Incidence Of Neurologic Events Research Articles

Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial. ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor-blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel. Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on d -5 through -3 followed by a single infusion of axi-cel (2 × 106 cells/kg) on d 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 h after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines). Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-mo minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 mo (95% CI, 5.4-not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid. Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell-related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL.

Health Care Resource Utilization (HCRU) and Cost of Management of Cytokine Release Syndrome (CRS) and Neurological Events (NEs) in Patients with R/R CLL/SLL Receiving Lisocabtagene Maraleucel (liso-cel) Treatment in the TRANSCEND CLL 004 Study

Background:Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells, which is currently being evaluated for treatment of patients with R/R CLL/SLL in the TRANSCEND CLL 004 study (NCT03331198). Initial study results suggested that a single infusion induced CRs or remission in patients with R/R CLL/SLL and had a manageable safety profile, with low to moderate incidence of severe CRS and NEs (Siddiqi T, et al. Lancet 2023). While the clinical consequences of CRS/NEs associated with CAR T cell therapies are well understood, limited data are available on the cost of management of these AEs. This analysis evaluated HCRU and estimated costs of managing CRS/NEs by grade in patients with R/R CLL/SLL who received liso-cel treatment in TRANSCEND CLL 004. Methods: Case report forms were analyzed from the trial database, capturing patient-level HCRU related to the management of CRS/NEs. Only patients that received liso-cel at a dose level of 100 × 10 6 CAR + T cells (dose level 2 [DL2]) and subsequently experienced treatment-emergent CRS and/or NEs were included in this study. Treatment-emergent AEs were defined as those initiated within a 90-day period of liso-cel administration. Costs for management of CRS/NEs were estimated using microcosting methodology. Relevant HCRU observed from the day of AE onset through resolution that was associated with the management of CRS/NEs per protocol management guidelines was identified; unit costs sourced from public databases were applied to each HCRU. Included HCRU categories were: facility (standard inpatient admission, ICU stay), diagnostics (laboratory, imaging), medications (tocilizumab, corticosteroids, vasopressors), and procedures (dialysis, intubation). Cost analyses were conducted from the United States (US) health care system perspective and adjusted to 2023 US dollars. Unit costs were obtained from the US Centers for Medicare & Medicaid Services Hospital Outpatient Prospective Payment System, laboratory and physician fee schedules, IBM ® Micromedex ® RED BOOK ®, and literature. Descriptive statistical analyses stratified by AE severity grade and type of AE experienced were performed. Results: Ninety-four of 108 (87%) patients who received liso-cel at DL2 experienced CRS and/or NEs; 68 (72%) were grade ≤ 2 and 26 (28%) were grade ≥ 3. Overall, 44 (47%) patients had CRS only, 1 (1%) had NEs only, and 49 (52%) experienced both CRS and NEs. The study sample had a mean (standard deviation) age of 64.5 y (7.9) and were predominantly male (69%), White (84%), and non-Hispanic or Latino (90%). HCRU and total length of stay (LOS; the sum of inpatient and ICU stay days) are shown in the Table. All patients had an inpatient stay. ICU admissions only occurred among patients who experienced both CRS and NEs (10/49 [20%]) and were more common among patients with grade ≥ 3 (29%) compared with grade ≤ 2 (12%) AEs. Among patients who had an ICU admission, the median duration of an ICU stay was 5 days. Median total LOS increased with increasing AE severity for patients who had CRS only (grade 1, 5 days; grade 2, 9 days; grade 3, 15 days) and for patients who experienced both CRS and NEs (grade ≤ 2, 12 days; grade ≥ 3, 15 days). Overall, 68% and 62% of patients received tocilizumab and corticosteroids, respectively. Patients with grade ≥ 3 CRS and/or NEs had higher rates of utilization of medications, diagnostics, and procedures than those with grade ≤ 2 (Table). Additionally, patients who experienced both CRS and NEs had higher rates of utilization across all HCRU categories compared with those who experienced CRS or NEs only (Table). Estimated median management costs for CRS or NEs ranged from $14,638 (CRS only grade 1) to $46,802 (experienced both CRS and NEs with CRS or NEs grade ≥ 3) (Figure). Facility-related costs were the largest contributor to median total costs. Conclusions: While most patients treated with liso-cel at DL2 in TRANSCEND CLL 004 experienced CRS and/or NEs, they were primarily of low severity. HCRU and associated costs for management of CRS and/or NEs after liso-cel infusion increased with AE severity.Although everyone in this study required hospitalization, ICU admissions were rare and only observed among patients who experienced both CRS and NEs. Overall, costs of managing CRS and/or NEs were modest.

