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Blood Advances Jan 2022Polatuzumab vedotin plus bendamustine and rituximab (pola + BR) received regulatory approvals for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) based on... (Randomized Controlled Trial)
Randomized Controlled Trial
Polatuzumab vedotin plus bendamustine and rituximab (pola + BR) received regulatory approvals for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) based on primary results from the randomized arms of the GO29365 study. After the randomized phase, 106 additional patients received pola + BR in a single-arm extension cohort. We report updated results from the randomized arms and results of the extension cohort. In this phase 1b/2 study, patients with R/R DLBCL who were transplant ineligible received up to six 21-day cycles of pola + BR or BR. The primary end point of the randomized arms was the complete response (CR) rate at end of treatment. Primary objectives of the extension cohort were safety, pharmacokinetic profile, and efficacy of pola + BR. As of 7 July 2020, a total of 192 patients with R/R DLBCL were enrolled in the pola + BR cohort (n = 152 [safety run-in, n = 6; randomized, n = 40; extension cohort, n = 106]) or the BR cohort (n = 40). Significant survival benefit with pola + BR vs BR persisted in the randomized arms (median progression-free survival, 9.2 vs 3.7 months [hazard ratio, 0.39; 95% confidence interval, 0.23-0.66]; median overall survival, 12.4 vs 4.7 months [hazard ratio, 0.42; 95% confidence interval, 0.24-0.72]). In the extension cohort, the independent review committee-assessed objective response rate was 41.5%, and the CR rate was 38.7%; median independent review committee-assessed progression-free survival and overall survival were 6.6 months and 12.5 months, respectively. No new safety signals with pola + BR were identified. Pola + BR is an effective treatment option for patients with R/R DLBCL, with a well-characterized and manageable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02257567.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Humans; Immunoconjugates; Rituximab
PubMed: 34749395
DOI: 10.1182/bloodadvances.2021005794 -
Blood Apr 2023Children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous... (Clinical Trial)
Clinical Trial
Children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous hematopoietic cell transplantation (auto-HCT) have poor survival outcomes. CheckMate 744, a phase 2 study for CAYA (aged 5-30 years) with R/R cHL, evaluated a risk-stratified, response-adapted approach with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. We present the primary analysis of the standard-risk cohort. Data from the low-risk cohort are reported separately. Patients received 4 induction cycles with nivolumab plus BV; those without CMR (Deauville score >3, Lugano 2014) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary end point was CMR any time before consolidation. Forty-four patients were treated. Median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59% after induction with nivolumab plus BV and 94% any time before consolidation (nivolumab plus BV ± BV plus bendamustine). One-year progression-free survival rate was 91%. During induction, 18% of patients experienced grade 3/4 treatment-related adverse events. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). Additional follow-up is needed to confirm durability of disease control. This trial was registered at www.clinicaltrials.gov as #NCT02927769.
Topics: Adolescent; Child; Humans; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Brentuximab Vedotin; Hodgkin Disease; Immunoconjugates; Neoplasm Recurrence, Local; Nivolumab; Treatment Outcome
PubMed: 36564047
DOI: 10.1182/blood.2022017118 -
Journal of Clinical Oncology : Official... Jan 2024Approximately 30%-40% of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) infused with CD19-targeted chimeric antigen receptor (CAR) T cells achieve...
Recent Bendamustine Treatment Before Apheresis Has a Negative Impact on Outcomes in Patients With Large B-Cell Lymphoma Receiving Chimeric Antigen Receptor T-Cell Therapy.
PURPOSE
Approximately 30%-40% of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) infused with CD19-targeted chimeric antigen receptor (CAR) T cells achieve durable responses. Consensus guidelines suggest avoiding bendamustine before apheresis, but specific data in this setting are lacking. We report distinct outcomes after CAR T-cell therapy according to previous bendamustine exposure.
METHODS
The study included CAR T-cell recipients from seven European sites. Safety, efficacy, and CAR T-cell expansion kinetics were analyzed according to preapheresis bendamustine exposure. Additional studies on the impact of the washout period and bendamustine dose were performed. Inverse probability treatment weighting (IPTW) and propensity score matching (PSM) analyses were carried out for all efficacy comparisons between bendamustine-exposed and bendamustine-naïve patients.
