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Monoclonal antibodies against checkpoint receptors or its ligands have demonstrated high response rates and durable remissions in patients with relapsed Hodgkin lymphoma (HL) and other lymphoid malignancies. However, most patients will eventually progress on therapy and may benefit from further treatments including allogenic hematopoietic cell transplantation (allo-HCT). Furthermore, the use of checkpoint inhibitors (CPI) has emerged as a treatment option for patients relapsing after allo-HCT. The immune effects of the checkpoint blockade leading to a T-cell activation have raised some concerns on the safety of these therapies used either before or after allo-HCT, due to the potential risk of graft-versus-host disease (GVHD). Furthermore, CPI might also induce other immune toxicities, that can affect almost any organ, as a result of the dysregulation on the immune system balance. This review aims to focus on the evidence behind the use of CPI in patients with lymphoma who undergo allo-HCT. We summarize the clinical data generated to date about the use of CPI in HL and other lymphoid malignancies, the mechanisms of checkpoint inhibition in the context of allo-HCT as well as the clinical and biological observations of different GVHD prophylaxis in this setting. Furthermore, we discuss the evidence from retrospective series and early clinical trials on the feasibility and safety of the use of CPI in patients who relapsed after allo-HCT.

Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the microenvironment for improved CAR-T expansion and persistence, and reduction of tumor load. However, most LD regimens provide a broad and fairly unspecific suppression of T-cells as well as other hematopoietic cells, which can also lead to severe side effects, particularly infections. We reviewed 1271 published studies (2011-2023) with regard to current LD strategies for approved anti-CD19 CAR-T products for large B cell lymphoma (LBCL). Fludarabine (Flu) and cyclophosphamide (Cy) (alone or in combination) were the most commonly used agents. A large number of different schemes and combinations have been reported. In the respective schemes, doses of Flu and Cy (range 75-120mg/m2 and 750-1.500mg/m2) and wash out times (range 2-5 days) differed substantially. Furthermore, combinations with other agents such as bendamustine (benda), busulfan or alemtuzumab (for allogeneic CAR-T) were described. This diversity creates a challenge but also an opportunity to investigate the impact of LD on cellular kinetics and clinical outcomes of CAR-T. Only 21 studies explicitly investigated in more detail the influence of LD on safety and efficacy. As Flu and Cy can potentially impact both the in vivo activity and toxicity of CAR-T, a more detailed analysis of LD outcomes will be needed before we are able to fully assess its impact on different T-cell subsets within the CAR-T product. The T2EVOLVE consortium propagates a strategic investigation of LD protocols for the development of optimized conditioning regimens.

BackgroundCD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity.MethodsIn this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates.ResultsIn a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThigh patients more frequently developed severe infections (40% vs 8%, p<0.0001)—particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HThigh (16% vs 46%, p<0.001), but not HTlow patients (0% vs 2%, p=n.s.). Collectively, HThigh patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HThigh patients was observed (8.0% vs 3.7%, p=0.09).ConclusionsThese data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.

Chimeric antigen receptor (CAR) T-cell therapy provides long-term remissions in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Total metabolic tumor volume (TMTV) assessed by 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) has a confirmed prognostic value in the setting of chemoimmunotherapy, but its predictive role with CAR T-cell therapy is not fully established. Thirty-five patients with R/R LBCL who received CAR T-cells were included in the study. TMTV and maximum standardized uptake value (SUVmax) were measured at baseline and 1-month after CAR T-cell infusion. Best response included 9 (26%) patients in complete metabolic response (CMR) and 16 (46%) in partial metabolic response (PMR). At a median follow-up of 7.6 months, median PFS and OS were 3.4 and 8.2 months, respectively. A high baseline TMTV (≥ 25 cm3) was associated with a lower PFS (median PFS, 2.3 vs. 8.9 months; HR = 3.44 [95% CI 1.18–10.1], p = 0.02). High baseline TMTV also showed a trend towards shorter OS (HR = 6.3 [95% CI 0.83–47.9], p = 0.08). Baseline SUVmax did not have a significant impact on efficacy endpoints. TMTV and SUVmax values showed no association with adverse events. Metabolic tumor burden parameters measured by 18FDG-PET before CAR T-cell infusion can identify LBCL patients who benefit most from this therapy.

Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses. This article provides real‐world European data on the results of relapsed/refractory large B‐cell lymphoma patients treated with tisagenlecleucel.

Optimal post-remission therapy for adolescents and young adults (AYAs) with Ph-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not established. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a cohort undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) in CR1. In univariate analysis, OS was superior with chemotherapy compared to MA allogeneic HCT (3-year OS 77% vs. 53%, P  < 0.001). In multivariate analysis, allogeneic HCT showed inferior OS (HR 2.00, 95% CI 1.5–2.66, P  < 0.001), inferior DFS (HR 1.62, 95% CI 1.25–2.12, P  < 0.001), and increased NRM (HR 5.41, 95% CI 3.23–9.06, P  < 0.001) compared to chemotherapy. A higher 5-year relapse incidence was seen with chemotherapy compared to allogeneic HCT (34% vs. 23%, P  = 0.011). Obesity was independently associated with inferior OS (HR 2.17, 95% CI 1.63–2.89, P  < 0.001), inferior DFS (HR 1.97, 95% CI 1.51–2.57, P  < 0.001), increased relapse (1.84, 95% CI 1.31–2.59, P  < 0.001), and increased NRM (HR 2.10, 95% CI 1.37–3.23, P  < 0.001). For AYA ALL patients in CR1, post-remission therapy with pediatric-style chemotherapy is superior to MA allogeneic HCT for OS, DFS, and NRM.

