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Journal of Clinical Oncology : Official... Nov 2020Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30...
PURPOSE
Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL).
METHODS
We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety.
RESULTS
Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent.
CONCLUSION
Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Combined Modality Therapy; Cyclophosphamide; Epitopes; Female; Hodgkin Disease; Humans; Immunotherapy, Adoptive; Ki-1 Antigen; Lymphocyte Depletion; Male; Middle Aged; Stem Cell Transplantation; Vidarabine; Young Adult
PubMed: 32701411
DOI: 10.1200/JCO.20.01342 -
Hematology. American Society of... Dec 2016Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder... (Review)
Review
Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder results in autoimmune hemolytic anemia. The immune hemolysis is entirely complement-dependent, predominantly mediated by activation of the classical pathway and phagocytosis of erythrocytes opsonized with complement protein C3b. Typical clinical features in CAD have diagnostic and therapeutic implications. Pharmacologic treatment should be offered to patients with symptom-producing anemia or disabling circulatory symptoms. CAD should not be treated with corticosteroids. Based on an individualized approach, rituximab monotherapy or rituximab-fludarabine in combination is recommended as first-line therapy. Rituximab-bendamustine is still an investigational therapy. Although complement-modulating agents are still to be considered experimental in CAD, therapy with the anti-C1s monoclonal antibody TNT009 seems promising.
Topics: Anemia, Hemolytic, Autoimmune; B-Lymphocytes; Bendamustine Hydrochloride; Complement C3b; Humans; Lymphoproliferative Disorders; Rituximab
PubMed: 27913484
DOI: 10.1182/asheducation-2016.1.226 -
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 -
Blood Aug 2022The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory... (Randomized Controlled Trial)
Randomized Controlled Trial
The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5 years' follow-up. Survival benefits with VenR vs BR were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P < .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], P < .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9% (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with VenR (93 days) vs BR (53 days; P = 1.2 × 10-7). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Recurrence; Rituximab; Sulfonamides
PubMed: 35605176
DOI: 10.1182/blood.2021015014 -
Journal of Clinical Oncology : Official... Apr 2019The BRIGHT study ( ClinicalTrials.gov identifier: NCT00877006) was initiated to compare the efficacy and safety of bendamustine plus rituximab (BR) with either rituximab... (Randomized Controlled Trial)
Randomized Controlled Trial
First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study.
PURPOSE
The BRIGHT study ( ClinicalTrials.gov identifier: NCT00877006) was initiated to compare the efficacy and safety of bendamustine plus rituximab (BR) with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) for treatment-naive patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma. This publication provides long-term follow-up data.
PATIENTS AND METHODS
Patients were monitored for a minimum of 5 years after completion of study treatment for the time-to-event end points of progression-free survival (PFS), event-free survival, duration of response, and overall survival per investigator assessment. Data on the number of patients who received second-line anticancer treatment and the occurrence of other malignancies were also collected.
RESULTS
The medians were not reached for any of the time-to event end points for either the BR or R-CHOP/R-CVP study treatment groups by study completion. PFS rates at 5 years were 65.5% in the BR treatment group and 55.8% in the R-CHOP/R-CVP group. The difference in PFS was considered significant with a hazard ratio of 0.61 (95% CI, 0.45 to 0.85; = .0025). The hazard ratio for event-free survival and duration of response ( = .0020 and .0134, respectively) also favored the BR regimen over R-CHOP/R-CVP. However, no significant difference in overall survival was observed. The overall safety profiles of BR, R-CHOP, and R-CVP were as expected; no new safety data were collected during long-term follow-up. A higher number of secondary malignancies was noted in the BR treatment group.
CONCLUSION
Overall, BR demonstrated better long-term disease control than R-CHOP/R-CVP and should be considered as a first-line treatment option for patients with indolent and mantle-cell lymphoma.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cyclophosphamide; Doxorubicin; Humans; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Prednisone; Progression-Free Survival; Proportional Hazards Models; Rituximab; Survival Rate; Vincristine
PubMed: 30811293
DOI: 10.1200/JCO.18.00605 -
Blood May 2014This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy... (Randomized Controlled Trial)
Randomized Controlled Trial
This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.
Topics: Adult; Aged; Aged, 80 and over; Alopecia; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Fatigue; Female; Humans; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Nausea; Nitrogen Mustard Compounds; Paresthesia; Peripheral Nervous System Diseases; Prednisone; Rituximab; Treatment Outcome; Vincristine; Vomiting
PubMed: 24591201
DOI: 10.1182/blood-2013-11-531327 -
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 Jul 2020We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to... (Clinical Trial)
Clinical Trial Observational Study
We retrospectively studied 232 patients with cold agglutinin disease (CAD) at 24 centers in 5 countries. In Norway and a northern region of Italy, the study was close to being population-based. For the first time, we demonstrate fourfold differences between cold and warmer climates regarding prevalence (20 vs 5 cases/million) and incidence (1.9 vs 0.48 cases/million per year). Mean baseline hemoglobin level was 9.3 g/dL, but 27% had hemoglobin <8 g/dL. Identification of typical features of CAD-associated lymphoproliferative disorder in the bone marrow was greatly increased by centralized biopsy assessment. CAD seems to be associated with a slightly increased risk of venous thrombosis. This work includes a follow-up study of therapies, focusing on the long-term outcomes of the rituximab plus bendamustine and rituximab plus fludarabine regimens. Rituximab plus bendamustine therapy resulted in responses in 35 (78%) of 45 patients; 24 (53%) achieved complete response. Interestingly, these rates were still higher than observed in the original (2017) prospective trial, and we also found a shift toward deeper responses with time. This is explained by the prolonged time to response seen in many patients, probably related to long-lived plasma cells. In patients responding to rituximab-bendamustine, median response duration was not reached after 88 months, and estimated 5-year sustained remission was 77%. The regimen appeared safe regarding late-occurring malignancies. Rituximab plus fludarabine therapy seems to carry a higher risk of long-term adverse effects.
Topics: Adult; Aged; Anemia, Hemolytic, Autoimmune; Bendamustine Hydrochloride; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Retrospective Studies; Rituximab; Vidarabine
PubMed: 32374875
DOI: 10.1182/blood.2020005674 -
Journal of Clinical Oncology : Official... May 2023Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma...
PURPOSE
Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication.
PATIENTS AND METHODS
Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines.
RESULTS
Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis.
CONCLUSION
In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.
Topics: Adult; Humans; Receptors, Chimeric Antigen; Lymphoma, Mantle-Cell; Bendamustine Hydrochloride; Neoplasm Recurrence, Local; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Antigens, CD19
PubMed: 36753699
DOI: 10.1200/JCO.22.01797 -
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