In the single-arm Phase Ib/II FELIX study (NCT04404660), obecabtagene autoleucel (obe-cel; CD19-directed autologous CAR T-cell therapy) demonstrated high overall remission rates (ORR) and a favorable safety profile in adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). To contextualize results from FELIX, we compared the efficacy and safety of obe-cel with matched external control arms (ECA) derived from historical trials using propensity score matching. ECAs represented standard of care (SoC) non-CAR T-cell therapies: blinatumomab, inotuzumab ozogamicin, and conventional chemotherapy. The primary endpoint was ORR; secondary endpoints included overall survival (OS). Event-free survival (EFS) and safety were exploratory endpoints. Among the intent-to-treat population in FELIX (n = 107), obe-cel demonstrated significantly higher ORR than non-CAR T-cell therapies (67.3% vs 51.4%; odds ratio 1.9; p = 0.0257). Median OS was longer with obe-cel when censoring for hematopoietic stem cell transplant (15.1 vs 7.0 months; p = 0.0015) and without censoring (13.9 vs 7.8 months; p = 0.0430). EFS was significantly improved with obe-cel (median 9.8 vs 2.5 months; p < 0.0001). Safety profiles were comparable between groups, with similar rates of Grade ≥3 adverse events. Obe-cel offers superior remission rates and survival benefits over current SoC non-CAR T-cell therapies, with an acceptable safety profile; its use could address unmet needs in adult R/R B-ALL.

Hematotoxicity and infections are the main drivers of non-relapse mortality after chimeric antigen receptor (CAR)-T therapy. Consequently, reliable predictive biomarkers are highly needed to improve risk assessment and optimize patient management. In this study, we applied the immune-related adverse outcome pathway concept to delineate key events and risk factors of CAR-T-associated hematotoxicity. To identify predictive biomarkers, we performed flow cytometry and multiplex assays before and early after CAR-T infusion on 78 patients (ide-cel n = 31; axi-cel n = 24; and cilta-cel n = 23) undergoing CAR-T therapy. Severe hematotoxicity was linked to endothelial dysfunction, as evidenced by reduced levels of ANG1, soluble selectins, and increased soluble VCAM-1 (sVCAM-1) early after CAR-T infusion. Increased sVCAM-1, reflecting endothelial dysfunction, elevated soluble IL-2R (sIL-2R), indicating a proinflammatory state, and high tumor burden before lymphodepletion were key risk factors for CAR-T-associated hematotoxicity. Patients with elevated sVCAM-1 and sIL-2R at baseline (pre-lymphodepletion) exhibited significantly reduced overall survival (OS) (sVCAM-1; P = 0.0009), prolonged Grade 4 neutropenia (sVCAM-1; 12.1 vs. 6.0 days; P = 0.0016), more aplastic neutrophil recovery (5% vs. 30%; P = 0.007), and more severe infections (22.4% vs. 55%; P = 0.011). Baseline sIL-2R and sVCAM-1 demonstrated robust predictive value for prolonged neutropenia, severe infections, and mortality independently of key clinical variables such as the underlying disease and CAR-T product. Integration of these markers improves existing models and can help to refine risk assessment and guide individualized patient management in CAR-T therapy.

Imatinib (IMA) plus chemotherapy followed by allogeneic hematopoietic cell transplantation (HCT) is established treatment for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). We investigated the use of dasatinib (DASA) combined with intensive chemotherapy in ALL (18-55 years) first-line in a prospective, multicenter phase II trial by the GMALL study group. 140 mg DASA QD was used with a pediatric-based induction and consolidation chemotherapy according to GMALL 07/2003 protocol with recommended consecutive HCT. Nineteen of 20 planned patients were enrolled in 12 centers. The hematologic CR rate after induction was 79% with an overall MRD negativity rate of 62.5%. Six patients died during induction and two discontinued therapy. This regimen achieved deep molecular responses but was associated with a higher than expected early mortality (21%) and was stopped prematurely due to toxicities. The GMALL therefore adopted a combination of low intensity chemotherapy plus IMA as its current induction regimen.