Matching-Adjusted Indirect Comparison (MAIC) of Efficacy and Safety of Lisocabtagene Maraleucel (liso-cel) and Mosunetuzumab for the Treatment (Tx) of Third Line or Later (3L+) Relapsed or Refractory (R/R) Follicular Lymphoma (FL)

Background:The tx landscape of R/R FL is evolving with the availability of anti-CD19 chimeric antigen receptor (CAR) T cell therapies and CD20xCD3 bispecific T-cell-engaging monoclonal antibodies (mAb). Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell therapy which recently reported a positive benefit-risk tx profile for the 3L+ tx of patients with R/R FL (Morschhauser F, et al. ICML 2023; LBA4). Mosunetuzumab, a CD20xCD3 bispecific T-cell-engaging mAb, is approved for the tx of R/R FL after 2 or more lines of therapy (LOT). In the absence of head-to-head data, we conducted an unanchored MAIC to compare the efficacy and safety of liso-cel and mosunetuzumab for the 3L+ tx of patients with R/R FL. Methods: Unanchored MAICs were used to estimate population-adjusted relative tx effects between individual patient-level data from TRANSCEND FL (NCT04245839; data as of January 27, 2023; median follow-up of 19.3 months) and aggregate data from GO29781 (NCT02500407; data as of August 27, 2021; median follow-up of 18.3 months; N = 90). For TRANSCEND FL, the leukapheresed (intention to treat [ITT]) set (N = 114) was used for primary comparisons of efficacy endpoints: Progression-free survival (PFS), objective response rate, and complete response rate (all per independent review committee assessment). Overall survival was not analyzed due to the low rate of events. The treated efficacy set (n = 101) was used for a sensitivity analysis of efficacy comparisons. The treated set (n = 107) was used for comparisons of safety endpoints: cytokine release syndrome (CRS), neurological events (NEs), serious infections, and use of corticosteroids or tocilizumab for CRS. Baseline characteristics and outcome measures in TRANSCEND FL were redefined to align with those reported in GO29781. Data from TRANSCEND FL were weighted using a method-of-moments propensity score model to match the marginal distribution (ie, mean, variance) of clinical factors among patients from GO29781. A panel of expert clinicians selected and ranked tx effect modifiers separately for efficacy and safety endpoints. For efficacy, factors adjusted for included number of prior systemic LOTs, progression of disease ≤ 24 months from initiation of immunochemotherapy, bulky disease at screening, FL International Prognostic Index risk factor, refractory to last therapy, double refractory to an anti-CD20 antibody and alkylating agent, ECOG PS at screening, sex, and prior autologous HSCT. For safety, factors adjusted for included age, bulky disease at screening, refractory to last therapy, number of prior systemic LOTs, ECOG PS at screening, Ann Arbor stage, and sex. Hazard ratios (HR) were used to compare PFS, and odds ratios (OR) were used for response rates and safety outcomes. Results: After adjusting for all available factors, when compared with mosunetuzumab, liso-cel was associated with higher objective response rate (OR, 3.78 [95% CI, 1.48‒9.67]), and complete response rate (OR, 6.46 [2.85‒14.65]), and improved PFS (HR, 0.28 [0.16‒0.49]) based on an effective sample size (ESS) of 71.4 (Figure). Results were consistent across all scenario analyses, including unadjusted comparisons and sensitivity analyses using the treated efficacy set for TRANSCEND FL. Although liso-cel was associated with higher incidence of any-grade CRS (OR, 1.86 [1.01‒3.43]) and any-grade NEs (OR, 2.16 [0.72‒6.44]), it demonstrated a lower incidence of grade ≥ 3 CRS (OR, 0.45 [0.04‒5.13]) and grade 3-4 serious infections (OR, 0.35 [0.12‒1.03]) based on an ESS of 81.9 compared with mosunetuzumab. Furthermore, liso-cel was associated with reduced use of corticosteroids for CRS management (OR, 0.14 [0.03‒0.65]), while the use of tocilizumab was higher in patients treated with liso-cel (OR, 2.27 [0.86‒5.99]). Conclusions: In this MAIC, liso-cel was associated with improved efficacy compared with mosunetuzumab. Liso-cel had a lower incidence of grade ≥ 3 CRS, grade 3-4 serious infections, and steroid use for management of CRS; however, liso-cel exhibited higher incidence of any-grade CRS, any-grade NEs, and tocilizumab use for CRS management. Safety comparisons were confounded by preventative use of corticosteroids in all patients in GO29781 and definition differences, most notably for NEs. These findings highlight a potential positive benefit-risk profile of liso-cel over mosunetuzumab as a 3L+ tx option for R/R FL.

