Bendamustine for the treatment of relapsed or refractory peripheral T cell lymphomas: A French retrospective multicenter study

Abstract

Peripheral T-cell lymphoma (PTCL) is a group of diseases with poor outcome and few therapeutic options. We aimed to assess the efficacy of bendamustine in real life cohort of patients.
Between November 2009 and March 2015, 138 PTCL patients were treated with bendamustine in 27 centers. Population median age was 64 (28-89) years with male/female ratio of 1.4. There were mainly angio-immunoblastic (AITL = 71), PTCL-not otherwise specified (PTCL-NOS = 40) and anaplastic large cell lymphoma (ALCL = 8). The majority of patients (96%) had disseminated disease and extranodal localizations (77%). Median number of chemotherapy lines prior to bendamustine was 2 (1-8). Median duration of response (DoR) after the last chemotherapy prior to bendamustine was 4.3 months (1-70) and 50% of patients had refractory disease.
Median number of administered bendamustine cycles was 2 (1-8) and 72 patients (52%) received less than 3 mostly because of disease progression. Median dose was 90 (50-150) mg/m². Overall response rate (ORR) was 32.6% with complete response (CR) rate of 24.6% and median DoR was 3.3 months (1-39). AITL patients were more sensitive than PTCL-NOS patients (ORR: 45.1 versus 20%, p = 0.01). Median PFS and OS were 3.1 (0.2-46.3) and 4.4 (0.2-55.4) months. On multivariate analysis, refractory disease (p = 0.001) and extranodal localization (p = 0.028) adversely influenced ORR. Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22, 17 and 23% of cases respectively.
Bendamustine as single agent could be considered as a therapeutic option for relapsed or refractory PTCL, particularly in chemosensitive or AITL patients. Combinations of bendamustine with other drugs warrant further evaluation.

Full text

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www.impactjournals.com/oncotarget/ Oncotarget, Advance Publications 2016
Bendamustine for the treatment of relapsed or refractory
peripheral T cell lymphomas: A French retrospective multicenter
study
Emilie Reboursiere1, Fabien Le Bras2, Charles Herbaux3, Emmanuel Gyan4, Aline
Clavert5, Franck Morschhauser3, Sandra Malak6, David Sibon7, Florence Broussais8,
Thorsten Braun9, Luc-Matthieu Fornecker10, Reda Garidi11, Sabine Tricot12, Roch
Houot13, Bertrand Joly14, Wajed Abarah15, Bachra Chou16, Anne-Dominique
Pham17, Anne-Claire Gac1, Christophe Fruchart1, Emilie Marin1, Violaine Safar18,
Anne Parcelier19, Hervé Maisonneuve20, Emmanuel Bachy21, Guillaume Cartron22,
Arnaud Jaccard23, Olivier Tournilhac24, Cédric Rossi25, Luciane Schirmer26, Jean-
Alain Martignoles27, Philippe Gaulard28, Hervé Tilly29, Gandhi Damaj1,30 and From
