Onset Of Cytokine Release Syndrome Research Articles

Identification of a Patient Suitable for CAR-T Cell Therapy in the Outpatient Setting: A Vodcast and Case Example.

Chimeric antigen receptor T cell (CAR-T) therapies targeting the CD19 antigen have been associated with high and durable response rates in patients with diffuse large B cell lymphoma (DLBCL). CAR-T cell therapies are commonly administered in the inpatient setting due to the average onset of cytokine release syndrome within the first 3days post infusion, but there has been growing interest in delivering CAR-T cell therapies in the outpatient setting to overcome frequent hospital bed shortages and the high cost of inpatient care. Although this approach could improve access whilst catering to patient preference, it requires a multidisciplinary approach as well as careful patient selection. Herein, Dr. Foley and Dr. Kuruvilla discuss the case of a patient presenting with the ideal profile for CAR-T cell therapy referral whilst also determining the key attributes for eligibility from a clinician's perspective. Solutions for successful outpatient management include proper education, caregiver support, and early referral to ensure a timely infusion. In conclusion, outpatient administration of CAR-T cell therapy in patients with DLBCLs should be assessed on a case-by-case basis.A vodcast feature is available for this article.

Outpatient Management of CAR-T and Teclistamab for Patients with Lymphoma and Multiple Myeloma

Background: Patients (pts) receiving FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy or Bispecific antibody Teclistamab (Tec) are commonly managed in the inpatient setting given the common adverse events such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome ICANS. We have previously reported that hospital-based outpatient (HBO) management of pts receiving CAR-T is feasible and safe (Bansal et al, ASH2022). In 2023, HBO management at our institution began incorporating home health visits and management of grade 1 CRS in outpatient setting for select pts receiving standard of care (SOC) CAR-T. Here, we report outcomes of our updated practice. Methods: We retrospectively analyzed medical records and remote monitoring data of adult pts who received SOC CAR-T or Tec between 10/2020 and 7/2023 at Mayo Clinic, Rochester under an IRB approved protocol. Results: In 3/2023, pts deemed to be low risk for severe CRS (fever onset >= 3 days from infusion, CRP<100) received HBO management for grade 1 CRS, including outpatient administration of tocilizumab. If CRS improved or resolved, outpatient monitoring was continued. If CRS persisted within the observation period on HBO, pts were admitted. Recurrent CRS after the first episode were all managed inpatient. Nine pts met these criteria for HBO CRS management and their outcomes were compared to those who received initial inpatient (INPT) CRS management (INPT, n=17) during the same timeframe, as well as the outcome of 164 pts who had CRS management INPT prior to our practice change (Table 1). Two-third of the pts with initial management of CRS outpatient did not require hospitalization. Median time to hospitalization trended later than those managed inpatient at the onset of CRS. The duration of hospitalization was comparable for all pts admitted between initial HBO and INPT CRS management. However with fewer admissions in the initial CRS HBO group, the average hospitalization days (LOS) per patient treated for that group was lower compared to initial INPT CRS management. Data on additional pts will be presented at ASH. In 1/2023, pts on RPM with no ongoing CRS symptoms, no language barriers, and no compliance concerns received home health visits during weeks 3 and 4 post CAR-T infusion in place of clinic visits on HBO. Home health visit team communicated with HBO staff to review assessment and plan. Changes in HBO utilization will be presented. Finally, 24 pts received 223 Tec infusions on HBO. Median age was 66 years, 15 (61%) were males, 9 (38%) had high risk cytogenetics. The median prior lines of therapy was 5. Among these pts, 220/223 (99%) doses were performed on HBO and 204/220 (93%) infusions never required admission for management. Twenty pts enrolled in RPM (Figure 1). An average of 2 alerts were generated per patient during the 2 week period and median time from infusion to alert was 1.5 days. Majority of alerts were resolved over a phone call and only 13/114 (11%) alerts required a physician visit/hospital admission. Of the 16 Tec infusions resulting in admission, 4/16 (25%) required re-admission resulting in a total of 20 hospitalizations. Admissions mostly occurred during step-up dosing (18/20; 90%). Most common reason for first admission was fever (13/16, 85%) and median time to admission was 1 day from infusion. Median LOS was 1.5 days (range, 0-12). In terms of CRS, majority were Grade 1 (12/13, 93%) which were managed with steroids (dexamethasone/ prednisone) alone. One patient had CRS grade 4 event, in the setting of concurrent decompensation during dialysis, and was treated with steroids, tocilizumab, vasopressor, CRRT, thoracentesis, intubation and mechanical ventilation. The rate of second CRS event after management of first CRS with steroid (dexamethasone/ prednisone) was 15% (2/13). These second CRS episodes also resolved with steroid alone. Data on additional pts receiving Tec will be presented at ASH. Conclusion: Our data showed that additional advances in outpatient practice, including initial outpatient management of CRS and outpatient administration of Tec step up dosing are feasible, safe and reduce hospital resource utilization.

Duvelisib for Cytokine Release Syndrome Prophylaxis during CD19-Targeted CAR T Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of patients with advanced non-Hodgkin lymphoma (NHL). However, treatment toxicity, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), can be significant. Effective prophylactic strategies may reduce the frequency and/or severity of CAR T cell therapy while also expanding the pool of patients eligible for such therapy. Duvelisib is an oral inhibitor of the gamma and delta isoforms of phosphoinositide 3-kinases (PI3K), which is an active therapy for CLL/NHL with an established safety profile. In addition, prior work from our group and others has demonstrated that PI3K inhibition can prevent CRS in an in vitro model (Amatya et al. ASH 2022) and can enhance antitumor cytotoxicity of CAR-T cells. Consequently, we performed a trial of duvelisib for CRS prophylaxis in patients undergoing standard-of-care (SoC) CAR T-cell therapy for NHL (NCT05044039). This was a phase I trial with a 3 + 3 dose escalation and two-arm dose expansion phase. The trial enrolled patients with NHL eligible for SoC CAR T-cell therapy and adequate organ function. Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS). 17 patients are included in this analysis, including 6 patients in dose escalation and 11 of 14 planned patients in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 68 years (range: 28 - 79) and 53% were male. Diagnoses included DLBCL (n = 13), MCL (2), FL (1) and PBMCL (1). For CAR-T cell therapy, patients received axi-cel (10), liso-cel (4), brexu-cel (2) and tisa-cel (1). 3 patients were enrolled on dose level 1 (15 mg BID) and 3 patients were enrolled on dose level 2 (25 mg BID). No patients experienced a dose-limiting toxicity (DLT) during dose escalation and consequently, 25 mg BID was selected as the recommended dose for expansion. 75 adverse events (AEs) were considered possibly (73) or probably (2) related to duvelisib by study investigators, including 14 severe (grade ≥3) AEs. The most common AEs were blood count abnormalities (41), liver function test abnormalities (12), fatigue (8) and nausea (6). The majority of severe AEs were cytopenias (13) and one patient had grade 3 hypokalemia. 13 patients (77%) had AEs attributed to duvelisib, including 6 patients (35%) with severe AEs. 76% of patients (13/17) experienced CRS at a median of 5 days following cell infusion (range 2 - 9) (Figure 1A). In 71% of patients (12/17), the onset of CRS was after day 3. Most were grade 1 (65%) and no patients experienced severe (grade 3 - 4) CRS. The median duration of CRS was 1 day (range: 1 - 7). ICANS occurred in 41% of patients (7/17) at a median of 7 days (range 4 - 10) and 12% of patients experienced severe (grade 3-4) ICANS. The median duration of ICANS was 5.5 days (range: 4 - 11 days). Toclizumab was given to 65% of patients for treatment of CRS and 53% received steroids for CRS and/or ICANS. All 17 patients were evaluable for disease response. At day +30, the overall response rate (ORR) was 71% (12/17) with 47% achieving complete response (CR) rate. At day +100, the ORR was 64% (9/14) with 50% CR. Best response was CR in 71% of patients and stable disease in 18% of patients. No patients had progressive disease (PD) as best response. CAR T cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B). With a median follow up of 93 days (range: 28 - 406), 53% of patients were alive and in remission. PD occurred in 6/17 (35%) patients with a median time to progression of 89 days (range: 28 - 182). Three patients enrolled on the study have died. One died from disease progression on day +266. Two died in remission from neutropenic sepsis (day +50) and vaping-induced lung injury (day +144). Data from this ongoing phase I study suggests that duvelisib with SoC CAR T-cell therapy is safe and tolerable. Preliminary data from this study suggest that the addition of duvelisib to CAR T-cell therapy may prevent grade 3-4 CRS and also delay the onset of CRS. Although limited follow-up is available, the depth and duration of response is similar to published data for CAR T-cells in this setting.