6576 Background: CD19 chimeric antigen receptor T-cell therapy (CAR T) exhibits good efficacy in adults with R/R B-ALL but is associated with higher toxicity with increasing age. Obe-cel, an autologous anti-CD19 CAR T, has shown high and durable response rates with low incidence of immunotoxicity in adult R/R B-ALL, and was recently approved by the US FDA. Here, we report a post-hoc analysis of the Phase Ib/II FELIX trial (NCT04404660) evaluating efficacy, safety, and persistence outcomes with obe-cel stratified by pt age. Methods: Adult R/R B-ALL pts received obe-cel using a tumor burden-guided dosing strategy to minimize toxicity. Overall remission rate (ORR; complete remission [CR]/CR with incomplete hematologic recovery), event-free survival (EFS), safety, and persistence are reported for pts aged <55 and ≥55 years (yrs; data cut-off: 7 Feb 2024). Results: Of 127 obe-cel infused pts, 79 (62.2%) were aged <55 yrs (median 36.0 [range: 20–54]) and 48 (37.8%) were aged ≥55 yrs (median 65.0 [range: 55–81]). A higher proportion of pts aged <55 yrs were Hispanic/Latino (36.7% vs 18.8%), had extramedullary disease at lymphodepletion (LD; 29.1% vs 8.3%), received prior blinatumomab (53.2% vs 22.9%), and prior inotuzumab ozogamicin (35.4% vs 25.0%) than those ≥55 yrs, while a higher proportion of pts aged ≥55 yrs had Philadelphia chromosome-positive disease (47.9% vs 16.5%). Median bone marrow blast burden at LD was higher in pts aged ≥55 yrs (45.5%) vs <55 yrs (30.0%). At 21.5 months’ (mos) median follow-up (range: 8.6–41.4), the ORR (95% CI) was 72.2% (60.9–81.7) in pts aged <55 yrs vs 87.5% (74.8–95.3) in pts aged ≥55 yrs. In responders, 84.2% of pts <55 yrs and 83.3% ≥55 yrs with ≥1 post-infusion next-generation sequencing result achieved measurable residual disease-negative remission to 10 –6 leukemic cells by Month 3. Durable remission at 1 yr post infusion was observed in 68.3% and 51.8% of pts aged <55 and ≥55 yrs, respectively. EFS was comparable in pts aged <55 and ≥55 yrs: median (95% CI) 14.3 mos (6.0–not estimable [NE]) vs 11.7 mos (6.6–NE), respectively. While in remission, 29.8% of pts aged <55 yrs and 2.4% aged ≥55 yrs proceeded to consolidative stem cell transplant (SCT). Incidence of Grade ≥3 cytokine release syndrome (CRS; 2.5% vs 2.1%) and immune effector cell-associated neurotoxicity syndrome (ICANS; 5.1% vs 10.4%) were low for pts aged <55 and ≥55 yrs, respectively. Treatment-related mortality within 3 mos post obe-cel infusion was 0% in pts aged <55 yrs vs 4.2% in pts aged ≥55 yrs. CAR T-cell persistence was similar in both age groups. Conclusions: Obe-cel treatment resulted in favorable ORR and EFS with low Grade ≥3 CRS/ICANS incidence in both age groups. These findings indicate that obe-cel is effective and has a positive benefit/risk profile regardless of age, including in older adults with R/R B-ALL despite few receiving consolidative SCT. Clinical trial information: NCT04404660 .

ABSTRACT:Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post-CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ≥3 events). No cases of immune effector cell-associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.

7003 Background: Approximately 30% of pts with R/R LBCL who relapse after CAR T-cell therapy experience CD19 antigen escape (Spiegel et al. Blood. 2021).KITE-363 is a bicistronic, autologous CAR T-cell therapy that can potentially prevent CD19 escape through upfront dual targeting of CD19 and CD20. Here we report safety and preliminary efficacy from an open-label, multicenter Phase 1 study of KITE-363 in R/R BCL. Methods: Eligible adults had LBCL, indolent NHL, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), or mediastinal gray zone lymphoma R/R after ≥2 lines of therapy (LoT). Pts with LBCL may have had primary refractory disease after ≥1 LoT. Study included dose escalation (1A) and expansion (1B; LBCL only) cohorts. After lymphodepleting chemotherapy, pts received KITE-363 at dose levels (DLs) 1, 2, or 3 (0.5×10 6 , 1×10 6 , or 2×10 6 CAR T cells/kg, respectively). Primary endpoints were incidence of dose-limiting toxicities (DLTs; Phase 1A) and investigator-assessed objective response rate (ORR per Lugano; Phase 1B). Results: As of 10/14/2024, 41 pts enrolled and 37 received KITE-363 (see table). For pts with LBCL (n = 34), 50% were primary refractory and 44% had IPI 3-4. No DLTs occurred. Grade ≥3 adverse events (AEs) occurred in 76% of treated pts and serious AEs in 49%. Grade 3 cytokine release syndrome (CRS; per Lee et al. 2014) occurred in 1 pt (3%; NLPHL; DL 3); Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3 pts (8%; 1 DL 2; 2 DL 3); no Grade ≥4 CRS/ICANS occurred. Median onset of ICANS was 6 d with median duration of 5 d, and median onset of CRS was 4 d with median duration of 5 d. Six pts died (5 to progression; 1 to myelodysplastic syndrome concurrent with LBCL relapse, unrelated to KITE-363). At 7.3 months median follow-up, ORR in CAR-naive pts at DL 3 was 87%; complete response (CR) rate was 78%. Among those, all 7 pts with LBCL who were CAR-naive after ≥2 LoT had a CR. Those in DL 3 who were primary refractory (n = 15) had an 80% ORR (CR rate, 67%). Median duration of response was not reached. In all pts at DL 3 (n = 26), median CAR T-cell expansion peak, area under the curve (AUC), and time to peak were 121.5 cells/µL, 711.1 cells/µL×d, and 10 d, respectively. For CAR-naive pts in DL 3, median peak and AUC were 132.2 cells/µL and 819.2 cells/µL×d; medians in those with prior CAR T-cell therapy (n = 3) were 5.7 cells/µL and 85.7 cells/µL×d, respectively. Conclusions: No DLTs occurred in Phase 1A. Safety profile of KITE-363 was tolerable, with no Grade ≥3 CRS in pts with LBCL and 2 cases of Grade 3 ICANS at the highest DL. KITE-363 demonstrated high responses in pts with highly refractory BCL, including those with primary refractory disease. Clinical trial information: NCT04989803 . Baseline characteristics. Treated Pts (N=37) a Median age, y (range) 62 (25-83) ECOG 1 59 Stage III/IV 73 ≥3 prior LoT 41 Prior CAR T-cell exposure 19 a Percent unless otherwise specified.

