CAR T-Cell Therapy Predictive Response Markers in Diffuse Large B-Cell Lymphoma and Therapeutic Options After CART19 Failure.
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ABSTRACT:
SUBMITTER: Caballero AC
PROVIDER: S-EPMC9299440 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chimeric antigen receptor (CAR) T-cell therapy has emerged as an option for relapsed/refractory aggressive B-cell lymphomas that have failed 2 lines of therapy. Failures usually occur early after infusion. The purpose of our study was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. With a median follow-up of 8.2 months, 55 patients failed treatment; 27 (49%) were early progressors. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 47.2% (95% confidence interval [CI], 38.0-58.6) and 67.0% (95% CI, 57-79), respectively. Univariate analyses for PFS and OS identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, stage III/IV disease, extranodal (EN) sites ≥2, elevated lactate dehydrogenase (LDH), increased C-reactive protein (CRP), high International Prognostic Index at TD and at TT, as well as increased CRP, bulky mass, and high TMTV at TT, as risk factors. Multivariate analyses for PFS, EP, and OS identified elevated LDH and EN sites ≥2 at TD and the same predictors at TT (ie, increased CRP, EN sites ≥2, and TMTV >80 mL). In summary, risk factors identified for early progression at TD and at TT were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).
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Project description:Peripheral T cell lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphomas with a very poor prognosis. The standard first-line treatments have resulted in unsatisfactory patient outcomes. With the exception of low-risk anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), the majority of patients relapse rapidly; the current 5-year overall survival rates are only 10-30%. Novel targeted therapies and combination chemotherapies are required for the treatment of patients with PTCL. In recent years, some retrospective and prospective studies have been performed concerning PTCL. Consequently, a number of novel agents and their relevant combination therapies have been identified, including histone deacetylase inhibitors, immunoconjugates, antifolates, monoclonal antibodies, immunomodulatory agents, nucleoside analogs, proteasome inhibitors, kinase inhibitors, bendamustine, L-asparaginase, and other targeted agents. It is hoped that these innovative approaches will finally improve outcomes in patients with PTCL. This review summarizes the currently available approaches for the treatment of PTCL with an emphasis on potential new agents, including the role of stem cell transplantation.
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Project description:BackgroundPIM serine/threonine kinases are often highly expressed in haematological malignancies. We have shown that PIM inhibitors reduced the survival and migration of leukaemic cells. Here, we investigated PIM kinases in diffuse large B-cell lymphoma (DLBCL) biopsy samples and DLBCL cell lines.MethodsImmunohistochemical staining for PIM kinases and CXCR4 was performed on tissue microarrays from a cohort of 101 DLBCL cases, and the effects of PIM inhibitors on the survival and migration of DLBCL cell lines were determined.ResultsPIM1 expression significantly correlated with the activation of signal transducer and activator of transcription (STAT) 3 and 5, P-glycoprotein expression, CXCR4-S339 phosphorylation, and cell proliferation. Whereas most cases exhibited cytoplasmic or cytoplasmic and nuclear PIM1 and PIM2 expression, 12 cases (10 of the non-germinal centre DLBCL type) expressed PIM1 predominately in the nucleus. Interestingly, nuclear expression of PIM1 significantly correlated with disease stage. Exposure of DLBCL cell lines to PIM inhibitors modestly impaired cellular proliferation and CXCR4-mediated migration.ConclusionThis work demonstrates that PIM expression in DLBCL is associated with activation of the JAK/STAT signalling pathway and with the proliferative activity. The correlation of nuclear PIM1 expression with disease stage and the modest response to small-molecule inhibitors suggests that PIM kinases are progression markers rather than primary therapeutic targets in DLBCL.
| S-EPMC3405213 | biostudies-literature
Project description:Most patients with Diffuse Large B-cell Lymphoma (DLBCL) are old (>65 years of age) and this population is expected to increase in the following years. A simplified geriatric assessment based on a careful evaluation of the fitness status and comorbidities is essential to choose the correct intensity of treatment. Fit older patients can benefit from a standard immunochemotherapy, while unfit/frail patients frequently need reduced doses or substitution of particular agents with less toxic ones. This review focuses on new therapies (e.g., polatuzumab vedotin, tafasitamab, bispecific antibodies) that have indicated promising results in relapsed/refractory patients, particularly in cases not eligible to transplant. Some of these new drugs have been tested as single agents or in combinations as first-line treatment, aiming to improve the outcome of the traditional chemotherapy. If preliminary efficacy and safety data are confirmed in future clinical trials, a chemo-free immunotherapic approach could become an alternative option to offer a curative treatment even in frail patients.
| S-EPMC10351275 | biostudies-literature
Project description:Patients with non-Hodgkin lymphomas (NHLs) resistant to standard therapies have a dismal prognosis. The outcome is even poorer in patients relapsing after autologous stem cell transplantation. Most of these patients do not qualify for an allogeneic hematopoietic cell transplantation (HCT) due to refractory disease, lack of a suitable allogeneic donor, higher age, or cumulative toxicity of previous chemotherapy. Despite patients undergoing allogeneic HCT normally profit from a graft-versus-lymphoma effect, overall survival in patients with NHL after HCT remains short. Therefore, novel treatment modalities are urgently needed. Chimeric antigen receptor (CAR)-T cells, a new class of cellular immunotherapy involving ex vivo genetic modification of T cells to incorporate an engineered CAR have been used in clinical trials. In the majority of studies, B cell malignancies treated with CD19 targeting CAR-T cells have been analyzed. Recently, results from 2 CD19 directed CAR-T cell trials with an increased follow-up of patients led to Food and Drug Administration and European Medicines Agency approval of tisagenlecleucel and axicabtagene ciloleucel. Common adverse events (AEs) include cytokine release syndrome and neurological toxicity, which may require admission to an intensive care unit, B cell aplasia and hemophagocytic lymphohistiocytosis. These AEs are manageable when treated by an appropriately trained team following established algorithm. In this review, we summarize the results of 3 large phase II CD19 CAR-T cell trials and focus on AEs. We also provide a perspective of ongoing activity in this field with the intend to improve the potency of this emerging novel therapy.