“Defining the Optimal Post-CART Monitoring Period in Recipients of Axicabtagene Ciloleucel and Tisagenlecleucel”

Background: Rigorous monitoring for approximately 4 weeks after chimeric antigen receptor T-cell therapy (CART) is mandated due the potentially fatal toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndromes (ICANS) during this period, and to allow early appropriate interventions. The US Food and Drug Administration implemented the Risk Evaluation and Mitigation Strategy (REMS) program for approved CART that mandates patients remain within the proximity of the authorized treating center for the monitoring period. The physical and financial burden of stringent monitoring may pose a barrier to CART access, especially for minorities and patients from rural areas and low-income groups. Therefore, evaluating the optimal duration of monitoring and causes of non-relapse mortality (NRM) is an area of unmet need. We evaluated safety outcomes for commercial axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) recipients. Methods: Patients (pts) ≥ 18 yrs who received an axi-cel or tisa-cel infusion for large B-cell lymphoma between April 2016 and July 2022 at nine academic US medical centers were identified from the Cell Therapy Consortium registry. Descriptive analysis was used to report outcomes. NRM was death due to causes other than disease progression. New-onset CRS and ICANS were reported as a percentage of pts at risk (alive with no prior CRS/ICANS). Results: A total of 374 pts were included with 216 (58%) receiving axi-cel, and 158 (42%) tisa-cel. Demographics are in Table 1. Median follow-up was 12.4 mo (0.3-58) Safety: Any grade CRS occurred in 63% pts, more common in axi-cel recipients (80%) compared to tisa-cel (41%), p<0.0001. During week 1 (Day 0-7), new-onset CRS occurred in 60.4% of the total population including 75.4% of axi-cel and 39.8% of tisa-cel recipients. New CRS onset in week 2 (Day 8-14) was seen in 6.1% of pts (15.4% axi-cel vs 1% tisa-cel). There was no new onset CRS in Week 3 or beyond. The median time to CRS onset was 3 days (0-13). (Figure 1) Unresolved CRS beyond Day 14 occurred in 7.2% (8.7% of axi-cel vs 3.1% of tisa-cel recipients), of which only 1.7% of pts (all axi-cel recipients) had unresolved CRS beyond Day 28. The median time to resolution was 4 days (IQR 25-75%: 2-7). 98.3% of CRS resolved by Day 28. Any grade ICANS was seen in 35% of pts, more common in axi-cel (52%) compared to tisa-cel (10%), p<0.0001. During Week 1, new-onset ICANS was seen in 27% of of the total population including 40.7% of axi-cel and 8.2% of tisa-cel recipients. New ICANS in week 2 was seen in 9.5% of pts (18.8% of axi-cel vs 2.8% of tisa-cel recipients). During week 3, new-onset ICANS occurred in only 1 tisa-cel recipient (0.4%). There were no new cases in week 4 and beyond. The median time to ICANS onset was 5 days (1-21). Unresolved or ongoing ICANS beyond Day 14 occurred in 32.8% of pts (34.8% of axi-cel: vs 18.7% of tisa-cel recipients), and beyond Day 28 in 7% of pts (7.1% of axi-cel vs 6.3% of tisa-cel recipients). The median time to ICANS resolution was 12 days (IQR 25-75%: 9-16). 93% of ICANS resolved by Day 28. Toxicity Management: Tocilizumab was utilized in 47% of pts (axi-cel 62% vs tisa-cel 26%) and 33% of pts received steroids (axi-cel 50% vs 10% tisa-cel) for management of CART-related toxicities. Other Complications: Infectious complications from Day 0-28 were seen in 18.5% of the total population and more commonly in axi-cel (22%) compared to tisa-cel (13.9%) recipients, p=0.006. Grade ≥4 neutropenia from Day 0-28 days was seen in 66% of the total population (81% axi-cel vs 46% tisa-cel). 82% of the total population did not have Grade ≥4 neutropenia beyond Week 2, and 93% had no Grade ≥4 neutropenia beyond Week 4. NRM: Day 0-28 NRM included 4 deaths (3 related to ICANS and 1 infection), and Day 29-90 NRM included 7 deaths (3 infections, 1 ICANS, 1 cardiac, 2 other). Conclusions: This large multicenter retrospective analysis evaluates patterns of CRS, ICANS, and NRM in recipients of axi-cel and tisa-cel. While NRM is mainly due to infections and ICANS, our study suggests that beyond 2 weeks following CART infusion, the incidence of new onset CRS and ICANS is low. This data supports further investigation into individualized monitoring strategies for stable patients. A flexible monitoring period may help to decrease the financial and physical burden for patients and make CART more accessible and feasible, especially for those with limited socioeconomic support.

Post CAR-T Peripheral Lymphocytosis and Its Kinetics Are a Potential Biomarker for Response and Immune Mediated Toxicities

Introduction Although expansion of chimeric receptor antibody (CAR)-T cells after infusion has previously been described, overt lymphocytosis with atypical morphology has not been widely reported in multiple myeloma (MM). Here we describe the kinetics of absolute lymphocyte count (ALC), its relationship with immune mediated toxicities, and clinical outcomes. Methods Thirty-nine patients (pts) receiving BCMA CAR-T (25 pts ciltacabtagene autoleucel (cilta-cel) and 14 pts idecabtagene vicleucel (ide-cel)) from two institutions were retrospectively reviewed. Data on baseline characteristics, presence of extramedullary disease (EMD), conditioning regimen, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), severity of CRS/ICANS (according to American Society of Transplantation and Cellular Therapy (ASTCT) classification), ALC on day -5 through 14, time to best response (TBR), time to first response (TFR), depth of response, and outcomes were collected. Response was evaluated in pts with >3 months of follow up. Peripheral blood flow cytometry was performed in 3 cases at time of highest ALC. ALC data for 84 pts who received CD19 CAR-T (77 pts with axicabtagene ciloleucel and 7 pts with brexucabtagene autoleucel) for non-Hodgkin lymphoma (NHL) were included as a comparison. Maximum ALC (max-ALC) was defined as the highest ALC between day 0 and +15, baseline ALC was defined as the lowest ALC during day 0 through +3, and absolute ALC increase was defined as the difference of max-ALC and baseline ALC. Results Baseline characteristics of the cohort are described in Table A. Pts who received cilta-cel had earlier onset of CRS (median day +6 (IQR 2 - 8) vs +2 (IQR 1 - 2), p = 0.02), had higher max-ALC after CRS (median 1.7 cel/uL (IQR 0.8 - 5.3) vs 0.81 cel/uL (IQR 0.6 - 1.1), p = 0.02), and had a trend towards later max-ALC (median day +12 (IQR 11 - 13) vs +10 (IQR 9 - 13), p = 0.1). Baseline ALC did not differ by BCMA CAR-T product or number of previous lines of therapy. When compared to the NHL cohort, patients who received BCMA CAR-T had higher max-ALC (1.01 cel/uL (IQR 0.6 - 1.9) vs 0.4 cel/uL (IQR 0.2 - 0.7), p < 0.001) and this max-ALC occurred later (median day max-ALC +12 (IQR 10 - 13) vs day +10 (8 - 10), p < 0.01) Figure C. Higher max-ALC and absolute ALC increase were associated with depth of response and occurrence of CRS/ICANS. Pts who had a deeper response (VGPR/CR) had a higher median max-ALC (1.2 cel/uL (IQR 0.77 - 1.81) vs 0.5 cel/uL (IQR 0.2 - 0.7) p < 0.01) and absolute ALC increase (1.2 cel/uL (IQR 0.7 - 1.8) vs 0.6 cel/uL (IQR 0.2 - 0.7) vs, p = 0.01) compared to those with PR or worse Figure B. Similarly, pts who did not progress on follow-up had higher median max-ALC (0.58 cel/uL (IQR 0.4 - 0.8) vs 1.3 cel/uL (IQR 0.9 - 1.9), p < 0.001) and absolute ALC increase (1.3 cel/uL (0.9 - 1.8) vs 0.6 cel/uL (0.5 - 0.8), p < 0.01) compared to progressors. Pts who experienced CRS had a higher absolute ALC increase i(1.05 cel/uL (0.7 - 2.7) vs 0.27 cel/uL (0.2 - 0.5), p = 0.02), and pts who had ICANS had higher max ALC (3.2 cel/uL (0.8 - 6.4) vs 1.01 cel/uL (0.6 - 1.8), p = 0.2). These results were consistent across BCMA CAR-T product, and there were no differences in baseline ALC across CAR-T product, response, disease progression, or number of previous lines. Furthermore, higher max-ALC was associated with higher odds of having VGPR/CR (OR 32.3 (2.23 - 240), p = 0.04) in univariable logistic regression. Flow cytometry data on 3 pts showed expansion of CD8+ T Cells during peak ALC with increase of CD8:CD4 ratio. Multicolor flow cytometry using an antibody BCMA at time of peak ALC showed expansion of CD4+ and CD8+ CAR-T, and further immunophenotypic characterization (differentiation, maturation, exhaustion) is currently being performed. Conclusions Post-CAR-T lymphocytosis was a common event after BCMA CAR-T therapy for MM, which presented a higher max-ALC, and at a later day when compared to CD19 CAR-T for NHL. Furthermore, ALC dynamics differed by BCMA CAR-T product, with cilta-cel exhibiting later CRS with higher max-ALC peaking at a later day when compared to ide-cel. Furthermore, higher max-ALC and absolute ALC increase were associated with deeper response (VGPR/CR) and sustainable response on follow up. Our findings suggest that peripheral lymphocytosis after CAR-T is disease specific (NHL vs MM) and post CAR-T lymphocytosis in peripheral blood is a potential biomarker for clinical outcomes and toxicity.

