0.391, HR 0.485, 95% CI HR 0.099–2.472).
Non-relapse mortality and secondary 
malignancies
In FL group, 2 patients (11.8%) died. One patient 
transformed into the diffuse large-B cell lympho-
ma and died due to complications of a massive 
transformation and in one patient the cause of 
death was unrelated to lymphoma. In MCL group, 
5 patients (17.2%) died. Two died of progression 
of MCL, one died due to histologically confirmed 
JC virus leukoencephalopathy and two of causes 
unrelated to lymphoma. The estimated probability 
of non-relapse mortality after 5 years equals 0.063 
in FL (95% CI 0–0.186) and 0.116 in MCL (95% CI 
0–0.245). 
In the FL group, 1 patient (5.9%) developed 
ovarian cancer (treated with surgery) and 1 patient 
(5.9%) bladder cancer, but there were no hemato-
logical malignancies. In MCL group, there were 
also no hematological malignancies, 1 patient was 
just suspected to have myelodysplastic syndrome 
due to prolonged thrombocytopenia but this sus-
picion was later on rejected. One patient (3.4%) de-
veloped prostate cancer and is receiving hormone 
treatment.
Transformations
Survival analyses were done also for the 3 patients 
with transformation of FL into the diffuse large-
B cell lymphoma at the time of HDT and ASCT. 
Median age of these patients was 42 years (range 
39–52). There were 2 males and one female. The 
FLIPI scores were 0, 1 (low risk group) and 2 (in-
termediate risk group). The disease status prior 
transplantation was CR in all three cases, one pa-
tient was transplanted to consolidate the second re-
mission and the other two to consolidate their third 
remission. They were all conditioned with TBI and 
high dose cyclophosphamide. Two of them died, 
one is still alive. With a median survival of 39.5 
months the difference between the OS of those 3 
patients and our FL group was not significant (p 
= 0.062, data not shown). The EFS, however, was 
in these patients significantly shorter (median EFS 
of 15 months) than in our FL group (p = 0.003, HR 
6.805, 95% CI HR 3.414–495.6).
Discussion
Follicular lymphoma
The estimated 5-year OS for our FL patients is 
87.8% and the median OS has not been reached. 
Compared to the study of El-Najjar et al., the sur-
vival of our patients is superior since their 5-year 
OS for TBI-based HDT was 77% while for carmus-
tine, etoposide, cytarabine, melphalan (BEAM) 
treated patients it was 74%. The difference between 
their treatment arms was statistically significant (p 
= 0.042).23 Due to our relatively small sample our CI 
is relatively wide, but the results are encouraging. 
Our projected 8-year OS was also 87.7%, since 
we had no further events in that period, but the 
8-year estimation is not so reliable as the sample 
gets smaller. Thereby, our results resemble more 
than ASCT studies the allogeneic transplantation 
A B
FIGURE 1. (A) Overall survival of follicular lymphoma (FL) patients (n = 17); (B) Overall 
survival of mantle cell lymphoma (MCL) patients (n = 29).
A B
FIGURE 2. (A) Event-free survival of follicular lymphoma (FL) patients (n = 17); (B) 
event-free survival of mantle cell lymphoma (MCL) patients (n = 29).
Radiol Oncol 2017; 51(1): 81-87.
Boltezar L et al. / Stem cell transplantation in follicular and mantle cell lymphomas 85
studies, for example a study of Khouri et al, where 
they reported the 11-year OS of 78% achieved by 
the addition of 90Y to the fludarabine and cyclo-
phosphamide conditioning regimen.24 Van Besien 
et al. conducted a study comparing allogeneic 
and autologous SCT. The TBI conditioning regi-
men was more used for allogeneic transplantation, 
which differs from our study. Their 5-year adjust-
ed probabilities of survival after allogeneic trans-
plantation were 51% and TBI was associated with 
higher transplant related mortality but a lower re-
currence of the disease.9 Our study confirms that 
the TBI including regimen is also appropriate for 
ASCT with a low rate of secondary malignancies 
and late toxicities.
The estimated 5-year EFS of our patients was 
76.0% (95% CI 48.0%–90.3%) which is also better 
than in El-Najjar et al. study, where the 5-year EFS 
for TBI-based HDT was 58%. Like in case of OS, 
the EFS was also significantly worse in patients 
with BEAM-based HDT (49%, p < 0.001).23 Eighty-
two point four percent of our patients were trans-
planted for their first relapse, with the HDT and 
ASCT being an established treatment regimen for 
relapsed disease in the rituximab era.25-27 Sebban et 
al. namely showed no benefit of HDT and ASCT 
after first line treatment regarding the EFS and OS 
in comparison to standard chemotherapy.25 
The significant difference in EFS between our 
patients with FL and those whose lymphomas 
transformed to the diffuse large-B cell lymphoma 
(p = 0.0034) is interesting despite the fact that our 
study groups were relatively small. These results 
emphasize the importance of appropriate patient 
selection for transplantation procedure as the out-
come of the patients with transformation cannot 
compare to our FL group (at least partially on ac-
count of a small number of transformations but al-
so on account of a significantly worse prognosis of 
patients having the transformation), showing that 
FL patients with a transformation to the diffuse 
large-B cell lymphoma are not ideal candidates for 
TBI and high dose cyclophosphamide followed by 
ASCT. However, the transformation cannot be pre-
dicted and for these patients an alternative salvage 
option should be sought - for example a different 
conditioning regimen.
