Days Of Infusion Research Articles

Outcomes of Patients Treated at First Transplant Center in Dubai, UAE

Introduction: Autologous stem cell transplant (ASCT) is a well-known treatment modality for decades with curative potential in the field of hematological malignancies such as lymphoma (Relapsed Hodgkin's Lymphoma) and multiple myeloma (MM), but access in the Middle East, specifically in the metropolitan city of Dubai, United Arab Emirates (UAE) has been limited. This is despite the fact that UAE is a high-income country according to the Gross national income (GNI) and has a population of approximately 9.5 million. In 2021, we developed the first and only ASCT unit in Dubai, United Arab Emirates (UAE). This was a milestone achievement to offer ASCT to residents. This service was available since approval by Dubai Health Authority (DHA) in September 2021 and capacity for 2 ASCT at a time. The unit comprises 2 positive pressure isolation rooms, with in-house apheresis, stem cell storage facilities. This is the first report of the safety and efficacy outcomes of patients (pts) who were transplanted to date at our center. Despite the modest volume, this data will serve as a resource for policymakers, healthcare professionals and is important for the ASCT community as we advance care of ASCT recipients in regions with previously limited access. Methods: This is a single-center retrospective study performed at American Hospital Dubai, UAE. We identified and included pts who received ASCT for lymphoma and MM between September 2021-June 2023. Per institutional protocols, mobilization was done with granulocyte colony-stimulating factor (GCSF). The stem cells were collected via Optia®spectra apharesis system. MM pts collected for 2 ASCT while those with relapsed HL collected for 1 ASCT. Conditioning chemotherapy administration was outpatient for melphalan (for MM) and inpatient for rHL with BEAM. Monitoring was per institutional standards. Descriptive analysis is reported. Results: There have been 17 ASCTs performed with at least one month follow-up. The most common indication was MM (9) followed by Relapsed lymphoma (8) and 1 case of multiply relapsed Ewing's Sarcoma. (Table 1) Mobilization:100% pts received granulocyte colony-stimulating factor (GCSF) mobilization with one patient required plerixafor in addition. The median days of collection was 1 (Range 1-2 days). All pts collected successfully. Neutropenic Events: Almost all patients (95%) had expected neutropenic fever by day +8.Median time to onset of Grade 4 neutropenia (absolute neutrophil count <500) was 6 days (3-8); Median time to onset of neutropenic fever was 7 days (3-10). Causative organisms were identified in 2 (11%) (Both bacterial infections). Antibiotic of choice was meropenem. ICU Admissions: Only one (6%) patient was admitted in ICU for neutropenic typhilitis on Day +3. That pt spent 20 days in ICU and total of 45 days in hospital with recovery to baseline. Resource Utilization: ASCT for MM was 100% outpatient chemotherapy and cell infusions. The patients were admitted on Day 6 post-transplant for neutropenic care, except 1 patient who presented at the emergency department with febrile neutropenia and diarrhea on day +3. The patients planned for ASCT for rHL were admitted for conditioning chemotherapy, stem cell infusion and neutropenic care until count recovery. Median duration of hospital stay was 17 days (8-45 days). The median days of GCSF post-cell infusion per patient was 8 days (6-15). Efficacy Outcomes: Of the 9 MM pts, all achieved complete response (CR). With a median follow up of 21 months, 100% continued to be on maintenance. For the rHL cohort, response rate was 100%, all CR, and continue to have ongoing responses. The patient with relapsed refractory Ewing's sarcoma has progression-free survival (PFS) of 5 months after ASCT. Overall survival (OS) was 100% for all diseases post-transplant. Conclusion: Our study describes promising outcomes of pts treated at our center, which is the first and only center offering ASCT in Dubai, UAE. This demonstrates that with available infrastructure and expertise, ASCT programs in countries similar to UAE are feasible and increase access to this therapy. Continued efforts at monitoring outcomes, education of the local population, and outreach partnerships with colleagues are essential to increase access to patients in the region.

Early Elevation of Absolute Eosinophil Count after Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Chronic Graft-Versus-Host Disease in Children