the Lymphoma Study Association (LYSA) centers30
1 Department of Hematology, University Hospital of Caen, Caen, France
2 Department of Hematology, Assistance Publique des Hôpitaux de Paris, Créteil, France.
3 Department of Hematology, University and Regional Hospital of Lille, Lille, France
4 Department of Hematology, University Hospital of Tours, UMR CNRS, Tours, France
5 Department of Hematology, University Hospital of Angers, Angers, France
6 Department of Hematology, Institut Curie, Paris, France
7 Department of Hematology, Hôpital Necker-Enfants Malades, Paris, France
8 Department of Hematology, Institut Paoli Calmettes, Marseille, France
9 Department of Hematology, Hôpital Avicenne, Bobigny, France
10 Department of Hematology, University Hospital of Strasbourg, Strasbourg, France
11 Department of Hematology, Saint Quentin Hospital, Saint Quentin, France
12 Department of Hematology, Centre Hospitalier Valenciennes, Valenciennes, France
13 Department of Hematology, University Hospital Pontchaillot, Rennes, France
14 Department of Hematology, Centre Hospitalier Sud Francilien, Corbeil, France
15 Department of Hematology, Meaux Hospital, Meaux, France
16 Department of Hematology, Boulogne-sur-Mer Hospital, Boulogne-sur-Mer, France
17 Department of Biostatistics and Clinical Research, University Hospital of Caen, Caen, France
18 Department of Hematology, Hospices Civils de Lyon, Pierre-Benite, France
19 Department of Hematology, University Hospital of Amiens, Amiens, France
20 Department of Hematology, La Roche-sur-Yon Hospital, La Roche sur-Yon, France
21 Department of Hematology, Hospices Civils de Lyon, Pierre-Benite, France
22 Department of Hematology, Université Montpellier, CHRU, UMR CNRS, Montpellier, France
23 Department of Hematology, University Hospital of Limoges, Limoges, France
24 Department of Hematology, University Hospital of Clermont-Ferrand, Clermont Ferrand, France
25 Department of Hematology, University Hospital of Dijon, Dijon, France
26 Department of Hematology, University Hospital of Nancy, Vandoeuvre Les Nancy, France
27 Department of Hematology, Institut de Cancérologie Lucien Neuwirth, Saint-Etienne, France
28 Department of Pathology, University Paris Est, Hôpital Henri Mondor, Créteil, France
29 Department of Hematology, Centre Henri Becquerel, Rouen, France
30 Microenvironnement Cellulaire et Pathologies, Normandie University, UNICAEN, MILPAT, Caen, France
Correspondence to: Gandhi Damaj, email: damaj-gl@chu-caen.fr
Keywords: peripheral T cell lymphoma, bendamustine, efcacy, safety

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INTRODUCTION
Peripheral T cell lymphoma (PTCL) is a
heterogeneous group of diseases, representing 10-15%
of lymphoma. Most PTCL have aggressive forms with
poor prognosis [1-3]. Histologic subtypes inuences
outcome with the best prognosis is attributed to ALK-
positive anaplastic-large cell lymphoma (ALCL) [4-7].
The International Prognostic Index (IPI) may be helpful
in prognosticating subtypes of PTCL especially ALCL,
whereas the Prognosis Index for T-cell lymphoma
(PIT) is better discriminant for PTCL-NOS [4, 8]. In
the absence of more eective chemotherapy, CHOP
(cyclophosphamide-anthracycline-vincristine-prednisone)
regimen is the most frequent chemotherapy used in front
line. Complete response (CR) rate is about 50% and 5-year
overall survival (OS) is 37% [9-13]. Autologous stem
cell transplantation (ASCT) as consolidation treatment
in rst-line showed 5-years OS and progression-free
survival (PFS) of 51% and 44%, respectively [14]. Recent
results of intensive chemotherapy with upfront autologous
stem cell transplantation (ASCT) in eligible patients is
promising [15, 16]. Refractory disease or relapses are
very frequent, concerning about 70% of patients with no
standardized salvage therapy [17, 18]. Cytarabine-based
salvage regimens showed an ORR of 63% with CR of
27% and grade 3-4 toxicities between 47 and 61% of cases
[19, 20]. Gemcitabine, a nucleoside analog, has shown
ecacy as monotherapy, in small cohort of patients,
with an ORR of 55% or in combination regimens with
oxaliplatin with 30% of CR, but uncommon long-term
duration of response (DoR) [21]. In a recently published
series describing the population-based experience of the
British Columbia Cancer Agency in 153 refractory or
relapsed PTCL patients, Mak et al. have reported a median
OS and PFS of 5.5 and 3.1 months respectively, with no
statistically signicant dierence in outcome after relapse
between each of the PTCL subtypes [22]. Pralatrexate,
an antifolate, and romidepsin, a histone deacytelase
(HDAC) inhibitor, were approved by the Food and Drug
Administration for relapsed or refractory PTCL. The ORR
and CR rates were 29 and 13% for pralatrexate and 25
and 15% for romidepsin. The median DoR is, however,
short with only small subset of patients with long term
duration of response under continuous therapy [23, 24].
Brentuximab vedotin, showed, an ORR of 86% in ALCL
[25] and 41% in other PTCL subtypes with a CR rate
of 24% [26]. Consolidation with ASCT or allogeneic
stem cell transplantation (HSCT) in relapse setting for
t patients is the standard of care. However, 2/3rd of
patients could not receive transplantation due to disease
progression [18, 22, 27, 28].