Extramedullary multiple myeloma (EMD) is associated with low response rates, short progression-free survival, and poor prognosis. CAR T cells and bispecific antibodies (bsABs) have shown efficacy in relapsed myeloma, but it remains uncertain whether one T cell redirection strategy should be preferred. We retrospectively analyzed 80 patients with EMD not adjacent to the bone treated with ide-cel, cilta-cel, teclistamab, or talquetamab at three academic centers in Germany. All patients were heavily pretreated, and a high-risk cytogenetic profile was prevalent in >41% of patients. All cohorts had a median of 5 to 7 prior lines of therapy. The vast majority of patients receiving cilta-cel, ide-cel, or teclistamab were BCMA-naive ( >88%). Response rates after CAR T cell infusion were significantly higher (100% with cilta-cel, 82% with ide-cel) than with bsABs (29% for talquetamab, 36% for teclistamab). Complete resolution of EMD was more frequent after CAR T cell therapies (50% and 41%) than after bsABs (16% and 14%). With a median follow-up of 12.2 months, median (m)PFS was not reached in patients that had received cilta-cel; mPFS was 7.3 months after ide-cel and significantly longer for both CAR T products compared to talquetamab or teclistamab (mPFS 4.0 and 2.6 months). Effective debulking therapy prolonged remissions after CAR T cell infusion compared to no debulking or no response to debulking. Visceral and soft tissue manifestations responded significantly less frequently than EMD in other locations. With significantly higher response rates, deeper remissions, and longer mPFS, our retrospective data suggest CAR T cells may provide a meaningful benefit in EMD.

Background A growing body of evidence suggests the crucial role of patient's baseline immune status prior to chimeric antigen receptor-modified T cell (CAR-T) therapy. Recently, low CD4/CD8 ratio has been reported as a negative prognostic factor and is associated with increased risk of manufacturing failure in CAR-T therapy (Jo et al, BJHaem 2023). Moreover, persistence of CD4+ CAR-T is related to long-term response in CLL (Melenhorst et al, Nature 2022). Thus, in relapsed/refractory (RR) multiple myeloma (MM), there is a clear need to elucidate the impact of classic anti-MM drugs on CD4/CD8 ratio and CD4+ T cell count for planning CAR-T therapy. As T cell immunotherapies are moving to the frontline, it is of interest to analyze the dynamics of immune cells from monoclonal gammopathy of undetermined significance (MGUS) to RRMM to tailor the optimal sequencing strategy for T cell immunotherapies. We therefore performed the current study to address these issues. Methods We collected peripheral blood (PB) of patients with MGUS, smoldering MM (SMM), newly diagnosed (ND) and RRMM, retrospectively between September 2009 and October 2022 as well as prospectively since November 2022. Immune status was determined by flow cytometry using the following markers: CD45, CD3, CD4, CD8, CD19 and CD56, and then combined with clinical data. Results As of July 2024, 1886 sequential PB samples (MGUS=91, SMM=61, NDMM=47, RRMM=1687) from 459 patients (MGUS=42, SMM=22, NDMM=43, RRMM=352) were included. The median age at sampling was 66 years (range 31-90). The RRMM patients had been treated with a median of 1 line of therapy (range 1-11), and 250 (71.0%) patients had received high-dose melphalan and autologous stem cell transplant (HD-Mel). Firstly, we compared the immune status in MGUS, SMM, NDMM and RRMM. We noticed significantly lower total T cell (CD3+CD19-), B cell (CD19+CD3-), CD4+ T cell (CD3+CD4+), NK cell (CD56+CD3-) counts and CD4/CD8 ratio in RRMM than MGUS, SMM and NDMM (all P<0.001). Moreover, CD8+ T cells (CD3+CD8+) and NK T cells (CD56+CD3+) increased from MGUS to SMM (P<0.001) and remained constant from SMM to NDMM. RRMM showed lower NK T cell count than NDMM (P<0.001), while CD8+ T cell counts were similar in NDMM and RRMM. Secondly, we evaluated the prognostic value of immunologic parameters in RRMM. In multivariate cox regression model, CD4+ T cells < 400/µl (HR: 7.8, 95%CI 1.9-33.1, P=0.005) and CD4/CD8 ratio <0.70 (HR: 2.3, 95%CI 1.1-4.7, P=0.023) were negative prognostic factors for progression free survival. Moreover, CD4+ T cells < 400/µl (HR: 2.3, 95%CI 1.2-4.2, P=0.008), NK cells < 200/µl (HR: 1.7, 95%CI 1.0-3.0, P=0.049) and CD4/CD8 ratio <0.70 (HR: 1.8, 95%CI 1.1-3.0, P=0.02) were associated with inferior overall survival. Thirdly, we analyzed the impact of classic anti-MM treatments on circulating immune cell subsets, particularly the immunologic features with prognostic relevance, using multivariate generalized linear model. Carfilzomib (CFZ) pretreatment negatively correlated with CD4+ T cell count (n/µl) (β=-103.6, P<0.001) and CD4/CD8 ratio (β=-0.4, P<0.001). Interestingly, prior bortezomib therapy showed positive correlation with CD4/CD8 ratio (β=0.5, P=0.001), possibly due to the reversible proteasome inhibition in contrast to CFZ. Prior HD-Mel resulted in lower CD4+ T cell (β=-184.7, P<0.001), higher CD8+ T cell counts (β=109.1, P<0.001) and lower CD4/CD8 ratio (β=-1.7, P<0.001). As expected, treatment-free interval (days) positively correlated with CD4+ T cell count (β=0.09, P<0.001). The number of prior lines of therapy negatively correlated with CD4+ T cell count (β=-21.4, P<0.001) and CD4/CD8 ratio (β=-0.06, P<0.001). Surprisingly, older patients showed higher CD4+ T cell count (β=3.3, P<0.001) and CD4/CD8 ratio (β=-0.03, P<0.001), probably due to the more intensive therapy in younger patients, e.g. HD-Mel. Conclusion Our findings suggest the changes of immune system from MGUS to RRMM and the potential impact of classic anti-MM drugs on immune status. The known biomarkers for a fit immune system, i.e. sufficient CD4+ T cell count and CD4/CD8 ratio, are associated with favorable survival outcome in RRMM, and the immune status recovers after a treatment-free interval. To achieve better anti-MM effect and to reduce the risk of manufacturing failure, leukapheresis for CAR-T should be considered prior to HD-Mel and CFZ due to their negative impact on CD4+ T cells and CD4/CD8 ratio.

Background Extramedullary disease (EMD) represents an aggressive variant of multiple myeloma (MM) associated with low response rates to conventional myeloma therapies, short progression-free survival (PFS) and high mortality. While CAR T cells and bispecific antibodies (bsABs) provide new opportunities in patients with relapsed/refractory MM (RRMM), their use in EMD is less clear. Furthermore, it remains uncertain whether one strategy is superior to the other in the setting of EMD and should therefore be preferred. Methods We retrospectively collected data of patients with EMD not adjacent to the bone treated with bsABs or CAR T cell therapies from two academic centers in Germany from 09/21 to 07/24. All patients had both serological assessment and EMD imaging prior to therapy initiation and follow-up after at least three months or at the point of progression. We analyzed demographics, outcomes, cytogenetics, and prior therapies. Results We enrolled all 78 RRMM patients with EMD treated with either cilta-cel (n=11), ide-cel (n=21), talquetamab (n=27), and teclistamab (n=18). Muscle (38%), skin (33%), pleural (30%) and retroperitoneal manifestations (22%) were the most common EMD localizations, and the median follow-up was 4.6 months. The four cohorts were comparable with a median of 5 to 7 prior lines of therapy. EMD was diagnosed 2.5-4 years after MM diagnosis. All patients were triple-refractory and more than 64% were penta-refractory in each cohort. The population was enriched for high-risk cytogenetics (>41% of patients with available FISH over all cohorts). The majority of CAR T cell patients received bridging therapy. Response to bridging therapy was not associated to PFS and 41/36% had extramedullary or serologic progressive disease at the time of cilta-cel or ide-cel cell infusion, respectively. The vast majority of patients receiving cilta-cel, ide-cel or teclistamab were BCMA-naive (>91% in each cohort). EMD response rates of patients receiving CAR T cells were significantly higher (93% for cilta-cel, 82% for ide-cel) than with bsABs (47% for talquetamab, 38% for teclistamab, p<0.0001). Complete resolution of EMD was also significantly more frequent after CAR T cell therapies (50% and 41%) than after bsABs (16% and 14%, p=0.001). Median PFS was not reached in patients after cilta-cel and significantly longer in ide-cel with 11.2 months when compared to talquetamab and teclistamab (3.2 and 2.8 months, p=0.03). OS was not reached for patients receiving cilta-cel, 24.6 months for ide-cel, 18.4 months for teclistamab, and 15.1 months for Talquetamab (ns). Serologic response ≥PR in patients with measurable serologic activity predicted EMD response (p<0.0001). Independent of treatment, visceral and soft tissue manifestations responded significantly less frequent than skin, mucosal, and lymph node lesions (p=0.02). Conclusion Both CAR T cells and bsABs show efficacy in EMD. However, CAR T cells appear to be superior to bsABs in this setting. With significantly higher response rates, deeper remissions and longer median PFS in our analysis, CAR T cells may provide a meaningful benefit in EMD and should be considered preferentially.

