-
British Journal of Haematology Jul 2023For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine...
For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 10 /μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3-24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 10 /μL; p = 0.022) or low CD4/CD8 ratios (
bendamustine administration without sufficient washout, and risk-adapted strategies may help to optimize CAR-T cell therapy for DLBCL patients. Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Cohort Studies; Japan; Bendamustine Hydrochloride; Receptors, Antigen, T-Cell; Lymphoma, Large B-Cell, Diffuse; Immunotherapy, Adoptive; Risk Factors
PubMed: 37096915
DOI: 10.1111/bjh.18831 -
Blood Advances Oct 2022Obinutuzumab (G) chemoimmunotherapy demonstrated improved progression-free survival (PFS) vs rituximab-based chemoimmunotherapy in patients with previously untreated...
Obinutuzumab (G) chemoimmunotherapy demonstrated improved progression-free survival (PFS) vs rituximab-based chemoimmunotherapy in patients with previously untreated follicular lymphoma (FL) in the GALLIUM trial. Atezolizumab (atezo) is a programmed death-ligand 1 inhibitor with a complementary mechanism of action to G by restoring cytotoxic T-cell function. We evaluated the safety and efficacy of atezo-G-bendamustine in patients with previously untreated FL in a phase Ib/II trial (#NCT02596971). A safety run-in phase was followed by an expansion phase with atezo-G-bendamustine induction and atezo-G maintenance for ≤24 months. Forty patients with previously untreated FL were enrolled and treated with atezo-G-bendamustine. The primary endpoint, complete response (CR) rate, assessed by an independent review committee (IRC; modified Lugano 2014 criteria) was 75.0% (95% confidence interval [CI], 61.3% to 85.8%). Three-year investigator-assessed PFS and overall survival rates were 80.9% (95% CI, 63.9% to 90.5%) and 89.3% (95% CI, 73.9% to 95.9%), respectively. At baseline, 21/40 patients had circulating lymphoma-specific clonotypes and underwent repeat testing at end of induction; all were minimal residual disease negative (10-5 sensitivity), with 16 (76.2%) CRs, 3 (14.3%) partial responses, and 2 (9.5%) with stable disease (IRC assessed). Grade 5 (fatal) adverse events (AEs) were reported in 5 patients. The efficacy of atezo-G-bendamustine in previously untreated FL did not appear superior to G-bendamustine efficacy as seen in the GALLIUM trial, and the addition of atezo to G-bendamustine was associated with an increased risk of AEs. Particularly due to the unfavorable safety profile, this regimen cannot be recommended in patients with previously untreated FL. This trial was registered at www.clinicaltrials.gov as #NCT02596971.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Gallium; Lymphoma, Follicular; Rituximab; Antibodies, Monoclonal, Humanized
PubMed: 35359000
DOI: 10.1182/bloodadvances.2021006131 -
Journal of Hematology & Oncology Apr 2024Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products...
Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.
Topics: Humans; Bendamustine Hydrochloride; Middle Aged; Male; Female; Aged; Immunotherapy, Adoptive; Retrospective Studies; Adult; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Agents, Alkylating; Biological Products; Aged, 80 and over; Treatment Outcome
PubMed: 38644469
DOI: 10.1186/s13045-024-01542-9 -
Annals of Oncology : Official Journal... Oct 2010Follicular lymphoma is an indolent and usually incurable disease. It has been therefore traditionally approached either by watch and wait or with single-agent... (Review)
Review
Follicular lymphoma is an indolent and usually incurable disease. It has been therefore traditionally approached either by watch and wait or with single-agent treatments. The purpose was to maintain a good quality of life for a prolonged time. More aggressive regimens, including polychemotherapy, high-dose chemotherapy with stem-cell rescue and the emergence of new cytotoxic drugs have significantly improved the remission duration but could never demonstrate an impact on overall survival. In the past decade, through the addition of drugs acting on the immune system such as interferon or rituximab, the survival of follicular lymphoma patients could be improved by the range of several years. As a consequence several clinicians believe that we are near to a cure for follicular lymphoma so that the first-line treatment should be more aggressive to reach this goal. Nevertheless, at present, none of the new strategies can be shown to cure. We believe that even in the presence of many possible treatment options, watch and wait remains a good option for many patients with follicular lymphoma. When treatment is needed, chemotherapy with rituximab is the standard even though none of the chemotherapy regimens can be shown to be superior. As quality of life remains an issue, the combination of rituximab and bendamustine, a drug with high efficacy and a favourable toxicity profile, is a good new option for patients.
Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Humans; Lymphoma, Follicular; Neoadjuvant Therapy; Nitrogen Mustard Compounds; Rituximab; Watchful Waiting
PubMed: 20943608
DOI: 10.1093/annonc/mdq287 -
BMJ Case Reports Jul 2019
Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Immunological; Bendamustine Hydrochloride; Conjunctival Neoplasms; Humans; Lymphoma, Non-Hodgkin; Rituximab
PubMed: 31296640
DOI: 10.1136/bcr-2019-229599 -
Hematology. American Society of... Dec 2022Marginal zone lymphomas (MZLs) represent about 7% of B-cell non-Hodgkin lymphomas and include 3 different subtypes-namely, extranodal (EMZL), nodal, and splenic (SMZL)....
Marginal zone lymphomas (MZLs) represent about 7% of B-cell non-Hodgkin lymphomas and include 3 different subtypes-namely, extranodal (EMZL), nodal, and splenic (SMZL). The initial assessment requires specific diagnostic and staging procedures depending on organ-related peculiarities. In particular, although positron emission tomography/computed tomography was not initially recommended, recent data have reassessed its role in the routine staging of MZL, especially when only localized treatment is planned or there is a suspicion of histologic transformation. Recent findings have improved the risk stratification of MZL patients, highlighting the association of early progression after frontline therapy with worse overall survival. A significant fraction of MZL cases may be related to specific bacterial (ie, Helicobacter pylori in gastric EMZL) or viral infections (hepatis C virus), and in the earlier phases of disease, a variable percentage of patients may respond to anti-infective therapy. Involved-site radiotherapy has a central role in the management of localized EMZL not amenable to or not responding to anti-infective therapy. Although rituximab-based treatments (bendamustine- rituximab in advanced EMZL or rituximab monotherapy in SMZL) have demonstrated favorable results, the current therapeutic scenario is predicted to rapidly change as emerging novel agents, especially Bruton's tyrosine kinase inhibitors, have demonstrated promising efficacy and safety profiles, leading to their approval in the relapsed setting. Moreover, a large variety of novel agents (phosphatidylinositol 3-kinase inhibitors, chimeric antigen receptor T-cells, bispecific antibodies) are being tested in MZL patients with encouraging preliminary results.
Topics: Humans; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Lymphoma, B-Cell, Marginal Zone; Bendamustine Hydrochloride; Rituximab
PubMed: 36485086
DOI: 10.1182/hematology.2022000362 -
Oncology Reports Jun 2022Bendamustine is an alkylating agent classified into the group of nitrogen mustard analogues, synthesized almost sixty years ago. It was registered in former East Germany... (Review)
Review
Bendamustine is an alkylating agent classified into the group of nitrogen mustard analogues, synthesized almost sixty years ago. It was registered in former East Germany in 1971 and approved by the US Food and Drug Administration in 2008 for treatment of chronic lymphocytic leukemia and indolent B‑cell non‑Hodgkin lymphoma. Considering its beneficial properties in the therapy of relapsed or refractory hematological malignancies, synergistic effects with other antineoplastic agents and increasing recent reports on its immunomodulatory effects, bendamustine has once again gained its justified attention. The uniqueness of bendamustine‑mediated effects should be observed keeping in mind its distinctive structure with structural similarities to both alkylating agents and purine analogs. In the present review, the current knowledge on the use of bendamustine in oncology, its pharmacokinetics, mechanism of action and toxicity was summarized. In addition, its immune‑modulating effects that have not been fully elucidated so far are emphasized, hoping to encourage further investigations of this unique drug.
