Lymphocyte morphology in a patient receiving CD19 chimeric antigen receptor T-cell therapy for mantle cell lymphoma.
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ABSTRACT:
SUBMITTER: Marzolini MAV
PROVIDER: S-EPMC9175998 | biostudies-literature | 2022 Feb
REPOSITORIES: biostudies-literature
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Lymphocyte morphology in a patient receiving CD19 chimeric antigen receptor T-cell therapy for mantle cell lymphoma.
Marzolini Maria A V MAV Neill Lorna L O'Reilly Maeve M Peggs Karl S KS Roddie Claire C
EJHaem 20211118 1
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Project description:Mantle cell lymphoma (MCL) is a rare B-cell malignancy that remains challenging to treat with high rates of relapse. Frontline strategies range from intensive chemotherapy followed by consolidation with autologous stem cell transplant (ASCT), to less-intensive therapies including combination regimens. The treatment landscape for relapsed patients includes Bruton tyrosine kinase (BTK) inhibitors among other targeted treatments. Novel agents such as the selective BCL2 inhibitor venetoclax showed high response rates when used as monotherapy for refractory relapsed MCL. The rituximab, bendamustine, and cytarabine (R-BAC) regimen, while response rates were high, were not durable. Chimeric antigen receptor (CAR) T-cell products targeting CD19 have been efficacious in relapsed and refractory MCL patients. Brexucabtagene autoleucel (brexu-cel, formerly KTE-X19) was approved by US Food and Drug Administration (FDA) in July, 2020, for treatment of refractory and relapsed MCL. This article provides an overview for the available management strategies for relapsed MCL and examines the role of CAR T-cell in the current and future treatment of MCL.
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Project description:Cerebral edema following chimeric antigen receptor (CAR) T-cell therapy can be fatal. ZUMA-2 is a pivotal phase 2, multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T-cell therapy, in relapsed/refractory mantle cell lymphoma. We describe a 65-year-old patient in ZUMA-2 who developed cerebral edema following CAR T-cell therapy and had complete recovery after multimodality clinical intervention including rabbit antithymocyte globulin (ATG). Biomarker results show early and robust CAR T-cell expansion and related induction of inflammatory cytokines, followed by rapid declines in CAR T-cell and proinflammatory cytokine levels after ATG administration. This clinical profile highlights a potential relevance of ATG in treating severe CAR T-cell-related neurotoxicity.
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Project description:B-cell non-Hodgkin lymphoma (B-NHL) is the most frequent hematological malignancy. Although refined chemotherapy regimens and several new therapeutics including rituximab, a chimeric anti-CD20 monoclonal antibody, have improved its prognosis in recent decades, there are still a substantial number of patients with chemorefractory B-NHL. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is expected to be an effective adoptive cell treatment and has the potential to overcome the chemorefractoriness of B-cell leukemia and lymphoma. Recently, several clinical trials have shown remarkable efficacy of anti-CD19 CAR T-cell therapy, not only in B-acute lymphoblastic leukemia but also in B-NHL. Nonetheless, there are several challenges to overcome before introduction into clinical practice, such as: (i) further refinement of the manufacturing process, (ii) further improvement of efficacy, (iii) finding the optimal infusion cell dose, (iv) optimization of lymphocyte-depleting chemotherapy, (v) identification of the best CAR structure, and (vi) optimization of toxicity management including cytokine release syndrome, neurologic toxicity, and on-target off-tumor toxicity. Several ways to solve these problems are currently under study. In this review, we describe the updated clinical data regarding anti-CD19 CAR T-cell therapy, with a focus on B-NHL, and discuss the clinical implications and perspectives of CAR T-cell therapy.
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Project description:Multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) comprise a large fraction of hematologic malignancies diagnosed each year. However, the co-occurrence of these conditions in the same patient is rare. CD19- and B-cell maturation antigen-targeted chimeric antigen receptor (CAR) T-cell therapies have been approved in recent years with promising responses. Here, we present a patient who presented following a bone marrow biopsy that revealed MM with 20% lambda-restricted plasma cells with no evidence of lymphoma involvement in the marrow. A subsequent lymph node biopsy of a right thigh mass was done and revealed DLBCL. The patient received CD19-targeted CAR T-cell therapy and has no detectable MM or DLBCL. To our knowledge, this is the first case report in the literature describing a patient with concomitant MM and DLBCL who received CD19-targeted CAR T-cell therapy.
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Project description:Background and purposeCD19-targeting chimeric antigen receptor T-cell (CART) therapy is a promising treatment for relapsed/refractory non-Hodgkin lymphoma, but most patients experience post-CART progression. We describe our institutional experience of salvage radiotherapy (SRT) in this setting.Materials and methodsOf 94 patients who received CART therapy from 2018 to 2020, 21 received SRT for post-CART progression. Patients were divided into two groups: locoregional disease (n = 9 [43 %], all disease encompassable within an RT field) and advanced disease (n = 12 [57 %]). Patterns of failure, progression-free survival (PFS), overall survival (OS), and toxicity were assessed.ResultsMedian time from CART infusion to SRT was 4.0 months (range, 0.6-11.5 months). In the locoregional disease group, 8/9 patients (89 %) were treated with comprehensive SRT to a median dose of 37.5 Gy in a median of 15 fractions. In the advanced disease group, all patients (n = 12) were treated with focal SRT to a median dose of 20.8 Gy in a median of 5 fractions. Median follow-up post-SRT was 15.2 months. In-field response was observed in 8/9 (89 %) in the locoregional disease and 8/9 (89 %) evaluable patients in the advanced disease groups. 17/18 evaluable patients (94 %) patients experienced post-SRT progression, all with a distant component. Median OS was 7.4 months; 21 months for locoregional disease versus 2.4 months for advanced disease (p = 0.0002). Median PFS was 1.1 month, and similarly poor regardless of group. No grade ≥ 3 toxicities occurred.ConclusionsSRT post-CART therapy appears safe with encouraging in-field response but high rates of out-of-field progression, even for those presenting with locoregional disease, highlighting the need for integration of novel systemic agents.