Bendamustine, a bifunctionnal molecule with
alkylating activity and antimetabolites properties has been
Received: April 06, 2016 Accepted: July 10, 2016 Published: July 21, 2016
ABSTRACT
Peripheral T-cell lymphoma (PTCL) is a group of diseases with poor outcome and
few therapeutic options. We aimed to assess the ecacy of bendamustine in real life
cohort of patients.
Between November 2009 and March 2015, 138 PTCL patients were treated with
bendamustine in 27 centers. Population median age was 64 (28-89) years with male/
female ratio of 1.4. There were mainly angio-immunoblastic (AITL = 71), PTCL-not
otherwise specied (PTCL-NOS = 40) and anaplastic large cell lymphoma (ALCL = 8).
The majority of patients (96%) had disseminated disease and extranodal localizations
(77%). Median number of chemotherapy lines prior to bendamustine was 2 (1-8).
Median duration of response (DoR) after the last chemotherapy prior to bendamustine
was 4.3 months (1-70) and 50% of patients had refractory disease.
Median number of administered bendamustine cycles was 2 (1-8) and 72 patients
(52%) received less than 3 mostly because of disease progression. Median dose was
90 (50-150) mg/m². Overall response rate (ORR) was 32.6% with complete response
(CR) rate of 24.6% and median DoR was 3.3 months (1-39). AITL patients were more
sensitive than PTCL-NOS patients (ORR: 45.1 versus 20%, p = 0.01). Median PFS and
OS were 3.1 (0.2-46.3) and 4.4 (0.2-55.4) months. On multivariate analysis, refractory
disease (p = 0.001) and extranodal localization (p = 0.028) adversely inuenced ORR.
Grade 3-4 thrombocytopenia, neutropenia and infections were reported in 22, 17 and
23% of cases respectively.
Bendamustine as single agent could be considered as a therapeutic option
for relapsed or refractory PTCL, particularly in chemosensitive or AITL patients.
Combinations of bendamustine with other drugs warrant further evaluation.

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shown to be eective in a large panel of hematological
malignancies [29, 30]. In a recently reported phase II
study, 60 patients with PTCL were treated for 6 cycles of
120mg/m2 infusions of bendamustine with an ORR of 50%
and complete response (CR) rates of 28% [31]. The DoR
was 3.5 months with more than one third of patients with
a DoR longer than 6 months. Median OS and PFS were
6.2 and 3.6 months, respectively. In a retrospective Italian
cohort of 20 PTCL patients, bendamustine demonstrated
an ORR of 55%, CR of 10% and 6 months estimated PFS
and OS of 44% and 57%, respectively [32]. However,
the precise place of bendamustine use among all PTCL
treatment strategies is still unclear [33, 34].
In order to assess the ecacy of bendamustine
outside clinical trials, we conducted a national
retrospective study of patients with the diagnosis of PTCL
and who were treated with bendamustine.
RESULTS
Patient’s characteristics
From November 2009 to March 2015, 138 patients
from 27 centers in France treated with bendamustine for
a PTCL were analyzed (Table 1). The median age was
64.0 (27.7 to 88.5) years with 22 patients (16%) older
than 75 years. The male/female ratio was 1.4 (83/59).