Lisocabtagene Maraleucel in Relapsed/Refractory Large B-Cell Lymphoma: Real World Analysis from the Cell Therapy Consortium

Introduction Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed CAR T cell therapy approved for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the TRANSCEND (Abramson et al, Lancet 2020), TRANSFORM (Kamdar et al, Lancet 2022), and PILOT studies (Sehgal et al, Lancet Oncol 2022). Extending clinical trial results for liso-cel to the real-world setting, we performed a multicenter retrospective study to evaluate the safety and efficacy of liso-cel in standard of care practice. Methods Patients (pts) aged ≥18 years with LBCL who received commercial liso-cel infusion between February 2021 (time of FDA approval) and June 2023 at 7 academic US medical centers were identified from the Cell Therapy Consortium registry. Pt and treatment characteristics were summarized descriptively, and the Kaplan Meier method was used for survival outcomes. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria. Tumor response was assessed per Lugano criteria locally by the treating clinician. Results As of 6/10/2023, 101 pts underwent liso-cel infusion. Detailed baseline pt characteristics are shown in Table 1. Median age at apheresis was 71 years (range: 30-85) with 35% of pts ≥75 years, 60% were male, 16% had an ECOG PS of ≥2 at apheresis, and 11% had active secondary CNS involvement. By histology, 86% of pts had DLBCL, 7% HGBL, 5% TFL, and 2% PMBCL. Baseline comorbidities included diabetes (18%), stage IV chronic kidney disease (5%), cerebrovascular disease (5%), impaired cardiac ejection fraction (2%), pulmonary dysfunction (2%), impaired hepatic function (2%), and active infection (3%), with 68% having a Charlson Comorbidity Index score of ≥3. Due to comorbidities, 30% of pts would have been ineligible for the TRANSCEND clinical trial. The median number of prior therapies was 3 (range: 1-8) and 16% of pts underwent prior autologous stem cell transplant. Bridging therapy was used in 62% of pts including 41% receiving polatuzumab-based treatment, 24% chemoimmunotherapy, and 21% radiation therapy. Seven (7%) pts received liso-cel on an expanded access trial (NCT04400591) due to a non-conforming product. Median time from apheresis to CAR T-cell infusion was 39 days (IQR: 34-43) and 85% of CAR T-cell infusions occurred inpatient. Any Grade CRS occurred in 49% (3% were Grade ≥3) and any Grade ICANS occurred in 26% (10% were Grade ≥3). Median onset of CRS and ICANS was 4 and 6 days following liso-cel infusion, respectively. Tocilizumab was administered in 31% and 31% of pts received steroids for toxicity management. Nine deaths (9%) unrelated to lymphoma progression occurred at a median of 1.2 months (range: 0.3-4.3) with 2 due to infectious complications, 2 due to other malignancy, 1 due to grade 5 neurologic toxicity, 1 due to concurrent grade 5 neurologic toxicity and grade 5 CRS, 1 due to accidental death, and 2 due to unknown causes. The 6-month incidence of non-relapse mortality was 8% (95% CI, 3.4% - 15%). The overall response rate (ORR) to bridging therapy, as assessed prior to lymphodepletion, was 45% with 17% achieving a complete response (CR). Following liso-cel infusion, response assessment was performed at day 30 and/or day 90 according to treating center practice, or in those determined to have clinical progression. Of the 89 pts evaluable at day 30, the ORR was 81% with 63% achieving a CR. Among 76 pts evaluable at day 90, the ORR was 63% with 58% achieving a CR. With a median follow-up of 10.3 months (range 0.3-22.8), month 6 outcomes were 62.7% (95% CI, 52.8% - 74.3%) for progression-free survival, 71.6% (95% CI, 60.9% - 84.1%) for duration of response, and 77.1% (95% CI, 68.4% - 86.9%) for overall survival ( Figure 1). Conclusions These analyses confirm that efficacy and safety are similar or superior to those of patients enrolled in liso-cel prospective clinical trials for R/R LBCL. Notably, these outcomes were achieved in pts predominately of advanced age and with a significant comorbid burden, recognizing that one-third would have been ineligible for TRANSCEND. These results also likely reflect advancements in patient selection and toxicity management including the real world utilization of novel bridging therapy to temporize and debulk disease. Follow-up is ongoing and updated data will be presented at the meeting.

Teclistamab Induces Favorable Responses in Patients with Relapsed and Refractory Multiple Myeloma after Prior BCMA-Directed Therapy

Introduction: Teclistamab (TEC) received regulatory approval for the treatment of patients with Relapsed/Refractory Multiple Myeloma (RRMM) after ≥ 3 prior lines of therapy based on the results of the pivotal MajesTEC-1 trial in which such patients achieved an overall response rate (ORR) of 63%, ≥ complete response (CR) of 39%, and median progression free survival (PFS) of 11.3 months (Moreau et al. N Engl J Med 2022). Patients who had received a prior B-cell maturation antigen-targeted therapy (BCMA-TT) were excluded from MajesTEC-1 trial. Data on the efficacy of TEC in patients who have received and relapsed after prior BCMA targeted therapy is lacking. Several studies have shown reduced efficacy of both FDA approved BCMA targeted chimeric antigen receptor T cell therapies (CAR-T) for myeloma, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), when administered after BCMA targeted bi-specific antibodies. There is a paucity of data on the efficacy of TEC when administered in patients who progress after ide-cel or cilta-cel. We evaluated the real-world outcomes of patients treated with standard of care (SOC) TEC after having previously received a BCMA-TT. Methods We performed a retrospective chart review to find patients treated at our center that were > 30 days from first dose of commercial TEC, received at least one prior BCMA-targeted therapy, and were consented to an IRB approved registry protocol. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria, while responses were graded based on the International Myeloma Working Group (IMWG) response criteria. Results: A total of 22 patients who had received prior BCMA-TT and TEC were evaluable for response, safety, and survival analyses. Median age was 66 years (range 48-81), 59% were male, and 13% had an ECOG PS ≥2. Beside prior BCMA-TT, other exclusion to MajesTEC-1 would have been cytopenias (27%), performance status ≥2 (9%), creatinine clearance <40 mL/min (5%), and plasma cell leukemia (5%). Eleven pts (50%) had high risk cytogenetics (defined as del17, t(4;14), t(14;16)), and 13 pts (59%) had gain 1q. Patients were heavily pretreated with a median of 8 (5-13) prior lines of therapy, 45% had R-ISS III, 14% had extramedullary disease (EMD), 27% had a high marrow burden (≥60% PCs in the marrow) and 11 (50%) were penta-class refractory. Sixty-eight percent (n=15) had received prior Chimeric Antigen Receptor T-cell Therapy (CAR-T), 9% (n=2) prior Antibody Drug Conjugate (ADC), and 23% (n= 5) both CAR-T and ADC, all BCMA-TT. Median time from prior BCMA-TT to TEC was 12.3 (1.3-33.5) months. With a median follow up of 4.16 (1.07-7.27) months, the best overall and ≥ CR response rates were 63% and 36% (N=8), respectively. Of those who had achieved a ≥ CR, 3 were MRD negative by clonoSEQ® (10 −6). Thirteen (57%) pts received TEC as the next line of therapy from prior BCMA-TT. Thirteen of 14 pts tested for BCMA expression were positive by IHC, with 9 expressors responding to TEC; the non-expressor responded to TEC. Toxicity was comparable to that seen in MajesTEC-1. Cytokine release syndrome (CRS) of any grade occurred in 16 (73%) pts. All events occurred during step-up and cycle 1 doses. All events of CRS were grade 1 (n=13; 59%) and 2 (n=3; 14%). The median time to onset of CRS was 3 (1-12) days after the most recent dose, and the median duration was 3 (1-9) days. Tocilizumab was administered to 4 (18%) pts. Only 1 patient had ICANS, grade 3 and requiring steroids. Infections were seen in 12 (55%) pts, including viral (10), bacterial (1), and fungal (1). 6 (50%) infections were deemed severe and required hospitalization. Prior to TEC, 13 (59%) pts had hypogammaglobulinemia (IgG< 400). After TEC, 6 pts developed new hypogammaglobulinemia. 11 (50%) pts had treatment delays, mainly due to CRS and infections. Four pts died due to progression of disease. Conclusions: This single center study in patients with heavily pretreated and prior BCMA-TT demonstrated favorable ORR (63%) and CR (36%) rates, comparable to pts in the MajesTEC-1 trial, without prior BCMA-TT exposure. No new safety signals were identified. Results on progression free survival (PFS) and overall survival (OS) will be reported with continued follow up and will be presented in the meeting.

Predictors of Cytokine Release Syndrome and Neurotoxicity in Patients with Large B-Cell Lymphoma and Their Impact on Survival

