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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 -
In Vivo (Athens, Greece) 2024Patients with malignant lymphoma, in a latent state of weakened immune function, are at risk of chemotherapy-induced immunosuppression and cytomegalovirus (CMV)...
BACKGROUND/AIM
Patients with malignant lymphoma, in a latent state of weakened immune function, are at risk of chemotherapy-induced immunosuppression and cytomegalovirus (CMV) infection. Concomitant therapy with bendamustine and rituximab or obinutuzumab intensifies immunosuppression, potentially affecting CMV onset. This study aimed to assess CMV onset differences between bendamustine monotherapy and combination therapy with rituximab or obinutuzumab using the Japanese Adverse Drug Event Report database (JADER).
PATIENTS AND METHODS
A JADER analysis dataset (April 2004 to September 2022) defined CMV infection using 31 preferred term (PT) words from MedDRA 25.1J HLT "Cytomegalovirus infection (10011827)". Reporting odds ratios (ROR) calculated CMV infection signals for bendamustine monotherapy, rituximab, obinutuzumab, bendamustine+rituximab (BR), and bendamustine+obinutuzumab (GB). ROR confidence intervals exceeding 1 indicated a CMV signal. Days of CMV infection were calculated based on adverse event onset and administration start.
RESULTS
CMV signals were confirmed for monotherapy and combination therapies. CMV infection durations (median, interquartile range) were 41.0 days (23.5-69.5) for bendamustine monotherapy, 63.5 days (35.2-95.0) for BR, and 61.0 days (33.0-102.5) for GB, with cases exceeding 200 days.
CONCLUSION
JADER analysis detected significant CMV signals for rituximab, obinutuzumab, and bendamustine. Caution may be warranted 7-9 months post-bendamustine administration, necessitating further investigation, including cell-mediated immunity suppression assessment.
Topics: Humans; Bendamustine Hydrochloride; Rituximab; Cytomegalovirus; Pharmaceutical Preparations; Drug-Related Side Effects and Adverse Reactions; Cytomegalovirus Infections; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38418128
DOI: 10.21873/invivo.13520 -
Indian Journal of Cancer Oct 2023Bendamustine-rituximab (BR) is the preferred regimen for the treatment of naïve follicular lymphoma (FL). Recently, lenalidomide-rituximab (LR), a chemotherapy-free... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Bendamustine-rituximab (BR) is the preferred regimen for the treatment of naïve follicular lymphoma (FL). Recently, lenalidomide-rituximab (LR), a chemotherapy-free protocol, has shown a good response rate in advanced FL. These regimens have never been compared in a randomized controlled trial for treatment-naïve FL in Indian patients.
MATERIALS AND METHODS
This Phase III open-label randomized controlled trial was conducted to compare the efficacy and safety of BR and LR. Treatment-naïve patients older than 18 years of age, ECOG PS (Eastern Cooperative Oncology Group Performance Status) ≤2, who were diagnosed with FL (Stages II-IV) were included in this study. Patients were randomized in a 1:1 ratio to receive six cycles of BR (bendamustine 90 mg/m 2 Days 1-2 and rituximab 375 mg/m 2 Day 1) every 4 weeks or LR (lenalidomide 20 mg Days 1-21 and rituximab 375 mg/m 2 ) every 4 weeks. The primary end point was complete response (CR) and secondary end points were overall response rate (ORR) and toxicity.
RESULT
We enrolled 40 patients, 20 in each group with a median age of 53 years. The CR rate was 60% and 20% in BR and LR arms, respectively ( P = 0.01); however, the ORR was 88.8% and 87.3% in BR and LR arms, respectively ( P = 1.0). Anemia (35% versus 10%), skin rash (35% versus 30%), diarrhea (30% versus 10%), vomiting (20% versus 10%), nephrotoxicity (15% versus 0%), and transaminitis (10% versus 0%) were more in LR than in BR, and thrombocytopenia was higher in the BR than in the LR group but statistically not different. All grade toxicities were seen in 90% and 45% in LR and BR, respectively ( P = 0.05), but there was no significant difference in Grade 3 or 4 toxicity between the BR and the LR regimens (20% versus 25%).
CONCLUSION
The ORR was similar in both the arms; however, the CR rate was significantly higher in the BR arm. BR was better tolerated than LR.(CTRI/2016/05/006904).
Topics: Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Lenalidomide; Lymphoma, Follicular; Rituximab; Adult
PubMed: 38185869
DOI: 10.4103/ijc.IJC_633_20 -
Annals of Hematology Mar 2024
Topics: Humans; Rituximab; Bendamustine Hydrochloride; Lymphohistiocytosis, Hemophagocytic; Antibodies, Monoclonal; Immunoconjugates; Antineoplastic Combined Chemotherapy Protocols; Lymphoma, Large B-Cell, Diffuse
PubMed: 38155243
DOI: 10.1007/s00277-023-05598-4 -
Blood Advances Feb 2024Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of...
Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites.
Topics: Humans; Bendamustine Hydrochloride; Cytokines; CD28 Antigens; Immunotherapy, Adoptive; Lymphoma, Follicular; Cyclophosphamide; Biological Products
PubMed: 38113468
DOI: 10.1182/bloodadvances.2023011492 -
Frontiers in Immunology 2023Patients with B-cell lymphoma are a fragile category of subjects, particularly exposed to infections and characterized by an impaired vaccination response due to the...
BACKGROUND
Patients with B-cell lymphoma are a fragile category of subjects, particularly exposed to infections and characterized by an impaired vaccination response due to the disease itself and, even more, to the chemotherapy regimen. For this reason, extensive knowledge of the immune response status of these subjects is of fundamental importance to obtain possible indications for a tailored immunization strategy.
METHODS
We enrolled two cohorts of patients with B-cell lymphoma under rituximab treatment or 3-24 months after treatment. In all patients, we evaluated both humoral and cellular immunological memory toward SARS-CoV-2, after standard vaccination and upon one booster dose.
RESULTS
We observed no Spike-specific IgG production in patients (n = 25) under anti-CD20 treatment, whereas patients (n = 16) vaccinated after the completion of chemotherapy showed a higher humoral response. Evaluating SARS-CoV-2-specific T-cell response, we found that patients in both cohorts had developed robust cellular immunity after vaccination. Of the 21 patients (51%) that experienced a breakthrough SARS-CoV-2 infection, only six patients developed severe disease. Interestingly, these six patients had all been treated with rituximab plus bendamustine. Notably, we observed that Spike-specific IgG levels in patients treated with rituximab plus bendamustine were absent or lower compared with those in patients treated with rituximab plus other chemotherapy, whereas Spike-specific T-cell response was not different based on chemotherapy regiment.
DISCUSSION
Our results show that, in patients with B-cell lymphoma under rituximab therapy, anti-SARS-CoV-2 mRNA vaccination induces a weak or absent humoral response but a consistent T-cell response. In addition, chemotherapy regimens with bendamustine further reduce patients' ability to mount a Spike-specific humoral response even after a long time period from chemotherapy discontinuation. These results provide evidence that different chemotherapeutics display different immunosuppressive properties that could be taken in to account in the choice of the right drug regimen for the right patient. Moreover, they question whether immunocompromised patients, particularly those treated with bendamustine, need interventions to improve vaccine-induced immune response.
Topics: Humans; Rituximab; Bendamustine Hydrochloride; COVID-19 Vaccines; SARS-CoV-2; COVID-19; Vaccination; Immunity, Cellular; Lymphoma, B-Cell; Immunoglobulin G
PubMed: 38106404
DOI: 10.3389/fimmu.2023.1322594 -
Frontiers in Immunology 2023The most common lymphodepletion regimen used prior to infusion of chimeric antigen receptor-T cells (CAR-T) is cyclophosphamide (CY) in combination with fludarabine... (Review)
Review
The most common lymphodepletion regimen used prior to infusion of chimeric antigen receptor-T cells (CAR-T) is cyclophosphamide (CY) in combination with fludarabine (Flu) (CY-FLU). While cyclophosphamide (CY) possesses lymphotoxic effects, it concurrently preserves regulatory T cell activity, potentially affecting the efficacy of CAR-T cells. Moreover, the use of fludarabine (FLU) has been linked to neurotoxicity, which could complicate the early detection of immune effector cell-associated neurotoxicity syndrome (ICANS) observed in CAR-T cell therapy. Given the ongoing shortage of FLU, alternative lymphodepleting agents have become necessary. To date, only a limited number of studies have directly compared different lymphodepleting regimens, and most of these comparisons have been retrospective in nature. Herein, we review the current literature on lymphodepletion preceding CAR-T cell therapies for lymphoid hematologic malignancies, with a specific focus on the use of bendamustine (BEN). Recent evidence suggests that administering BEN before CAR-T cell infusion yields comparable efficacy, possibly with a more favorable toxicity profile when compared to CY-FLU. This warrants further investigation through randomized prospective studies.
Topics: Bendamustine Hydrochloride; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Retrospective Studies; Prospective Studies; Cyclophosphamide
PubMed: 38077398
DOI: 10.3389/fimmu.2023.1329850 -
Journal of Nippon Medical School =... Dec 2023Drug resistance remains a significant impediment in leukemia treatment. While Bendamustine hydrochloride (BH) stands out as a promising therapeutic agent for...
