Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Look at the Approved and Emerging Therapies.
Ontology highlight
ABSTRACT:
SUBMITTER: Sawalha Y
PROVIDER: S-EPMC8708171 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The most common type of non-Hodgkin lymphoma in adults is diffuse large B-cell (DLBCL). There is a historical unmet need for more effective therapies in the 2nd and 3rd line setting. Emerging immunochemotherapies have shown activity in small studies of heavily pre-treated patients with prolonged remissions achieved in some patients. Anti-CD19 CAR (chimeric antigen receptor) T cells are potentially curative in the 3rd line and beyond setting and are under investigation in earlier lines of therapy. Antibody-drug conjugates (ADC's) such as polatuzumab vedotin targeting the pan-B-cell marker CD79b has proven effectiveness in multiply-relapsed DLBCL patients. Tafasitamab (MOR208) is an anti-CD19 monoclonal antibody producing prolonged remissions when combined with Lenalidomide (LEN) in patients who were not candidates for salvage chemotherapy or autologous stem cell transplant. Selinexor, an oral, small-molecule selective inhibitor of XPO1-mediated nuclear export (SINE), demonstrated prolonged activity against heavily-pretreated DLBCL without cumulative toxicity and is being investigated as part of an oral, chemotherapy-free regimen for relapsed aggressive lymphoma. This article reviews current strategies and novel therapies for relapsed/refractory DLBCL.
| S-EPMC7698117 | biostudies-literature
Project description:Overall, around 40% of patients with diffuse large B-cell lymphoma (DLBCL) have refractory disease or relapse after the first line of treatment. Until relatively recently, the prognosis of patients with relapsed or refractory DLBCL was very poor and treatment options were very limited. In recent years, several novel therapies have been approved that provide more effective options than conventional chemotherapy and that have manageable toxicity profiles. CAR-T cell therapy has become the new standard treatment for patients with refractory or early relapsed DLBCL, based on the positive results of the phase 3 ZUMA-7 and TRANSFORM clinical trials. This review addresses the role of CAR-T therapy and autologous stem cell transplantation in the treatment of these patients and other approved options for patients who are not candidates for transplant, such as the combinations of polatuzumab vedotin with bendamustine and rituximab, and tafasitamab with lenalidomide.
| S-EPMC10779497 | biostudies-literature
Project description:BackgroundOutcomes in patients with relapsed/refractory (R/R) diffuse large b-cell lymphoma (DLBCL) who are ineligible for and/or fail high-dose chemotherapy and autologous stem cell transplantation in the second line are poor. There is no preferred palliative-intent treatment for patients in this setting.Patients and methodsA retrospective cohort study was performed using the nationwide de-identified electronic health record-derived Flatiron Health database. Event-free survival (EFS) and overall survival (OS) was evaluated for patients with R/R DLBCL who were ineligible for and/or failed autologous stem cell transplantation in the second line and received bendamustine, gemcitabine, or lenalidomide.ResultsThree hundred eighty-three patients were included. Therapy received was bendamustine in 158 patients, gemcitabine in 142 patients, and lenalidomide in 83 patients. The median EFS and OS for all patients was 4.1 months and 8.7 months, respectively. Compared with patients receiving bendamustine or gemcitabine, those receiving lenalidomide demonstrated significantly longer median EFS (6.8 vs. 3.8 months; P = .006) and median OS (15.4 vs. 7.7 months; P = .045). Survival outcomes were also improved for lenalidomide-treated patients specifically in the second- as well as third- or fourth-line settings.ConclusionUse of lenalidomide resulted in prolonged EFS and OS as compared with bendamustine or gemcitabine in this cohort of patients with R/R DLBCL receiving palliative therapy. This first large-scale analysis of real-world outcomes for this patient population may guide current clinical management as well as serve as a benchmark for survival outcomes in the standard-of-care setting, which may aid in the design of future clinical trials.