RESULTS
The study included 439 patients with R/R LBCL infused with CD19-targeted commercial CAR T cells, of whom 80 had received bendamustine before apheresis. Exposed patients had significantly lower CD3 cells and platelets at apheresis. These patients had a lower overall response rate (ORR, 53% 72%; < .01), a shorter progression-free survival (PFS, 3.1 6.2 months; = .04), and overall survival (OS, 10.3 23.5 months; = .01) in comparison with the bendamustine-naïve group. Following adjustment methods for baseline variables, these differences were mitigated. Focusing on the impact of bendamustine washout before apheresis, those with recent (<9 months) exposure (N = 42) displayed a lower ORR (40% 72%; < .01), shorter PFS (1.3 6.2 months; < .01), and OS (4.6 23.5 months; < .01) in comparison with bendamustine-naïve patients. These differences remained significant after IPTW and PSM analysis. Conversely, the cumulative dose of bendamustine before apheresis did not affect CAR-T efficacy outcomes.
CONCLUSION
Recent bendamustine exposure before apheresis was associated with negative treatment outcomes after CD19-targeted CAR T-cell therapy and should be therefore avoided in CAR T-cell candidates.
Topics: Humans; Receptors, Chimeric Antigen; Bendamustine Hydrochloride; Immunotherapy, Adoptive; Blood Component Removal; Lymphoma, Large B-Cell, Diffuse; Antigens, CD19; Cell- and Tissue-Based Therapy
PubMed: 37874957
DOI: 10.1200/JCO.23.01097 -
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 -
Annals of Oncology : Official Journal... Sep 2022Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a...
BACKGROUND
Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T.
PATIENTS AND METHODS
We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading.
RESULTS
Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide.
CONCLUSIONS
Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.
Topics: Bendamustine Hydrochloride; Cyclophosphamide; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Lymphocyte Depletion; Lymphoma, Large B-Cell, Diffuse; Receptors, Antigen, T-Cell
PubMed: 35690221
DOI: 10.1016/j.annonc.2022.05.521 -
Blood Advances Mar 2020The addition of high-dose cytarabine to rituximab/bendamustine (RB) induction could improve outcomes for transplant-eligible patients with mantle cell lymphoma (MCL). We...
The addition of high-dose cytarabine to rituximab/bendamustine (RB) induction could improve outcomes for transplant-eligible patients with mantle cell lymphoma (MCL). We conducted a pooled analysis of 2 phase 2 trials and an off-trial cohort each testing 3 cycles of RB and 3 cycles of rituximab/high-dose cytarabine (RC) followed by autologous stem cell transplantation (ASCT) among untreated, transplant-eligible patients with MCL. Dana-Farber Cancer Institute (DFCI) and Washington University in St. Louis (WUSTL) led separate phase 2 trials testing sequential and alternating cycles of RB/RC, respectively. Patients treated at DFCI with sequential RB/RC off trial were retrospectively identified. Minimal residual disease (MRD) was assessed in the DFCI trial. A total of 88 patients (23 DFCI trial, 18 WUSTL trial, and 47 off trial) received RB/RC; 92% of patients completed induction, and 84% underwent planned consolidative ASCT. Grade 3 or 4 adverse events among trial patients included lymphopenia (88%), thrombocytopenia (85%), neutropenia (83%), and febrile neutropenia (15%). There were no treatment-related deaths during induction and 2 following ASCT. Among 87 response-evaluable patients, the end-of-induction overall and complete response rates were 97% and 90%, respectively. After a median follow-up of 33 months, 3-year progression-free survival and overall survival were 83% and 92%, respectively. Patients undergoing MRD testing experienced prolonged MRD negativity after ASCT with emergence of MRD occurring in only 1 patient who subsequently relapsed. RB/RC followed by ASCT achieves high rates of durable remissions in transplant-eligible patients with MCL. These trials were registered at www.clinicaltrials.gov as #NCT01661881 (DFCI trial) and #NCT02728531 (WUSTL trial).