Histopathologic subtypes were predominantly angio-
immunoblastic T-cell lymphoma (AITL = 71, 51.4%),
PTCL not otherwise specied (PTCL-NOS = 40, 29.0%),
and ALCL (n = 8, 5.8%). The other subtypes were rare
including extranodal NK/T cell lymphoma, nasal-type
(ENKTCL = 4, 2.9%), advanced-stage mycosis fungoide
Table 1: Patients’ demographics and disease characteristics at Bendamustine
Characteristics N. %
Patients 138
Age, years
Median (range)
> 65 years 64 (27.7-88.5)
62 43.7
Sex
Male
Female 82
56
59.4
40.6
Histology
AITL
PTCL-NOS
ALCL
NKTCL
MF
others
71
40
8
4
9
6
51.4
29.0
5.8
2.9
6.5
4.4
Ann Arbor Stage
I-II
III-IV
132
5
127
3.6
96.2
IPI
1-2
3-5
135
34
101
25.2
74.8
Extra-nodal site involvement 99/128 77.3
Bone marrow involvement 52/124 41.9
Previous lines of treatment
Median (range)
1
2
3 or more
2(1-8)
46
55
37
33.3
39.9
26.8
Prior therapy
ASCT
CHOP/CHOP-like regimen
Cytarabine-based regimens
Others
16
122
53
11
11.5
88.4
38.4
8.0
Time from diagnosis to bendamustine, months
Median (range) 12.1 (1.5-108.1)
Refractory to last prior therapy 69 50.0
Patients’ demographics and disease characteristics at Bendamustine Abbreviations: AITL, angioimmunoblastic lymphoma;
ALCL, anaplastic large-cell lymphoma; ASCT, autologous stem-cell transplantation; CHOP, cyclophosphamide, doxorubicin,
vincristine, and prednisone; IPI, International Prognostic Index; MF, mycosis fungoides; NKTCL, NK/T cell lymphoma;
PTCL-NOS, peripheral T cell lymphoma non other specied

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(MF = 9, 6.5%), EATL (n = 2), subcutaneous panniculitis-
like-TCL (n = 1), hepatosplenic-TCL (n = 1) and
unclassied PTCL (n = 2).
The majority of patients had disseminated-stage
disease (n = 127; 96.2%), with extranodal localizations
(n = 99/128; 77.3%) including bone marrow involvement
(n = 52/124; 41.9%). The most common extranodal
localizations outside bone marrow involvement were skin
(n = 17/138; 12.3%) and lung (n = 3/138; 2.2%). The IPI
was high in 74.8% of patients (n = 101).
The median number of prior lines of chemotherapy
was 2 (range 1-8) (Table 1). The most frequent prior
chemotherapy used was CHOP/CHOP-like regimens in
122 patients (88.4%) and cytarabine-based regimens in
53 (38.4%) patients. Only 16 patients had autologous
stem cells transplantation (ASCT = 11%) and 7 (5%)
patients had allogeneic SCT prior to bendamustine. The
median DoR of chemo-sensitive patients after the last
chemotherapy was 4.3 months (1-70). Sixty-nine (50%)
patients had refractory disease when bendamustine
treatment was initiated. Median time from diagnosis
to bendamustine rst infusion was 12.1 months (range
1.5-108.1). Of note, there were no signicant dierence
for main patients’ characteristics such as age, disease
stage, number of previous line and disease status at
bendamustine between AITL and PTCL-NOS patients at
study entry (data not shown).
Bendamustine administration schedule
Bendamustine was given in all patients as
monotherapy at a median dose of 90mg/m2 (40-150).
The dosage varied according to patients’ age, previous
treatments and comorbidities based on physician discretion
(Table 2). Fifty-four (39.1%) patients received 120 mg/
m² at day 1 and 2. Seventy-two (52.2%) patients received
fewer than 3 cycles, mainly due to disease progression
(95.8%, 69/72). Overall, they received a median of 2
cycles (1-8). Sixty-six (47.8%) patients received 3 cycles
or more and 30 (21.7%) patients received 6 cycles.
Ecacy
The best ORR, as per the IWGC, was 32.6%
(45/138) with a PR rate of 7.2% (10 patients), and a CR
rate of 24.6% (34 patients) (Table 3). The median DoR
was 3.3 months (1-39), 3.54 months for CR patients and
3.18 months for PR patients (p = 0.45). One third (31%)
of responders had durable response for more than 6
months. Six patients with PR after 3 cycles converted their
response to CR after 6 cycles (6/18; 33.3%).
Median PFS was 3.1 months (range 0.2-46.3) and
median OS was 4.4 months (range 0.2-55.4) (Figure 1).
Of note, 9 patients (6.5%) received allogeneic SCT in CR.
