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Journal of Clinical Oncology : Official... Jan 2020Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug conjugate polatuzumab vedotin targets CD79b, a B-cell receptor component.
METHODS
Safety and efficacy of polatuzumab vedotin with bendamustine and obinutuzumab (pola-BG) was evaluated in a single-arm cohort. Polatuzumab vedotin combined with bendamustine and rituximab (pola-BR) was compared with bendamustine and rituximab (BR) in a randomly assigned cohort of patients with transplantation-ineligible R/R DLBCL (primary end point: independent review committee [IRC] assessed complete response [CR] rate at the end of treatment). Duration of response, progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression methods.
RESULTS
Pola-BG and pola-BR had a tolerable safety profile. The phase Ib/II pola-BG cohort (n = 27) had a CR rate of 29.6% and a median OS of 10.8 months (median follow-up, 27.0 months). In the randomly assigned cohort (n = 80; 40 per arm), pola-BR patients had a significantly higher IRC-assessed CR rate (40.0% 17.5%; = .026) and longer IRC-assessed PFS (median, 9.5 3.7 months; hazard ratio [HR], 0.36, 95% CI, 0.21 to 0.63; < .001) and OS (median, 12.4 4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75; = .002; median follow-up, 22.3 months). Pola-BR patients had higher rates of grade 3-4 neutropenia (46.2% 33.3%), anemia (28.2% 17.9%), and thrombocytopenia (41% 23.1%), but similar grade 3-4 infections (23.1% 20.5%), versus the BR group. Peripheral neuropathy associated with polatuzumab vedotin (43.6% of patients) was grade 1-2 and resolved in most patients.
CONCLUSION
Polatuzumab vedotin combined with BR resulted in a significantly higher CR rate and reduced the risk of death by 58% compared with BR in patients with transplantation-ineligible R/R DLBCL.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Biomarkers, Tumor; Female; Humans; Immunoconjugates; Immunohistochemistry; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Progression-Free Survival; Survival Rate
PubMed: 31693429
DOI: 10.1200/JCO.19.00172 -
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 -
American Journal of Hematology Feb 2023Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia,...
DISEASE OVERVIEW
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity.
DIAGNOSIS
Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients. MYD88 is not required for the diagnosis.
RISK STRATIFICATION
Age, hemoglobin level, platelet count, β microglobulin, LDH, and monoclonal IgM concentrations are characteristics that are predictive of outcomes.
RISK-ADAPTED THERAPY
Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or a BTK inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib.
MANAGEMENT OF REFRACTORY DISEASE
Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection.
Topics: Humans; Waldenstrom Macroglobulinemia; Rituximab; Bendamustine Hydrochloride; Myeloid Differentiation Factor 88; Antibodies, Monoclonal; Paraproteins; Risk Assessment; Immunoglobulin M
PubMed: 36588395
DOI: 10.1002/ajh.26796 -
Blood Mar 2021The last decades have seen great progress in the treatment of cold agglutinin disease (CAD). Comparative trials are lacking, and recommendations must be based mainly on... (Review)
Review
The last decades have seen great progress in the treatment of cold agglutinin disease (CAD). Comparative trials are lacking, and recommendations must be based mainly on nonrandomized trials and will be influenced by personal experience. Herein, current treatment options are reviewed and linked to 3 cases, each addressing specific aspects of therapy. Two major steps in CAD pathogenesis are identified, clonal B-cell lymphoproliferation and complement-mediated hemolysis, each of which constitutes a target of therapy. Although drug treatment is not always indicated, patients with symptomatic anemia or other bothersome symptoms should be treated. The importance of avoiding ineffective therapies is underscored. Corticosteroids should not be used to treat CAD. Studies on safety and efficacy of relevant drugs and combinations are briefly described. The author recommends that B cell-directed approaches remain the first choice in most patients requiring treatment. The 4-cycle bendamustine plus rituximab combination is highly efficacious and sufficiently safe and induces durable responses in most patients, but the time to response can be many months. Rituximab monotherapy should be preferred in frail patients. The complement C1s inhibitor sutimlimab is an emerging option in the second line and may also find its place in the first line in specific situations.
