Inferior Outcomes of EU Versus US Patients Treated With CD19 CAR-T for Relapsed/Refractory Large B-cell Lymphoma: Association With Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization, and CAR-T Product Use

B-cell lymphoma; Tumor burden; Systemic inflammationLinfoma de células B; Carga tumoral; Inflamación sistémicaLimfoma de cèl·lules B; Càrrega tumoral; Inflamació sistèmicaReal-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use.This work was supported by a Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/1 2021 – 452881907, and DFG research grant 451580403 (to MS). The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 2018.087.1), the Else-Kröner-Fresenius Stiftung (to MS), the Bavarian Center for Cancer Research (BZKF), and NCI Cancer Center Support Grant P30 CA076292. VLB, KR, and VB were funded by the Else-Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP)

Safety and feasibility of stem cell boost as a salvage therapy for severe hematotoxicity after CD19 CAR T-cell therapy

Stem cell; Hematotoxicity; T-cellCélulas madre; Hematotoxicidad; Células TCèl·lules mare; Hematotoxicitat; Cèl·lules TThis work was supported by a fellowship from School of Oncology of German Cancer Consortium (DKTK) (K.R.) and was funded by the Else Kröner Forschungskolleg; a Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) research grant provided within the Sonderforschungbereich (SFB-TRR 388/1 2021–452881907) and DFG research grant (451580403) (M.S.); the Bavarian Elite Graduate Training Network (M.S.), the Wilhelm-Sander Stiftung (project no. 2018.087.1) (M.S.), the Else-Kröner-Fresenius Stiftung (M.S., K.R., V. Bücklein, V. Blumenberg), and the Bavarian Center for Cancer Research (BZKF)

Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion

Hematotoxicity; Suppressive immune dysregulationHematotoxicidad; Desregulación inmunesupresoraHematotoxicitat; Desregulació immunesupressoraProlonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with “intermittent” neutrophil recovery (e.g., recurrent neutrophil dips) compared to either “quick” or “aplastic” recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion.K.Rej. received a fellowship from the School of Oncology of the German Cancer Consortium (DKTK) and was funded by the Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP). This work was supported by a grant within the Gilead Research Scholar Program (to K.Rej. and M.S.), the Bruno & Helene Jöster Foundation (to K.R., M.S.), and by a Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 338/1 2021 – 452881907 and DFG research grant 451580403 (to M.S.). The work was further supported by the Bavarian Elite Graduate Training Network (to M.S.), the Wilhelm-Sander Stiftung (to M.S., project no. 2018.087.1), the Else-Kröner-Fresenius Stiftung (to M.S.), and the Bavarian Cancer Research Center (BZKF)

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

CAR-T cell therapy; Infections; MortalityTerapia con células CAR-T; Infecciones; MortalidadTeràpia amb cèl·lules CAR-T; Infeccions; MortalitatCytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post–CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies.K.R. received a fellowship from the School of Oncology of the German Cancer Consortium and was funded by the Else Kröner Forschungskolleg within the Munich Clinician Scientist Program. This work was supported by a grant within the Gilead Research Scholar Program (to K.R. and M.S.), grant funds from a translational group of the Bavarian Center for Cancer Research (BZKF, to K.R., F.M. and M.S), and the Bruno and Helene Jöster Foundation (to K.R. and M.S.). This work was also supported by a Deutsche Forschungsgemeinschaft (German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 338/1 2021 – 452881907, and DFG research grant 451580403 (to M.S.). The work was further supported by the Bavarian Elite Graduate Training Network (to M.S.), the Wilhelm Sander-Stiftung (to M.S., project no. 2018.087.1), the Else Kröner-Fresenius-Stiftung (to M.S.), and the Bavarian Center for Cancer Research. M.D.J. acknowledges funding from the Bankhead-Coley Cancer Research Program and the Mark Foundation

The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

Hematological toxicity; Infectious complicationsToxicidad hematológica; Complicaciones infecciosasToxicitat hematològica; Complicacions infecciosesCD19-directed CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu-cel. Furthermore, we report associations between the baseline CAR-HEMATOTOX (HT) score and toxicity events, non-relapse mortality (NRM), and progression-free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HTlow (score 0–1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1-year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90-day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not-reached, p < .0001), and OS (median 26 months vs. not-reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu-cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.KR received a fellowship from the School of Oncology of the German Cancer Consortium (DKTK) and was funded by the Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP). This work was supported by a grant within the Gilead Research Scholar Program (to KR, MS), the Bruno & Helene Jöster foundation (to KR, MS), and by a Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/12021–452881907 and DFG research grant 451580403 (to MS). This work was in part supported by NCI/NIH P30CA076292. FLL is in part supported as a Clinical Scholar by the Leukemia and Lymphoma Society. The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 2018.087.1), the Else-Kröner-Fresenius Stiftung (to MS), and the Bavarian Center for Cancer Research (BZKF)

Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL

Infections; Serum proteomicsInfeccions; Proteòmica sèricaInfecciones; Proteómica séricaEarly fever after chimeric antigen receptor T-cell (CAR-T) therapy can reflect both an infection or cytokine release syndrome (CRS). Identifying early infections in the setting of CRS and neutropenia represents an unresolved clinical challenge. In this retrospective observational analysis, early fever events (day 0–30) were characterized as infection versus CRS in 62 patients treated with standard-of-care CD19.CAR-T for relapsed/refractory B-cell non-Hodgkin lymphoma. Routine serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], procalcitonin [PCT]) were recorded daily. Exploratory plasma proteomics were performed longitudinally in 52 patients using a multiplex proximity extension assay (Olink proteomics). Compared with the CRSonly cohort, we noted increased event-day IL-6 (median 2243 versus 64 pg/mL, P = 0.03) and particularly high PCT levels (median 1.6 versus 0.3 µg/L, P < 0.0001) in the patients that developed severe infections. For PCT, an optimal discriminatory threshold of 1.5 µg/L was established (area under the receiver operating characteristic curve [AUCROC] = 0.78). Next, we incorporated day-of-fever PCT levels with the patient-individual CAR-HEMATOTOX score. In a multicenter validation cohort (n = 125), we confirmed the discriminatory capacity of this so-called HT10 score for early infections at first fever (AUCROC = 0.87, P < 0.0001, sens. 86%, spec. 86%). Additionally, Olink proteomics revealed pronounced immune dysregulation and endothelial dysfunction in patients with severe infections as evidenced by an increased ANGPT2/1 ratio and an altered CD40/CD40L-axis. In conclusion, the high discriminatory capacity of the HT10 score for infections highlights the advantage of dynamic risk assessment and supports the incorporation of PCT into routine inflammatory panels. Candidate markers from Olink proteomics may further refine risk-stratification. If validated prospectively, the score will enable risk-adapted decisions on antibiotic use.This work was supported by a grant within the Gilead Research Scholar Program (to KR, MS). Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/1 2021 – 452881907, and DFG research grant 451580403 (to MS). The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 2018.087.1), the Else-Kröner-Fresenius Stiftung (to MS), and the Bavarian Center for Cancer Research (BZKF). KR received a fellowship from the School of Oncology of the German Cancer Consortium (DKTK). KR, VB, and VLB were funded by the Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP)

Transformation of diffuse large B cell lymphoma into dendritic sarcoma under CAR T cell therapy detected on 18F-FDG PET/CT

Purpose!#!With the spread of transjugular intrahepatic portosystemic shunts (TIPS), portosystemic shunt surgery (PSSS) has decreased and leaves more complex patients with great demands for accurate preoperative planning. The aim was to evaluate the role of imaging for predicting the most suitable PSSS approach.!##!Material and methods!#!Forty-four patients who underwent PSSS (2002 to 2013) were examined by contrast-enhanced CT (n = 33) and/or MRI (n = 15) prior to surgery. Imaging was analyzed independently by two observers (O1 and O2) with different levels of experience (O1 &amp;gt; O2). They recommended two shunting techniques (vessels and anastomotic variant) for each patient and ranked them according to their appropriateness and complexity. Findings were compared with the actually performed shunt procedure and its outcome.!##!Results!#!The first two choices taken together covered the performed PSSS regarding vessels in 88%/100% (CT/MRI, O1) and 76%/73% (O2); and vessels + anastomosis in 79%/73% (O1) and 67%/60% (O2). The prediction of complex surgical procedures (resection of interposing structures, additional thrombectomy, use of a collateral vessel, and use of a graft interposition) was confirmed in 87%, resulting in 80% sensitivity and 96% specificity. Larger shunt vessel distances were associated with therapy failure (p = 0.030) and a vessel distance of ≥ 20 mm was identified as optimal cutoff, in which a graft interposition was used. There was no significant difference between MRI and CT in predicting the intraoperative decisions (p = 0.294 to 1.000).!##!Conclusion!#!Preoperative imaging and an experienced radiologist can guide surgeons in PSSS. CT and MRI provide the information necessary to identify technically feasible variants and complicating factors

An International Survey on Grading, Diagnosis, and Management of Immune Effector Cell-Associated Hematotoxicity (ICAHT) Following CAR T-cell Therapy on Behalf of the EBMT and EHA

Hematological toxicity represents the most common grade =3 toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, its underlying pathophysiology is incompletely understood and its grading and management remains ill-defined. To inform the forthcoming European Hematology Association/European Society for Blood and Marrow Transplantation (EHA/EBMT) guidelines on the management of immune effector cell-associated hematotoxicity (ICAHT), we undertook a survey of experienced clinicians using an online survey focusing on (1) grading, (2) risk-stratification and diagnostic work-up, (3) short-term, and (4) long-term management of ICAHT. There were 81 survey respondents across 18 countries. A high degree of variability was noted for cytopenia grading in regards to depth, duration, and time from CAR-T infusion. The majority of experts favored pre-CAR-T bone marrow studies, especially in case of a high-risk profile. Most respondents felt that the work-up for patients with severe hematotoxicity should rule-out viral infections (96%), substrate deficiency (80%), or coincident sHLH/MAS (serum ferritin, 92%), and should include bone marrow aspiration (86%) and/or biopsy (61%). Clinicians were divided as to whether the occurrence of coincident immunotoxicity should influence the decision to apply G-CSF, and when to initiate G-CSF support. In case of prolonged thrombocytopenia, most survey participants favored thrombopoietin agonists (86%). Conversely, autologous hematopoietic cell boosts represented the preferred choice for neutropenia (63%), although they were frequently not available and no consensus was reached regarding the optimal trigger point. These findings underline the current heterogeneity of practice patterns regarding ICAHT and invite the development of consensus guidelines, which may harmonize grading, establish standard operating procedures for diagnosis, and set management guidelines

The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL

Hematologic neoplasms; Receptors; Chimeric antigenNeoplasias hematológicas; Receptores; Antígeno quiméricoNeoplàsies hematològiques; Receptors; Antigen quimèricBackground CD19-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. Methods In 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. Results In 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). Conclusions These 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.This work was supported by a Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/1 2021-452881907, and DFG research grant 451580403 (to MS). The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 20180871), the Else-Kröner-Fresenius Stiftung (to MS), and the Bavarian Center for Cancer Research (BZKF)