For the 54 (39.1%) patients who received the dose
Table 2: Bendamustine administration schedule
N. %
Dose
Median (range)
<90 mg/m2
≥90 mg/m2
90.0 (40-150)
19
119
13.7
86.2
Dose reduction 15 10.8
Number of cycles
Median (range)
<3 cycles
≥3 cycles
2.0 (1-8)
72
66
52.2
47.8
Table 3: Response to Bendamustine
AITL
N = 71
PTCL-NOS
N = 40
Total
N = 138
Overall response rate at the end of treatment N.
(%)
ORR
CR
PR
Stable
Progressive
32 (45.1)
25 (35.2)
7 (9.9)
0 (0.0)
39 (54.9)
8 (20.0)
6 (15.0)
2 (5.0)
2 (5.0)
32 (80.0)
45 (32.6)
34 (24.6)
10 (7.2)
3 (2.2)
90 (65.2)
Median time from bendamustine to response,
months (95CI) 3.3 (0.9-11.1) 3.4 (1.0-7.7) 3.1 (0.4-11.1)
Median DoR, months (95CI) 3.3 (1.0-35.5) 3.2 (1.0-38.8) 3.3 (1.0-38.8)
Median OS, months (95CI) 4.5 (0.2-55.4) 4.4 (0.7-46.3) 4.4 (0.2-55.4)
Abbreviations: AITL, angioimmunoblastic lymphoma; CR: complete response; DOR: Duration of response; OS: overall
survival; OS: overall survival; PFS: progression free survival; PR: partial response; PTCL-NOS, peripheral T cell lymphoma
non-otherwise specied.

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Figure 1: Progression-free survival (PFS) and Overall survival (OS) in the intent-to-treat population (n=129)

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of 120mg/m2, the ORR was 37% (n = 20/54) including
31.4% of CR (n = 17). The median DoR and PFS were 3.5
months and 3.9 months, respectively.
Patients older than 75 years represent 16% of the all
cohort (n = 22) with an ORR of 50% including 37.5% of
CR. The median DoR was 5.9 months (1-28.5).
Responses according to PTCL subtypes were
dierent. ORR and CR were respectively of 45.1%
(32/71) with 35.2% of CR for AITL patients, whereas
it was 20.0% (8/40) with 15% of CR for patients with
PTCL-NOS (p = 0.01) (Table 3-4). For AITL patients, the
median DoR was 3.3 months (1-35.5) and median PFS
was 3.6 months (0.2-41.7) with no dierence with PTCL-
NOS patients (Table 3).
Table 4: ORR and PFS Analysis According to Key Subsets (univariate analysis)
Characteristics N. OR
ORR*
95CI pHR
PFS†
95CI p
Age
< 65 years
≥ 65 years
76
62
1
2.75 (1.3-5.7) 0.007
1
0.91 (0.62-1.3) 0.640
Sex
Male
Female 82
56
1
2.28 (1.1-4.7) 0.025
1
0.51 (0.34-0.8) 0.001
Histology
AITL
PTCL-NOS 71
40
1
0.2 (0.1-0.5) 0.010
1
1.69 (1.08-2.6) 0.040
Ann Arbor stage
I-II
III-IV 5
127
1
2.00 (0.2-18.4) 0.541
1
1.22 (0.49-3.0) 0.663
IPI
1-2
3-5 34
101
1
1.47 (0.6-3.5) 0.381
1
1.47 (0.93-2.3) 0.097
Extra-nodal site involvement
No
Yes 29
99
1
0.42 (0.2-0.9) 0.036
1
1.31 (0.84-2.0) 0.238
Bone marrow involvement
No
Yes 72
52
1
0.52 (0.2-1.2) 0.119
1
1.47 (0.94-2.3) 0.090
Previous lines of treatment
1
2 or + 46
92
1
0.49 (0.2-1.0) 0.059
1
1.68 (1.12-2.5) 0.013
Status at bendamustine
Sensitive
Refractory 69
69
1
0.17 (0.1-0.4) <0.001
1
1.89 (1.28-2.8) 0.001
Abbreviations: AILT, angioimmunoblastic lymphoma; HR, hazard ratio; IPI, International Prognostic Index; N, number of
patients; OR, odds ratio; ORR, overall response rate; PFS, progression-free survival; PTCL-NOS peripheral T-cell lymphoma
non other specied *Logistic regression. †Cox regression.