| S-EPMC8075299 | biostudies-literature
Project description:PurposePatients 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.MethodsSafety 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.ResultsPola-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% v 17.5%; P = .026) and longer IRC-assessed PFS (median, 9.5 v 3.7 months; hazard ratio [HR], 0.36, 95% CI, 0.21 to 0.63; P < .001) and OS (median, 12.4 v 4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75; P = .002; median follow-up, 22.3 months). Pola-BR patients had higher rates of grade 3-4 neutropenia (46.2% v 33.3%), anemia (28.2% v 17.9%), and thrombocytopenia (41% v 23.1%), but similar grade 3-4 infections (23.1% v 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.ConclusionPolatuzumab 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.
| S-EPMC7032881 | biostudies-literature
Project description:Patients with diffuse large B-cell lymphoma who have refractory or relapsed disease following first line treatment have a poor prognosis when treated with conventional therapies. Significant efforts have been made in recent years to bring a broad spectrum of novel targeted therapies, the most noteworthy of which is chimeric antigen receptor T-cell therapy (CAR-T). Not all patients are eligible for CAR-T given the relatively high risk of complications and limited availability. Here we discuss promising novel biologic therapies that have been introduced in the last few years and go over ongoing clinical trials in the field.
| S-EPMC8728095 | biostudies-literature
Project description:IntroductionPatients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) require further treatment options, especially in cases that cannot tolerate stem cell transplant or cytotoxic chemotherapy. CD19 has emerged as an attractive target in B-cell malignancy and is the subject of several therapeutic strategies. The anti-CD19, humanized, monoclonal antibody tafasitamab (MOR208) has an engineered, modified Fc region with increased affinity for Fcγ receptors, leading to increased cytotoxicity via natural killer cells and macrophages (antibody-dependent cellular cytotoxicity and antibody-dependent cell-mediated phagocytosis) in a promising approach.Areas coveredThe development of tafasitamab is reviewed, together with the pharmacokinetics and clinical experience of tafasitamab in R/R DLBCL; clinical data have led to FDA approval and inclusion in NCCN treatment guidelines for tafasitamab in combination with lenalidomide in this indication.Expert opinionPatients with R/R DLBCL who have failed rituximab-containing regimens may be resistant to CD20-directed therapies; therefore, therapies with an alternative mode of action are of great interest in this setting. Tafasitamab, an anti-CD19 monoclonal antibody, in combination with lenalidomide has demonstrated promising efficacy for patients with R/R DLBCL who are ineligible for autologous stem cell transplantation. This could provide an alternative approach to classical chemotherapy-based regimens in the relapsed setting.
| S-EPMC8363059 | biostudies-literature
Project description:Primary refractory/relapsed diffuse large B-cell lymphoma (rrDLBCL) is an unresolved issue for DLBCL treatment and new treatments to overcome resistance is required. To explore the genetic mechanisms underlying treatment resistance in rrDLBCL and to identify candidate genes, we performed targeted deep sequencing of 430 lymphoma-related genes from 58 patients diagnosed with rrDLBCL. Genetic alterations found between the initial biopsy and biopsy at recurrence or refractory disease were investigated. The genes most frequently altered (> 20%) were (in decreasing order of frequency) CDKN2A, PIM1, CD79B, TP53, MYD88, MYC, BTG2, BTG1, CDKN2B, DTX1, CD58, ETV6, and IRF4. Genes mutation of which in pretreatment sample were associated with poor overall survival included NOTCH1, FGFR2, BCL7A, BCL10, SPEN and TP53 (P < 0.05). FGFR2, BCL2, BCL6, BCL10, and TP53 were associated with poor progression-free survival (P < 0.05). Most mutations were truncal and were maintained in both the initial biopsy and post-treatment biopsy with high dynamics of subclones. Immune-evasion genes showed increased overall mutation frequency (CD58, B2M) and variant allele fraction (CD58), and decreased copy number (B2M, CD70) at the post-treatment biopsy. Using the established mutational profiles and integrative analysis of mutational evolution, we identified information about candidate genes that may be useful for the development of future treatment strategies.
