A multicenter phase II study of bendamustine, rituximab, and cytarabine (BRAC) for relapsed or refractory patients with follicular lymphoma or mantle cell lymphoma

Abstract

This phase II clinical trial aimed to evaluate the efficacy and safety of the combination therapy of bendamustine, cytarabine, and rituximab (BRAC) in patients with relapsed or refractory follicular lymphoma (FL) or mantle cell lymphoma (MCL). Thirteen patients were enrolled and received a median of 4 cycles (range 2–6) of BRAC. The complete response rate was 61.5%, and the overall response rate was 84.6%; the 2-year overall survival was 76.9%, and the 2-year progression-free survival was 69.2%. Although all patients received G-CSF prophylaxis, grade 3 or higher neutropenia was observed in all cycles, and the incidence of febrile neutropenia was 20%. Grade 4 thrombocytopenia was observed in 92.5% of all cycles, and platelet transfusion was performed in 94%. Although hematological toxicity was relatively high, BRAC therapy was effective for relapsed and refractory FL or MCL. Further studies are needed to determine the optimal dose of BRAC therapy.
Trial registration The UMIN Clinical Trials Registry, UMIN000009797. Registered 17 January 2013, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000011103

Full text

Nakamuraetal.
Experimental Hematology & Oncology (2022) 11:9
https://doi.org/10.1186/s40164-022-00264-3
LETTER TO THE EDITOR
A multicenter phase II study
ofbendamustine, rituximab, andcytarabine
(BRAC) forrelapsed orrefractory patients
withfollicular lymphoma ormantle cell
lymphoma
Nobuhiko Nakamura1* , Senji Kasahara2, Junichi Kitagawa2, Hiroshi Nakamura1, Michio Sawada3,
Kenji Fukuno4, Yuhei Shibata2, Yuto Kaneda4, Takeshi Hara5, Nobuhiro Kanemura1, Hisashi Tsurumi1,5 and
Masahito Shimizu1
Abstract
This phase II clinical trial aimed to evaluate the efficacy and safety of the combination therapy of bendamustine, cyta-
rabine, and rituximab (BRAC) in patients with relapsed or refractory follicular lymphoma (FL) or mantle cell lymphoma
(MCL). Thirteen patients were enrolled and received a median of 4 cycles (range 2–6) of BRAC. The complete response
rate was 61.5%, and the overall response rate was 84.6%; the 2-year overall survival was 76.9%, and the 2-year pro-
gression-free survival was 69.2%. Although all patients received G-CSF prophylaxis, grade 3 or higher neutropenia was
observed in all cycles, and the incidence of febrile neutropenia was 20%. Grade 4 thrombocytopenia was observed
in 92.5% of all cycles, and platelet transfusion was performed in 94%. Although hematological toxicity was relatively
high, BRAC therapy was effective for relapsed and refractory FL or MCL. Further studies are needed to determine the
optimal dose of BRAC therapy.
Trial registration The UMIN Clinical Trials Registry, UMIN000009797. Registered 17 January 2013, https:// upload. umin. ac.
jp/ cgi- open- bin/ ctr/ ctr_ view. cgi? recpt no= R0000 11103
Keywords: Follicular lymphoma, Mantle cell lymphoma, Bendamustine, Rituximab, Cytarabine
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To theEditor
e combination of rituximab and chemotherapy has
significantly improved outcomes for B-cell non-Hodgkin
lymphoma (NHL) patients. However, conventional thera-
pies cannot cure follicular lymphoma (FL) and mantle
cell lymphoma (MCL) [1, 2]. Bendamustine has demon-
strated high efficacy as monotherapy and in combination
with rituximab for relapsed or refractory indolent B-cell
NHL and MCL [3]. Cytarabine has been reported to be
synergistic with bendamustine and is a new candidate for
combination therapy [4]. Results of three-drug combina-
tion therapy of bendamustine, cytarabine, and rituximab
(BRAC) in patients with MCL patients conducted over-
seas have shown high efficacy and safety [5, 6]. Although
no validated phase III comparative study has yet been
conducted, bendamustine and cytarabine combination
therapy may be a promising treatment regimen. ere-
fore, we conducted a phase II clinical trial to evaluate
Open Access
Experimental Hematology &
Oncology
*Correspondence: nnaka@gifu-u.ac.jp
1 Department of Hematology and Infectious Disease, Gifu University
Hospital, 1-1, Yanagido, Gifu 501-1194, Japan
Full list of author information is available at the end of the article