INTRODUCTION The GHSG-HD21 trial in adult patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (AS-cHL) compares BrECADD (Brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Superior treatment-related morbidity (TRMB) and at least non-inferior efficacy of BrECADD with high progression-free survival (PFS) rates after three years were presented previously. Fertility following chemotherapy is a major concern for these mostly young AS-HL patients. Therefore, we analyzed pregnancies and childbirth rates reported in HD21. METHODS This international open-label phase III trial included adult patients aged ≤ 60 yrs with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4-6 cycles of either eBEACOPP or BrECADD. PET2 and PFS events were assessed by blinded panel review. Frequency of pregnancies among patients or their partners were analyzed in all female patients below 40 years and male patients below 50 years included in the ITT cohort for the safety endpoint TRMB. Descriptive statistics were used to report pregnancy rates. Childbirth rates per year were compared to German population data for women between 18-40 years in the years 2016-2020, obtained from the German Federal Statistical Office (Destatis). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. RESULTS Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries and 233 trial sites. The final cohort for this analysis comprised 1200 patients (496 women and 704 men; 80.1% of ITT). Baseline characteristics were well balanced between treatment arms and median follow-up for this analysis was 40 months. 55.6% of the patients had cryocpreservation prior to chemotherapy (46.1% women, 76.4% men). At time of this analysis, there were 126 reported pregnancies during follow-up. Data was incomplete in 25 cases, and these were excluded from analysis. Overall, 97 (9.1%) patients had at least one documented pregnancy; 38 (7.2%) and 53 (9.8%) in eBEACOPP and BrECADD arm, respectively. Nine patients had more than one pregnancy. Compared to eBEACOPP, pregnancy rates following BrECADD were higher in males (5.7% vs. 2.5%) and females (13.2% vs. 11.8%). 8.2% of patients with reported pregnancy made use of cryopreservation. 82.2% of all pregnancies resulted in childbirth and 17.9% ended early (4% due to induced abortion; 13.9% due to abortion). Among patients with reported childbirth, there was a greater proportion of female patients vs. partners of male patients (63.9% vs. 36.1%); otherwise there were no notable differences between baseline characteristics or total cycles of chemotherapy in patients with reported pregnancy compared to the rest of the cohort. Median time from last day of chemotherapy until date of birth was 32 months (range 4-57). In women between 18 and 40 years, the childbirth rate per year increased during the first two years after treatment (first year: 0.6% [CI95: -0.1-1.3]; second year: 4.4% [CI95: 2.4-6.3]) and were numerically above the population reference (6.51%) starting from the third year (third year: 8.8% [CI95: 5.9-11.7]; fourth year: 8.0% [CI95: 4.5-11.4]; fifth year: 7.8% [CI95: 2.9-12.8]). CONCLUSION We report high rates of pregnancy following chemotherapy in the HD21 trial; approximately one tenth of patients below age 40 (female) or 50 (male) in the HD21 trial have reported a pregnancy during follow-up. Compared to eBEACOPP, pregnancy rates were twofold higher in partners of men who received BrECADD and slightly higher in women. Notably, childbirth rates in women after the second year of follow-up were comparable to the German population. Together with unparalleled primary cure rates achieved with BrECADD, our data supports its use in young patients with a desire to have children.