Background: Autologous CAR-T therapy targeting CD19 is an effective treatment for relapsed or refractory large B-cell lymphoma (LBCL). However, morbidity and mortality related to CAR-T toxicity remain significant concerns. This study aims to evaluate the patterns, risk factors, and implications of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19-CAR-T therapy in LBCL. Methods: This retrospective analysis includes 1916 LBCL patients treated with CD19-CAR-T cell therapy (axicabtagene-ciloleucel [axi-cel] 75% and tisagenlecleucel 25%) between 2018 and 2020 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patient demographics, baseline characteristics, treatment-related variables, and clinical outcomes were collected. The incidence, severity and timing of onset of CRS and ICANS (according to median time to onset) were analyzed, factors associated with these outcomes and their impact on overall survival as time dependent covariates were done using Cox Regression multivariate analyses. Results: The median age of the patients was 64 years, with a majority having a Karnofsky performance status (KPS) below 90% (61%) and not receiving bridging therapy (67%). CRS was observed in 75.1% of patients, with 9% experiencing severe CRS (grades ≥ 3). Similarly, 43% of patients experienced ICANS, with 20% having severe ICANS (grade ≥ 3). The median time to toxicity was shorter for CRS (4 days) compared to ICANS (7 days). Nearly all the patients who developed ICANS also experienced CRS (98%; ), and the correlation between these two events and respective severities are shown in the Figure 1a. In the multivariate analyses, factors associated with development of CRS were gender (women, Odds ratio [OR] 1.39, 95% confidence interval [CI] 1.10- 1.76, p=0.006), high LDH at time of infusion (OR 1.56; 95% CI 1.22 - 2.00, p=0.002) and product (axi-cel OR 4.60, 95% CI 3.56 -5.81, p<0.001). Factors associated with the development of ICANS included age (> 65 years, OR 1.83; 1.50-2.24, p<0.001), KPS (<80%, OR 2.48; 1.88-3.27, p<0.001), disease status at infusion (treatment resistant disease, OR 1.98; 1.09-3.58, p=0.024; and untreated relapse OR 2.62, 1.35-5.10, p=0.004) and product (axi-cel, OR 5.85; 4.47-7.64, p<0.0001). Factors associated with severe and early onset CRS and ICANS are listed in the table below. The median follow-up of 14.2 months, the estimated 12-month overall survival, progression-free survival (PFS), and treatment-related mortality were 61.6% (95% CI: 59.4-63.9), 42.2% (39.9-44.5), and 4.3% (3.4-5.3), respectively. Overall CRS, early onset CRS and overall ICANS were not associated with higher mortality, however grade >3 CRS (HR 1.79; 1.41-2.28, p<0.001), grade >3 ICANS (hazard ratio [HR] 1.34; 95% CI 1.13-1.59, p=0.002) and early onset ICANS (<7 days, HR 1.23; 1.05-1.44, p=0.01) were associated with higher mortality. The impact of severe CRS on survival are shown in the landmark analysis at 30 days from infusion in the figure 1B. Conclusion: In the largest analysis of CD19-CAR-T cell therapy toxicities to date, we observed a high burden of CRS and ICANS among LBCL patients. The CAR T cell product type was consistently associated with higher incidence, shorter onset and higher severity of both toxicities. High LDH, older age and low performance score also influence the severity and onset of these outcomes. Additionally, patients who developed higher grades of CRS/ICANS and earlier onset ICANS had a higher mortality, stressing the need to develop novel strategies to mitigate the incidence and optimize management of these patients to improve their outcomes.

Real-World Incidence, Characteristics and Management of Cytokine Release Syndrome Induced By Chimeric Antigen Receptor T-Cell Therapy across Hematologic Malignancies

Background: Cytokine release syndrome (CRS) is a potentially life-threatening, supraphysiologic response following immunotherapy resulting in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. CRS occurs with varying frequency and severity, depending on the underlying disease and immunotherapy used, such as chimeric antigen receptor T-cell (CAR-T) therapy or off-the-shelf T-cell engaging bispecific antibodies. Limited research exists on the diagnosis and management of CRS in the real world. This study describes the real-world incidence, severity and clinical management of CRS induced by commercially available CAR-T therapies for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and multiple myeloma (MM). Methods: Real-world data (RWD) were obtained from the Flatiron Health, US, nationwide electronic health record (EHR)-derived, de-identified database of cancer patients within a network comprised primarily of community cancer practices. The Flatiron Health network also includes practices designated as academic sites by the National Cancer Institute; however, relative proportions of community/academic practices may vary depending on the study cohort. Data as of August 31, 2022, on CAR-T therapy, clinical characteristics and disease outcomes specific to CAR-T therapy, as well as CRS and its clinical management, were abstracted from unstructured documents in EHRs (in addition to routinely available structured data), in a cohort of patients receiving commercial CAR-T therapy. Specifically, data for CRS including treatments and resolution were abstracted based on explicit mention of and attribution to CRS in charts. Results: Table 1 summarizes data by indication. Incidence of CRS ranged from 56% (104/185) in DLBCL to 72% (66/92) in MCL. Excluding categories with small numbers of cases (<15), CRS incidence also varied by individual CAR-T therapy and underlying indication and ranged from 35% for idecabtagene vicleucel in MM to 73% for brexucabtagene autoleucel in MCL. Highest incidence of Grade ≥2 CRS was observed among MCL patients, whereas Grade ≥3 CRS was most commonly observed among FL patients. Time to onset of CRS ranged from 0 to 16 days, with median onset between 3-4 days among lymphoma patients and earlier median onset of 1 day for MM patients. Median time to CRS resolution ranged from 2 to 6 days across indications. While 81-95% of patients received CAR-T therapy at an academic center, 5-14% received CAR-T therapy at a community center. Tocilizumab and corticosteroids were the most commonly used treatments for CRS, including 37-48% use of tocilizumab for Grade 1 CRS (Table 2). Discussion: This study uniquely summarizes RWD on CRS following the use of commercially available CAR-T therapies across multiple hematologic malignancies, based on information from clinical notes abstracted retrospectively from EHRs. Consistent with the timing of approval of commercially available CAR-T therapies, the sample size for MM was limited compared with other malignancies. Safety events are typically under-reported in RWD sources, specifically for CRS when relying on information documented in patients' EHRs, compared with other published literature. In accordance with other RWD on CRS, grading criteria for CRS as well as vasopressor and oxygen use were not consistently reported in patients' EHRs. CAR-T treatments were predominantly administered in academic centers. Limited use in community practices was also observed; however, further information to accurately characterize the size and capabilities of community centers was not available in this database. Data also showed considerable use of tocilizumab to treat low-grade CRS, suggesting the need for additional evidence on its role to treat CRS beyond its current regulatory approval. Increased evidence generation, specifically from usual clinical practice, can contribute to increased awareness and knowledge about CRS diagnosis and management, and in turn realize the maximum potential of T-cell therapeutics.

Two-Year Follow-up Results of C-CAR066, a Novel Anti-CD20 Chimeric Antigen Receptor Cell Therapy (CAR-T) in Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL) Patients after Failure of CD19 CAR-T Therapy

Background: Disease recurrence or progression represents a significant challenge in r/r LBCL treated with CAR-T. In a large analysis of r/r LBCL pts who receive further therapy after CD19 CAR-T treatment failure, the overall response rate (ORR) is 39% (CR 20%; PR 19%) and the median post-treatment-OS and post-treatment-EFS are 8.5 months and 1.9 months respectively. C-CAR066 is a novel 2nd generation CAR-T therapy targeting CD20 antigen. We previously reported that C-CAR066 had shown a favorable safety profile and promising efficacy in pts with r/r LBCL following failure to CD19 CAR-T therapy. At a median follow-up of 4.2 months, the ORR was 100%, with 70.0% (7/10) achieving complete response (CR) (Liang et al. ASCO 2021. #2508). Here we present the updated results to include more pts (n=14) and a longer follow-up period. Methods: This first-in-human (FIH) study is an open-label, dose-finding, phase 1 investigator-initiated trial (IIT) to determine the safety and efficacy of C-CAR066 in r/r LBCL (including DLBCL, tFL and PMBCL) after previous CD19 CAR T-cell treatment failure. This study was conducted at two clinical sites in China. C-CAR066 was administered at doses of 2.0x10 6 CAR-T cells/kg and 3.0x10 6 CAR-T cells/kg after a 3-day conditioning chemotherapy. The primary objective was to assess the safety and tolerability of C-CAR066. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. The secondary objectives were to evaluate C-CAR066 efficacy and pharmacokinetics (PK). Response was assessed per Lugano 2014 criteria. The study follow-up period was 2 years. Results: Between Oct 16, 2019, and Aug 17, 2021, a total of 14 pts received C-CAR066. 11 pts (78.6%) were DLBCL, 3 pts (21.4%) were tFL. The median age was 54.5 years (range, 37-67) with 2 pts (14.3%) ≥65 years. 12 pts (85.7%) were in Ann Arbor Stage III/IV. 7 pts (50.0%) were double-expressor lymphoma. Median number of prior lines of therapy was 5 (range, 2-7). All pts had prior CAR-T therapy, which included CD19 CAR-T (12 pts), CD19/CD22 bispecific CAR-T (1 pts), and CD19/CD79b bispecific CAR-T (1 pts). 12 pts responded to the prior CAR-T therapy (2 CR and 10 PR), and the median duration of response (DOR) was 1.5 months. Median time from prior CAR-T to C-CAR066 infusion were 5.45 months (range, 3.4-14.2). 7 pts (50.0%) received bridging therapy. As of Jan 15, 2023, 12/14 pts (85.7%) experienced CRS, all were grade 1/2, except for 1 pt dosed at 3.0×10 6 CAR- T cells/kg experienced a grade ≥3 CRS. This pt recovered after receiving corticosteroids and tocilizumab. The median time to CRS onset was 5.5 days (range, 2-15), and the median time to resolution was 4.0 days (range, 1-15). No pts experienced ICANS. Grade ≥3 neutropenia, anemia, thrombocytopenia, and infection were reported in 92.9%, 50.0%, 21.4% and 14.3% of pts, respectively. No new safety signals were observed in this updated 2-year follow-up. Investigator assessed ORR was 92.9%, with 57.1% CR. Median time to first response and CR were 1.0 month (range, 0.9-2.8) and 2.5 month (range, 1.0-2.8), respectively. With the median follow-up of 19.5 months, median PFS and DOR were 9.4 months and 8.3 months, respectively. 5 pts remained in CR 12 months after infusion, and 4 of them remained in CR after 24 months. 6 deaths occurred due to progressive disease. Median post-treatment-OS had not been reached at 24 months. 13 of 14 pts had assessable PK and pharmacodynamic data (one pt dropped out before day 28). The median T max was 11 days (range, 10-23), the median C max was 398,996 copies/µg gDNA (range, 51,667-1,286,932), and the median AUC 0-28day of 4,437,474 copies/µg∙day (range, 431,534-17,842,217), the median T last was 59 days (21~571). We have observed that C-CAR066 can effectively expand and eliminate CD19+/CD20+ B cells in patients. The median time to B cell depletion was 5.5 days (range, 4-11). B cell recovery was observed in 6 (46.2%) pts from 53 to 366 days after the C-CAR066 infusion, 3 of them remained in CR by the data cutoff date. Conclusions: Longer term follow-up demonstrated that C-CAR066 can produce a deep and durable response with a favorable safety profile in pts with r/r LBCL who failed prior CD19 CAR-T therapy.

