ArticlePDF Available

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

Authors:

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
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
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom-
mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
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
Page 2 of 4
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
fast, convenient online submission
thorough peer review by experienced researchers in your field
rapid publication on acceptance
support for research data, including large and complex data types
gold Open Access which fosters wider collaboration and increased citations
maximum visibility for your research: over 100M website views per year
At BMC, research is always in progress.
Learn more biomedcentral.com/submissions
Ready to submit your research
Ready to submit your research
? Choose BMC and benefit from:
? Choose BMC and benefit from:
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
References
1. Hanel W, Epperla N. Evolving therapeutic landscape in follicular lym-
phoma: a look at emerging and investigational therapies. J Hematol
Oncol. 2021;14:104.
2. Ladha A, Zhao J, Epner EM, Pu JJ. Mantle cell lymphoma and its manage-
ment: where are we now? Exp Hematol Oncol. 2019;8:2.
3. Rummel M, Kaiser U, Balser C, et al. Bendamustine plus rituximab versus
fludarabine plus rituximab for patients with relapsed indolent and
mantle-cell lymphomas: a multicentre, randomised, open-label, non-
inferiority phase 3 trial. Lancet Oncol. 2016;17:57–66.
4. Castegnaro S, Visco C, Chieregato K, et al. Cytosine arabinoside potenti-
ates the apoptotic effect of bendamustine on several B- and T-cell leuke-
mia/lymphoma cells and cell lines. Leuk Lymphoma. 2012;53:2262–8.
5. Visco C, Finotto S, Zambello R, et al. Combination of rituximab, ben-
damustine, and cytarabine for patients with mantle-cell non-Hodgkin
lymphoma ineligible for intensive regimens or autologous transplanta-
tion. J Clin Oncol. 2013;31:1442–9.
6. Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-
dose cytarabine as induction therapy in elderly patients with mantle cell
lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi.
Lancet Haematol. 2017;4:e15-23.
7. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World
Health Organization classification of lymphoid neoplasms. Blood.
2016;127:2375–90.
8. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for
malignant lymphoma. J Clin Oncol. 2007;25:579–86.
9. Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter
study of bendamustine plus rituximab in patients with relapsed
indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol.
2008;26:4473–9.
10. Albertsson-Lindblad A, Freiburghaus C, Jerkeman M, Ek S. Ibrutinib
inhibits antibody dependent cellular cytotoxicity induced by rituximab or
obinutuzumab in MCL cell lines, not overcome by addition of lenalido-
mide. Exp Hematol Oncol. 2019;8:16.
11. Hirayama AV, Gauthier J, Hay KA, et al. High rate of durable complete
remission in follicular lymphoma after CD19 CAR-T cell immunotherapy.
Blood. 2019;134:636–40.
12. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or
refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331–42.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Follicular Lymphoma (FL) is the most common subtype of indolent B cell non-Hodgkin lymphoma. The clinical course can be very heterogeneous with some patients being safely observed over many years without ever requiring treatment to other patients having more rapidly progressive disease requiring multiple lines of treatment for disease control. Front-line treatment of advanced FL has historically consisted of chemoimmunotherapy but has extended to immunomodulatory agents such as lenalidomide. In the relapsed setting, several exciting therapies that target the underlying biology and immune microenvironment have emerged, most notable among them include targeted therapies such as phosphoinositide-3 kinase and Enhancer of Zeste 2 Polycomb Repressive Complex 2 inhibitors and cellular therapies including chimeric antigen receptor T cells and bispecific T cell engagers. There are several combination therapies currently in clinical trials that appear promising. These therapies will likely reshape the treatment approach for patients with relapsed and refractory FL in the coming years. In this article, we provide a comprehensive review of the emerging and investigational therapies in FL and discuss how these agents will impact the therapeutic landscape in FL.
Article
Full-text available
Background Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton’s tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma. Methods In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×10⁶ CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months. Results A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred. Conclusions KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.)
