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Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies: a living systematic review on comparative studies
Saiz, L. C., Leache, L., Gutiérrez-Valencia, M., Erviti, J., Rojas Reyes, M. X.
Therapeutic advances in hematology. 2023;14:20406207231168211
Abstract
BACKGROUND Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to different characteristics, and these therapies are associated with important adverse events such as cytokine release syndrome, neurologic adverse events, and B-cell aplasia. OBJECTIVES This living systematic review aims to provide a timely, rigorous, and continuously updated synthesis of the evidence available on the role of CAR-T therapy for the treatment of patients with hematologic malignancies. DESIGN A systematic review with meta-analysis of randomized controlled trials (RCTs) and comparative non-randomized studies of interventions (NRSI), evaluating the effect of CAR-T therapy versus other active treatments, hematopoietic stem cell transplantation, standard of care (SoC) or any other intervention, was performed in patients with hematologic malignancies. The primary outcome is overall survival (OS). Certainty of the evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. DATA SOURCES AND METHODS Searches were performed in the Epistemonikos database, which collates information from multiple sources to identify systematic reviews and their included primary studies, including Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, DARE, HTA Database, Campbell database, JBI Database of Systematic Reviews and Implementation Reports, EPPI-Centre Evidence Library. A manual search was also carried out. We included the evidence published up to 1 July 2022. RESULTS We included the evidence published up to 1 July 2022. We considered 139 RCTs and 1725 NRSI as potentially eligible. Two RCTs (N = 681) comparing CAR-T therapy with SoC in patients with recurrent/relapsed (R/R) B-cell lymphoma were included. RCTs did not show statistical differences in OS, serious adverse events, or total adverse events with grade ⩾ 3. Higher complete response with substantial heterogeneity [risk ratio = 1.59; 95% confidence interval (CI) = (1.30-1.93); I (2) = 89%; 2 studies; 681 participants; very low certainty evidence] and higher progression-free survival [hazard ratio for progression or death = 0.49; 95% CI = (0.37-0.65); 1 study; 359 participants; moderate certainty evidence] were reported with CAR-T therapies. Nine NRSI (N = 540) in patients with T or B-cell acute lymphoblastic leukemia or R/R B-cell lymphoma were also included, providing secondary data. In general, the GRADE certainty of the evidence for main outcomes was mostly low or very low. CONCLUSION So far, assuming important limitations in the level of certainty due to scarce and heterogenous comparative studies, CAR-T therapies have shown some benefit in terms of progression-free survival, but no overall survival, in patients with R/R B-cell lymphoma. Despite one-arm trials have already facilitated approval of CAR-T cell treatments, additional evidence from large comparative studies is still needed to better characterize the benefit-harm ratio of the use of CAR-T in a variety of patient populations with hematological malignancies. REGISTRATION https://doi.org/10.12688/openreseurope.14390.1. PROSPERO/OSF PREREGISTRATION 10.17605/OSF.IO/V6HDX.
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Efficacy of Salvage Treatments in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta-Analysis
Kim, J., Cho, J., Yoon, S. E., Kim, W. S., Kim, S. J.
Cancer research and treatment. 2023
Abstract
PURPOSE We intend to evaluate the efficacy of salvage treatments for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) through meta-analysis. MATERIALS AND METHODS R/R DLBCL trials were divided into two groups based on eligibility for autologous stem-cell transplantation (ASCT), and meta-analysis of each group was performed. Random effects models were used to estimate the 1-year progression-free survival (PFS) rate, and CAR T-cell therapy was used as reference treatment. RESULTS 26 ASCT-eligible cohorts from 17 studies comprising 2924 patients and 59 ASCT-ineligible cohorts from 53 studies comprising 3617 patients were included in the pooled analysis. In the ASCT-eligible group, the pooled 1-year PFS rate was 0.40 (95% confidence interval (CI) 0.15-0.65) for the CAR T-cell group and 0.34 (95% CI 0.30-0.37) for the group with chemotherapy followed by ASCT intention. The two treatments were not significantly different in meta-regression analysis. In the ASCT-ineligible group, the pooled 1-year PFS was 0.40 (95% CI 0.35-0.46) for CAR T-cell, and the highest primary outcome was 0.47 (95% CI 0.37-0.57) for the tafasitamab group. CAR T-cell therapy showed significantly better outcomes than chemotherapy and therapies based on ibrutinib, lenalidomide, and selinexor. However, loncastuximab, polatuzumab plus bendamustine and rituximab, and the tafasitamab group showed no different efficacy than CAR T-cell therapy after adjusting for median number of previous lines of treatment. . CONCLUSION Although several regimens were crudely grouped for classification, CAR T-cell therapy did not outperform chemotherapy followed by ASCT in the second-line setting or several recently developed agents in the ASCT-ineligible setting.