Dexamethasone is Associated with a Lower Incidence and Severity of Cytokine Release Syndrome Compared with Other Corticosteroid Regimens When Given as Premedication for Glofitamab Monotherapy in Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background: Glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format, induced frequent and durable complete responses (CRs) with a manageable safety profile in pivotal expansion cohorts of an ongoing Phase I/II study (NCT03075696) in patients (pts) with R/R LBCL (Dickinson et al. NEJM 2022, Falchi et al. ASCO 2023). Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation that can be triggered non-specifically by T-cell engaging therapies. As previously reported, corticosteroid (steroid) premedication was required to prevent or mitigate CRS in pts treated with glofitamab. Dexamethasone (Dex) was mandated in one expansion cohort to assess if this could reduce the rate and severity of CRS versus other steroids. Here, we report data from the dose-escalation and expansion cohorts in pts with R/R LBCL who received Dex only versus non-Dex premedication. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [DLBCL NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal LBCL [PMBCL], or LBCL arising from follicular lymphoma [trFL]) and ≥2 prior therapies received 1000mg obinutuzumab pretreatment (Gpt) 7 days prior to the first glofitamab dose. IV glofitamab was administered with step-up dosing during Cycle (C) 1 (Day 8, 2.5mg; Day 15, 10mg) followed by the target dose (30mg) on Day 1 of C2-12 (21-day cycles; 8.4 months). Steroid premedication (80mg IV methylprednisolone, or equivalent dose of prednisone [100mg] or prednisolone [100mg], or 20mg IV Dex) was given at least 60 minutes prior to Gpt and each glofitamab dose. Responses were assessed using Lugano criteria (Cheson et al. JCO 2014). CRS events were graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of May 1, 2023, 145 pts with R/R LBCL had received glofitamab, including 33 (22.8%) pts (DLBCL NOS, n=24 [72.7%]; HGBCL, n=2 [6.1%]; trFL, n=7 [21.2%]) who received Dex premedication before each glofitamab dose (Dex only cohort) and 112 (77.2%) pts (DLBCL NOS, n=81 [72.3%]; HGBCL, n=5 [4.5%]; PMBCL, n=6 [5.4%]; trFL, n=20 [17.9%]) who had not received Dex premedication before each glofitamab dose (non-Dex cohort). In the Dex only and non-Dex cohorts, median age was 73.0 years (range: 27-86) and 66.0 years (range: 21-90), and 26/33 (78.8%) pts and 83/112 (74.1%) pts had Ann Arbor stage III/IV disease, respectively. Median number of prior therapies was 3.0 for both cohorts. Ten (30.3%) and 37 (33.0%) pts had previously received chimeric antigen receptor T-cell therapy, and 6 (18.3%) and 22 (19.6%) pts had received autologous stem cell transplant in the Dex only and non-Dex cohorts, respectively. Median number of glofitamab cycles was 5.0 in both cohorts. CRS of any grade occurred in 48.5% of pts in the Dex only cohort and 73.2% of pts in the non-Dex cohort, and CRS leading to serious adverse events occurred in 5 (15.2%) and 27 (24.1%) pts, respectively. In both cohorts, CRS events were mostly low grade and primarily occurred during C1 (Table; Figure). Recurring Grade (Gr) ≥2 CRS was not observed in the Dex only cohort and 6 (5.4%) pts had recurring Gr ≥2 CRS in the non-Dex cohort. Median time to CRS onset and median time to resolution were similar in the two cohorts. Treatment discontinuation rate was lower in the Dex only cohort (n=21, 63.6%) versus the non-Dex cohort (n=80, 71.4%), mainly due to progressive disease (Dex only cohort, n=12 [36.4%]; non-Dex cohort, n=52 [46.4%]). In the DLBCL NOS and trFL population, the best overall response assessed by Independent Review Committee was similar between the Dex only (n=31) and non-Dex (n=101) cohorts, with CR reported in 14 (45.2%) and 44 (43.6%) pts, and 12 (38.7%) and 34 (33.7%) pts remaining in CR at data cutoff, respectively. The estimated event-free rate among complete responders at 12 months after the first CR was 83.1% (95% CI: 61.5-100.0) in the Dex only cohort and 77% (95% CI: 63.8-90.2) in the non-Dex cohort. Conclusions: The incidence, severity, and seriousness of CRS after glofitamab administration in pts with R/R LBCL were numerically lower with Dex premedication versus premedication with other steroid regimens. Response rates in the Dex only cohort were similar to those reported in the non-Dex cohort. We therefore propose Dex as the steroid of choice for premedication to prevent or mitigate CRS in pts with LBCL treated with glofitamab monotherapy, considering its half-life and potency.

Second Vs Third Line Treatment with Axicabtagene Ciloleucel for Large B Cell Lymphoma - a Real-Life National Multicenter Retrospective Cohort Study with Propensity Score Matching

Background: Superiority of Axicabtagene Ciloleucel (Axi-Cel) in relapsed/refractory (R/R) large B cell lymphomas (LBCL) compared with standard of care was shown in both the 3 rd and 2 nd line setting. However, optimal timing for incorporation of CAR-T is not well established. We aimed to compare efficacy, toxicity profile, and product kinetics of Axi-Cel as 2 nd vs 3 rd line of treatment. Methods: we performed a national real world retrospective study of consecutive patients treated with Axi-Cel as 2 nd line with propensity score-matched patients treated with 3 rd line treatment. Patients were matched for age (±2 years), Eastern Cooperative Oncology Group (ECOG) performance status, and disease status at lymphodepletion. Disease status and response were defined by the Lugano criteria, cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS) were defined by ASTCT Consensus (2019) and progression-free survival (PFS) was calculated from infusion to index event. Immunophenotyping from peripheral blood at day 7+ was used to analyze expansion of CAR-T cells. Results: Between 01/2019and 06/2023, 44 patients treated with Axi-Cel fulfilled the inclusion criteria, 22 in each cohort. Groups were well matched in the propensity score domains (mean difference 2, p=.65 for age, mean square .32, p=.57 for ECOG, and mean square .26, p=.61 for disease status at lymphodepletion). Median follow up was 2.2 (range, 1-28.8) months in 2 nd line group and 10.8 (range, 1-39) months in the 3 rd group. Median age was 68 (range, 39 - 84) and 66 (range, 32 - 80) years in the 2 nd and 3 rd line groups, respectively. There were no differences between gender (p=.76), LBCL subtypes (p=.16), % of patients receiving bridging therapy (p=.55), % of patients with elevated LDH levels prior to lymphodepletion (p=.98), and n days from collection to treatment (p=.29) between the 2 groups. There was a lower % of patients with primary refractory disease in the 2 nd, compared to 3 rd line therapy group (63% vs. 36%, respectively, p=.09) and a higher % of patients with transformed disease (42% vs. 14%, respectively, p=.04). Both overall and grade 3-4 incidences of CRS were similar between the 2 nd line and the 3 rd line groups (86% vs. 95%, p=.16 and 18% in both groups, p=1, respectively). Median days to CRS onset was also similar (1, range 0 - 5 and 2, range 0 - 7, p=.1, respectively). Both overall and grade 3-4 incidences of ICANS) were similar between the 2 nd line and the 3 rd line groups (41% vs. 64%, p=.48 and 14% vs. 18%, p=.73, respectively. Median days to ICANS onset was lower in the 2 nd line compared to the 3 rd line group (4, range 0 - 8 and 6, range 0 - 7, p=.06, respectively). There were no differences between the groups in the median tocilizumab doses (p=.21), % of patients receiving steroids (p=.12), cumulative steroids dose (p=.17), % of patients receiving growth factors (p=1), and duration of admission (p=.51). Median day +7 CAR-T blood levels were higher in the 2 nd line compared to the 3 rd line group (126 (range,1-791) vs. 18.1 (range, 0-988) cells/microL, p=.05, respectively). 1-month overall response rate (ORR) was 86% (CR=77%) in the 2nd line group vs 64% (CR=45%), in the 3rd line group, p=.081 Figure 1a. Three-months progression-free survival was 88% (95%, CI 64%-100%) vs. 59% (45%-73%), respectively, Figure 1b. Cox regression identified 2 nd line treatment associated with better progression-free survival (HR=.15, p=.007) and progressive disease at lymphodepletion associated with worse progression-free (HR=8.5, p=.007), while age, gender, and ECOG performance status did not impact progression. Conclusions: This matched comparison showed favorable ORR and PFS rates when Axi-Cel is utilized as a 2nd line treatment vs 3rd line. Toxicity profile is similar. Higher CAR-T expansion in the 2nd line might provide insight regarding product quality and exhaustion phenotype when manufactured earlier in the LBCL treatment course. A longer follow-up is needed to test whether these findings translate to durable remission and cure.

