Integration of cell therapies and bispecific antibodies into the treatment pathway of relapsed diffuse large B-cell lymphoma
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ABSTRACT:
SUBMITTER: Rampotas A
PROVIDER: S-EPMC8558790 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Diffuse large B-cell lymphoma is an aggressive and biologically heterogeneous disease. R-CHOP is the standard first line therapy and cures more than 60% of patients. Salvage high-dose chemotherapy with autologous stem cell transplant remains the standard second-line treatment for relapsed or refractory patients, and recently, three CD19 chimeric antigen receptor T cells (CART) cell products have been approved beyond 2 prior lines of systemic therapy. Nevertheless, some patients are not eligible for transplant or CARTs, or progress after these treatments. In this context, IgG-like bispecific antibodies (BsAbs) have been designed to treat B-cell lymphomas. They combine two different monospecific antigen-binding regions that target CD20 on B cells and engage T cells via CD3 in a 1:1 or 2:1 CD20:CD3 antigen binding fragment (Fab) format. The results of different phase 1 trials with BsAbs, including mosunetuzumab, glofitamab, epcoritamab and odeonextamab, have been recently published. They are infused intravenously or subcutaneously, and have a favorable toxicity profile, with reduced cytokine release syndrome and neurological toxicity. Moreover, these BsAbs have demonstrated very promising efficacy in B-cell lymphomas, including in aggressive lymphomas. New trials are currently ongoing to confirm BsAbs efficacy and tolerability, as well as to explore its efficacy in different lines of therapy or in combination with other drugs.
| S-EPMC9344863 | biostudies-literature
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:Approximately 40% of patients with diffuse large B cell lymphoma (DLBCL) do not respond or develop relapsed disease after first-line chemoimmunotherapy. A minority of these patients can be cured with autologous hematopoietic stem cell transplantation (AHCT). Although chimeric antigen receptor (CAR) T cells have transformed the treatment paradigm of relapsed/refractory DLBCL, only 30-40% of patients achieve durable remissions. In addition, many patients with relapsed/refractory DLBCL are ineligible to receive treatment with CAR T cells due to comorbidities or logistical limitations. Since 2019, the following four non-CAR T-cell treatments have been approved in relapsed/refractory DLBCL: polatuzumab in combination with bendamustine and rituximab, selinexor, tafasitamab plus lenalidomide, and loncastuximab. In this article, I review the data behind these four approvals and discuss important considerations on their use in clinical practice. I also review emerging therapies that have shown promising early results in relapsed/refractory DLBCL including the bispecific antibodies, antibody-drug conjugates, Bruton tyrosine kinase inhibitors, BCL2 inhibitors, immune checkpoint inhibitors, and epigenetic modifiers.
| S-EPMC8708171 | biostudies-literature
Project description:Current genomic models in diffuse large B-cell lymphoma (DLBCL) are based on single tumor biopsies, which might underestimate heterogeneity. Data on mutational evolution largely remains unknown. An exploratory study using whole exome sequencing on paired (primary and relapse) formalin fixed paraffin embedded DLBCL biopsies (n = 14) of 6 patients was performed to globally assess the mutational evolution and to identify gene mutations specific for relapse samples from patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. A minority of the mutations detected in the primary sample (median 7.6%, range 4.8⁻66.2%) could not be detected in the matching relapse sample. Relapsed DLBCL samples showed a mild increase of mutations (median 12.5%, range 9.4⁻87.6%) as compared to primary tumor biopsies. We identified 264 genes possibly related to therapy resistance, including tyrosine kinases (n = 18), (transmembrane) glycoproteins (n = 73), and genes involved in the JAK-STAT pathway (n = 7). Among the potentially resistance related genes were PIM1, SOCS1, and MYC, which have been reported to convey a risk for treatment failure. In conclusion, we show modest temporal heterogeneity between paired tumor samples with the acquisition of new mutations and identification of genes possibly related to therapy resistance. The mutational evolution could have implications for treatment decisions and development of novel targeted drugs.
| S-EPMC6265691 | biostudies-literature
Project description:Few patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) achieve prolonged disease-free survival. Blinatumomab, a bispecific T-cell engaging antibody construct, transiently links CD3-positive T cells to CD19-positive B cells. This phase 2 study evaluated stepwise (9-28-112 ?g/d with weekly dose increases; n = 23) or flat (112 ?g/d; n = 2) dosing of blinatumomab by continuous infusion, with dexamethasone prophylaxis, in patients with relapsed/refractory DLBCL. Patients received a median of 3 prior lines of therapy. Median time since last regimen was 1.5 months. Seventeen patients ended treatment in cycle 1 (induction), 7 in cycle 2 (consolidation), and 1 in retreatment. Among 21 evaluable patients, the overall response rate after 1 blinatumomab cycle was 43%, including complete responses (CRs) in 19%. Three patients had late CR in follow-up without other treatment. The most common adverse events with stepwise dosing were tremor (48%), pyrexia (44%), fatigue (26%), and edema (26%). Grade 3 neurologic events with stepwise dosing were encephalopathy and aphasia (each 9%) and tremor, speech disorder, dizziness, somnolence, and disorientation (each 4%). Of 5 (22%) patients who discontinued stepwise dosing because of adverse events, 4 (17%) had neurologic events. Most neurologic events resolved. The flat-dose cohort was stopped because of grade 3 neurologic events in both patients. Blinatumomab monotherapy appears effective in patients with relapsed/refractory DLBCL, a heavily pretreated patient population with a high unmet medical need. Further studies need to define the optimal approach to achieve the target dose without early dropout. The study was registered at www.clinicaltrials.gov as #NCT01741792.
| S-EPMC4797019 | 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:Diffuse large B-cell lymphoma (DLBCL) is an aggressive and biologically heterogeneous disease. Approximately 40% of patients with DLBCL will experience disease relapse or will be refractory to first-line chemo immunotherapy. In recent years, there have been several new therapeutic agents approved for the treatment of relapsed/refractory (R/R) DLBCL. These agents include anti-CD19 chimeric antigen receptor T-cell (CAR T-cell) and monoclonal antibody therapies such as polatuzumab and tafasitamab. Nevertheless, despite the high efficacy of all these new therapies, there are still patients who do not respond or relapse, representing an unmet clinical need. This review describes new promising therapies that are in clinical development to treat R/R DLBCL.
| S-EPMC10707233 | 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:Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma, is typically treated with chemotherapy combined with the immunotherapy rituximab, an antibody targeting the B cell receptor, CD20. Despite the success of this treatment regimen, approximately a third of DLBCL patients experience either relapse or have refractory disease that is resistant to rituximab, indicating the need for alternative therapeutic strategies. Here, we identified that CD74 and IL4R are expressed on the cell surface of both CD20 positive and CD20 negative B cell populations. Moreover, genes encoding CD74 and IL4R are expressed in lymphoma biopsies isolated from all stages of disease. We engineered bispecific antibodies targeting CD74 or IL4R in combination with rituximab anti-CD20 (anti-CD74/anti-CD20 and anti-IL4R/anti-CD20). Bispecific antibody function was evaluated by measuring direct induction of apoptosis, antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity in both rituximab-sensitive and rituximab-resistant DLBCL cell lines. Both anti-CD74/anti-CD20 and anti-IL4R/anti-CD20 were able to mediate ADCC and ADCP, but CD74-targeting therapeutic antibodies could also mediate direct cytotoxicity. Overall, this study strongly indicates that development of bispecific antibodies that target multiple B cell receptors expressed by lymphoma could provide improved defense against relapse and rituximab resistance.
| S-EPMC9637670 | biostudies-literature