Postoperative atrial fibrillation in mitral valve surgery is not benign

ObjectivePostoperative atrial fibrillation (POAF) is common after cardiac surgery and is often considered to be benign despite recent data suggesting worse outcomes. There are no guidelines for the amount of POAF that triggers anticoagulation or for postoperative surveillance. We examined the rate of POAF, incidence of neurologic events, development of permanent atrial fibrillation, and mortality in patients undergoing isolated mitral valve surgery at a Mitral Foundation reference center. MethodsThis is a retrospective cohort study of 922 adult patients from 2011 to 2022 with no preoperative history of arrhythmias. Multivariable logistic regression was used to identify independent risk factors for the primary outcomes. Kaplan-Meier analysis and Cox proportional-hazards model were used to characterize long-term survival. ResultsThe incidence of POAF was 39%. Median follow-up was 4.9 months (interquartile range, 1.1-42.6 months). Diabetes (odds ratio [OR], 2.2; 95% CI, 1.2-4.1; P = .01) and increasing age (OR, 1.1; 95% CI, 1.0-1.1; P < .001) were risk factors for POAF, whereas New York Heart Association functional class was not. POAF was a risk factor for the development of permanent atrial fibrillation (OR, 3.2; 95% CI 1.9-5.4; P < .001), which was associated with increased risk of neurologic events (OR, 3.8; 95% CI, 1.5-9.7; P = .004). Ultimately, patients with POAF had worse unadjusted (P < .001) and adjusted long-term mortality (hazard ratio, 1.8; 95% CI, 1.1-3.1; P = .03). ConclusionsPOAF is associated with an increased rate of neurologic events, portends development of permanent atrial fibrillation, and is associated with worse long-term survival. POAF is not benign and carries a long-term mortality implication.

ZUMA‐24: A PHASE 2, OPEN‐LABEL STUDY OF AXICABTAGENE CILOLEUCEL IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA GIVEN OUTPATIENT WITH CORTICOSTEROIDS

ZUMA‐24: A PHASE 2, OPEN‐LABEL STUDY OF AXICABTAGENE CILOLEUCEL IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA GIVEN OUTPATIENT WITH CORTICOSTEROIDS

Incidence of Acute Neurological Events in Neonates and Infants Undergoing Cardiac Surgery Using a High-Hematocrit/ High-Flow Bypass Strategy.

Background: The incidence of new acute neurological injury occurring in neonates and infants during cardiac surgery utilizing cardiopulmonary bypass is reportedly 3% to 5%. In 2013, we adopted a high flow rate, and high hematocrit bypass strategy, and sought to assess the incidence of early neurological injuries associated with this strategy. Methods: Neonates and infants undergoing cardiopulmonary bypass between January 2013 and December 2019 (n = 714) comprise the study. Adverse neurological events (ANEs) were defined as any abnormality of pupils, delayed awakening, seizures, focal neurological deficits, concerns prompting neurological consultation, or any abnormality on neurological imaging in the postoperative period. Our bypass strategy included a high flow rate (150-200 mL/kg/min), without reduction of flow rates during cooling and maintaining a target hematocrit on bypass > 32% with a terminal hematocrit of > 42%. Results: Median weight at the time of the procedure was 4.6 kg (IQR 3.6-6.1 kg) with the smallest patient weighing 1.36 kg. There were 46 premature patients (6.4%). There were 149 patients (20.9%) patients who underwent deep hypothermic circulatory arrest with a median time of 26 min (IQR 21-41 min). Hospital mortality was 3.5% (24/714, 95% CI: 2.28-5.13). The incidence of neurological events as defined above was 0.84% (6/714, 95% CI: 0.31-1.82). Neurological imaging identified ischemic injury in 4 patients and intraventricular hemorrhage in 2. Conclusions: High flow/high hematocrit bypass strategy was associated with a low incidence of ANE in this vulnerable population.

