-
1.
Adoptive therapy with cytomegalovirus-specific cytotoxic T lymphocytes for refractory cytomegalovirus DNAemia and disease after allogeneic haematopoietic stem cell transplantation
Jiang, Z., Fan, Z., Zhang, T., Lin, R., Xu, H., Xu, N., Huang, F., Chi, P., Ou, X., Wang, Z., et al
British journal of haematology. 2024
Abstract
Cytomegalovirus (CMV) DNAemia and disease are common complications in patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Few studies have compared the efficacy and safety of the HSCT donor and third-party CMV-specific cytotoxic T lymphocytes (CMV-CTLs) in the treatment of CMV DNAemia and disease. In this study, we retrospectively compared the efficacy and safety of HSCT donor and third-party CMV-CTLs in patients with refractory CMV DNAemia or disease after allo-HSCT at our centre from January 2017 to September 2021. Fifty-three patients who received CMV-CTL therapy were enrolled, including 40 in the donor group and 13 in the third-party group, and they were adults aged 18 years or older. Within 6 weeks of treatment, 26 (65.0%) and 9 (69.2%) patients achieved complete response in the donor and third-party groups (p = 1.000). The 2-year overall survival was 59.6% (95% CI 46.1%-77.1%) and 53.8% (32.6%-89.1%) in the donor and third-party groups (p = 0.860). Four (10.0%) patients in the donor group and two (15.4%) patients in the third-party group developed acute graft-versus-host disease within 3 months after CMV-CTL infusions. In conclusion, our data suggest that donor and third-party CMV-CTLs have comparable efficacy and safety for refractory CMV DNAemia and disease.
-
2.
Phase I study of zoledronic acid combined with escalated doses of interleukine-2 for early in vivo generation of Vγ9Vδ2 T-cells after haploidentical stem cell transplant with posttransplant cyclophosphamide
Jullien, M., Guillaume, T., Le Bourgeois, A., Peterlin, P., Garnier, A., Eveillard, M., Le Bris, Y., Bouzy, S., Tessoulin, B., Gastinne, T., et al
American journal of hematology. 2024
-
-
-
-
Editor's Choice
Abstract
The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (h-HSCT) has been associated with improved disease-free survival. These cells kill tumor cells in a non-MHC restricted manner, do not induce graft-versus-host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin-2 (IL-2). This monocentric phase I, open-label, dose-escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T-cells early after h-HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low-doses of IL-2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T-cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h-HSCT recipients. Twenty-six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h-HSCT only. At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T-cells was observed during IL-2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T-cells is feasible after h-HSCT by using a combination of ZA and repeated IL-2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.
PICO Summary
Population
Adults with haematological malignancy, eligible for haploidentical transplant from a single centre in France (n=26)
Intervention
Increasing low-doses of IL-2 (5 days per week, 4 weeks) in combination with a single dose of zoledronic acid (ZA) to generate Vγ9Vδ2 T-cells early after h-HSCT (n=16)
Comparison
Haploidentical HSCT only (n=7)
Outcome
At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. Maximum tolerated dose was not reached.
-
3.
Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
Locke, F. L., Filosto, S., Chou, J., Vardhanabhuti, S., Perbost, R., Dreger, P., Hill, B. T., Lee, C., Zinzani, P. L., Kröger, N., et al
Nature medicine. 2024
Abstract
The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10(-9) for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10(-9) for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
-
4.
Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant
Cao, X. Y., Zhang, J. P., Zhao, Y. L., Xiong, M., Zhou, J. R., Lu, Y., Sun, R. J., Wei, Z. J., Liu, D. Y., Zhang, X., et al
Frontiers in immunology. 2023;14:1191382
-
-
-
Free full text
-
Editor's Choice
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. METHODS A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. RESULTS The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). CONCLUSIONS Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia who were minimal residual disease-positive after first transplant at a single centre in China (n=95)
Intervention
CAR-T therapy followed by consolidation allogeneic transplant, using a different donor
Comparison
None
Outcome
The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24) and OS(HR, 2.67, 95%CI, 1.24-5.74), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24).
-
5.
