CD34+-selected stem cell boost can safely improve cytopenias following CAR T-cell therapy.
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ABSTRACT:
SUBMITTER: Mullanfiroze K
PROVIDER: S-EPMC9631677 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
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CD34+-selected stem cell boost can safely improve cytopenias following CAR T-cell therapy.
Mullanfiroze Khushnuma K Lazareva Arina A Chu Jan J Williams Lindsey L Burridge Saskia S Silva Juliana J Chiesa Robert R Rao Kanchan K Lucchini Giovanna G Ghorashian Sara S O'Reilly Maeve M Carpenter Ben B Grandage Victoria V Hough Rachael R Roddie Claire C Amrolia Persis J PJ
Blood advances 20220801 16
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Project description:AbstractThe use of CD34+ selected stem cell boost (SCB) after allogeneic hematopoietic cell transplant (allo-HCT) has been increasing. Predictors of treatment failure after SCB, both in the context of poor graft function (PGF) or other settings, are not well characterized. We report among the largest single-center retrospective experiences of the use of SCB and evaluate potential predictors of response and outcomes. A total of 58 patients who underwent HCT between 2015 and 2022 and who received SCB, were identified. The indication for SCB was predominantly PGF, defined as the presence of ≥2 cytopenias for at least 2 consecutive weeks beyond day +14 after allo-HCT in the presence of ≤30% bone marrow cellularity and ≥90% donor myeloid chimerism in the absence of morphologic disease. The median dose of infused CD34+ selected SCB products was 3.88 × 106 CD34+ cells per kg (range, 0.99 × 106 to 9.92 × 106). The median 2-year overall survival and nonrelapse mortality after SCB was 47% and 38%, respectively. The cumulative incidences of 6-month grade 3 to 4 acute and 2-year moderate-severe chronic graft-versus-host disease after SCB were 3.4% and 12%, respectively. Overall response (complete response + partial response) was attained in 36 of 58 patients (62%) and in 69% of patients with PGF. On multivariable analysis, an active infection at the time of SCB was the greatest predictor of poor response and survival (P = .013) after SCB. SCB can restore hematopoiesis in the majority of patients, particularly for those with PGF and in whom there is no active infection at the time of infusion.
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Project description:BackgroundChimeric antigen receptor (CAR)-T therapy has emerged as a promising treatment for hematologic malignancies. However, cytopenia remains one of the most frequent and challenging adverse effects of this therapy.MethodsWe conducted a retrospective analysis of 26 patients with relapsed/refractory aggressive B-cell lymphoma who received CAR-T therapy at our center. Subsequently, to investigate measures to address cytopenias following CAR-T therapy, we isolated and generated murine CAR-T cells and bone marrow-derived mesenchymal stem cells (MSCs), establishing a murine syngeneic CAR-T therapy model. We assessed the impact of MSC infusion on hematopoietic recovery post-CAR-T therapy by evaluating complete blood count, bone marrow hematopoietic stem cells and their subpopulations, bone marrow histomorphology, and hematopoiesis-related genes.ResultsAll patients experienced cytopenias to varying degrees, with complete lineage involvement in half of the patients. Grade ≥ 3 cytopenias were observed in 88.46% of the patients. CAR-T therapy was associated with a higher incidence of biphasic, late-onset, or prolonged cytopenias. Survival analysis indicated that neutropenia and lymphopenia tended to be associated with better prognosis, whereas thrombocytopenia tended to be related to poorer outcomes. Through animal experiments, we discovered that MSCs infusion boosted HSCs and their long-term subpopulations, enhancing hematopoietic recovery, particularly in the megakaryocyte lineage, and mitigating bone marrow damage. Importantly, both in vitro and in vivo experiments demonstrated that MSCs did not compromise the activity or antitumor efficacy of CAR-T cells.ConclusionsOur findings propose MSCs infusion as a promising strategy to address cytopenias, particularly thrombocytopenia, after CAR-T therapy. This approach could help overcome certain limitations of cellular immunotherapy by enhancing hematopoietic recovery without compromising the efficacy of CAR-T cells.Highlights1 Cytopenia is a frequently observed adverse effect following CAR-T therapy, and it is often characterized by biphasic and prolonged patterns. 2 MSCs play a critical role in promoting hematopoietic recovery and mitigating bone marrow damage in a murine model of CAR-T therapy 3 The activity and antitumor efficacy of CAR-T cells were not impaired by MSCs.