Table 5: ORR and PFS Analysis According to Key Subsets (multivariate analysis)
Characteristics ORajusted
ORR
95CI pHRajusted
PFS
95CI pHRajusted
OS
95CI p
IPI
1-2
3-5 1
1.45 (1.41-
3.48) 0.050
1
3.19 (1.34-
7.59) 0.009
Extra-nodal site
involvement
No
Yes 1
0.2 (0.0-
0.8) 0.028
Previous lines of
treatment
0, 1
2 or + 1
1.77 (1.18-
2.67) 0.006
1
1.85 (1.17-
2.93) 0.008
Status at bendamustine
Sensitive
Refractory 1
0.10 (0.0-
0.4) 0.001
1
3.28 (2.77-
3.79) 0.001
1
5.61 (2.33-
13.53) <0.001

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Figure 2: Progression-free survival (PFS) (p=0.001) and Overall survival (OS) (p<0.001) according to chemotherapy
status at the bendamustine initiation in the intent-to-treat population (n=129) Blue curve: chemosensitive patients at
bendamustine institution Green curve: chemo-refractory patients at bendamustine institution

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Prognostic factors
In univariate analysis, ORR was aected by age (p =
0.007), sex (p = 0.025), PTCL subtype (PTCL-NOS versus
AITL) (p = 0.01), extranodal localizations (p = 0.036) and
disease status (refractory versus relapsed) at bendamustine
(p < 0.001) (Table 4).
In multivariate analysis, disease status [OR 0.1;
CI(0.0-0.4); p = 0.001] and extranodal disease [OR
0.2; CI(0.0-0.8); p = 0.028] at bendamustine initiation
remained the only factors that negatively inuenced the
ORR (Table 5).
Overall survival was negatively impacted by
the number of previous chemotherapy lines [HR 1.85;
CI(1.17-2.93); p = 0.008], disease status at bendamustine
[HR 5.61; CI(2.33-13.53); p < 0.001] and IPI [HR 3.19;
CI(1.34-7.59); p = 0.009]. In the same way, the number
of prior treatment [HR 1.77; CI(1.18-2.67); p = 0.006],
disease status [HR 3.28; CI(2.77-3.79); p = 0.001] and IPI
[HR 3.13; CI(1.41-6.96); p = 0.005] inuenced PFS (Table
5 and Figure 2).
Safety
After a median follow up 4.4 months, 72% of
patients (99/138) died. The causes of death were:
disease progression (93.9%, n = 94) or toxicities (5.0%,
n = 5). Grade ¾ thrombocytopenia, neutropenia and
infections occurred in 22.4%, 16.7% and 22.5% of cases,
respectively (Table 6). The main grade 3-4 infections
included bacterial sepsis, septic shock, Clostridium colitis
and pneumonia. The ve toxic deaths were secondary to
septic shock with clostridium colitis (n = 1), pneumonia
with pseudomonas aeruginosa (n = 1), toxicity related
mortality post allogeneic stem cell transplantation (n = 2)
and pneumocystis jiroveci pneumonia (n = 1).
DISCUSSION
This retrospective study conrms the ecacy of
bendamustine in a large cohort of PTCL patients treated
outside clinical trials with a CR rate of 24.6%. These
results are concordant with the two prior studies, the
prospective BENTLY trial [31] and the retrospective
Italian study [32]. However, the ORR (32.6%) and
PR rate (7.2%) rate are lower in this cohort than in the
prospective BENTLY study (ORR = 50%; PR = 26%).
In this study, patients were more intensely treated before
bendamustine with an increased number of patients with
more than 2 lines of previous chemotherapy, lower dose
(90 mg/m²) and less cycles of bendamustine than in the
BENTLY study. The low percentage of partial responders
as compared to the previous studies is dicult to explain.
However, we could hypothesize that lower stringent
criteria were applied to stop the treatment in this cohort
of highly aggressive disease than in a prospective study.
We emphasize that one third of patients in PR after 3
cycles converted their response to CR at 6 cycles, which
may indicate an advantage to pursue the treatment if any
response is reached.
Patients’ other characteristics in this cohort are
similar to those reported in the two previous ones
regarding age, sex ratio and disease stage. However, the
high frequency of AITL in the current cohort is in keeping
with the recent report of the high prevalence of AITL in
France [35].