Transcatheter Patent Foramen Ovale Closure in Patients With Transient Ischemic Attack

Limited data exist on patients with a transient ischemic attack (TIA) who underwent patent foramen ovale (PFO) closure. The objectives of this study were to determine the clinical and procedural characteristics and long-term outcomes of patients with TIA who underwent transcatheter PFO closure. This was a multicenter study including 1,012 consecutive patients who underwent PFO closure after a cerebrovascular event. Patients were divided into 2 groups according to their index event leading to PFO closure: TIA (n=183 [18%]), and stroke (n=829 [82%]). The median follow-up was 3 (2 to 8) years (complete in 98% of patients). There were no significant differences between patients with TIA and stroke, except for a lower Risk of Paradoxical Embolism score in the TIA group (6.1 vs 6.9 in the stroke group, p <0.001). PFO closure was successful in all patients with a low rate of complications (<1%) in both groups. There were no differences in the incidence of neurologic events during long-term follow-up. There was 1 stroke event in the TIA group and 6 in the stroke group (0.08 vs 0.17 per 100 patients-years, p=0.584). There were 2 TIA events in the TIA group and 10 in the stroke group (0.17 vs 0.28 per 100 patients-years, p=0.557). In conclusion, our study showed that patients with TIA who underwent PFO closure have similar clinical characteristics as patients with stroke including a high Risk of Paradoxical Embolism score. Furthermore, these results suggest that PFO closure procedural results and long-term clinical outcomes are similar to their stroke counterparts, with a very low incidence of recurrent neurologic events. Further prospective randomized clinical trials are needed on this population.

P1464: DECREASING HPK1 EXPRESSION IN CD19 CAR-T CELLS: A NOVEL STRATEGY TO OVERCOME CHALLENGES OF CELL THERAPY FOR ADULT (R/R) B-ALL

Background: Since the FDA approved the first CD19 directed chimeric antigen receptor (CAR) T-cell therapy (Kymriah) for pediatric and young adult patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL), cytokine release syndrome (CRS) has still been a life-threatening toxicity that limits the full therapeutic potential in adults [1,2]. So far, Tecartus was the first and only approved CAR-T-cell therapy for adult (r/r) B-ALL, which was based on results from ZUMA-3 study. CRS occurred in 92% patients, and neurologic toxicities occurred in 87% patients in ZUMA-3 study[3], suggesting that therapeutic developments are needed to ensure more safe and potent options for adult B-ALL. Aims: Our preclinical data demonstrated that CAR-T cells with decreased HPK1 expression had significantly enhanced antitumor effects and did not induce higher grade CRS [4]. Thus, the first-in-human clinical study is ongoing, to test CD19 CAR-T cells with decreased HPK1 expression (XYF19 CAR-T cells) for adult (r/r) B-ALL (NCT04037566). Methods: Dose-escalation study was initiated to explore the safety and efficacy of XYF19 CAR-T cells in adult (r/r) B-ALL. 11 eligible adult (r/r) B-ALL patients with a median age of 37 years (range 19 - 61 years) were enrolled. The cell dosage of XYF19 was significantly lower than Tecartus and Kymriah, participants were infused with XYF19 CAR-T cells: 3 at low dose (2.0×105/kg), 5 at medium dose (5.0×105/kg), and 3 at high dose (1.0×106/kg). All patients received a conditioning regimen of IV fludarabine (30mg/m2/d) for 4 days and cyclophosphamide (500mg/m2/d) for 2 days. Results: 30 days after infusion with XYF19 CAR-T cells, 8 of the 11 (72.7%) patients had achieved complete remission (CR) or CR with incomplete count recovery (CRi). Considering the low dosage of XYF19 and that the CR/CRi rate is 71% with Tecartus [2] and 69% with Kymriah [3], the clinical response of XYF19 is similar or even the highest in these three studies. Strikingly, in this clinical trial, no patient developed neurotoxicity and none has yet experienced dose-limiting toxicity. No grade 3 or higher CRS occurred in XYF19 treated patients, while Grade 3 or higher CRS was observed in 26% of patients with Tecartus [2], and 72% of patients with Kymriah[3]. No neurologic events occurred in the current study, while the incidence of neurological events was 51% with Tecartus [2] and 43% with Kymriah[3]. Thus, XYF19 is a strong potential novel treatment for CD19 CAR-T cell therapy in adult B-ALL. Summary/Conclusion: Treatment with XYF19 CAR-T cells promises a novel treatment that can alleviate some of the stern challenges of CD19 CAR-T cell therapy for adult patients with r/r B-ALL. In the current study, this treatment showed robust activity against adult (r/r) B-ALL without >Grade 2 toxicity. This efficacy and safety will be demonstrated in further trials with larger sample sizes.