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Project description:Prolonged myelosuppression after chimeric antigen receptor (CAR) T-cell therapy is common and poorly understood. A retrospective analysis of 43 patients was conducted to investigate factors contributing to CAR T-cell-related cytopenias. Thirty-five patients were evaluable for analysis of delayed cytopenias occurring after initial hematologic recovery. Time to hematologic recovery (TTHR) was defined as number of days after CAR T-cell infusion for recovery to hemoglobin ≥8.0 g/dL, platelets ≥50.0 k/µL, and neutrophil count ≥1.0 k/µL without transfusions or growth factors for 7 days. Baseline percent bone marrow (BM) malignancy involvement correlated with TTHR (p = .0047). Patients with grades 3-4 cytokine-release syndrome (CRS) had longer TTHR than those with grades 0-2 CRS (p = .0479). Patients who developed prolonged or delayed cytopenias after anti-BCMA CAR T cells had a higher percentage of BM aspirate CAR+ cells at 2 months (n = 10; p = .0159).
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Project description:To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T-cell therapy, we retrospectively reviewed pediatric/young adult patients with relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1-20 years) with a median potential follow-up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0-37%), 20% (95% CI: 0-40%), and 80% (95% CI: 60-100%), respectively. Severe toxicity following CAR T cells did not impact OS (p = 0.27), while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T-cell depleted (TCD; n = 9) vs unmodified (n = 6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24 months was 22% (95% CI: 0-49%) vs 0% (p = 0.14), 0% vs 50% [95% CI: 10-90%] (p = 0.02) and 100% vs 50% [95% CI: 10-90%] (p = 0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared with unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.
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Project description:BackgroundCytopenia is one of the most common adverse events following the CAR-T cell infusion, affecting the quality of life and potentially leading to life-threatening bleeding and infection. This study aimed to systematically review the cytopenias following anti-CD19 CAR-T therapy and further analyse the contributing factors.MethodsDatabases including PubMed, MEDLINE, Embase and Cochrane were systematically searched on 8 May 2022. A random-effect meta-analysis was used to estimate the incidence of cytopenia, and subgroup analyses were applied to explore heterogeneity.ResultsA total of 68 studies involving 2950 patients were included in this study. The overall incidence of all grade anaemia, thrombocytopenia, neutropenia, leukopoenia, lymphocytopenia and febrile neutropenia was 65%, 55%, 78%, 62%, 70% and 27%, respectively, and the corresponding cytopenias of grade 3 or worse were 33%, 31%, 61%, 45%, 46%, and 21%, respectively. Subgroup analysis showed increased incidence of cytopenias in subgroups with lower median age, proportion of males (<65%) and proportion of bridging therapy (<80%) and in the subgroup with a median line of prior therapy ≥3. In terms of disease and therapeutic target, cytopenias were more frequent in ALL patients and in dual-target CAR-T therapies (targeting CD19 in combination with other targets). Furthermore, CAR-T products manufactured by lentiviral vectors and those with the costimulatory domain of CD28 were more likely to cause haematological toxicity. No significant differences were observed in cytopenia between patients treated with CAR-T products with murine and humanized scFv.ConclusionIn conclusion, neutropenia is the most frequent cytopenia after CAR-T therapy, both in all grades or grade ≥3. The incidence of cytopenias following CAR-T therapy is influenced by the age, sex, disease and number of prior therapy lines of the patients, as well as the target and costimulatory domain of CAR-T cells, and viral vectors used for manufacturing.KEY MESSAGESNeutropenia is the most frequent cytopenia after CAR-T therapy.The clinical characteristics of the patients, the design of CAR-T cells and the protocol of CAR-T treatment can influence the occurrence of cytopenias following the CAR-T therapy.