| S-EPMC6746029 | 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:Diffuse large B-cell lymphoma (DLBCL) represents a curable disease with a 60-70% chance of cure with current R-CHOP chemoimmunotherapy. However, 30-40% of patients are refractory or relapsing. Many attempts failed to improve the outcome of DLBCL patients, including the intensification of R-CHOP regimen, consolidation, or maintenance therapy since the introduction of R-CHOP in 2000. Better understanding of both molecular biology of lymphoma cells and the tumor microenvironment raised the hope for future improvement of DLBCL patients' survival. Novel molecular findings have initiated clinical trials exploring targeted therapy based on driver genetic alterations with an intent to improve survival of high-risk subsets of patients. But the preliminary results remain ambiguous. The approach "agnostic" to specific molecular alterations of lymphoma cell includes antibody-drug conjugates (especially polatuzumab vedotin), immunotherapy comprising different antibodies with immunomodulatory effect (tafasitamab, lenalidomide), and T-cell engaging therapy (bispecific antibodies, early use of CAR T-cell). This approach could increase the cure rates and change the current therapeutic paradigm. However, better prognostic stratification, smarter designs of clinical trials, modification of endpoints including the use of ctDNA are needed. This review covers the complexity of DLBCL management.
| S-EPMC9739046 | biostudies-literature
Project description:Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of DLBCL with limited data on patterns of failure. This multicenter study aimed to define the optimum treatment strategy and patterns of failure for PB-DLBCL patients. We retrospectively reviewed data on 108 PB-DLBCL patients from 21 Chinese medical centers. Only patients with localized disease (involvement of breast and localized lymph nodes) were included. After a median follow-up of 3.2 years, 32% of patients developed progression or relapse. A continuous pattern of relapse was observed, characterized by frequent late relapses in the contralateral breast and central nervous system (CNS). Although rituximab significantly reduced the overall cumulative risk of progression or relapse (5-year cumulative risk 57% vs 24%, P = .029), it had limited effect on the reduction of breast relapse (P = .46). Consolidative radiotherapy significantly decreased the risk of breast relapse, even in the subgroup of patients treated with rituximab (5-year cumulative risk 21.2% vs 0%, P = .012). A continuous risk of CNS progression or relapse up to 8.2 years from diagnosis was observed (10-year cumulative risk 28.3%), with a median time to CNS relapse of 3.1 years. Neither rituximab nor prophylactic intrathecal chemotherapy significantly decreased the risk of CNS relapse. In summary, our study indicates that PB-DLBCL has a continuous pattern of relapse, especially with frequent late relapses in the CNS and contralateral breast. Rituximab and RT confer complementary benefit in the reduction of relapse. However, neither the addition of rituximab nor prophylactic intrathecal chemotherapy could effectively prevent CNS relapse for PB-DLBCL patients.
| S-EPMC6272095 | biostudies-literature
Project description:BackgroundFailure to CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), is an emerging clinical problem. There is no consensus on the treatment for these patients and treatment remains empirical.Case reportWe reported a case of an elderly R/R DLBCL patient who had TP53 mutation and relapsed 12 months after initial response to CAR T-cell therapy. The patient did not respond to salvage chemotherapy with the GDP regimen and could not tolerate any aggressive chemotherapy. Thereafter, the patient was given chidamide and zanubrutinib. After two months of treatment, the patient achieved sustained complete remission. At the last follow-up, the patient remains in radiographic CR 22 months after CAR-T infusion and 10 months after the initiation of the combination treatment.ConclusionWe report the first successful case of dual inhibition of HDAC and BTK for the treatment of R/R DLBCL after failure to CAR-T cell therapy, which opens a new therapeutic possibility for the future.
| S-EPMC9226330 | biostudies-literature
Project description:Although rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment for patients with diffuse large B-cell lymphoma (DLBCL), ?30% to 50% of patients are not cured by this treatment, depending on disease stage or prognostic index. Among patients for whom R-CHOP therapy fails, 20% suffer from primary refractory disease (progress during or right after treatment) whereas 30% relapse after achieving complete remission (CR). Currently, there is no good definition enabling us to identify these 2 groups upon diagnosis. Most of the refractory patients exhibit double-hit lymphoma (MYC-BCL2 rearrangement) or double-protein-expression lymphoma (MYC-BCL2 hyperexpression) which have a more aggressive clinical picture. New strategies are currently being explored to obtain better CR rates and fewer relapses. Although young relapsing patients are treated with high-dose therapy followed by autologous transplant, there is an unmet need for better salvage regimens in this setting. To prevent relapse, maintenance therapy with immunomodulatory agents such as lenalidomide is currently undergoing investigation. New drugs will most likely be introduced over the next few years and will probably be different for relapsing and refractory patients.
| S-EPMC6142522 | biostudies-literature