Decreasing HPK1 expression in CD19 CAR-T cells: A novel strategy to overcome challenges of cell therapy for adult (r/r) B-ALL.

7041 Background: Since the FDA approved the first CD19 CAR T cell therapy (Kymriah) for pediatric and young adult patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL), cytokine release syndrome (CRS) has still been a life-threatening toxicity that limits the full therapeutic potential in adults [1,2]. So far, Tecartus was the first and only approved CAR-T cell therapy for adult r/r B ALL, which was based on results from ZUMA-3 study. CRS occurred in 92% patients, and neurologic toxicities occurred in 87% patients in ZUMA-3 study[3], suggesting that therapeutic developments are needed to ensure more safe options for adult B-ALL. Our preclinical data demonstrated that CAR-T cells with decreased HPK1 expression had enhanced antitumor effects and did not induce higher grade CRS [4]. Thus, the first-in-human clinical study is ongoing to test CD19 CAR-T cells with decreased HPK1 expression (XYF19 CAR-T cells) for adult (r/r) B-ALL (NCT04037566). Methods: Dose-escalation study was initiated to explore the safety and efficacy of XYF19 CAR-T cells in adult r/r B-ALL. 11 eligible adult r/r B-ALL patients were enrolled. The cell dosage of XYF19 was significantly lower than Tecartus and Kymriah, participants were infused with XYF19 CAR-T cells: 3 at low dose (2.0×105/kg), 5 at medium dose (5.0×105/kg), and 3 at high dose (1.0×106/kg). All patients received a conditioning regimen of IV fludarabine (30mg/m2/d) for 4 days and cyclophosphamide (500mg/m2/d) for 2 days. Results: 30 days after infusion with XYF19 CAR-T cells, 8 of the 11 (72.7%) patients had achieved complete remission (CR) or CR with incomplete count recovery (CRi). Considering the low dosage of XYF19 and that the CR/CRi rate is 71% with Tecartus [2] and 69% with Kymriah [3], the clinical response of XYF19 is similar or even the highest in these three studies. Strikingly, in this clinical trial, no patient has yet experienced dose-limiting toxicity. No grade 3 or higher CRS occurred in XYF19 treated patients, while Grade 3 or higher CRS was observed in 26% of patients with Tecartus [2], and 72% of patients with Kymriah[3]. No neurologic events occurred in the current study, while the incidence of neurological events was 51% with Tecartus [2] and 43% with Kymriah[3]. Thus, XYF19 is a strong potential novel treatment for CD19 CAR-T cell therapy in adult B-ALL. Conclusions: Treatment with XYF19 CAR-T cells promises a novel treatment that can alleviate some of the stern challenges of CD19 CAR-T cell therapy for adult patients with r/r B-ALL. In the current study, this treatment showed robust activity against adult (r/r) B-ALL without &gt; Grade 2 toxicity. This efficacy and safety will be demonstrated in further trials with larger sample sizes.

Preoperative Serum Alkaline Phosphatase and Neurological Outcome of Cerebrovascular Surgery.