Article
Full-text available
Background: The Bruton's Tyrosine Kinase (BTK)-inhibitor ibrutinib is highly active in mantle cell lymphoma (MCL) but may inhibit response to anti-CD20 antibody as previously shown in CLL models. We investigated how antibody-dependent cellular cytotoxicity (ADCC) induced by type I/II anti-CD20 antibodies was affected by treatment with ibrutinib in MCL. Furthermore, we investigated if lenalidomide, a potential sensitizer to anti-CD20 treatment, could prevent an inhibitory effect of ibrutinib. Methods: Anti-CD20 (rituximab/obinutuzumab) opsonized MCL cell lines were co-cultured with ibrutinib (± lenalidomide)-exposed effector cells, and analyzed for evaluation of cell death. Results: Cell death induced by rituximab was reduced with 75% at 0.5 µM ibrutinib and with 52% at 0.1 µM ibrutinib when induced by obinutuzumab, even by addition of lenalidomide. Moreover, obinutuzumab was associated with higher rate of cell death compared to rituximab. Conclusion: Ibrutinib negatively affects anti-CD20 induced cell death in MCL, not reversed by lenalidomide. Explorations of sequential administration and selective BTK-inhibitors may reveal the optimal combination of novel agents in MCL.
Article
Full-text available
Abstract Mantle cell lymphoma is a relatively new recognized hematological malignant disease, comprising of 2.5–6% non-Hodgkin’s lymphomas. The complexity of its clinical presentations (nodular pattern, diffuse pattern, and blastoid variant), variety in disease progression, and treatment response, make this disease a research focus to both experimental oncology and clinical oncology. Overexpression of cyclin D1 and chromosome t(11,14) translocation are the known molecular biomarkers of this disease. Mantle cell international prognostic index (MIPI), ki-67 proliferation index, and TP53 mutation are emerging as the prognostic biomarkers. Epigenetic profile variance and SOX11 gene expression profile correlate with treatment response. Over the years, the treatment strategy has been gradually evolving from combination chemotherapy to combination of targeted therapy, epigenetic modulation therapy, and immunotherapy. In a surprisingly short period of time, FDA specifically approved 4 drugs for treating mantle cell lymphoma: lenalidomide, an immunomodulatory agent; Bortezomib, a proteasome inhibitor; and Ibrutinib and acalabrutinib, both Bruton kinase inhibitors. Epigenetic agents (e.g. Cladribine and Vorinostat) and mTOR inhibitors (e.g. Temsirolimus and Everolimus) have been showing promising results in several clinical trials. However, treating aggressive variants of this disease that appear to be refractory/relapse to multiple lines of treatment, even after allogeneic stem cell transplant, is still a serious challenge. Developing a personalized, precise therapeutic strategy combining targeted therapy, immunotherapy, epigenetic modulating therapy, and cellular therapy is the direction of finding a curative therapy for this subgroup of patients.
Article
Patients with follicular lymphoma (FL) with early relapse after initial chemoimmunotherapy, refractory disease, or histologic transformation (tFL) have limited progression-free and overall survival. We report efficacy and long-term follow-up of 21 patients with relapsed/ refractory (R/R) FL (n 5 8) and tFL (n 5 13) treated on a phase 1/2 clinical trial with cyclophosphamide and fludarabine lymphodepletion followed by infusion of 2 3 10⁶ CD19-directed chimeric antigen receptor-modified T (CAR-T) cells per kilogram. The complete remission (CR) rates by the Lugano criteria were 88% and 46% for patients with FL and tFL, respectively. All patients with FL who achieved CR remained in remission at a median follow-up of 24 months. The median duration of response for patients with tFL was 10.2 months at a median follow-up of 38 months. Cytokine release syndrome occurred in 50% and 39%, and neurotoxicity in 50% and 23% of patients with FL and tFL, respectively, with no severe adverse events (grade ‡3). No significant differences in CAR-T cell in vivo expansion/persistence were observed between FL and tFL patients. CD19 CAR-T cell immunotherapy is highly effective in adults with clinically aggressive R/R FL with or without transformation, with durable remission in a high proportion of FL patients. This trial was registered at clinicaltrials.gov as #NCT01865617. © 2011 by The American Society of Hematology; all rights reserved.