Phase 2 Study of Anakinra to Prevent CRS and Neurotoxicity after Treatment with Lisocabtagene Maraleucel: Planned Interim Analysis

BACKGROUND CD19 chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment landscape for patients (pts) with relapsed/refractory B-cell malignancies, but they remain limited by significant toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). While a more favorable toxicity profile had been reported with lisocabtagene maraleucel (liso-cel), based on our real-world experience CRS and ICANS are still observed in 70% and 30% of pts, respectively (Portuguese et al., ASH abstract #172978). Data from our group (Gazeau, TCT, 2023) and others (Strati, Blood, 2023; Park, Nat Med, 2023) suggested the recombinant interleukin-1 receptor antagonist anakinra may successfully prevent and treat CRS and ICANS. Thus, we conducted a phase 2 investigator-initiated clinical trial of anakinra to prevent CRS and ICANS after liso-cel (NCT04359784). We report here our planned interim analysis (n = 15). METHODS Adults ≥18 years of age with Karnofsky performance status ≥60% and B-cell non-Hodgkin lymphoma receiving liso-cel per the FDA label were eligible for this study. Anakinra was administered at 200 mg/day SC from day 0 through day +13 after liso-cel infusion, with the first dose administered approximately 2-4 hours prior to liso-cel infusion. CRS and ICANS severity were assessed per 2019 ASTCT criteria. The primary endpoint was the absence of any grade CRS assessed using the Bayesian optimal phase 2 design.The primary endpoint was not met if ≥6 of the first 15 pts developed any grade CRS. RESULTS Nineteen pts were screened for the study and 15 pts were enrolled. All 15 pts received liso-cel and all doses of SC anakinra. All pts were evaluable for toxicity assessment; 12 pts were evaluable for disease response assessment at day +28 (n = 3, no measurable disease prior to lymphodepletion [LD]). Pt and disease characteristics are shown in Table 1. Eleven pts (73%) had diffuse large B-cell lymphoma, 3 (20%) had active CNS involvement, and 5 (33%) had bulky disease (≥5 cm). Median pre-LD serum ferritin and C-reactive protein (CRP) were 153 ng/mL (IQR, 129-231) and 6.8 (IQR, 1.5-17.2), respectively. All 15 pts received anakinra as planned without dose adjustment or interruption. There were no injection-site reactions or AEs attributed to anakinra. Two pts developed infections during anakinra treatment and were both due to mild Clostridium difficile colitis requiring oral antibiotics. Eight pts (53%) developed any grade CRS, including 1 (7%) case of grade 3 CRS. Four pts (27%) developed any grade ICANS, including 3 (20%) with grade 3 (Figure 1). Median CRS onset and duration were 2 and 2.5 days, respectively, and median ICANS onset and duration were 6 and 9 days, respectively. Three pts (20%) required tocilizumab (range, 0-1 doses), 4 (50%) required dexamethasone (median total dose, 5 mg; range, 0-200 mg), and 1 (12%) required high-dose methylprednisolone. The best overall response rate (ORR) by Lugano criteria was 67% (complete response, n = 5 [42%]). Study pts were retrospectively compared to pts who received liso-cel per standard of care off trial without prophylactic anakinra at our center (n = 42). Despite higher median pre-LD CRP and IL-6 levels, the incidence of CRS was lower in anakinra-treated compared to anakinra-untreated pts (53% vs. 69%, respectively) with comparable median duration of CRS (2.5 vs. 3 days, respectively). The incidence and duration of ICANS were similar (27% vs. 28%; median 9 vs. 8 days, respectively), as was the incidence and duration of hospitalization (67% vs. 74%, median 9.5 vs. 10 days, respectively). Based on Locally Estimated Scatterplot Smoothing (LOESS) estimates, time from liso-cel infusion to CRP normalization was faster in patients receiving anakinra (9 days) compared to those receiving liso-cel alone (14 days). CONCLUSION Low-dose SC anakinra prophylaxis during liso-cel treatment was very well tolerated with preserved anti-tumor efficacy. While our primary endpoint was not reached at our planned interim analysis, we observed lower CRS rates and faster resolution of CRS in comparison to a real-world cohort of pts receiving liso-cel without prophylactic anakinra. To further enhance the preventative effects of anakinra, we plan to change the administration route from SC to intravenous, and to allow anakinra dose uptitration for the last 10 participants in the study.

C-CAR039, a Novel Anti-CD20/CD19 Bi-Specific CAR T-Cell Therapy Shows Deep and Durable Clinical Benefits in Patients with Relapsed or Refractory (r/r) B-Cell Non-Hodgkin Lymphoma (B-NHL) in Long Term Follow up

Background: We previously reported that C-CAR039, an autologous anti-CD20/CD19 bispecific chimeric antigen receptor (CAR) T-cell therapy, demonstrated a favorable safety profile and promising efficacy in patients (pts) with r/r B-NHL. Of the initial 28 pts treated with C-CAR039 with a median of 3 prior lines of therapy. Only 1 patient experienced grade ≥3 cytokine release syndrome (CRS), and no patient reported grade ≥2 immune effector cell-associated neurotoxicity syndrome (ICANS). The overall response rate (ORR) was at 92.6%, with 85.2% complete response (CR). After a median follow-up of 7 months, 74.1% of pts remained in CR, and the Kaplan-Meier (KM) estimation of progression-free survival (PFS) at 6 months was 83.2%. (Liang et al. ASCO 2021. #2507). Here we present the updated results to include more pts (48 pts) and a longer duration of follow-up (median 23.9 months). Methods: This is an open-label, dose escalation and expansion investigator-initiated trial (IIT) of C-CAR039. This trial was conducted at 4 sites to determine the safety and efficacy of C-CAR039 in pts with r/r B-NHL. Pts with r/r diffuse large B cell lymphoma (DLBCL), primary mediastinal large B cell lymphoma (PMBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL) were enrolled and received a single C-CAR039 infusion at a dose of 1.0-5.0x10 6 CAR-T cells/kg after a 3-day conditioning chemotherapy. The primary objective was to assess the safety and tolerability. CRS and ICANS were graded according to ASTCT 2019 criteria. The secondary objectives were to evaluate C-CAR039 efficacy and pharmacokinetics. Response was assessed per Lugano 2014 criteria. Results: Between Nov 5, 2019, and Jan 11, 2022, 48 pts received C-CAR039 manufactured using Miltenyi Biotec CliniMACS Prodigy® System. Of the 48 pts, 44 pts had large B-Cell Lymphoma (LBCL) (DLBCL, n = 37; PMBCL, n = 3; tFL, n=4), 3 pts had FL and 1 patient had MCL. The median age was 55 (range, 25-71) years, and 11 (22.9%) pts were ≥ 65 years. Thirty-six (75%) pts were in Ann Arbor Stage III/IV with 3 median prior lines of therapy (range, 1-7). All pts received anti-CD20 antibody and alkylating agents. Eight (16.7%) pts had prior ASCT, 32 (66.7%) pts were refractory to their last treatment, and 22 (45.8%) pts never achieved CR to their prior therapies. Prior to C-CAR039 infusion, 12 (25%) pts received bridging therapy. As of Jan 15, 2023, 45 pts (93.8%) experienced CRS, of which 44 (91.7%) pts reported grade 1 or 2, only 1 (2.1%) patient experienced grade 3 CRS. Median time to CRS onset was 3 days (range, 1-12), with median duration of 5 days (range, 2-78). Three pts had ICANS at a dose of 5.0x10 6 CAR-T cells/kg, of which 2 were grade 1 and 1 was grade 2. The median time to onset of ICANS was 6 days (range, 5-29), with a median duration of 12 days (range, 3-53). All CRS and ICANS were resolved. Grade ≥3 neutropenia, anemia, thrombocytopenia and infection were reported in 83.3%, 14.6%, 27.1% and 10.4% of pts, respectively. Second primary malignancy after C-CAR039 infusion were observed in 3 pts; 2 acute myeloid leukemia (AML) occurred at 2 and 10 months, and 1 Epstein-Barr virus-positive cytotoxic T-cell lymphoma was at 8 months, the tumor biopsy was tested with qPCR and CAR transgene was negative and none were related to C-CAR039. Twelve deaths occurred, 9 due to disease progression, 2 due to AE of AML, and 1 due to unknown cause. Of the 48 pts, 47 pts were evaluable for efficacy (1 patient with DLBCL had no measurable disease at baseline). The ORR and CR rate among evaluable pts were 91.5% and 85.1% respectively. Median time to first response and CR was 1.0 month (range, 0.9-1.9) and 1.1 month (range, 0.9-8.9), respectively. Of the 43 LBCL pts, the ORR was 90.7%, with 86.0% CR. Median DOR, PFS and OS were not reached. The KM estimation of PFS and OS rate at 24 months was 66.0% (95%CI 53.2%-81.9%) and 77.9% (95% CI, 66.6%-91.1%) respectively. C-CAR039 showed cellular kinetic profile consistent with commercial CAR-T therapies. In 48 evaluable pts, the median T max was 11.5 day (range, 7-31), the median C max was 139,416 copies/g gDNA (range, 708-962,445), and the median AUC 0-28day was 1,513,442 copies/ug∙day (range, 3,818-11,594,912.5). Conclusions: At a longer median follow-up of 23.9 months, C-CAR039 demonstrated a favorable safety profile with deep and durable response in pts with r/r B-NHL, especially in LBCL pts.