Patients receiving an allogeneic hematopoietic cell transplantation (allo-HCT) after the use of PD-1 inhibitors seem to be at a higher risk of developing acute graft-versus-host disease (aGHVD) through etiopathogenetic mechanisms not fully elucidated. Herein, we investigated the effect of nivolumab administered prior to allo-HCT on the following early T-cell reconstitution and its modulation by the GVHD prophylaxis (tacrolimus/sirolimus vs. posttransplant cyclophosphamide [PTCY]). In all nivolumab-exposed patients we detected circulating nivolumab in plasma for up to 56 days after allo-HCT. This residual nivolumab was able to bind and block PD-1 on T-cells at day 21 after allo-HCT, inducing a T cell activation that was differentially modulated depending on the GVHD prophylactic regimen. Among patients receiving tacrolimus/sirolimus, nivolumab-exposed patients had a higher incidence of severe aGVHD and a more effector T-cell profile compared with anti-PD-1-naïve patients. Conversely, patients receiving PTCY-based prophylaxis showed a similar risk of aGVHD and T-cell profile irrespective of the previous nivolumab exposure. In conclusion, nivolumab persists in plasma after transplantation, binds to allogeneic T cells and generates an increased T-cell activation. This T-cell activation status can be mitigated with the use of PTCY, thus reducing the risk of aGVHD.

Real-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 patients included and 192 treated, 101 with axicabtagene ciloleucel [axi-cel], and 91 with tisagenlecleucel [tisa-cel]) and compared the results with a historical refractory population of patients (n = 81) obtained from the GELTAMO-IPI study. We observed superior efficacy for CAR-T therapy (for both axi-cel and tisa-cel) over pSOC, with longer progression-free survival (PFS) (median of 5.6 vs. 4–6 months, p ≤ 0.001) and overall survival (OS) (median of 15 vs. 8 months, p < 0.001), independently of other prognostic factors (HR: 0.59 (95% CI: 0.44–0.80); p < 0.001] for PFS, and 0.45 [(95% CI: 0.31–0.64)] for OS). Within the CAR-T cohort, axi-cel showed longer PFS (median of 7.3 versus 2.8 months, respectively, p = 0.027) and OS (58% versus 42% at 12 months, respectively, p = 0.048) than tisa-cel. These differences were maintained in the multivariable analysis. On the other hand, axi-cel was independently associated with a higher risk of severe cytokine release syndrome and neurotoxicity. Our results suggest that the efficacy of CAR-T cell therapy is superior to pSOC in the real-world setting. Furthermore, axi-cel could be superior in efficacy to tisa-cel, although more toxic, in this group of refractory patients according to SCHOLAR-1 criteria.

Optimal fludarabine dosing in the conditioning regimen based on population pharmacokinetic analysis (popPK) can predict outcomes in patients receiving hematopoietic stem cell transplantation. To date, there is no popPK tailored for patients receiving fludarabine as part of the lymphodepleting regimen before chimeric antigen receptor (CAR) T-cell infusion. The objective of this study was to develop a PopPK model of fludarabine in patients receiving CAR T-cell therapy. A prospective study was conducted at a tertiary hospital, from January 2021 to July 2022. Demographic, clinical, and analytical variables were collected. Blood samples were obtained on days 1 and 3 of the lymphodepleting regimen at 1.5, 2, 7 and 24 h post-fludarabine doses, and 30 min prior to CART-cell infusion. Fludarabine levels were analyzed through an ultra-performance liquid chromatography tandem mass spectrometry assay based on liquid-liquid extraction. Population pharmacokinetic analysis modeling was performed using nonlinear mixed-effects models (NONMEM). Fifty-six patients (59% male) with a median age of 59 years (range 23-82) received CAR T-cell therapy (38 [68%] axicabtagene ciloleucel, 18 [32%] tisagenlecleucel) for relapsed/refractory large B-cell lymphoma. A total of 348 samples were collected for model development. A three-compartment model with first-order elimination best described the data. Body size, as represented by weight (WGT) with allometric scaling, was a significant predictor of all pharmacokinetic parameters ( < 0.05). Estimated glomerular filtration rate (eGFR) and the CAR T-cell construct type also showed statistical significance for fludarabine clearance (CL) ( < 0.05). Clearance was differentiated into non-renal and renal components. Estimates of V1, V2 and V3 volumes (the apparent volume of distribution of the central, shallow and deep compartments) were 41.2, 14.5 and 10.8 L, respectively. WGT, eGFR and type of CAR-T were predictors of fludarabine pharmacokinetics. This model offers a step toward precision-guided lymphodepletion and might support individualized dosing to optimize efficacy and minimize toxicity.