Prevention of CMV/EBV reactivation by double-specific T cells in patients after allogeneic stem cell transplantation: results from the randomized phase I/IIa MULTIVIR-01 study
Gerbitz, A., Gary, R., Aigner, M., Moosmann, A., Kremer, A., Schmid, C., Hirschbuehl, K., Wagner, E., Hauptrock, B., Teschner, D., et al
Frontiers in immunology. 2023;14:1251593
-
-
-
Free full text
-
Editor's Choice
Abstract
INTRODUCTION Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. METHODS We report the results of a randomized controlled multi centre phase I/IIa study (MULTIVIR-01) using a newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. The study aimed at prevention and preemptive treatment of both viruses in patients after allogeneic stem cell transplantation targeting first infusion on day +30. Primary endpoints were acute transfusion reaction and acute-graft versus-host-disease after infusion of activated T cells. RESULTS Thirty-three patients were screened and 9 patients were treated with a total of 25 doses of the T cell product. We show that central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation. DISCUSSION Our study results indicate peptide stimulated epitope specific T cells derived from stem cell grafts can be administered safely for prevention and preemptive treatment of reactivation without evidence for induction of acute graft versus host disease. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov, identifier NCT02227641.
PICO Summary
Population
Adults undergoing allogeneic transplant from a matched donor who was seropositive for cytomegalovirus (CMV) and Epstein-barr virus (EBV) and enrolled in the MULTIVIR-01 study in centres in Germany (n=33)
Intervention
A newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. (n=16; 9 received full treatment)
Comparison
Control (n=13)
Outcome
Central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation
-
6.
Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma
Westin, J. R., Locke, F. L., Dickinson, M., Ghobadi, A., Elsawy, M., van Meerten, T., Miklos, D. B., Ulrickson, M. L., Perales, M. A., Farooq, U., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;:Of1-of12
Abstract
PURPOSE Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. PATIENTS AND METHODS Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2-3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). RESULTS Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and <65 years. CONCLUSIONS Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.
-
7.
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.
-
8.
A pro-inflammatory environment in bone marrow of Treg transplanted patients matches with graft-versus-leukemia effect
Guardalupi, F., Sorrentino, C., Corradi, G., Giancola, R., Baldoni, S., Ulbar, F., Fabi, B., Andres Ejarque, R., Timms, J., Restuccia, F., et al
Leukemia. 2023
-
9.
Clinical and Radiographic Predictors of Progression and Survival in Relapsed/Refractory Lymphoma Patients Receiving Anti-CD19 CAR T-cell Therapy
Jodon, G., Colton, M. D., Abbott, D., Cai, A., Haverkos, B., Morgan, R., Kamdar, M.
Clinical lymphoma, myeloma & leukemia. 2023;23(1):49-56
Abstract
INTRODUCTION Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory (R/R) B-cell lymphomas, though certain patients do not respond to treatment or relapse afterwards. The purpose of this study is to determine patient variables that are predictive of response to CAR-T therapy. METHODS We conducted a retrospective review of 59 R/R B-cell non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy. Risk factors for progression free survival (PFS) and overall survival (OS) were identified and multivariate logistic regression models for PFS and OS at 1 year were created using stepwise selection. The final multivariate logistic regression models were used to estimate the area under the receiver operating curve (AUROC). RESULTS At median follow up of 25.6 months, median overall survival was not reached, and median progression free survival was 5.7 months. Stage IV disease (odds ratio (OR) 9.335, P = .025) was identified as a predictive variable for progression at day 365 with an AUC of 0.7922 (P < .001). IPI (OR 2.828, P = .014), ALC ≥ 0.50 at collection (OR 0.183, P = .043), CRP ≥ 11 (OR 6.177, P = .019), and tocilizumab administration (OR 0.062, P = .005) as predictors for death at day 365 with an AUC 0.8626 (P < .001). CONCLUSION Clinical variables identify R/R lymphoma patients who are at risk for progression and poor overall survival after CAR T-cell therapy. IPI, CRP, ALC, and tocilizumab administration may be predictors of survival.
-
10.
ASCT vs CART for Patients with Relapsed LBCL in PR: Role of TMTV
Strati, P., Pasvolsky, O., Feng, L., Xu, G., Tewari, S., Varghese, J., Ow, K., Santiago, M. S., Al Zaki, A., Jallouk, A., et al
Blood advances. 2023