Mantle cell lymphoma
In our study population, the estimated 5-year OS 
for MCL was 79.3% (95% CI 56.1%–91.1%) and 
the median OS has not been reached. Also in this 
population, our results are comparable to the 
ones reported by other authors11,28,29, for example 
by Dreyling et al. where they compared survival 
after TBI and ASCT versus maintenance with 
α-interferon after completion of induction therapy. 
The 3-year OS was 83% after ASCT versus 77% in 
the IFN group (p = 0.18).11 The prospective trial of 
Nordic Lymphoma Group, however, reports of 
a 4-year OS of 81% and a 4-year EFS of 63%, but 
their patients were conditioned with the BEAM 
regimen.30 We can also estimate the 7-year OS for 
our MCL as 79.3% since there were no additional 
events, but that estimation is not as reliable as the 
5-year OS.
In a study by Oinonen et al., the median EFS was 
set at 39 months31, while in our group the median 
has not been achieved yet with a median observa-
tion period of 31.5 months. Delarue et al. revealed 
the same, comparing the BEAM treatment to TBI - 
the median EFS of patients receiving BEAM was 55 
months, whereas the median EFS for the TBI regi-
men group has not been reached (p = 0.05).15 This 
again proves that TBI conditioning regimen is safe 
and appropriate for ASCT in MCL.
The ASCT performed in line of first line treat-
ment to consolidate the first remission was docu-
mented to have a significantly better EFS and OS 
compared to delayed ASCT.11,32 In our study, the 
impact of early or late transplantation on OS and 
EFS was not statistically significant (OS: p = 0.141, 
HR 0.284, 95% CI HR 0.015–1.82; EFS: p = 0.393, 
HR 0.497, 95% CI HR 0.057–3.080). That could be 
due to our relatively small study group and a small 
proportion of transplantations to consolidate the 
second or further remissions. Most of our patients 
were namely transplanted after first line treatment.
TBI conditioning
The TBI regimen has been linked to secondary ma-
lignancies, mostly hematological - myelodysplastic 
syndromes (MDS) and acute myeloid leukemias 
(AML).17,26,33-35 The numbers vary among different 
studies - they range from a 5-year estimated risk of 
3.8%17 to a 7-year cumulative probability of 8.9%34 
and a 6-year incidence of 12%.33 The therapy-relat-
ed-MDS/therapy-related-AML (t-MDS/t-AML) al-
so depended on amount of radiation used for TBI. 
In Metayer et al. multicenter case-control study, 
there was a nonsignificant excess risk of tMDS/
tAML with use of conditioning regimens with TBI, 
compared with no TBI (relative risk [RR]  =  2.0; 
95% CI 0.95–4.18; p  =  0.07). The dose-response 
analysis, however, revealed that the excess risk 
was limited to patients receiving TBI doses of 13.2 
Radiol Oncol 2017; 51(1): 81-87.
Boltezar L et al. / Stem cell transplantation in follicular and mantle cell lymphomas86
Gy (RR  =  6.6; p  = 0 .003). Those with lower TBI 
doses (5–12 Gy) had no evidence of elevated risk 
of tMDS/tAML.34 Hypotheses on cellular level are 
that HDT and TBI cause similar cellular and ge-
netic damages as the pre-transplant therapy to the 
hematopoietic progenitor cells and therefore pro-
vide opportunity for causing damage to the stem 
cells. Reinfusion of peripheral blood progenitor 
cells with previously damaged DNA can result in 
clonal abnormal hematopoiesis.35 In this study, we 
had no hematological malignancies in either of our 
groups. Even though the number of our patients 
is relatively small we may assume that TBI with 
high doses of cyclophosphamide is a safe method 
of conditioning prior to transplantation in regard 
of the secondary hematological malignancies. 
Conclusions
Follicular lymphoma and mantle cell lymphoma 
remain incurable diseases even in modern era. 
Treatment modalities are improving and trans-
plantation of stem cells is gaining a more and more 
important role each year. We present good long 
term survivals after autologous stem cell trans-
plantation following conditioning with TBI and 
high dose cyclophosphamide with minimal toxici-
ties and low incidence of secondary malignancies. 
Our study also demonstrates a low relapse rate and 
therefore we conclude that the autologous stem 
cell transplantation represents a reliable option for 
treatment of follicular and mantle cell lymphoma 
with good long term results. 
Acknowledgments
This study was partially financed by Ministry of 
Science and Technology of Slovenia – grant P3-
0321.
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