Sequential Administration of Selinexor and CAR-T Therapy in Relapsed/ Refractory Multiple Myeloma

Introduction: Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) that binds to exportin 1 and exhibits anti-tumor activity by impairing nuclear export of proteins including oncogenes and tumor suppressor proteins and is approved for use in patients with relapsed refractory multiple myeloma(RRMM). Anti-BCMA directed CAR-T therapy for patients with relapsed/refractory multiple myeloma (RRMM) is a promising new class of therapy, which has shown a high level of efficacy. Sequential administration of selinexor followed by CD19 CAR-T has shown enhanced efficacy in human phase II trials and animal models of human non-hodgkin lymphoma(Stadel et al., 2022). In this retrospective single institutional study, we report outcomes of patients with RRMM who were treated with Selinexor based regimen prior to apheresis for CAR-T therapy. Methods: We conducted a retrospective study on an IRB-approved protocol for all patients who were treated with Selinexor based regimen immediately prior to apheresis as a prior line of therapy at Hackensack University Medical Center between June 2015 and July 2022. Demographic characteristics, molecular studies, treatment and response information were recorded and included in the study. Response to CAR-T was assessed by the treating physician per International Myeloma Working Group (IMWG) criteria. Survival analysis was performed using the Kaplan-Meier method including PFS and Overall survival (OS). Results: Between September 9, 2021, and April 3, 2023, 7 patients received CAR-T who were treated with Selinexor immediately prior to apheresis. The median age was 65.7 years (range: 55.1-77.1 years). Patients had a median of 6 (range: 4-10) lines of therapy (LOT) prior to CAR-T. 5 out of the 7 patients had double hit myeloma (all 5 with 17p and one other high risk). Four patients were treated with selinexor, carfilzomib and dexamethasone; two patients were treated with selinexor, daratumumab and dexamethasone and one patient was treated with selinexor, pomalidomide and dexamethasone. Four patients received Idecabtagene vicleucel (ide-cel) and three patients received ciltacabtagene autoleucel (cilta-cel). ORR was 100% with all 7 pts achieving very good partial response or better (>=VGPR). 2 patients had bone marrow biopsies that confirmed MRD -ve sCR in both patients. None of the patients have progressed so far, although median follow-up is short at 5.6 months. All patients had hematologic toxicities, 4/7 with grade III anemia (57.1%), 3/7 (42.8%) with grade or higher thrombocytopenia and 4/7 (57.1%) had grade 3 neutropenia. 2 of 7 patients had prolonged cytopenia for >6 months because of pre-existing underlying diagnoses of CCUS and MDS. 5 out of 7 patients had grade 1 Cytokine release syndrome (CRS). The other two patients did not experience CRS. Time of CRS onset was variable 2-10 days. No ICANS or infectious complications were observed. Conclusions: These results suggest that sequential use of Selinexor and CART in high risk RRMM may be an effective treatment strategy to provide deep and durable responses. The findings of our study are promising although it is limited by a small sample size and short follow-up. Further investigation in a larger study and longer follow up would be important to confirm our findings.

Itacitinib for the Prevention of Immune Effector Cell Therapy-Associated Cytokine Release Syndrome: Results from the Phase 2 Incb 39110-211 Placebo-Controlled Randomized Cohort

Introduction: Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common adverse effects following IEC therapy. Janus kinase (JAK) pathways are important for the signaling of several cytokines involved in CRS pathogenesis. Itacitinib is a potent, selective JAK1 inhibitor with broad anti-inflammatory activity. We describe preliminary results from the randomized, placebo-controlled portion of the study evaluating itacitinib 200 mg twice daily (bid) for the prevention of CRS. Methods: This randomized, placebo-controlled portion of the phase 2 Study INCB 39110-211 (NCT04071366) enrolled patients ≥18 years old planning to receive axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma (rrLBCL) and follicular lymphoma (rrFL). Participants received oral itacitinib 200 mg bid beginning 3 days before axicabtagene ciloleucel infusion and continued itacitinib through Day 26. Protocol did not allow tocilizumab for treatment of grade 1 CRS unless CRS did not improve after 72 hours of supportive treatment. Patients who received tocilizumab for grade 1 CRS were not censored. Primary endpoint was incidence of CRS grade ≥2 by Day 14 using American Society for Transplantation and Cellular Therapy grading system. Secondary endpoints included incidence of ICANS by Day 28, duration of CRS and ICANS, and itacitinib safety. Results: 47 patients with rrLBCL were randomized to itacitinib (n=23; median age, 66 [range: 29-80] years; male, 65%) or placebo arms (n=24; median age, 64 [range: 31-79] years; male, 71%). Median (range) number of prior regimens was 2 (1-6) and 1.5 (1-4), respectively. No rrFL patients enrolled in the study. Two (8%) patients in the itacitinib arm received platelet transfusions after Day 28; no transfusions were received in the placebo group. A total of 15 (65.2%) patients in the itacitinib arm developed CRS (grade 1, n=11 [47.8%]) compared with 20 (87.0%) patients in placebo arm (grade 1, n=7 [30.4%]; Figure). No hypotension or hypoxia was observed in patients with grade 1 CRS who received tocilizumab. Grade 2 CRS was experienced by 4 (17.4%) and 13 (56.5%) patients, respectively ( P=0.003; 95% CI: 0.14-0.65). There was no grade 3 or 4 CRS in either arm. Median (range) time to any-grade CRS onset was 2 (0-8) days and 3 (0-9) days, respectively; median (range) duration of grade 2 CRS was 2 (1-8) and 2 (1-5) days. Overall, tocilizumab was used for CRS treatment in 4 (17.4%) patients in the itacitinib arm and in 15 (65.2%) patients in the placebo arm, including 2 and 6 patients, respectively, who received tocilizumab for grade 1 CRS. ICANS occurred in 3 (13%; 95% CI: 3-34) patients in the itacitinib arm and 8 (34.8%; 95% CI: 16-57) patients in the placebo arm (Figure). ICANS grade ≥2 was reported in 2 (8.6%; 95% CI: 1-28) and 5 (21.7%; 95% CI: 8-44) patients, respectively. No grade 4 ICANS occurred in either arm. Median (range) time to any-grade ICANS onset was 5 (4-9) days and 6.5 (2-11) days, respectively; median (range) duration was 2 (2-11) and 3.5 (2-13) days. Persistent grade 3 or 4 thrombocytopenia at Day 28 in the itacitinib arm was reported in 8 (38.1%; [grade 4: n=4]) patients; in the placebo arm in 4 (18.2%; [grade 4: n=0]) patients. Persistent grade 3 or 4 neutropenia at Day 28 in the itacitinib arm was reported in 7 (33.3%; [grade 4: n=3]) patients; in the placebo arm in 3 (13.6%; [grade 4: n=0]) patients. Infections grade ≥3 occurred before Day 28 in 2 (8.7%) patients in the itacitinib arm (urinary tract infection [UTI], n=2) and in 3 (12.5%) patients in the placebo arm (sepsis, n=2; UTI, n=1). There were no fatal adverse events. With a minimum follow-up of 28 days, lymphoma best overall response to axicabtagene ciloleucel showed no difference between the 2 arms. Conclusions: Results from the randomized, placebo-controlled portion of Study INCB 39110-211 have shown prophylaxis treatment with itacitinib 200 mg bid to be well tolerated and resulted in a lower rate and grade of CRS and ICANS after lymphoma treatment with axicabtagene ciloleucel. Incidence of grade 3/4 neutropenia and thrombocytopenia not resolved at Day 28 was higher with itacitinib vs placebo. Rates of severe infections were comparable in both arms. Longer follow-up data on lymphoma response will be available upon presentation. Biomarker analyses comparing the effect of itacitinib on CAR-T cells expansion and function are ongoing.

Clinical Outcomes with Prophylactic Corticosteroid Use for Axicabtagene Ciloleucel (axi-cel) in Patients with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): A Multicenter Analysis

Introduction: In Cohorts 1+2 of the ZUMA-1 Phase 1/2 study of axi-cel in R/R LBCL, 11% and 31% of patients (pts) experienced Grade ≥3 cytokine release syndrome (CRS) or neurologic evenets), respectively. To minimize the toxicities seen with axi-cel, a safety management cohort, Cohort 6 (N=40), was added to evaluate whether prophylactic (ppx) corticosteroids (CS) could decrease grade ≥ 3 CRS or ICANS. The 2-year update of ZUMA-1 Cohort 6 showed no grade ≥3 CRS and 15% grade ≥3 ICANS without any difference in objective response rate (ORR) or complete response rate (CR) when compared to cohorts 1+2 (Oluwole Blood 2022). The FDA had previously approved an update to the prescribing information for axi-cel to include use of ppx CS across all approved indications in January 2022. However, ppx CS is not a mandatory standard treatment and we sought to establish the clinical outcomes in the real-world practice. Methods: To assess the clinical outcomes of pts receiving ppx CS, we conducted a multicenter retrospective analysis of pts with R/R LBCL who were treated with axi-cel since the FDA approval of ppx CS in January 2022. Baseline characteristics, toxicities, and efficacy were compared between the no ppx and ppx CS groups. CRS and ICANS were graded based on ASTCT 2019 guidelines. Event-free survival (EFS) was defined as time from axi-cel infusion to progression, re-treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death due to any cause. Results: A total of 66 pts at 5 centers received axi-cel between Jan 31, 2022, and June 20, 2023. Thirty-five (52%) pts received ppx CS, with a median age of 63 years (26-85 years). By histology, 75% (n=50) of the pts had DLBCL, 13.6% (n=9) had high grade B-cell lymphoma (HGBL), 9.1% (n=6) had transformed follicular lymphoma (TFL) and 1.5% (n=1) primary mediastinal LBCL (PMBCL). 59% of the pts (n=37) had IPI >2 and 66% (n=43) had stage III/IV disease. The baseline characteristics at the time of apheresis are shown in Table 1 and were comparable between the 2 groups, except for more HGBL, fewer prior lines of therapy and longer median time from apheresis to axi-cel infusion in the ppx CS group. Among the entire cohort, only 37% (n=25) met ZUMA-1 eligibility criteria at the time of lymphodepletion, and 67% (n=44) needed bridging therapy. Any grade CRS occurred in 88% (n=58) of the pts, with grade ≥2 CRS in 38% (n=25). Any grade ICANS occurred in 55% (n=37) of the pts, with grade ≥2 ICANS in 41% (n=27). Any grade ICANS was significantly lower in the ppx CS group than the no ppx group (45.7% vs 65.5%). The rates of any grade CRS, grade ≥2 CRS, grade ≥2 ICANS, the median time to CRS onset, ICANS onset, CRS duration, and ICANS duration were comparable between the 2 groups. Tocilizumab and steroids use was similar between two groups with a trend towards less ICU admission in patients in the ppx CS group. Overall, 14 (21%) pts developed infectious complications within 30 days of axi-cel infusion. The day 30 ORR was 84% and was comparable between the 2 groups (77% in the ppx group vs 93% in the no ppx group). The CR was 45.7% in ppx CS group compared to 65.5% in no ppx group. At a median follow up of 219 days (27-1178), 37 (56.1%) pts had progressed and 25 (37.9%) pts had died. The number of days to progress was significantly lower in the ppx CS arm. The median EFS and OS were not significant between the 2 groups. Conclusions: This multicenter retrospective study showed that the efficacy of treatment with axi-cel in R/R LBCL did not decrease with the use of ppx CS. No significant differences in efficacy or CAR-T-associated toxicities were noted in the 2 groups, potentially due to selective use with patients at presumed higher risk of severe CRS and ICANS. A larger dataset and longer follow-up is needed for risk-stratified analysis and the study is ongoing.