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Comparative effectiveness of salvage chemotherapy regimens and chimeric antigen T-cell receptor therapies in relapsed and refractory diffuse large B cell lymphoma: a network meta-analysis of clinical trials
Gong, I. Y., Aminilari, M., Landego, I., Hueniken, K., Zhou, Q., Kuruvilla, J., Hodgson, D. C.
Leukemia & lymphoma. 2023;:1-12
Abstract
The optimal salvage chemotherapy regimen (SC) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant remains unclear. Moreover, although chimeric antigen receptor T cell (CAR-T) therapies were recently approved for primary refractory DLBCL, head-to-head comparisons are lacking. We searched MEDLINE, EMBASE and CENTRAL to July 2022, for randomized trials that enrolled adult patients with R/R DLBCL and performed network meta-analyses (NMA) to assess the efficacy of SC and CAR-T therapies. NMA of SC (6 trials, 7 regimens, n = 1831) indicated that rituximab with gemcitabine, dexamethasone, cisplatin (R-GDP) improved OS and PFS over compared regimens. NMA of 3 CAR-T trials (n = 865) indicated that both axi-cel and liso-cel improved PFS over stand-of-care, with no difference in OS. Our results indicate that R-GDP may be preferred for R/R DLBCL over other SC compared. Longer follow-up is required for ongoing comparative survival analysis as data from CAR-T trials matures.
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Comparison of blinatumomab and CAR T-cell therapy in relapsed/refractory acute lymphoblastic leukemia: a systematic review and meta-analysis
Zhai, Y., Hong, J., Wang, J., Jiang, Y., Wu, W., Lv, Y., Guo, J., Tian, L., Sun, H., Li, Y., et al
Expert review of hematology. 2023
Abstract
OBJECTIVES This study evaluated the benefits and risks of patients with refractory or relapsed acute lymphocytic leukemia (R/R ALL) treated with Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and blinatumomab. METHODS PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies. RESULTS The pooled complete remission (CR) rate and minimal residual disease (MRD) negative rate were 48%, 31% for blinatumomab, and 86% and 80% for CAR T-cell therapy. CONCLUSIONS The CAR T-cell therapy group exhibited a higher likelihood of CR rate than the blinatumomab group in every analysis regardless of adjustment subgroups. CAR T-cell therapy was associated with a significantly prolonged overall survival (OS) and relapse-free survival (RFS) compared with blinatumomab (2-year OS 55% vs 25%; 2-year RFS 40% vs 22%). CAR T-cell therapy was more effective for achieving CR and bridging to allogeneic hematopoietic stem cell transplantation (allo-SCT) than blinatumomab (2-year OS 75% vs. 57%). An emerging role for blinatumomab is as a bridging agent pre-SCT and for patients who achieve an MRD-negative state pre-SCT, post-SCT outcomes are expected to be the same as CAR-T. For adverse effects (AEs), blinatumomab was associated with a lower rate of grade ≥ 3 hematological toxicity, CRS, and neurological events.
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5.