| S-EPMC7992425 | biostudies-literature
Project description:In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. Approval was based on SADAL, a multicenter trial of selinexor monotherapy in patients with DLBCL after two to five systemic regimens. Efficacy was based on independent review committee-assessed objective response rate (ORR) and duration of response using Lugano criteria. In 134 patients treated with the approved dosage (60 mg orally on days 1 and 3 of each week), the ORR was 29% (95% confidence interval, 22-38), with complete response in 13% and with 38% of responses lasting at least 6 months. Gastrointestinal toxicity developed in 80% of patients, hyponatremia in 61%, central neurological toxicity (such as dizziness and mental status changes) in 25%, and ocular toxicity in 18%. New or worsening grade 3 or 4 thrombocytopenia, lymphopenia, neutropenia, anemia, or hyponatremia developed in ≥15%. Adverse reactions led to selinexor dose interruption in 61% of patients, dose reduction in 49%, and permanent discontinuation in 17%, with thrombocytopenia being the leading cause of dose modifications. Postmarketing studies will evaluate reduced dosages of selinexor and further evaluate clinical benefit in patients with relapsed or refractory DLBCL. IMPLICATIONS FOR PRACTICE: Selinexor is a new potential option for adults with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, in the third-line setting or beyond. Toxicities are typically manageable but can be difficult to tolerate and necessitate close monitoring and supportive care.
| S-EPMC8488790 | biostudies-literature
Project description:With no treatment standard having been established for relapsed and refractory follicular lymphoma, a number of therapeutic approaches are used in Canada. In patients who relapse early or who eventually become resistant to subsequent treatment, prognosis is poor, and new approaches are needed. A number of novel therapies are being examined in this setting, including monoclonal antibodies, immunoconjugates, immunomodulatory agents, and signal transduction inhibitors. With the body of evidence for those emerging therapies accumulating and the standard upfront treatment changing from rituximab and chop (cyclophosphamide-doxorubicin-vincristine-prednisone) or rituximab and cvp (cyclophosphamide-vincristine-prednisone) to bendamustine and rituximab, treatment decisions in the relapsed and refractory setting have become more complex. The choice of subsequent treatment must consider type of upfront treatment; duration of remission; and patient-related factors such as age, comorbidities, and treatment preferences. This paper summarizes the evidence for novel therapies and proposes recommendations for subsequent treatment options by remission duration after induction and maintenance.
| S-EPMC5176374 | biostudies-literature
Project description:Patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) are treated with salvage regimens and may be considered for high-dose chemotherapy and autologous stem cell transplantation if disease is chemosensitive. Bendamustine is active in indolent B cell lymphomas and chronic lymphocytic leukemia but has not been extensively studied in aggressive lymphomas. This trial examines the combination of bendamustine and rituximab in patients with relapsed and refractory DLBCL. Patients received bendamustine at 90 mg/m² (n = 2) or 120 mg/m² (n = 57) on days 1 and 2 and rituximab at 375 mg/m² on day 1 every 28 days for up to 6 cycles. The study evaluated objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and treatment safety. Fifty-nine patients were treated, and 48 were evaluable for response. Median age was 74; 89 % had stage III or IV disease, and 63 % had high revised International Prognostic Index scores; the median number of prior therapies was 1. Based on analysis using the intent-to-treat population, the ORR was 45.8 % (complete response, 15.3 %; partial response, 30.5 %). The median DOR was 17.3 months, and the median PFS was 3.6 months. Grade 3 or 4 hematological toxicities included neutropenia (36 %), leukopenia (29 %), thrombocytopenia (22 %), and anemia (12 %). The combination of bendamustine and rituximab showed modest activity in patients with relapsed and refractory DLBCL and has an acceptable toxicity profile.
| S-EPMC3918114 | biostudies-literature