Background Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative modality in the treatment of patients with cancer. However, it is increasingly evident that this therapeutic approach is not without its challenges. The unique nature of CAR-T cells as living drugs introduces a distinct set of side effects. As the application of CAR-T cell therapy expands to treat a broader range of diseases, it becomes increasingly important to devise effective strategies for handling the associated toxicities. Challenges in treating patients with CAR-T cells include addressing complications such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and cytopenias. This comprehensive review seeks to systematically identify, categorize and elucidate all previously described neurological and psychological side effects associated with CAR-T cell therapy, shedding light on the pertinent laboratory findings that underscore these phenomena.Methods PubMed, Springer Link, and ScienceDirect were systematically searched for empirical studies on adult patients with cancer receiving CAR-T cell therapy for hemato-oncological malignancies. Quality assessment was conducted using Version 2 of the Cochrane risk-of-bias tool (RoB 2) for randomized trials and adherence to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist for observational studies. The synthesis of findings was conducted via a narrative approach, consolidating the diverse array of data into a coherent framework.Results From an initial pool of 2,276 citations, 546 studies met the inclusion criteria, exhibiting a rich tapestry of heterogeneity in terms of study characteristics and patient samples. The incidence of neuropsychological symptoms varied notably across different CAR-T cell products and hematological malignancies. Among the most frequently reported neuropsychological symptoms were aphasia, attention deficits, impaired consciousness, and disorientation, alongside a constellation of other symptoms including confusion, cognitive impairment, memory loss, writing difficulties, fatigue, headache, agitation, tremor, seizures, and psychomotor retardation. Early intervention strategies, including corticosteroids and tocilizumab, have shown the potential to reduce the intensity of neuropsychological symptoms and prevent their progression to critical complications.Conclusion These insights underscore the imperative of extending neuropsychological assessments beyond the conventional Immune Effector Cell-Associated Encephalopathy score framework.

Introduction Odronextamab, a novel, investigational, CD20×CD3 bispecific antibody, has demonstrated compelling efficacy and a generally manageable safety profile in heavily pretreated patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the CAR-T-naïve and post-CAR-T therapy settings (Ayyappan S et al. ASH 2023; Crombie J et al. ASH 2023). Here, we report long-term efficacy and safety data for odronextamab from a pooled analysis of the DLBCL post-CAR-T cohort in the ELM-1 study (NCT02290951), which was the only pivotal study of a bispecific antibody with a prespecified cohort dedicated to this population, and the CAR-T-naïve DLBCL cohort in the ELM-2 study (NCT03888105). Methods Odronextamab was administered intravenously in 21-day cycles. A step-up dosing regimen with steroid prophylaxis was employed during Cycle 1, followed by 160 mg on Days 1, 8, and 15 of Cycles 2-4. Maintenance therapy consisted of 320 mg every 2 weeks until disease progression or unacceptable toxicity. Patients with durable complete response (CR) for ≥9 months transitioned to dosing every 4 weeks. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using the Lugano classification. Key secondary endpoints included CR rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results The analysis set consisted of a pooled population of 187 patients with R/R DLBCL from ELM-1 (n=60; data cutoff date of January 22, 2024) and ELM-2 (n=127; data cutoff date October 20, 2023). Median duration of follow-up was 23.0 months. Median age was 65.0 years (range 24-88), 61.5% of patients were male, 78.6% had Ann Arbor stage III-IV, 56.7% had an IPI score ≥3, and the median number of prior lines of therapy was 3 (range 2-9). The 60 patients included from ELM-1 had all received prior CAR-T therapy, representing 32.1% of the total pooled population (60/187), and of these, 48.3% (29/60) had relapsed within ≤90 days of initiating CAR-T therapy, and 71.7% (43/60) had CAR-T-refractory disease. Overall, 83.4% of the pooled population had disease that was refractory to the last line of therapy. Median duration of odronextamab exposure was 14.7 weeks; 91.4% (171/187) of the population completed ≥1 cycle, and 59.4% (111/187) completed ≥4 cycles. ORR and CR rate confirmed by ICR were 50.8% (95/187) and 31.6% (59/187), respectively, and were generally consistent across multiple high-risk subgroups, including the post-CAR-T therapy subgroup. Median DOR was 10.5 months (95% CI 5.4-24.8) and median duration of CR was 36.3 months (95% CI 12.4-not evaluable); the probability of maintaining CR for 36 months was 51.0%. The probability of PFS and OS at 36 months was 17.5% and 27.0%, respectively. Safety was generally consistent with previous reports. The most common treatment-emergent adverse events (>30% all grades) were cytokine release syndrome (CRS; 52.9%), anemia (35.8%), pyrexia (39.6%), and neutropenia (31.6%). Adverse events led to treatment discontinuation in 25 patients (13.4%). With the optimized 0.7/4/20 mg step-up regimen (n=100), 48.0% of patients (48/100) had CRS events that were Grade (Gr) 1/2, and one Gr 3 CRS event (confounded by pancreatitis) was reported. All CRS events resolved with supportive measures. No immune effector cell-associated neurotoxicity syndrome events were reported with the 0.7/4/20 mg step-up regimen. Gr ≥3 infections occurred in 46 patients (24.6%; Gr 5, n=16 [8.6%]). COVID-19 infections were reported in 30 patients (16.0%), of which Gr 5 was reported in 6 patients (3.2%). Conclusions This pooled analysis of patients with R/R DLBCL from the ELM-1 and ELM-2 studies, which represents the largest dataset reported for a bispecific antibody in the third-line or later setting, confirms that with longer follow-up the recommended odronextamab dose retains highly encouraging efficacy. Responses were durable, with a 51% probability of maintaining CR for 3 years. The safety profile was generally consistent with earlier reports and CRS events with the 0.7/4/20 mg step-up dosing regimen were predominantly low grade and generally manageable. Importantly, continued treatment with odronextamab demonstrated no detrimental effects on survival outcomes over a longer follow-up period. Odronextamab may be an important potential option in future management of R/R DLBCL, and Phase 3 trials are ongoing. Updated data will be presented.