This study evaluated the relationship between the preoperative alkaline phosphatase (ALP) level and major postoperative neurological complications in patients undergoing cerebral bypass surgery. This was a retrospective analysis of a prospective database of all patients undergoing cerebral bypass surgery after a diagnosis of cerebrovascular stenosis or occlusion between May 2003 and August 2017. The patients were divided into tertiles based on serum alkaline phosphatase (ALP) levels (low: <63, intermediate: 63~79, and high: ALP > 79 IU/mL). The incidence of neurological events according to ALP level was analyzed. The study analyzed 211 cases. The incidence of acute infarction was highest in the third serum ALP tertile (5.7% vs. 2.9% vs. 16.9% in the first, second, and third tertile, respectively, p = 0.007). Logistic regression analysis showed that the third tertile of serum ALP was an independent predictor of acute cerebral infarction (odds ratio 3.346, 95% confidence interval 1.026–10.984, p = 0.045). On Kaplan–Meier time-to-event curves, the incidence of acute infarction increased significantly with ALP (log rank = 0.048). Preoperative serum ALP level can be used as a biomarker to predict acute cerebral infarction in patients undergoing cerebral bypass surgery for vascular stenosis or occlusion.

Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): One-Year Follow-up of ZUMA-1 Cohort 6 (C6)

Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): One-Year Follow-up of ZUMA-1 Cohort 6 (C6)

Prediction of Early Onset Cytokine Release Syndrome and Neurologic Events after Axicabtagene Ciloleucel in Large B-Cell Lymphoma Based on Machine Learning Algorithms

Prediction of Early Onset Cytokine Release Syndrome and Neurologic Events after Axicabtagene Ciloleucel in Large B-Cell Lymphoma Based on Machine Learning Algorithms

Metronidazole-induced neurotoxicity.

Metronidazole, usually prescribed for anaerobic and protozoal infections, can uncommonly cause adverse effects involving the central nervous system. The exact mechanism is unclear. In 1 case–control study, the incidence of neurologic events was 0.25%, although this is likely an underestimate.[1][1

Anakinra (AKR) prophylaxis (ppx) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) receiving orvacabtagene autoleucel (orva-cel).

2537 Background: Orva-cel is a B-cell maturation antigen–targeted chimeric antigen receptor (CAR) T cell therapy being evaluated in the phase 1/2 EVOLVE study (NCT03430011) in pts with RRMM who had at least 3 prior lines of therapy (Tx). We previously reported safety and efficacy in the phase 1 study and established the recommended dose (RD) of orva-cel as 600 × 106 CAR+ T cells (Mailankody et al, ASCO 2020). Cytokine release syndrome (CRS), a dominant toxicity of CAR T cell therapy, is mediated in part by IL-1. We explore the role of ppx with AKR, an IL-1 signaling inhibitor, on reducing the incidence of grade (G) ≥2 CRS after orva-cel treatment at the RD. Methods: Fourteen pts were enrolled sequentially for AKR ppx and treated with orva-cel at the RD. The non-AKR ppx control group comprised the remainder of the phase 1 pts receiving orva-cel at the RD (n = 19). The median follow-up (range) was 3.0 mo (1.8–6.2) for the AKR ppx group and 8.8 mo (5.3–12.2) for the non-AKR ppx group. AKR was administered as 100 mg SC the night before orva-cel infusion, 3 h before the infusion (Day 1), and q24 h on Days 2–5. Dosing was increased to q12 h if CRS developed. CRS was graded by Lee (2014) criteria. Tocilizumab (T) and steroids (S) were used per protocol-specified treatment management guidelines. Results: Disease characteristics and outcomes are shown in the table. In AKR ppx and non-AKR ppx groups, median number of prior regimens was 6 and 5, and bridging Tx was used in 57% and 68% of pts, respectively. The total frequency of CRS was similar in the 2 groups, but with less G 2 in the AKR ppx pts; relative risk (95% CI) = 0.54 (0.21, 1.38). No G ≥3 CRS was seen in either group. The incidence of neurological events (NE), G ≥3 infection, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) was similar. T and S use was numerically lower with AKR ppx. Orva-cel expansion kinetics were similar in the 2 groups. All pts had a 2-month efficacy assessment, with ORR in 100% of AKR ppx and 95% of non–AKR ppx pts. Conclusions: In this nonrandomized evaluation of AKR ppx with orva-cel treatment, the incidence of G ≥2 CRS was lower in pts receiving AKR ppx. The use of AKR ppx produced no adverse effect on the incidence of NE, infection, or MAS/HLH, nor on orva-cel expansion or disease response. These results warrant further study of AKR ppx in CAR T cell therapy. Clinical trial information: NCT03430011. [Table: see text]

