Suzanne van Dorp

Chimeric antigen receptor (CAR) T‐cell therapy has significantly improved outcomes in patients with relapsed/refractory aggressive large B‐cell lymphoma (R/R LBCL). Although thrombosis and bleeding complications have been increasingly reported, their clinical relevance and risk factors remain unclear, also due to heterogeneity between reporting studies. We investigated the incidence of thrombosis and bleeding in a more homogeneous real‐world multicenter cohort by analyzing 250 adults with R/R LBCL who were included in the Dutch “Follow that CAR!” multicenter registry, and all received axicabtagene ciloleucel (axi‐cel) CAR T‐cell therapy. We assessed the impact of thrombosis and bleeding, incorporated as time‐dependent covariates on overall survival and explored associations with cytokine release syndrome (CRS), immune effector cell‐associated neurotoxicity syndrome (ICANS), anticoagulant therapy, and laboratory parameters. One‐year cumulative incidences of thrombosis and bleeding were 6.3% and 11.0%, respectively. Median time to thrombosis or bleeding was 28 days after infusion for both events. Bleeding was associated with poorer overall survival (hazard ratio [HR] 3.77, 95% CI 1.96–7.27). Patients with a CAR‐HEMATOTOX score ≥2 before CAR T‐cell therapy (HR 3.62, 95% CI 1.23–10.69), therapeutic anticoagulation at time of infusion (HR 3.74, 95% CI 1.33–10.49), or thrombocytopenia grade ≥3 (platelet count < 50 × 10 ⁹ /L) at time of infusion (HR 3.55, 95% CI 1.12–11.26, P = 0.03) had a significantly higher risk of bleeding. Our study confirms the high risk and clinical relevance of bleeding in patients receiving CAR T‐cell therapy. Prospective studies are necessary to confirm these results and to guide recommendations regarding modifiable risk factors such as the use of anticoagulation or transfusion thresholds during CAR T‐cell therapy.

Early identification of patients at risk of immune effector cell–associated hematotoxicity (ICAHT) is essential to minimize nonrelapse mortality. The CAR-HEMATOTOX (HT) score is an implemented risk-stratification tool for ICAHT, infections, and survival in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) receiving chimeric antigen receptor T-cell therapy (CART). Although validated in its defining study, the HT score was developed in a small cohort, necessitating independent external validation. This study externally validates the HT score in a real-world population-based cohort of adults with R/R LBCL receiving CART. The HT score, based on absolute neutrophil count (ANC), hemoglobin, platelets, C-reactive protein, and ferritin, was calculated before lymphodepleting chemotherapy. Of 245 consecutive patients, 171 (70%) had an HT score of ≥2 (HThigh). The initial end point, clinically significant neutropenia (ANC of <500/μL for ≥14 days), occurred in 21% of patients. The binary HT score was associated with clinically significant neutropenia (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.27-6.80; P = .012) with a good predictive performance (area under the curve = 0.73). Similar results were achieved for early and late ICAHT grade ≥3 (OR, 2.92; 95% CI, 1.19-7.14; P = .019; and OR, 2.42; 95% CI, 1.31-4.47; P = .005). A trend toward an association with severe infections was observed (OR, 2.02; 95% CI, 0.91-4.48; P = .085). HThigh patients had a lower progression-free and overall survival (hazard ratio [HR], 1.84; 95% CI, 1.15-2.93; P = .011; and HR, 2.83; 95% CI, 1.64-4.87; P < .001, respectively). The HT score identified CART-treated patients with R/R LBCL at risk of clinically significant neutropenia, poor survival outcomes, and potentially severe infections.

Tuberculosis (TB) can induce secondary hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory syndrome with high mortality. We integrated all published reports of adult HIV-negative TB-associated HLH (TB-HLH) to define clinical characteristics, diagnostic strategies, and therapeutic approaches associated with improved survival. PubMed, Embase, and Global Index Medicus were searched for eligible records. TB-HLH cases were categorized into (1) patients with a confirmed TB diagnosis receiving antituberculosis treatment while developing HLH and (2) patients presenting with HLH of unknown cause later diagnosed with TB. We used a logistic regression model to define clinical and diagnostic parameters associated with survival. We identified 115 individual cases, 45 (39.1%) from countries with low TB incidence (Mycobacterium tuberculosis was identified in the bone marrow in 78.4% of patients for whom examination was reported (n = 74). Only 10.5% (4/38) of patients tested had a positive result upon a tuberculin skin test or interferon-γ release assay. In-hospital mortality was 28.1% (27/96) in those treated for TB and 100% (18/18) in those who did not receive antituberculosis treatment (P < .001). Tuberculosis should be considered a cause of unexplained HLH. TB-HLH is likely underreported, and the diagnostic workup of patients with HLH should include bone marrow investigations for evidence of Mycobacerium tuberculosis. Prompt initiation of antituberculosis treatment likely improves survival in TB-HLH.

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment.

The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020–May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.