Factors Associated with Prolonged CRS and Neurotoxicity after Treatment with Axicabtagene Ciloleucel

BACKGROUND While chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of high-risk B-cell malignancies, it causes significant toxicities, specifically, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Most of the research to date has focused on the identification of factors associated with the peak severity of CRS and ICANS, which does not capture the duration of these toxicities. Yet protracted toxicities are observed in a subset of patients, and risk factors predictive of CRS/ICANS duration have not been reported. To address this limitation, we have previously reported the use of a novel clinical endpoint: time to CRS and ICANS (CRS/ICANS) resolution, which captures the longitudinal impact of these toxicities while allowing for censoring in the event of early deaths (Gazeau et al, TCT, 2023). Here, we applied this framework to provide the first characterization of factors associated with time to CRS/ICANS resolution in patients receiving the FDA-approved CD19 CAR T-cell product axicabtagene ciloleucel (axi-cel). METHODS Eighty-four patients (pts) treated at the Fred Hutch Bezos Family Immunotherapy Clinic with axi-cel per the FDA label outside of a clinical trial between 1/2018 and 4/2022 were included. CRS and ICANS were graded (G) using ASTCT criteria. Cause-specific Cox regression models were used to estimate associations between 60+ pre/post-infusion patient, disease-related, laboratory variables (e.g., platelet count, creatinine, PT, PTT, CRP, IL-6, fibrinogen, ferritin), and time to CRS/ICANS resolution. Endothelial Activation and Stress Index (EASIX) score was calculated at pre-/post-infusion timepoints. Time to CRS/ICANS resolution was defined as the time from axi-cel infusion left-truncated at the time of CRS/ICANS onset until CRS/ICANS symptom resolution (first day of grade 0 for at least three consecutive days), whichever toxicity happened last, censoring for death from any cause. RESULTS Baseline characteristics and toxicity outcomes are shown in Table1. The median age at infusion was 62 (range, 25-79). Histology was large B cell lymphoma in 79 pts (94%), and follicular lymphoma in 5 pts (6%). We observed any-grade CRS in 72 pts (86%) and G≥3 CRS in 7 pts (8%). Fifty-two pts (62%) developed any-grade ICANS, and 16 pts (19%) G≥3 ICANS (G1: 15 [18%], G2: 21 [25%], G3: 15 [18%], G4: 1 [1.2%]). The median time to CRS/ICANS resolution was 10 days (95%CI: 9,11). Two pts (2%) died prior to CRS/ICANS resolution. Using univariate cause-specific Cox regression, the following pre-infusion factors were associated with longer time to CRS/ICANS resolution: lower platelet count at day 0 (HR=0.41, 95%CI: 0.17-0.98, p=0.044), higher PTT at day 0 (HR=0.05, 95%CI: 0.00-0.86, p=0.039), higher preLD creatinine (HR=0.06, 95%CI: 0.01-0.50, p=0.009) and higher EASIX score preLD (HR=0.57, 95%CI:0.35-0.94, p=0.028) and at day 0 (HR=0.52, 95%CI: 0.29-0.96, p=0.035). Cumulative incidence curves of time to CRS/ICANS resolution for select predictors are shown in Figure 1B. At the time of CRS onset, a higher ferritin level (HR=0.51, 95%CI: 0.27-0.94, p=0.031) and peak CRS severity (HR = 0.73, 95%CI: 0.55-0.97, p=0.029) were associated with longer time to CRS/ICANS resolution. Higher ferritin levels over time (time dependent HR [tdHR]=0.38, 95%CI: 0.19-0.72, p=0.004), higher PTT (tdHR=0.028, 95%CI: 0.01-0.76, p=0.028), and peak ICANS severity (HR=0.58, 95%CI: 0.046, 0.72, p<0.001) were associated with longer time to CRS/ICANS resolution. In a multivariable Cox model after LASSO variable selection including day 0 PTT, ferritin, EASIX score, and peak CRS severity, lower day 0 platelet count remained independently associated with longer time to CRS/ICANS resolution (HR=6.96 per log10 increase, 95%CI:1.09-44.5, p=0.04; model discrimination: C-index=0.65). CONCLUSION This is to our knowledge the first study aimed at the identification of factors associated specifically with the duration of CRS and ICANS after CD19 CAR T-cell therapy. We successfully identified pre- and post-infusion factors associated with prolonged CRS/ICANS duration after CD19 CAR T-cell therapy with axi-cel. Our findings suggest that point-of-care assessments can identify patients at risk of prolonged toxicities and could guide the use of prophylactic corticosteroids or early interventions (e.g., anakinra).

Observation of liver indexes in patients with relapsed/refractory multiple myeloma treated with CAR-T-cells based on BCMA

Objective: To observe the characteristics of the evolution of liver indexes in patients with relapsed/refractory multiple myeloma (RRMM) treated with CAR-T-cells based on BCMA. Methods: Retrospective analysis was performed of patients with RRMM who received an infusion of anti-BCMA CAR-T-cells and anti-BCMA combined with anti-CD19 CAR-T-cells at our center between June 1, 2019, and February 28, 2023. Clinical data were collected to observe the characteristics of changes in liver indexes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL) in patients, and its relationship with cytokine-release syndrome (CRS) . Results: Ninety-two patients were included in the analysis, including 41 patients (44.6%) in the group receiving a single infusion of anti-BCMA CAR-T-cells, and 51 patients (55.4%) in the group receiving an infusion of anti-BCMA combined with anti-CD19 CAR-T-cells. After infusing CAR-T-cells, 31 patients (33.7%) experienced changes in liver indexes at or above grade 2, which included 20 patients (21.7%) with changes in one index, five patients (5.4%) with changes in two indexes, and six patients (6.5%) with changes in three or more indexes. The median time of peak values of ALT and AST were d17 and d14, respectively, and the median duration of exceeding grade 2 was 5.0 and 3.5 days, respectively. The median time of peak values of TBIL and DBIL was on d19 and d21, respectively, and the median duration of exceeding grade 2 was 4.0 days, respectively. The median time of onset of CRS was d8, and the peak time of fever was d9. The ALT, AST, and TBIL of patients with CRS were higher than those of patients without CRS (P=0.011, 0.002, and 0.015, respectively). CRS is an independent factor that affects ALT and TBIL levels (OR=19.668, 95% CI 18.959-20.173, P=0.001). The evolution of liver indexes can be reversed through anti-CRS and liver-protection treatments, and no patient died of liver injury. Conclusions: In BCMA-based CAR-T-cell therapy for RRMM, CRS is an important factor causing the evolution of liver indexes. The evolution of liver indexes after CAR-T-cell infusion is transient and reversible after treatment.

Host metabolome predicts the severity and onset of acute toxicities induced by CAR T-cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a highly effective treatment option for patients with relapsed/refractory large B-cell lymphoma. However, widespread use is deterred by the development of clinically significant acute inflammatory toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), that induce significant morbidity and require close monitoring. Identification of host biochemical signatures that predict the severity and time-to-onset of CRS and ICANS may assist patient stratification to enable timely mitigation strategies. Here, we report pretreatment host metabolites that are associated with CRS and ICANS induced by axicabtagene ciloleucel or tisagenlecleucel therapy. Both untargeted metabolomics analysis and validation using targeted assays revealed a significant association between the abundance of specific pretreatment biochemical entities and an increased risk and/or onset of clinically significant CRS (q< .1) and ICANS (q< .25). Higher pretreatment levels of plasma glucose and lower levels of cholesterol and glutamate were associated with a faster onset of CRS. In contrast, low baseline levels of the amino acids proline and glycine and the secondary bile acid isoursodeoxycholate were significantly correlated with clinically significant CRS. Lower concentration of the amino acid hydroxyproline was associated with higher grade and faster onset of ICANS, whereas low glutamine was negatively correlated with faster development of ICANS. Overall, our data indicate that the pretreatment host metabolome has biomarker potential in determining the risk of clinically significant CRS and ICANS, and may be useful in risk stratification of patients before anti-CD19 CAR T-cell therapy.