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cytarabine; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Lymphoma, Mantle-Cell; Retrospective Studies; Rituximab; Transplantation, Autologous
PubMed: 32126141
DOI: 10.1182/bloodadvances.2019001355 -
Hematological Oncology Dec 2017Data in the literature are lacking regarding the infection-related adverse events of bendamustine-containing regimens. Therefore, we aimed to assess this risk. We... (Meta-Analysis)
Meta-Analysis Review
Data in the literature are lacking regarding the infection-related adverse events of bendamustine-containing regimens. Therefore, we aimed to assess this risk. We conducted a systematic review and meta-analysis of all randomized controlled trials including bendamustine-containing regimens and those administered for any lymphoproliferative disorder or plasma cell dyscrasia compared with any other regimens. A comprehensive search was conducted until December 2015. Two reviewers appraised the quality of trials and extracted data. Primary outcomes were any infections, grade 3 to 4 infections; secondary outcomes were grade 3 to 4 neutropenia and grade 3 to 4 lymphopenia. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. A fixed-effect model was used to pool data unless there was significant heterogeneity, in which case a random-effects model was used. Nine trials published between 2006 and 2016 and randomizing 2620 patients were included. There was no statistically significant effect for bendamustine on the rate of any infection (RR 1.09 [95% CI, 0.87-1.36]) or on the rate of grade 3 to 4 infections (RR 1.04 [95% CI, 0.64-1.71]). There was no increase in the rate of grade 3 to 4 neutropenia in the bendamustine arm (RR 0.84 [95% CI, 0.63-1.12]). Our systematic review demonstrates no effect of bendamustine on the rate of infections when compared with either alkylating agents or fludarabine. Thus, bendamustine remains a safe therapeutic option.
Topics: Antineoplastic Agents, Alkylating; Bendamustine Hydrochloride; Humans; Infections; Randomized Controlled Trials as Topic
PubMed: 27734524
DOI: 10.1002/hon.2350 -
Blood Jul 2018Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline...
Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Brentuximab Vedotin; Disease-Free Survival; Female; Hodgkin Disease; Humans; Immunoconjugates; Male; Middle Aged; Recurrence; Salvage Therapy; Survival Rate; Time Factors
PubMed: 29703778
DOI: 10.1182/blood-2017-11-815183 -
European Journal of Haematology Nov 2015The advent of high-dose melphalan with autologous stem-cell transplantation (ASCT), the availability of novel agents such as thalidomide, lenalidomide (immunomodulatory... (Review)
Review
The advent of high-dose melphalan with autologous stem-cell transplantation (ASCT), the availability of novel agents such as thalidomide, lenalidomide (immunomodulatory drugs or IMiDs) and bortezomib (proteasome inhibitor) and improvements in supportive care have allowed to increase overall survival in multiple myeloma (MM) patients; nevertheless, MM remains an incurable pathology. For this reason, newer agents are required for continued disease control. Bendamustine is an old drug rediscovered in the last decade. In fact, its unique mechanism of action with structural similarities to both alkylating agents and antimetabolities, but which is not cross-resistant to alkylating agents, has reawakened interest in the use of this drug in the treatment of MM. Studies have proven the safety and efficacy of bendamustine administered alone or in combination with new drugs in both upfront and relapse/refractory settings of MM patients, including those with renal impairment. Moreover, bendamustine has been successfully used as conditioning for autologous stem-cell transplantation. Finally, the use of bendamustine does not compromise peripheral blood stem-cell collection. This drug is generally well tolerated, with the majority of adverse events being due to myelosuppression. Non-haematological adverse events are infrequent and usually mild.
Topics: Autografts; Bendamustine Hydrochloride; Humans; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Transplantation Conditioning
PubMed: 26085055
DOI: 10.1111/ejh.12609 -
Expert Review of Hematology Aug 2017The majority of patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) present with comorbidities. Many of them are poor candidates for... (Review)
Review
The majority of patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) present with comorbidities. Many of them are poor candidates for intensive chemo-immunotherapy regimens, such as FCR (fludarabine, cyclophosphamide, rituximab). Still, most clinical trials aim to enroll 'fit' patients, who poorly represent the community oncology population. Areas covered: In the past decade, bendamustine hydrochloride, a cytotoxic agent with structural similarities to both alkylating agents and purine analogs, has received widespread use in therapy of NHL and CLL, and has demonstrated a relatively favorable toxicity profile. However, bendamustine has not been well studied in patients with hematologic malignancies who have comorbidities. Here we review the clinical data on use of bendamustine in older and unfit patients with NHL and CLL, and analyze whether there is an optimal dose of bendamustine in patients who have significant comorbidities, including renal dysfunction. Expert commentary: Reduced intensity regimens of bendamustine are effective in CLL patients with comorbidities and renal dysfunction. Even with the introduction of targeted therapies, bendamustine will likely continue to be an important therapeutic option in patients with comorbidities because of its tolerability, efficacy and cost.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Clinical Trials as Topic; Comorbidity; Humans; Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Treatment Outcome
PubMed: 28664772
DOI: 10.1080/17474086.2017.1350166