Efficacy of chimeric antigen receptor T cell therapy and autologous stem cell transplant in relapsed or refractory diffuse large B-cell lymphoma: A systematic review
Tian, L., Li, C., Sun, J., Zhai, Y., Wang, J., Liu, S., Jiang, Y., Wu, W., Xing, D., Lv, Y., et al
Frontiers in immunology. 2022;13:1041177
Abstract
BACKGROUND We aimed to compare the efficacy of chimeric antigen receptor T (CAR-T) cell therapy with that of autologous stem cell transplantation (auto-HSCT) in relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). RESEARCH DESIGN AND METHODS We searched eligible publications up to January 31st, 2022, in PubMed, Cochrane Library, Springer, and Scopus. A total of 16 publications with 3484 patients were independently evaluated and analyzed using STATA SE software. RESULTS Patients who underwent CAR-T cell therapy showed a better overall response rate (ORR) and partial response (PR) than those treated with auto-HSCT (CAR-T vs. auto-HSCT, ORR: 80% vs. 73%, HR:0.90,95%CI:0.76-1.07,P = 0.001; PR: 20% vs. 14%, HR:0.65,95%CI:0.62-0.68,P = 0.034). No significant difference was observed in 6-month overall survival (OS) (CAR-T vs. auto-HSCT, six-month OS: 81% vs. 84%, HR:1.23,95%CI:0.63-2.38, P = 0.299), while auto-HSCT showed a favorable 1 and 2-year OS (CAR-T vs. auto-HSCT, one-year OS: 64% vs. 73%, HR:2.42,95%CI:2.27-2.79, P < 0.001; two-year OS: 54% vs. 68%, HR:1.81,95%CI:1.78-1.97, P < 0.001). Auto-HSCT also had advantages in progression-free survival (PFS) (CAR-T vs. auto-HSCT, six-month PFS: 53% vs. 76%, HR:2.81,95%CI:2.53-3.11,P < 0.001; one-year PFS: 46% vs. 61%, HR:1.84,95%CI:1.72-1.97,P < 0.001; two-year PFS: 42% vs. 54%, HR:1.62,95%CI:1.53-1.71, P < 0.001). Subgroup analysis by age, prior lines of therapy, and ECOG scores was performed to compare the efficacy of both treatment modalities. CONCLUSION Although CAR-T cell therapy showed a beneficial ORR, auto-HSCT exhibited a better long-term treatment superiority in R/R DLBCL patients. Survival outcomes were consistent across different subgroups.
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6.
Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis
Luo, W., Li, C., Zhang, Y., Du, M., Kou, H., Lu, C., Mei, H., Hu, Y.
BMC cancer. 2022;22(1):98
Abstract
BACKGROUND Recently, chimeric antigen receptor-modified (CAR) T cell therapy for hematological malignancies has shown clinical efficacy. Hundreds of clinical trials have been registered and lots of studies have shown hematologic toxic effects were very common. The main purpose of this review is to systematically analyze hematologic toxicity in hematologic malignancies treated with CAR-T cell therapy. METHODS We searched databases including PubMed, Web of Science, Embase and Cochrane up to January 2021. For safety analysis of overall hematologic toxicity, the rate of neutrophil, thrombocytopenia and anemia were calculated. Subgroup analysis was performed for age, pathological type, target antigen, co-stimulatory molecule, history of hematopoietic stem cell transplantation (HSCT) and prior therapy lines. The incidence rate of aspartate transferase (AST) increased, alanine transaminase (ALT) increased, serum creatine increased, APTT prolonged and fibrinogen decreased were also calculated. RESULTS Overall, 52 studies involving 2004 patients were included in this meta-analysis. The incidence of any grade neutropenia, thrombocytopenia and anemia was 80% (95% CI: 68-89%), 61% (95% CI: 49-73%), and 68% (95%CI: 54-80%) respectively. The incidences of grade ≥ 3 neutropenia, thrombocytopenia and anemia were 60% (95% CI: 49-70%), 33% (95% CI: 27-40%), and 32% (95%CI: 25-40%) respectively. According to subgroup analysis and the corresponding Z test, hematological toxicity was more frequent in younger patients, in patients with ≥4 median lines of prior therapy and in anti-CD19 cases. The subgroup analysis of CD19 CAR-T cell constructs showed that 41BB resulted in less hematological toxicity than CD28. CONCLUSION CAR-T cell therapy has dramatical efficacy in hematological malignancies, but the relevant adverse effects remain its obstacle. The most common ≥3 grade side effect is hematological toxicity, and some cases die from infections or severe hemorrhage in early period. In long-term follow-up, hematological toxicity is less life-threatening generally and most suffered patients recover to adequate levels after 3 months. To prevent life-threatening infections or bleeding events, clinicians should pay attention to intervention of hematological toxicity in the early process of CAR-T cell therapy.