Introduction The optimal duration of treatment with bispecfic antibodies in the setting of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) has not been prospectively determined. In the Phase 2 ELM-2 study (NCT03888105), odronextamab, a CD20×CD3 bispecific antibody, was evaluated in patients with R/R follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of systemic therapy. Patients received intravenous (IV) odronextamab in 21-day cycles with step-up dosing in Cycle 1, 80 mg (FL)/160 mg (DLBCL) QW in Cycles 2-4, then 160 mg (FL)/320 mg (DLBCL) Q2W post-Cycle 4 until disease progression or unacceptable toxicity (as described previously). During step-up dosing, patients received premedication with dexamethasone (10 mg orally [or equivalent] prior to the first split infusion, and 20 mg IV on each day of split infusion). Serious infections, including fatal infections, are an important risk with B-cell-depleting therapies, including odronextamab. Given the risks of persistent B-cell depletion with continued odronextamab therapy, a retrospective analysis was performed to evaluate the risk of fatal infections and the probability of progression-free survival (PFS) based on the duration of odronextamab treatment, specifically in patients with R/R FL and DLBCL obtaining a complete response (CR) in the ELM-2 study. Methods Patients with a CR in the ELM-2 study were grouped based on different observed durations of odronextamab treatment: Analysis 1, odronextamab treatment duration of <6 months, 6-<12 months, and ≥12 months; and Analysis 2, odronextamab treatment duration of <12 months, 12-<18 months, and ≥18 months. Fatal infection incidence and PFS were analyzed in all patient subgroups. Results In ELM-2, 94/128 patients with FL and 40/127 patients with DLBCL achieved a CR and were available for analysis. Overall, 13.4% of patients (8/94 FL and 10/40 DLBCL) with a CR experienced fatal infections. The majority (72.2%, 13/18; 5 FL and 8 DLBCL) of fatal infections occurred early (within 12 months) in odronextamab treatment; 44.4% (8/18 patients) occurred within 6 months, 27.8% (5/18) occurred within 6-<12 months, 22.2% (4/18) occurred within 12-<18 months, and 5.6% (1/18) occurred after ≥18 months of treatment. Median time to fatal infection from first dose was 8.8 months (range 2.5-22.9). In Analysis 1, 31 patients were treated with odronextamab for <6 months, 29 patients were treated for 6-<12 months, and 74 patients were treated for ≥12 months. The rates of fatal infections in these subgroups were 25.8% (8/31 patients), 17.2% (5/29), and 6.8% (5/74), respectively. The Kaplan-Meier (KM) estimate of PFS showed a higher probability of PFS in patients treated for ≥12 months, compared with those treated for <6 months or 6-<12 months. In Analysis 2, 60 patients were treated with odronextamab for <12 months, 41 patients were treated for 12-<18 months, and 33 patients were treated for ≥18 months. The rates of fatal infections in these subgroups were 21.7% (13/60 patients), 9.8% (4/41), and 3.0% (1/33), respectively. The KM estimate of PFS showed a higher probability of PFS in patients treated for ≥18 months compared with those treated for <12 months or for 12-<18 months. Conclusions In the setting of FL and DLBCL in the third line and beyond, achieving and maintaining a CR is an important treatment goal, as it consistently translates into long-term survival benefit. In ELM-2, odronextamab monotherapy resulted in high rates of CR with associated durability; however, serious and fatal infections were observed. The risk of fatal infections was higher in patients treated for less than 6 or 12 months, likely due to increased susceptibility from prior treatments in the R/R setting. This analysis indicates that longer treatment duration was not associated with an increased risk of fatal infections but was associated with an increased probability of PFS. This suggests that patients who achieve a CR and continue receiving treatment for longer periods may have a different underlying susceptibility to infection compared with those on treatment for shorter periods. Prospective trials are warranted to investigate the optimal duration of treatment with bispecific antibodies in the setting of R/R B-NHL.