Topics: Aged; Aged, 80 and over; Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bendamustine Hydrochloride; Complement Inactivating Agents; Disease Management; Female; Humans; Middle Aged; Rituximab; Thrombosis
PubMed: 33512410
DOI: 10.1182/blood.2019003809 -
Journal of Clinical Oncology : Official... Jan 2023Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell...
PURPOSE
Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). Outcomes after a 3-year follow-up in the pivotal ZUMA-2 study of KTE-X19 in relapsed/refractory MCL are reported, including for subgroups by prior therapy (bendamustine and type of Bruton tyrosine kinase inhibitor [BTKi]) or high-risk characteristics.
METHODS
Patients with relapsed/refractory MCL (one to five prior therapies, including prior BTKi exposure) received a single infusion of KTE-X19 (2 × 10 CAR T cells/kg).
RESULTS
After a median follow-up of 35.6 months, the objective response rate among all 68 treated patients was 91% (95% CI, 81.8 to 96.7) with 68% complete responses (95% CI, 55.2 to 78.5); medians for duration of response, progression-free survival, and overall survival were 28.2 months (95% CI, 13.5 to 47.1), 25.8 months (95% CI, 9.6 to 47.6), and 46.6 months (95% CI, 24.9 to not estimable), respectively. Post hoc analyses showed that objective response rates and ongoing response rates were consistent among prespecified subgroups by prior BTKi exposure or high-risk characteristics. In an exploratory analysis, patients with prior bendamustine benefited from KTE-X19, but showed a trend toward attenuated T-cell functionality, with more impact of bendamustine given within 6 versus 12 months of leukapheresis. Late-onset toxicities were infrequent; only 3% of treatment-emergent adverse events of interest in ZUMA-2 occurred during this longer follow-up period. Translational assessments revealed associations with long-term benefits of KTE-X19 including high-peak CAR T-cell expansion in responders and the predictive value of minimal residual disease for relapse.
CONCLUSION
These data, representing the longest follow-up of CAR T-cell therapy in patients with MCL to date, suggest that KTE-X19 induced durable long-term responses with manageable safety in patients with relapsed/refractory MCL and may also benefit those with high-risk characteristics.
Topics: Adult; Humans; Receptors, Chimeric Antigen; Lymphoma, Mantle-Cell; Immunotherapy, Adoptive; Follow-Up Studies; Bendamustine Hydrochloride; Neoplasm Recurrence, Local
PubMed: 35658525
DOI: 10.1200/JCO.21.02370 -
Oncology (Williston Park, N.Y.) Feb 2022Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic... (Review)
Review
Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Benzamides; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Doxorubicin; Genetic Testing; Humans; Immune Checkpoint Inhibitors; Immunoconjugates; Immunotherapy, Adoptive; Lenalidomide; Lymphoma, Follicular; Maintenance Chemotherapy; Morpholines; Neoplasm Recurrence, Local; Phosphoinositide-3 Kinase Inhibitors; Prednisone; Pyridones; Rituximab; Sulfonamides; Vincristine
PubMed: 35180337
DOI: 10.46883/2022.25920946 -
Blood Cancer Journal Apr 2021Newer, more effective and non-cytotoxic therapies are an unmet need for patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. Recently... (Review)
Review
Newer, more effective and non-cytotoxic therapies are an unmet need for patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. Recently approved agents include polatuzumab with bendamustine and rituximab, selinexor, and tafasitamab plus lenalidomide. Three CAR-T cell products are currently approved by the FDA, with others in clinical trials. Additional agents in development include bispecific antibodies and antibody drug conjugates. Combinations of targeted therapies should lead to further improvement in the outcome of patients with B-cell malignancies.
Topics: Animals; Antibodies, Bispecific; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Drug Development; Humans; Immunoconjugates; Immunotherapy, Adoptive; Lenalidomide; Lymphoma, Large B-Cell, Diffuse; Molecular Targeted Therapy; Rituximab
PubMed: 33820908
DOI: 10.1038/s41408-021-00456-w -
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 -
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 -
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