Ascending aortic aneurysm: propensity score matching analysis of hemiarch and non-hemiarch replacement

Aim. To compare the shortand medium-term outcomes of hemiarch and nonhemiarch replacement for ascending aortic aneurysm (AAA).Material and methods. The study included 151 patients with non-syndromic AAA who underwent an elective replacement. Patients were divided into two groups: group 1 (non-hemiarch, n=40) — standard ascending aortic replacement; group 2 (hemiarch, n=111) — ascending aortic replacement with the hemiarch anastomosis in conditions of moderate hypothermia and circulatory arrest with unilateral antegrade cerebral perfusion. To eliminate systematic differences between the compared groups, the propensity score matching (PSM) method was used.Results. Before PSM, there were no significant intergroup differences in the incidence of neurological complications, myocardial infarction, prolonged ventilation, or acute kidney injury. Bleeding-related reoperation rates and hospital mortality significantly differed between groups. After pseudo-randomization between the non-hemiarch and hemiarch groups, there were no significant differences in the incidence of neurological events, myocardial infarction, prolonged ventilation, reoperations for bleeding, acute renal injury, and hospital mortality. Median-term survival and freedom from aortic reoperations also did not show significant intergroup differences.Conclusion. Hemiarch replacement for AAA does not lead to an increase in the incidence of postoperative complications, as well as the risk of shortand mediumterm mortality compared with non-hemiarch.

Metronidazole-associated Neurologic Events: A Nested Case-control Study.

Case reports have described instances of peripheral and central nervous system toxicity during treatment with metronidazole; however, no large-scale studies have examined this association. We conducted a population-based nested case-control study of adults aged 66 years or older living in Ontario, Canada, between 1 April 2003 and 31 March 2017. Cases were individuals who attended hospital for any of cerebellar dysfunction, encephalopathy, or peripheral neuropathy within 100 days of a prescription for either metronidazole or clindamycin. We matched each case patient with up to 10 event-free control subjects who also received metronidazole or clindamycin. We used conditional logistic regression to test the association between metronidazole exposure and neurologic events, with clindamycin as the reference exposure. We identified 1212 cases with recent use of either metronidazole or clindamycin and 12 098 controls. Neurologic adverse events were associated with an increased odds of metronidazole exposure compared to clindamycin (odds ratio [OR], 1.72 [95% confidence interval {CI}, 1.53-1.94]), which persisted after accounting for patient demographics, comorbidities, and other medication exposures (adjusted odds ratio [aOR], 1.43 [95% CI, 1.26-1.63]). We found a consistent association limited to either central (aOR, 1.46 [95% CI, 1.27-1.68]) or peripheral (aOR, 1.34 [95% CI, 1.02-1.76]) nervous system events. Among metronidazole recipients, the overall incidence of neurologic events at 100 days was approximately 0.25%. Metronidazole is associated with an increased risk of adverse peripheral and central nervous system events relative to clindamycin. Clinicians and patients should be aware of these rare but potentially serious adverse events.

Racial Disparities among Patients Undergoing Left Ventricular Assist Device: A Single Center Experience

The impact of race on outcomes of left ventricular assist device (LVAD) recipients remains a topic of debate as prior studies have demonstrated inconsistent results. We thought to investigate clinical outcomes of Hispanics LVAD recipients compared to Caucasians and African Americans at our institution. We retrospectively identified LVAD recipients between 2009 and 2018. Patients were stratified according to race. Demographics and clinical acuity data were collected. The primary endpoint was survival. Secondary outcomes included the incidence of thrombosis, neurological events (NE), infection (INX), and right heart failure (RHF). The Kaplan-Meier method was used to compare survival between the two groups. The Cox proportional hazards regression model was used to conduct multivariable analysis. A total of 147 patients were included in the analysis (62 Hispanics, 39 Caucasians, 46 African Americans). The prevalence of hypertension was highest among Hispanics (69%) compared to Caucasians (41%) and African Americans (54%), p = 0.018. Similarly, more Hispanics suffered from diabetes (55%, 31%, 30%, p = 0.015). Unadjusted 1-year survival was not significantly different among the groups (p = 0.222 by log-rank test). Among the clinical acuity factors analyzed, total bilirubin was a predictor of mortality (HR 1.24 95% CI 1.05-1.47, p = 0.010). The incidence of thrombosis, NE, INX, and RHF were not significantly different among the three groups. Race does not appear to impact clinical outcomes of advanced heart failure patients undergoing LVAD implantation. Total bilirubin at the time of LVAD implantation is a strong predictor of mortality.

Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B Cell Lymphoma (R/R LBCL)

Background Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment (Tx) of patients (pts) with R/R LBCL with ≥ 2 prior systemic therapies. In Cohorts 1+2 (C1+2) of the ZUMA-1 study, Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 11% and 32% of pts, respectively (Locke FL et al, Lancet Oncol 2019). A nonrandomized safety expansion cohort (Cohort 4 [C4]) evaluated the impact of earlier steroid use on CRS and NE rates. Here we present the primary analysis of ZUMA-1 C4 with a greater number of pts and longer follow-up (F/U). Methods Eligible pts were leukapheresed, could receive optional bridging chemotherapy (not allowed in C1+2), and received conditioning chemotherapy before axi-cel infusion at a targeted 2 × 106 anti-CD19 CAR T cells/kg. C4 pts received early steroid intervention at Grade 1 NE and at Grade 1 CRS after 3 days of supportive care. Primary endpoints were incidence and severity of CRS and NEs. ORR and CAR T cell levels were compared across quartiles of tumor burden (TB). Results As of May 6, 2019, 41 pts had received axi-cel, with a median F/U of 8.7 mo. Pts who received bridging therapy prior to axi-cel (68%) all had evidence of disease after bridging, documented by a new baseline PET/CT scan. The median age was 61 y (range, 19 – 77 y; 32% ≥ 65 y). The majority of pts (63%) had DLBCL; 49% had an ECOG 1; 70% had disease stage III/IV; 68% were refractory to ≥ 2nd-line therapy; 63% had ≥ 3 prior lines of therapy; and 20% had relapsed after ASCT. C4 pts had a lower median TB by sum of product diameters (SPD; C4: 2100 mm2; C1+2: 3723 mm2) and lower pre-Tx serum LDH level than C1+2 pts. A greater proportion of C4 pts received steroids and tocilizumab vs C1+2 (73% and 76% vs 27% and 43%). Fewer C4 pts experienced Grade ≥ 3 CRS (2%) and NE (17%) than C1+2 pts. The ORR in C4 was 73% with a CR rate of 51%. Response was ongoing in C4 54% of pts with ≥ 6 mo F/U vs the 44% ongoing response rate at the primary analysis of C1+2 (also ≥ 6 mo F/U). Although most pts in C4 had lower SPDs than those in C1+2, responses were comparable when evaluated by TB. Median DOR was 8.9 mo, consistent with that observed for C1+2 (8.1 mo; Locke, AACR 2017; Figure). Median PFS was 11.7 mo; median OS was not reached. Peak CAR T cell levels were 42 cells/µL blood in C1+2 vs 59 cells/µL in C4. C1+2 had a median CAR AUC of 462 cells/µL × days vs 512 cells/µL in C4. CAR T cell expansion was comparable between cohorts when adjusted by TB. Levels of key NE-associated biomarkers including ferritin (pre- and post-Tx) and IL-2 (post-Tx) appeared lower in C4 than in C1+2. Conclusions Earlier steroid use may reduce the rates of CAR T cell Tx-related CRS and NEs without affecting efficacy. Conclusions are limited by the nonrandomized study design and differences in population sizes and baseline characteristics between cohorts. Optimizing AE management is important to improve the benefit–risk profile of CAR T cell therapy.

Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B Cell Lymphoma

Earlier Steroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B Cell Lymphoma

Pivotal Safety and Efficacy Results from Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B Cell Lymphomas

Pivotal Safety and Efficacy Results from Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B Cell Lymphomas