C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in a multitude of cancers, including neoplasms of hematopoietic origin. This feature can be leveraged by a theranostic approach, which provides a read-out of the actual CXCR4 expression in vivo, followed by CXCR4-targeted radioligand therapy (RLT) exerting anti-cancer as well as myeloablative efficacy. In a recent meeting of hematooncology and nuclear medicine specialists, statements on the current clinical practice and future perspectives of this innovative concept were proposed and summarized in this opinion article. Experts concluded that i) CXCR4-directed [68Ga]Ga-PentixaFor PET/CT has the potential to improve imaging for patients with marginal zone lymphoma; ii) CXCR4-targeted RLT exerts anti-lymphoma efficacy and myeloablative effects in patients with advanced, treatment-refractory T-cell lymphomas; iii) prospective trials with CXCR4-based imaging and theranostics are warranted.

Introduction: The use of ciltacabtagen autoleucel (cilta-cel) in RRMM patients within the CARTITUDE-1 study has exposed previously unknown late onset neurotoxicities, referred to as movement, neurocognitive treatment emergent events (MNT) (Cohen, A et al., 2022). In addition to their late occurrence, MNTs are characterized by their failure to respond to standard therapy such as corticosteroids. Hence, this patient population (5.0 % in CARTITIUDE-1) is at high risk of severe and persistent neurological complications evoking the necessity for further research into the yet poorly understood pathophysiology of MNTs. So far, CAR-T “on-target-off-tumor”-toxicity due to BCMA expression in the basal ganglia has been proposed as one of the driving pathomechanisms of MNTs (Van Oekelen, O et al., 2021). We report the case of a 63-year-old male patient with IgA-kappa myeloma, who received 7 prior lines of treatment. Besides prolonged CRS °I, which was successfully managed by a single dose of tocilizumab, no other adverse events or signs of neurotoxicity occurred immediately post CAR-T infusion. Patient case and methods: 14 days post CAR-T infusion the patient presented with shakiness, subjective slowing of motor skills and concentration disorders. However, it was not until a second hospitalization period 30 days post CAR-T, when neurological examination confirmed a clinical syndrome of parkinsonism including bradykinesia, rigor, tremor and postural instability. Consistent with the clinical presentation, 123I-FP-CIT-SPECT-imaging revealed reduced presynaptic dopamine transporter density in the striatum. On day 54 after CAR-T, the patient developed a massive deterioration of parkinsonism reflected by an increased MDS-UPDRS part III score of 65. Ultimately, the patient was treated with intrathecal chemotherapy, dasatinib orally, cyclophosphamide and corticosteroids. From 149 days post CAR-T a slight improvement of parkinsonism was observed (MDS-UPDRS part III score of 32) following levodopa/benserazide delivery via PEG, and after achieving CAR-T eradication with prior therapies. Multimodal analysis, including flow cytometry, and simultaneous scRNA- and scTCR-seq, was performed on peripheral blood (PB) and cerebrospinal fluid (CSF) longitudinally to the course of illness. Results: CAR-T expansion in PB peaked in the first month post CAR-T (day 17: 7966.7 CAR-T/µl, day 30: 8299.6 CAR-T/µl), while peak infiltration of the CSF occurred at day 57 (367 cells/µl) coinciding with parkinsonism deterioration. Throughout the patient's course, CAR-T were the most abundant cell population in the CSF, with CD4+ CAR-T dominating at the beginning (day 17-30). We performed scRNA-seq and scTCR-seq on 7 longitudinally collected samples (d20-d143 post CAR-T) of the patient's CSF and 6 matched PB samples, collectively representing 74603 cells. CAR-T as well as non-CAR-T cells were present in the CSF with CAR-T proportions decreasing over time. CD8+ as well as CD4+ CAR-T showed marked expression of cytotoxicity associated genes (PRF1, granzymes, GNLY). While CAR-T did not clonally expand, scTCR-seq revealed clonally expanded CD8+ non-CAR-T in the CSF concurring with the deterioration of parkinsonism. Major CD8+ non-CAR-T clones were detectable from day 30 post CAR-T, albeit at low numbers, and were also detectable in the PB. Phenotypically, these clones were marked by the expression of cytotoxicity genes, and tissue residency markers (ZNF683). Cell-cell interaction inference indicated activating signaling of CD4+ CAR-T towards clonally expanded CD8+ non-CAR-T in CSF. Furthermore, we observed an increased interferon response in the CSF that preceded the deterioration of the patient, which was absent in PB. Notably, the interferon response was abrogated after treatment with dasatinib, consistent with reduced activation of CAR-T and non-CAR-T as determined by flow cytometry. Conclusion: Our longitudinal case study shows for the first time that CD4+ CAR-T are most likely the initiators of MNTs and that clonally expanded CD8+ non-CAR-T cells could drive the deterioration of parkinsonism. These findings are consistent with recent reports that CD8+ T cells promote neurodegeneration in other diseases. The coincidence of an interferon response with clinical worsening and the potential abrogation of this response by dasatinib requires further investigation.