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Can GCSF-stimulated donor lymphocyte infusions improve outcomes for relapsed disease following allogeneic hematopoietic cell transplantation? A systematic review and meta-analysis
Kirkham, A. M., Bailey, A. J. M., Masurekar, A., Shorr, R., Bredeson, C., Sabloff, M., Allan, D. S.
Leukemia & lymphoma. 2022;:1-12
Abstract
Donor lymphocyte infusions (DLI) can produce graft-versus tumor effects to treat relapse after allogeneic hematopoietic cell transplantation, however, durable responses remain uncommon. A systematic review and meta-analysis are needed to clarify whether DLI collected after stimulation with granulocyte colony-stimulating factor (GCSF; G-DLI) can improve clinical outcomes. Sixteen studies (4 controlled) involving 585 patients were identified in a systematic search up to 17 September 2020. A meta-analysis demonstrated no significant difference in the risk of all-cause mortality (RR: 0.94, 95% CI 0.52-1.68, p = 0.82; n = 3 studies) or relapse-related mortality (RR: 0.72, 0.44-1.18, p = 0.19; n = 3 studies) between G-DLI and conventional DLI (C-DLI) groups. G-DLI products had similar mean CD3+ cells compared to C-DLI products, but median CD34+ cells/kg were increased. No improvement in disease progression, complete response rates, or risk of developing GVHD was observed with G-DLI, however, greater non-relapse mortality was observed compared to C-DLI. Alternative approaches to enhancing graft-versus-tumor effects are needed.
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8.
Chimeric antigen receptor T-cell therapy is superior to standard of care as second-line therapy for large B-cell lymphoma: A systematic review and meta-analysis
Shargian, L., Raanani, P., Yeshurun, M., Gafter-Gvili, A., Gurion, R.
British journal of haematology. 2022
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Abstract
Treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered standard of care (SOC) second-line treatment for relapsed or refractory large B-cell lymphoma (LBCL). However, outcomes remain suboptimal. A systematic review and meta-analysis of randomised controlled trials comparing efficacy and safety of SOC versus chimeric antigen receptor T-cell (CAR-T) therapy as second-line for patients with LBCL refractory or relapsing within 12 months. Outcomes included overall survival (OS), event-free survival (EFS), overall response rate (ORR) and safety. Three trials published in 2021 (involving 865 participants) fulfilled the eligibility criteria. EFS as well as OS were significantly improved with CAR-T therapy as compared to SOC, hazard ratio (HR) 0.57 (95% confidence interval [CI] 0.49-0.68) and HR 0.77 (95% CI 0.60-0.98) respectively. CAR-T therapy was associated with significantly better ORR, relative risk (RR) 1.55 (95% CI 1.12-2.13, p = 0.001). The risk of Grade III/IV adverse event was comparable between the two arms, RR 1.03 (95% CI 0.93-1.14). In summary, CAR-T therapy has superior outcomes as compared to SOC in patients with LBCL refractory or relapsing within 12 months, without excess of toxicity. Longer follow-up is needed to confirm these results and determine the optimal sequencing of CAR-T therapy in the management of LBCL.