| S-EPMC9883177 | biostudies-literature
Project description:Adoptive immunotherapy using B-cell-targeted chimeric antigen receptor (CAR)-modified T cells to treat hematologic malignancies is transforming cancer care for patients with refractory or relapsed diseases. Recent and anticipated regulatory approval for products targeting acute lymphoblastic leukemia, lymphomas, and multiple myeloma have led to global implementation of these novel treatments. The rapidity of commercial utilization of CAR-T-cell therapy has created a largely unexplored gap in patient supportive-care approaches. Such approaches are critical in these complex patients given their high net state of immunosuppression prior to CAR-T-cell infusion coupled with unique acute and persistent insults to their immune function after CAR-T-cell infusion. In this "How I Treat" article, we focus on key questions that arise during 3 phases of management for patients receiving CD19-targeted CAR-T cells: pre CAR-T-cell infusion, immediate post CAR-T-cell infusion, and long-term follow-up. A longitudinal patient case is presented for each phase to highlight fundamental issues including infectious diseases screening, antimicrobial prophylaxis, immunoglobulin supplementation, risk factors for infection, and vaccination. We hope this discussion will provide a framework for institutions and health care providers to formulate their own approach to preventing infections in light of the paucity of data specific to this treatment modality.
| S-EPMC7441168 | biostudies-literature
Project description:Chimeric antigen receptor T-cell therapy (CAR-T) has transformed the treatment for relapsed/refractory hematologic malignancies; however, data on patient-reported outcomes in CAR-T are limited. We conducted a longitudinal study of adults with hematologic malignancies receiving CAR-T. We assessed quality of life (QOL; functional assessment of cancer therapy-general), psychological distress (hospital anxiety and depression scale, patient health questionnaire-9, posttraumatic stress disorder [PTSD] checklist), and physical symptoms (Edmonton symptom assessment scale-revised) at baseline, 1 week, 1, 3, and 6 months after CAR-T. We used linear mixed models to identify factors associated with QOL trajectory. We enrolled 103 of 142 eligible patients (3 did not receive CAR-T). QOL (B = 1.96; P < .001) and depression (B = -0.32; P = .001) worsened by 1 week and improved by 6 months after CAR-T. At 6 months, 18%, 22%, and 22% reported clinically significant depression, anxiety, and PTSD symptoms, respectively. At 1 week, 52% reported severe physical symptoms, declining to 28% at 6 months after CAR-T. In unadjusted linear mixed models, worse Eastern Cooperative Oncology Group performance status (B = 1.24; P = .042), receipt of tocilizumab (B = 1.54; P = .042), and receipt of corticosteroids for cytokine release syndrome and/or neurotoxicity (B = 2.05; P = .006) were associated with higher QOL trajectory. After CAR-T, QOL declined, and depression increased early, followed by improvements in QOL, psychological distress, and physical symptoms by 6 months after infusion. A significant minority of patients reported substantial psychological distress and physical symptoms longitudinally.
| S-EPMC10368828 | biostudies-literature
Project description:T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed. Importantly, CRs continued after recovery of non-malignant polyclonal B cells in three of four patients with long-term complete remissions. In these three patients, recovery of CD19+ polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these three patients remained in CR at the last follow-up. Non-malignant CD19+ B cell recovery with continuing CRs demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T cell populations. Patients had a low incidence of severe infections despite long periods of B cell depletion and hypogammaglobulinemia. Only one hospitalization for an infection occurred among the four patients with long-term CRs. Anti-CD19 CAR T cells caused long-term remissions of chemotherapy-refractory DLBCL without substantial chronic toxicities.
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Project description: Not available
| S-EPMC8212512 | biostudies-literature
Project description:BackgroundChimeric antigen receptor (CAR) T-cell therapy (CAR-T therapy) has demonstrated significant efficacy in the ZUMA-2 study. After regulatory approvals, several clinical trials and real-world studies on CAR-T therapy for relapsed or refractory mantle cell lymphoma (R/R MCL) were conducted. However, data on clinical safety and efficacy are inconsistent. In this study, we aimed to conduct a systematic analysis of the effectiveness and safety of CAR-T therapy across a wider and more representative cohort of patients with R/R MCL.MethodsWe performed a systematic review and meta-analysis of studies on patients with R/R MCL who received CAR-T cell therapy. Data were extracted and consolidated, with primary focus on the evaluation of safety and efficacy outcome measures. This study has not been registered with PROSPERO.ResultsThis meta-analysis identified and included 16 studies with 984 patients. The pooled estimate for overall response rate (ORR) was 89%; complete remission (CR) rate was 74%. The 6-month and 12-month progression-free survival (PFS) rates were 69% and 53%, respectively, while the overall survival (OS) rates were 80% and 69%, respectively. Cytokine release syndrome (CRS) of grade 3 or higher was observed in 8% of patients, whereas neurotoxicity of grade 3 or higher was observed in 22% of patients. The risk of bias was assessed as low in 9 studies and moderate in 7 studies.ConclusionCAR-T therapy exhibited promising efficacy and manageable adverse reactions in patients with R/R MCL.
| S-EPMC11412868 | biostudies-literature