BACKGROUND
Drug resistance remains a significant impediment in leukemia treatment. While Bendamustine hydrochloride (BH) stands out as a promising therapeutic agent for non-Hodgkin' s lymphoma and mantle cell lymphoma, the mechanisms of resistance to BH are not yet fully understood. Our study focuses on elucidating the mechanisms behind bendamustine resistance in leukemia cells, with a specific emphasis on epigenetics.
METHODS
Bendamustine-resistant cells were cultivated from human B cell lymphoblastic leukemia cell lines through systematic and sustained exposure to bendamustine, using the limiting dilution method. Gene expression was assessed via real-time polymerase chain reaction, while the expression of the multidrug resistance protein 1 (MDR1) was evaluated using flow cytometry.
RESULTS
Bendamustine-resistant leukemia cells exhibited a decreased RNA expression level for Polo-like kinase-1 (PLK-1). Notably, after treatment with the demethylating agent 5-aza-2'-deoxycytidine, PLK-1 gene expression surged significantly, enhancing bendamustine's cytotoxicity in the resistant leukemia cells. However, MDR1 expression, as determined by flow cytometry, remained consistent between parental and bendamustine-resistant leukemia cells.
CONCLUSIONS
Our findings indicate that the methylation of the PLK-1 gene plays a pivotal role in modulating PLK-1 expression and is central to the development of bendamustine resistance in leukemia cells.
PubMed: 38072417
DOI: 10.1272/jnms.JNMS.2024_91-206 -
BMC Health Services Research Dec 2023The incidence and mortality rates of patients with chronic lymphocytic leukemia (CLL) in China have recently increased. This study performed a long-term economic...
Ibrutinib versus bendamustine plus rituximab for first-line treatment of 65 or older patients with untreated chronic lymphocytic leukemia without del(17p)/TP53 mutation in China: a lifetime economic research study.
BACKGROUND
The incidence and mortality rates of patients with chronic lymphocytic leukemia (CLL) in China have recently increased. This study performed a long-term economic evaluation of the first-line treatment strategies ibrutinib (IB) or bendamustine (BE) plus rituximab (RI) for previously untreated older patients with CLL without the del(17p)/TP53 mutation in China.
METHODS
Based on clinical data from large, randomized trials, a Markov model including four disease states (event-free survival, treatment failure, post-treatment failure, and death) was used to estimate the incremental costs per quality adjusted-life year (QALY) gained from the first-line IB strategy versus the BE plus RI strategy over a 10-year period. All costs were adjusted to 2022 values based on the Chinese Consumer Price Index, and all costs and health outcomes were discounted at an annual rate of 5%. Sensitivity analysis was performed to confirm the robustness of base-case results.
RESULTS
Compared to the first-line BE plus RI strategy, first-line IB treatment achieved 1.17 additional QALYs, but was accompanied by $88,046.78 (estimated in 2022 US dollars) in decremental costs per patient over 10 years. Thus, first-line treatment with IB appeared to have absolute dominance compared to the BE plus RI strategy. Sensitivity analysis confirmed the robustness of these results.
CONCLUSIONS
The first-line treatment with IB is absolutely cost-effective compared to the first-line BE plus RI treatment strategy for 65 or older patients with CLL without the del (17p)/TP53 mutation from the Chinese payer perspective. Therefore, it is strongly recommended that Chinese health authorities select the former strategy for these CLL patients.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cost-Benefit Analysis; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Rituximab; Tumor Suppressor Protein p53
PubMed: 38049834
DOI: 10.1186/s12913-023-10402-0 -
Clinical Medicine & Research Sep 2023Here we report development of hemophagocytic lymphohistiocytosis (HLH), along with unmasking of a TET2-mutated myeloid neoplasm, after initial doses of bendamustine and...
Here we report development of hemophagocytic lymphohistiocytosis (HLH), along with unmasking of a TET2-mutated myeloid neoplasm, after initial doses of bendamustine and rituximab for longstanding chronic lymphocytic leukemia (CLL). After many years of CLL showing minimally progressive lymphocytosis, the patient's white blood cell count began to decline in parallel with neutrophil count, hemoglobin, and platelet count. Bone marrow biopsy showed partial CLL involvement; bendamustine+rituximab therapy was augmented with granulocyte colony-stimulating factor (g-CSF) and romiplostim to mitigate worsening pancytopenia, without response. Laboratory evaluation revealed a pattern supportive of the clinical impression of HLH, while bone marrow biopsy showed persistent CLL, new reticulin fibrosis, megakaryocytic proliferation, and 32% mutated TET2, but no compelling morphologic evidence of hemophagocytosis. The patient recovered with dexamethasone and g-CSF support.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphohistiocytosis, Hemophagocytic; Rituximab; Bendamustine Hydrochloride; Granulocyte Colony-Stimulating Factor; DNA-Binding Proteins; Dioxygenases
PubMed: 37985171
DOI: 10.3121/cmr.2023.1804