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Impact of natural killer cells on outcomes after allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis
Mushtaq, M. U., Shahzad, M., Shah, A. Y., Chaudhary, S. G., Zafar, M. U., Anwar, I., Neupane, K., Khalid, A., Ahmed, N., Bansal, R., et al
Frontiers in Immunology. 2022;13:1005031
Abstract
BACKGROUND Natural killer (NK) cells play a vital role in early immune reconstitution following allogeneic hematopoietic stem cell transplantation (HSCT). METHODS A literature search was performed on PubMed, Cochrane, and Clinical trials.gov through April 20, 2022. We included 21 studies reporting data on the impact of NK cells on outcomes after HSCT. Data was extracted following the PRISMA guidelines. Pooled analysis was done using the meta-package (Schwarzer et al.). Proportions with 95% confidence intervals (CI) were computed. RESULTS We included 1785 patients from 21 studies investigating the impact of NK cell reconstitution post-HSCT (8 studies/1455 patients), stem cell graft NK cell content (4 studies/185 patients), therapeutic NK cell infusions post-HSCT (5 studies/74 patients), and pre-emptive/prophylactic NK cell infusions post-HSCT (4 studies/77 patients). Higher NK cell reconstitution was associated with a better 2-year overall survival (OS) (high: 77%, 95%CI 0.73-0.82 vs low: 55%, 95%CI 0.37-0.72; n=899), however, pooled analysis for relapse rate (RR) or graft versus host disease (GVHD) could not be performed due to insufficient data. Higher graft NK cell content demonstrated a trend towards a better pooled OS (high: 65.2%, 95%CI 0.47-0.81 vs low: 46.5%, 95%CI 0.24-0.70; n=157), lower RR (high: 16.9%, 95%CI 0.10-0.25 vs low: 33%, 95%CI 0.04-0.72; n=157), and lower acute GVHD incidence (high: 27.6%, 95%CI 0.20-0.36 vs low: 49.7%, 95%CI 0.26-0.74; n=157). Therapeutic NK or cytokine-induced killer (CIK) cell infusions for hematologic relapse post-HSCT reported an overall response rate (ORR) and complete response (CR) of 48.9% and 11% with CIK cell infusions and 82.8% and 44.8% with NK cell infusions, respectively. RR, acute GVHD, and chronic GVHD were observed in 55.6% and 51.7%, 34.5% and 20%, and 20.7% and 11.1% of patients with CIK and NK cell infusions, respectively. Pre-emptive donor-derived NK cell infusions to prevent relapse post-HSCT had promising outcomes with 1-year OS of 69%, CR rate of 42%, ORR of 77%, RR of 28%, and acute and chronic GVHD rates of 24.9% and 3.7%, respectively. CONCLUSION NK cells have a favorable impact on outcomes after HSCT. The optimal use of NK cell infusions post-HSCT may be in a pre-emptive fashion to prevent disease relapse.
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Emerging Targets and Cellular Therapy for Relapsed Refractory Multiple Myeloma: A Systematic Review
George, L. L., Deshpande, S. R., Cortese, M. J., Kendall, E. K., Chattaraj, A., Shah, Z., Zhao, J., Anwer, F.
Clinical lymphoma, myeloma & leukemia. 2021
Abstract
Multiple myeloma is the second most common hematologic malignancy and remains incurable. Patients who fail multiple lines of therapy typically have a poor prognosis despite recent advances in myeloma treatment. Chimeric antigen receptor T (CAR T) cell treatment has emerged as a promising therapy for many hematologic malignancies, including recently approved and emerging applications for myeloma treatment. A systematic review of the available clinical trial data for CAR T therapies in multiple myeloma was undertaken. All multiple myeloma trials registered at ClinicalTrials.gov were reviewed and studies mentioning CAR T and studying relapsed/refractory multiple myeloma (R/R MM) were included. PubMed, Google Scholar, and conference proceedings were also reviewed to determine which trials had reported data. Twenty-seven registered clinical trials in humans with published data were identified as of March 10, 2021. The majority of these trials were CAR T cells targeting B-cell maturation antigen (BCMA), and many were Phase I studies. Data demonstrated promising short-term (<12 months) efficacy with low incidence of grade 3 or higher toxicities. CAR T cell therapy in R/R MM remains a promising treatment modality. While one biologic has recently received FDA-approval, the majority of products remain investigational and in early-phase trials. More investigation is needed to determine which CAR T constructs and combination therapies optimize patient outcomes.