Article
Patients with follicular lymphoma (FL) with early relapse after initial chemoimmunotherapy, refractory disease, or histologic transformation (tFL) have limited progression-free and overall survival. We report efficacy and long-term follow-up of 21 patients with relapsed/refractory (R/R) FL (n = 8) and tFL (n = 13) treated on a phase 1/2 clinical trial with cyclophosphamide and fludarabine lymphodepletion followed by infusion of 2 × 106 CD19-directed chimeric antigen receptor-modified T (CAR-T) cells per kilogram. The complete remission (CR) rates by the Lugano criteria were 88% and 46% for patients with FL and tFL, respectively. All patients with FL who achieved CR remained in remission at a median follow-up of 24 months. The median duration of response for patients with tFL was 10.2 months at a median follow-up of 38 months. Cytokine release syndrome occurred in 50% and 39%, and neurotoxicity in 50% and 23% of patients with FL and tFL, respectively, with no severe adverse events (grade ≥3). No significant differences in CAR-T cell in vivo expansion/persistence were observed between FL and tFL patients. CD19 CAR-T cell immunotherapy is highly effective in adults with clinically aggressive R/R FL with or without transformation, with durable remission in a high proportion of FL patients. This trial was registered at clinicaltrials.gov as #NCT01865617.
Article
Background: The combination of rituximab, bendamustine, and cytarabine (R-BAC) was highly active in a pilot trial of mantle cell lymphoma, but its use was restricted by high haematological toxicity. We aimed to assess the efficacy and safety of an R-BAC regimen with low-dose cytarabine (RBAC500). Methods: In this multicentre, phase 2 trial, we recruited previously untreated patients with an established histological diagnosis of mantle cell lymphoma from 29 Fondazione Italiana Linfomi centres in Italy. Patients had to be older than 65 years and fit according to the comprehensive geriatric assessment, or aged 60-65 years if they were ineligible for high-dose chemotherapy plus autologous stem-cell transplantation and were fit or unfit. All patients received RBAC500 (rituximab 375 mg/m2 on day 1, bendamustine 70 mg/m2 on days 2 and 3, and cytarabine 500 mg/m2 on days 2-4; all administered intravenously) every 4 weeks for up to six cycles. Primary endpoints were the proportion of patients achieving complete response at the end of treatment and toxicity, defined as the occurrence of any of the stop treatment criteria or of any episode of relevant toxicity. All patients who started at least one cycle of RBAC500 were included in the primary and safety analyses. Using efficacy and toxicity as a composite primary endpoint, we considered the final conclusion positive if more than 28 of 57 patients achieve complete response and fewer than 18 of 57 patients report toxicities. This study is registered with EudraCT, number 2011-005739-23, and ClinicalTrials.gov, number NCT01662050, and is completed. Findings: Between May 2, 2012, and Feb 25, 2014, we enrolled 57 patients (median age 71 years, IQR 67-75). 54 (95%) patients received at least four RBAC500 cycles (three discontinued because of toxicity), and 38 (67%) completed six cycles. Two (4%) had disease progression (one after the fourth cycle and one after the sixth cycle). All 52 (91%, lower limit of one-sided 95% CI 85%) remaining patients achieved complete response at the end of treatment. 23 (40%, upper limit of one-sided 95% CI 53%) of 57 patients had at least one episode of relevant toxicity. The most frequent grade 3-4 haematological toxicities were neutropenia (149 [49%] of 304 cycles) and thrombocytopenia (158 [52%]). Most treatment-related non-haematological adverse events were of grade 1-2, with the most frequent ones being fatigue (14 [25%] patients), nausea or vomiting (12 [21%]), and infusion-related reactions or tumour lysis syndrome (12 [21%]). 41 (72%) patients required a dose reduction. 12 patients died during the study, but no deaths were related to treatment. Interpretation: RBAC500 is an effective treatment for elderly patients with mantle cell lymphoma and, despite not meeting our prespecified safety boundary, haematological toxicity was manageable with appropriate supportive care and dose reduction. Since maintenance therapy is not required, RBAC500 could be considered an option and should be studied in phase 3 trials. Funding: Fondazione Italiana Linfomi and Mundipharma.
Conference Paper
A revision of the nearly 8 year old WHO classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations and therapeutic strategies for the lymphoid neoplasms.