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Nakamuraetal. Experimental Hematology & Oncology (2022) 11:9
efficacy and safety of BRAC. Due to slow accrual, the
study was prematurely closed with a total of only 13
patients.
A multicenter, open-label, single-arm, phase II clini-
cal trial was conducted in 3 hospitals from the Gifu
Hematology Study Group in Japan. Patients were eligi-
ble if they were aged 20–80years, Eastern Cooperative
Oncology Group performance status of 0–2 and had
histologically confirmed, relapsed or refractory FL or
MCL according to the WHO classification [7]. Patients
with histological transformation to a higher degree of
lymphoma have been ruled out before the initiation of
BRAC treatment. All patients received BRAC (rituxi-
mab 375 mg/m2 on day 1; bendamustine 90 mg/m2
over 30–60min on days 2 and 3; cytarabine 600mg/
m2 over a 2-h infusion on days 2–4; all administered
intravenously) every 4weeks for up to 6 cycles. Prophy-
laxis with G-CSF (filgrastim 50μg/m2) was given 24h
after the last cytarabine dose in every cycle. If grade 3
or higher non-hematologic toxicity was observed, the
dose of bendamustine was reduced from 90mg/m2 to
60mg/m2 in the subsequent cycles. e dose of rituxi-
mab and cytarabine was not reduced. e primary
endpoint was the complete response (CR) rate. e
response was evaluated according to the Cheson cri-
teria, 2007 [8]. e CR rate for BR therapy in patients
with relapsed or refractory indolent B-cell NHL and
MCL is 54–59% [9]. In addition, the CR rate for BRAC
therapy in relapsed MCL is 70% [5]. erefore, we set
the expected CR rate at 70% and the threshold CR rate
at 45%, one-sided α error of 0.05, and β error of 0.2,
and the minimum number of patients required at 24.
We assumed that 10% of the enrolled patients would be
ineligible, and the sample size was set at 27.
ough enrollment of 27 patients was planned, 13
patients were enrolled from May 2013 to May 2018. e
demographics and characteristics of patients are shown
in Table1. e median age was 65 (53–73) years, and 6
patients (46.2%) were male. e histological types were
FL in 9 patients and MCL in 4 patients. e median num-
ber of previous treatment regimens was 1 (range: 1–6),
and 3 patients (23.1%) were refractory to their last chem-
otherapy. All patients had received rituximab-containing
chemotherapy, four patients had been treated with ben-
damustine, two patients had been treated with cytara-
bine, and none had been treated with Bruton’s tyrosine
kinase (BTK) inhibitor. Patients received a median of
4 cycles (range 2–6) of BRAC. Seven of 13 patients
(53.8%) were able to complete the scheduled treat-
ment. One patient received an autologous hematopoi-
etic stem-cell transplantation (HSCT) after 4 cycles, one
patient received an allogeneic HSCT after 3 cycles, and
no patient received BTK inhibitor maintenance. e CR
rate was 61.5% [95% confidence interval (CI) 31.6–86.1],
and the overall response (OR) rate was 84.6% (95% CI
54.6–86.1). In 9 patients with FL, the CR rate was 66.7%,
and the OR rate was 100%. e median follow-up for 10
survivors from enrolment was 31.2months (range 20.8–
39.6months). e 2-year overall survival (OS) was 76.9%
(95% CI 44.2–91.9%) [Additional file 1: Figure S1(A)],
Table 1 Patients demographics and characteristics
FL: follicular lymphoma; G: grade; MCL: mantle cell lymphoma; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; R-THP-COP:
rituximab, cyclophosphamide, pirarubicine, vincristine, and prednisolone; R-IMVP-16/CBDCA: rituximab, ifosfamide, methotrexate, etoposide, carboplatin, and
methylprednisolone; R-B: rituximab, bendamustine; CHASER: cyclophosphamide, high dose cytarabine, dexamethasone, etoposide, and rituximab; R-HyperCVAD/MA:
rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high dose methotrexate and cytarabine; R: rituximab;
R-Flu: rituximab, udarabine; GCD-R: gemcitabine, carboplatin, dexamethasone, and rituximab; PR: partial response; CR: complete response; NA: not applicable; HSCT:
hematopoietic stem cell transplantation
Patient Age, gender Diagnosis Previous regimen Cycles of
BRAC Response Treatment after BRAC
1 61, F FL G1 R-CHOP 5 PR –
2 53, F FL G3b R-CHOP 4 CR auto HSCT
3 71, F FL G2 R-THP-COP, R-IMVP-16/CBDCA, R-B, CHASER 4 CR –
4 66, M FL G1 R-THP-COP 6 PR –
5 63, F FL G2 R-CHOP 4 CR –
6 61, M MCL R-HyperCVAD/MA 3 CR –
7 67, M MCL R-CHOP, R-IMVP-16/CBDCA, CHASER, R-HyperCVAD/MA 2 NA –
8 57, M FL G2 R-CHOP, R-B 3 PR allo HSCT
9 69, F FL G2 R-THP-COP, R-B, R, R-Flu, GCD-R, Ibritumomab Tiuxetan 3 CR –
10 72, M MCL R-CHOP, R-B 2 NA –
11 72, M FL G2 R-CHOP, R-B 4 CR –
12 65, F FL G1 R-CHOP 4 CR –
13 69, F MCL R-CHOP 6 CR –