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Project description:Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown.Patients and Methods: We performed a multicenter phase I trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution.Results: Nineteen patients with high-risk acute leukemia or myelodysplasia were enrolled. Engraftment occurred in 18 of 19 patients (95%). Pre-aDLI, 12 patients (63%) had bacteremia, nine of 17 at-risk patients (53%) reactivated CMV, and one developed acute GvHD. Sixteen patients received aDLI at dose levels 1 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, n = 4). After aDLI, five patients developed clinically significant acute GvHD, and four of 14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater, and functional virus- and tumor-associated antigen-specific T cells were detectable earlier in patients receiving dose level 2 or 3 versus dose level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI, which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T cells.Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T cells in vivo after CD34-selected myeloablative haploidentical HSCT. Clin Cancer Res; 24(17); 4098-109. ©2018 AACR.
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Project description:Hematotoxicity after chimeric antigen receptor (CAR) T-cell therapy is associated with infection and death but management remains unclear. We report results of 31 patients receiving hematopoietic stem cell boost (HSCB; 30 autologous, 1 allogeneic) for either sustained severe neutropenia of grade 4 (<0.5 × 109/L), sustained moderate neutropenia (≤1.5 × 109/L) and high risk of infection, or neutrophil count ≤2.0 × 109/L and active infection. Median time from CAR T-cell therapy to HSCB was 43 days and median absolute neutrophil count at time of HSCB was 0.2. Median duration of neutropenia before HSCB was 38 days (range, 7-151). Overall neutrophil response rate (recovery or improvement) was observed in 26 patients (84%) within a median of 9 days (95% confidence interval, 7-14). Time to response was significantly associated with the duration of prior neutropenia (P = .007). All nonresponders died within the first year after HSCB. One-year overall survival for all patients was 59% and significantly different for neutropenia (≤38 days; 85%) vs neutropenia >38 days before HSCB (44%; P = .029). In conclusion, early or prophylactic HSCB showed quick response and improved outcomes for sustained moderate to severe neutropenia after CAR-T.
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Project description:Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). A myeloablative conditioning regimen, including busulfan, is commonly used in patients undergoing T-cell depletion (TCD) and allo-HCT, but data on optimal busulfan pharmacokinetic (PK) exposure in this setting are limited. Between 2012 and 2019, busulfan PK was performed to target an area under the curve exposure between 55 and 66 mg × h/L over 3 days using a noncompartmental analysis model. We retrospectively re-estimated busulfan exposure following the published population PK (popPK) model (2021) and correlated it with outcomes. To define optimal exposure, univariable models were performed with P splines, wherein hazard ratio (HR) plots were drawn, and thresholds were found graphically as the points at which the confidence interval crossed 1. Cox proportional hazard and competing risk models were used for analyses. 176 patients were included, with a median age of 59 years (range, 2-71). Using the popPK model, the median cumulative busulfan exposure was 63.4 mg × h/L (range, 46.3-90.7). The optimal threshold was at the upper limit of the lowest quartile (59.5 mg × h/L). 5-year overall survival (OS) with busulfan exposure ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40% (95% CI, 53-68), respectively (P = .02), and this association remained in a multivariate analyses (HR, 0.5; 95% CI, 0.29; 0.88; P = .02). In patients undergoing TCD allo-HCT, busulfan exposure is significantly associated with OS. The use of a published popPK model to optimize exposure may significantly improve the OS.
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Project description:Severe combined immunodeficiencies (SCIDs) correspond to the most severe form of primary immunodeficiency. Allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy are curative treatments, depending on the donor's availability and molecular diagnostics. A partially human leukocyte antigen (HLA)-compatible donor used has been developed for this specific HSCT indication in the absence of a matched donor. However, the CD34+ selected process induces prolonged post-transplant T-cell immunodeficiency. The aim here was to investigate a modeling approach to predict the time course and the extent of CD4+ T-cell immune reconstitution after CD34+ selected transplantation. We performed a Bayesian approach based on the age-related changes in thymic output and the cell proliferation/loss model. For that purpose, we defined specific individual covariates from the data collected from 10 years of clinical practice and then evaluated the model's predicted performances and accuracy. We have shown that this Bayesian modeling approach predicted the time course and extent of CD4+ T-cell immune reconstitution after SCID transplantation.
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