This study can be helpful to predict patients who
are more likely to respond to bendamustine. Patients
with AITL were more sensitive to this drug than patients
with other pathological subtypes (univariate analyses)
as has been suggested previously [31]. We found a good
prognosis impact of having chemosensitive disease status
without extranodal localization on response and outcome.
We showed also an improved outcome if patients had
lower than 3 prior therapies lines or IPI lower than 3
(multivariate analysis).
Bendamustine is eective and safe, even in elderly
patients, older than 75 years. ORR and CR rates were not
dierent from those of younger patients. This ecacy
and the toxicity proles of the drug could suggest its
preferential use in this group of patients aged more than
70 years old. Furthermore, it could be used as a bridge to
transplant in younger patients.
In conclusion, bendamustine may represent an
alternative therapy for relapsed or refractory PTCL
patients in real-life settings and could be considered as
Table 6: Grade 3 to 4 adverse events in patients
Adverse event N. %
Total events 94 60.9
Thrombocytopenia 31 22.4
Neutropenia 23 16.7
Infections* 31 22.5
Others† 75.0
*Infections include bacterial sepsis, septic shock, Clostridium colitis, pneumonia, Pneumocystis jiroveci pneumonia (n=1)
†Others include cardiac arrhythmia (n=1), anaphylactic shock (n=1), hemolytic anemia (n=1), hepatitis (n=1), skin rash (n=1),
venous thrombosis (n=1) and myelodysplasia (n=1; after 18 months of 8 Bendamustine courses).

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www.impactjournals.com/oncotarget
a salvage strategy. These results could be helpful to
select patients who will be more likely to respond to
bendamustine. Having chemosensitive disease at relapse
after being treated with less than 3 lines of chemotherapy
are predictive factors for response. The DoR is
unfortunately short as with other multiple single agent
treatment suggesting the need for evaluating combination
drugs in prospective trials.
MATERIALS AND METHODS
Hematological French centers were asked to report
retrospectively the results of the use of bendamustine
in refractory or relapsed PTCL patients. Patients aged
18 years old or more with the diagnosis of PTCL were
included. Primary cutaneous T_cell lymphoma with a
stage less than IIB [36], Sezary syndrome, the leukemic
forms according to the WHO classication [3] and
patients who received bendamustine in the BENTLY
trial [31] were excluded from the analysis. Patients’
demographics and clinical characteristics, histologic
subtypes, prior therapies, disease status, bendamustine
dosage and schedule were reported. Pathological
review through Lymphopath was available for 80 (58%)
patients [35]. Responses were evaluated according to
the International Working group criteria (IWGC) [37]
and International Society for Cutaneous Lymphomas/
European Organization for Research and Treatment
of Cancer (ISCL/EORTC) revision classication [36].
Toxicities were assessed according to the adverse events
recording using the National Cancer Institute’s Common
terminology Criteria for Adverse Events (NCI CTCAE)
version 4. PFS and OS distribution were calculated
using Kaplan-Meier estimates. Patients who underwent
allogeneic stem cell transplant after bendamustine
treatment were excluded from the analyses of the DoR, OS
and PFS. PTCL-NOS and AITL comparison was assessed
by Chi-2 or Fisher’s exact tests for qualitative variable and
Mann-Whitney test for quantitative variable. Predictive
variables for ORR were determined by using uni- and
multivariate logistic regression. Results were expressed
as odds ratios and condence intervals (95CI). For OS and
PFS, we used the Cox proportional hazards models with
a stepwise backward variable selection approach (p≤0.20)
for multivariate analysis and to obtain hazard ratios with
condence intervals. All reported p values were two-sided,
and the signicance limit was set at 5%.
ACKNOWLEDGMENTS
The authors thank all the participants who helped
to collect data: Catherine Ollivier and Alexandra Hebert
(CHU Caen).
CONFLICTS OF INTERESTS
Gandhi Damaj and Guillaume Cartron received
unrestricted research grant from Mundipharma. Emmanuel
Gyan is coordinating investigator for a clinical study
supported by Mundipharma.
FUNDING
This work had no specic funding.
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