Page 3 of 4
Nakamuraetal. Experimental Hematology & Oncology (2022) 11:9
and the 2-year progression-free survival (PFS) was 69.2%
(95% CI 37.3–87.2%) [Additional file1: Figure S1(B)].
Fifty cycles of BRAC were given. Table2 summarizes
the hematological and non-hematological toxicities.
Although all patients received G-CSF prophylaxis, grade
3 or higher neutropenia was observed in all cycles, and
the incidence of febrile neutropenia was 20%. Grade 4
thrombocytopenia was observed in 92.5% of all cycles,
and platelet transfusion was performed in 47 of 50
cycles (94%). Treatment initiation was delayed in 7 of
13 patients (53.8%), primarily due to treatment toxicity.
e dose of bendamustine was reduced in 6 of 50 patient
cycles (12.0%).
In the present study, the efficacy and safety of BRAC
therapy for relapsed or refractory FL or MCL were
evaluated. A good response rate (CR rate: 61.5%, OR
rate: 84.6%) was seen. In particular, this is the first
study to confirm the response to BRAC therapy of
relapsed or refractory FL (CR rate: 66.7%, OR rate:
100%). On the other hand, hematological toxicity was
relatively high, with 20% (10/50 cycles) having febrile
neutropenia and the need for platelet transfusion in
almost all cycles. Visco etal. reported the use of R-BAC
(rituximab 375mg/m2, bendamustine 70mg/m2, cyta-
rabine 800mg/m2) in elderly patients with previously
untreated or relapsed or refractory MCL [5], and they
reduced the dose of cytarabine to 500 mg/m2 in the
next study because of high hematological toxicity [6].
Unfortunately, sufficient conclusions could not be
drawn because the present study closed prematurely
due to slow accrual, but it was possible to show that
BRAC therapy might be useful, especially for FL. e
reason for the slow accrual is uncertain, but one reason
may have been the emergence of new drugs. For exam-
ple, obinutuzumab and lenalidomide were approved for
the treatment of FL, and bortezomib and ibrutinib were
approved for the treatment of MCL in Japan during the
study period which may have increased the number of
treatment options and slowed patient enrollment. BTK
inhibitors, such as ibrutinib, have been reported to be
synergistic with rituximab [10] and are effective agents
against MCL. Furthermore, the usefulness of anti-
CD19 chimeric antigen receptor (CAR) T-cell therapy
for FL and MCL has been recently reported [11,12].
Although administration of BRAC before leukocyte
apheresis should be avoided because bendamustine
reduces the efficiency of lymphocyte collection, BRAC
may be effective as bridging chemotherapy to CAR-T.
Further studies are needed to determine the optimal
dose and timing of BRAC therapy.
Abbreviations
NHL: Non-Hodgkin lymphoma; FL: Follicular lymphoma; MCL: Mantle cell
lymphoma; CR: Complete response; PR: Partial response; OR: Overall response;
OS: Overall survival; PFS: Progression-free survival; CI: Confidence interval; BTK:
Bruton’s tyrosine kinase; CAR : Chimeric antigen receptor.
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s40164- 022- 00264-3.
Additional le1: Figure. S1 Overall survival (A) and progression-free sur-
vival (B) for all patients (n = 13). Overall survival (C) and progression-free
survival (D) for follicular lymphoma (FL) (n = 9) and mantle cell lymphoma
(n = 4).
Acknowledgements
The authors are grateful to the members of the Gifu Hematology Study Group
for their support of this study.
Authors’ contributions
NN collected, analyzed, and interpreted the data and wrote the manuscript;
SK, JK, MS, KF, TH, NK and HT conceived and designed the study; NN, SK, JK,
HN, MS, KF, YS and YK recruited patients; All authors read and approved the
final manuscript.
Funding
None.
Availability of data and materials
The datasets used and/or analysed during the current study are available from
the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
Ethics approval was granted by the institutional review board at each partici-
pating institution. All patients provided written informed consent.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Table 2 Treatment cycles with hematological toxicities and non-
hematological toxicities (50 patient-cycles)
* The causative organism of sepsis was Bacillus spp
Toxicity, n (%) Grade 3 Grade 4
Hematologic
Neutropenia 5 (10.0) 41 (82.0)
Anemia 39 (78.0) 1 (2.0)
Thrombocytopenia 4 (8.0) 46 (92.0)
Non-hematologic
Sepsis* 0 (0.0) 1 (2.0)
Febrile neutropenia 10 (20.0) 0 (0.0)
Cytomegalovirus infection 2 (4.0) 0 (0.0)
Hypokalemia 1 (2.0) 0 (0.0)
Hemothorax 0 (0.0) 1 (2.0)
Hyperamylasemia 2 (4.0) 0 (0.0)

Page 4 of 4
Nakamuraetal. Experimental Hematology & Oncology (2022) 11:9
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Author details
1 Department of Hematology and Infectious Disease, Gifu University Hospital,
1-1, Yanagido, Gifu 501-1194, Japan. 2 Department of Hematology, Gifu Munici-
pal Hospital, Gifu, Japan. 3 Department of Hematology, Gifu Red Cross Hospital,
Gifu, Japan. 4 Department of Hematology, Takayama Red Cross Hospital, Gifu,
Japan. 5 Department of Hematology, Matsunami General Hospital, Gifu, Japan.
Received: 26 October 2021 Accepted: 16 February 2022
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