Topics: Antineoplastic Agents; Bendamustine Hydrochloride; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Nitrogen Mustard Compounds
PubMed: 35506458
DOI: 10.3892/or.2022.8325 -
American Journal of Hematology May 2023Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and...
Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not well-established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively (p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m compared with those receiving 800-999 mg/m (p = 0.04). In the relapsed cohort, those who received doses of <600 mg/m had poorer PFS outcomes compared with those who received ≥600 mg/m (p = 0.02). Attaining CR/VGPR following BR results in superior survival, and total bendamustine dose significantly impacts response and survival outcomes, in both frontline and relapsed settings.
Topics: Humans; Rituximab; Bendamustine Hydrochloride; Waldenstrom Macroglobulinemia; Treatment Outcome; Retrospective Studies; Neoplasm Recurrence, Local; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36866925
DOI: 10.1002/ajh.26895 -
Blood Advances Aug 2023The combination of rituximab, bendamustine, and low-dose cytarabine (R-BAC) has been studied in a phase 2 prospective multicenter study from Fondazione Italiana Linfomi...
The combination of rituximab, bendamustine, and low-dose cytarabine (R-BAC) has been studied in a phase 2 prospective multicenter study from Fondazione Italiana Linfomi (RBAC500). In 57 previously untreated elderly patients with mantle cell lymphoma (MCL), R-BAC was associated with a complete remission rate of 91% and 2-year progression-free survival (PFS) of 81% (95% confidence interval [CI], 68-89). Here, we report the long-term survival outcomes, late toxicities, and results of minimal residual disease (MRD) evaluation. After a median follow-up of 86 months (range, 57-107 months), the median overall survival (OS) and PFS were not reached. The 7-year PFS and OS rates were 55% (95% CI, 41-67), and 63% (95% CI, 49-74), respectively. Patients who responded (n = 53) had a 7-year PFS of 59% (95% CI, 44-71), with no relapse or progression registered after the sixth year. In the multivariate analysis, blastoid/pleomorphic morphology was the strongest adverse predictive factor for PFS (P = .04). Patients with an end of treatment negative MRD had better, but not significant, outcomes for both PFS and OS than patients with MRD-positive (P = 0.148 and P = 0.162, respectively). There was no signal of late toxicity or an increase in secondary malignancies during the prolonged follow-up. In conclusion, R-BAC, which was not followed by maintenance therapy, showed sustained efficacy over time in older patients with MCL. Survival outcomes compare favorably with those of other immunochemotherapy regimens (with or without maintenance), including combinations of BTK inhibitors upfront. This study was registered with EudraCT as 2011-005739-23 and at www.clinicaltrials.gov as #NCT01662050.
Topics: Humans; Adult; Aged; Rituximab; Lymphoma, Mantle-Cell; Bendamustine Hydrochloride; Follow-Up Studies; Cytarabine; Prospective Studies; Neoplasm Recurrence, Local
PubMed: 37171620
DOI: 10.1182/bloodadvances.2023009744 -
Medical Oncology (Northwood, London,... May 2014Recently, bendamustine has become an important agent in the treatment for patients with lymphoid malignancies. Although the drug has received approval for second-line... (Review)
Review
Recently, bendamustine has become an important agent in the treatment for patients with lymphoid malignancies. Although the drug has received approval for second-line therapy in indolent lymphoma, a growing body of evidence suggests its efficacy and safety in first-line use. The results of randomised and observational studies with bendamustine as front-line therapy in non-Hodgkin lymphoma (NHL) with emphasis on efficacy and toxicity are presented. Furthermore, completed and ongoing clinical trials evaluating upfront bendamustine effectiveness in combination with other agents are discussed. The review refers mainly to indolent lymphoma, mantle cell lymphoma and aggressive lymphoma, as the most commonly diagnosed NHL types. Finally, we elaborated on the safety profile of bendamustine and the perspectives of using the drug as a first-line therapy.
Topics: Antineoplastic Agents, Alkylating; Bendamustine Hydrochloride; Humans; Lymphoma, Non-Hodgkin; Nitrogen Mustard Compounds; Prognosis
PubMed: 24752517
DOI: 10.1007/s12032-014-0944-1