BACKGROUND Chronic graft-versus-host disease (cGVHD) is the most frequent late complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with non-relapse mortality. If recipients with cGVHD are not properly treated at the appropriate time, cGVHD can lead to severe complications. Therefore, early prediction of cGVHD is required to improve quality of life among the pediatric survivors who undergo allo-HSCT. The significance of eosinophilia in peripheral blood after allo-HSCT remains to be elucidated. Previous studies found that eosinophilia after allo-HSCT reduced the risk of relapse of malignancies or non-relapse mortality and was also associated with cGVHD. However, the subjects of these reports were mainly adults and there were limited data focused on eosinophilia after allo-HSCT in children. The aim of this study was to evaluate whether an early elevation of absolute eosinophil count after allo-HSCT was associated with the development of cGVHD in children. METHODS A total of 165 consecutive patients who received allo-HSCT in our institute were included. Patients who had previously received allo-HSCT, relapsed or died before day 100, and did not achieve engraftment, were excluded. Eosinophilia was defined as an eosinophil count of more than 500 /µL in peripheral blood within 60 days of stem cell infusion. The primary outcome of the present study was the development of cGVHD. RESULTS In our cohort, eosinophilia was detected in 67 patients (40.6%), with a median maximum eosinophil count of 1,050 /µL (range, 504 - 7,812 /µL) at a median of 40 days (range, 24 - 59 days), while median maximum eosinophil count in those without eosinophilia was 189 /µL (range, 0 - 495 /µL). There were no significant differences between the patients with or without eosinophilia in disease type, graft source, donor type, conditioning regimen, and GVHD prophylaxis and treatment. The median time from day 0 to the date of diagnosis of cGVHD was 120 days (range, 100 - 1,302 days). The cumulative incidence rate of cGVHD at 3 years in the entire cohort was 39.3% (95% confidence interval: 32.2 - 47.4). Patients with eosinophilia had a higher 3-year cumulative incidence rate of cGVHD, compared with those without eosinophilia (49.1% vs. 32.7%, P = 0.007). Cox proportional hazards model analysis with adjustments for the potential confounding factors of HLA mismatched donor, unrelated donor, aGVHD, use of ATG as conditioning regimen revealed that eosinophilia was associated with an increased risk of cGVHD (adjusted hazard ratio: 2.12; 95% confidence interval: 1.16-3.85, P = 0.014). In the 165 patients who underwent allo-HSCT, there was no significant difference in 5-year overall survival (OS) between the eosinophilia and the non-eosinophilia groups (80.1% vs. 80.5%, P=0.76). In the 121 patients with malignant diseases, there was no significant difference in 5-year OS between the eosinophilia and the non-eosinophilia groups (75.5% vs. 76.3%, P = 0.70). There was also no significant difference in 5-year disease-free survival between the eosinophilia and the non-eosinophilia groups (69.1% vs. 77.1%, P = 0.34). On the other hand, there was a significant difference in 5-year GVHD-free relapse-free survival between the eosinophilia and the non-eosinophilia groups (41.1% vs. 62.4%, P = 0.04). DISCUSSION & CONCLUSION In the present study, we revealed that an early elevation of absolute eosinophil count after allo-HSCT was associated with cGVHD in children. Because eosinophilia after allo-HSCT occurs before the development of cGVHD, early eosinophilia after allo-HSCT may predict the development of cGVHD in children.

An Open Label Study Comparing Photobiomodulation Therapy to Cryotherapy in Patients at High Risk for Drug-Induced Oral Mucositis

Background and rationale Oral mucositis (OM) is one of the most common side effects of chemotherapy and may lead to weight loss and increased risk for infection ultimately impairing overall survival. Evaluated options for mucositis prophylaxis in patients receiving a high-dose chemotherapy include oral cryotherapy (CT) and photobiomodulation therapy (PBMT) using laser diodes to reduce incidence and severity of OM. However, standards of mucositis prophylaxis in German hospitals differ substantially. While CT has been standard of care in melphalan treated patients, the German guidelines for supportive oncology do not recommend the use of PBMT for patients receiving high-dose chemotherapy. Several clinical trials have demonstrated the beneficial effect of PBMT, however, no randomized clinical trials (RCT) exist to compare the efficacy of oral CT versus PBMT. Study design This is a single-center, open-label, randomized, two-arm interventional trial to evaluate the efficacy of PBMT and CT as prophylaxis of OM in patients with hematological malignancies receiving high-dose chemotherapy as part of a conditioning regimen prior to hematopoietic cell transplantation (HCT) or high-dose methotrexate (MTX, defined as ≥ 500 mg/m 2). Randomization will occur 1:1, stratified according to conditioning regimen/chemotherapy protocol. The primary endpoint of the trial is rate of severe OM as assessed by the world health organization (WHO) OM grading scale grade 3 or higher. Key secondary endpoints include duration of OM, patient reported pain, total parenteral nutrition, opioid usage, weight loss, length of in-patient stay and overall survival. Eligible patients randomized to receive PBMT will undergo daily laser therapy at 4 J/cm² of the oral mucosal areas most frequently affected by OM, starting on the first day of the administration of chemotherapy, until neutrophil engraftment or resolution of OM, whatever occurs first. Eligible patients randomized to oral CT will receive ice chips (IC) made from filtered tap water or flavored ice popsicles on days of chemotherapy infusions only, starting 5 min prior to chemotherapy until 30 min after the end of infusion. Patients ≥ 18 years of age, receiving therapies with high potential to induce OM, including the conditioning regimen high-dose melphalan, carmustine/etoposide/cytarabine/melphalan (BEAM), thiotepa/etoposide/cytarabine/melphalan (TEAM), fludarabine/thiotepa/melphalan (FTM) and fludarabine/melphalan (FM) or chemotherapy protocols with high-dose MTX, are included in this trial. The trial tests the null hypothesis (H 0) that the observed rate of severe OM with PBMT and CT prophylaxis are equal versus the alternative hypothesis (H 1) that the observed rate of severe OM differs between CT and PBMT. We estimate a rate of severe OM of 45 % in our trial population (H 0). With a power of 80 %, a type 1 error rate of 5 %, and an expected difference in severe OM rate of 30 % considered relevant between both arms, with an expected dropout rate of 5 %, n = 86 patients should participate in the study to ensure discrimination of H 0 and H 1. Conclusion This study aims to compare PBMT and CT with regard to their effectiveness in the prevention of severe OM in a randomized trial for the first time. Our objective is to provide data that may guide the development of a standardized OM prophylaxis for patients undergoing high-dose chemotherapy. At the time of abstract submission, 8 patients have been randomized in the study. Acknowledgments This is an independent academic trial conducted under the sponsor role of the University Cancer Center Schleswig-Holstein, Germany. This study is conducted in compliance with the protocol, Good Clinical Practice (GCP), all applicable regulatory requirements and the ethical principles of the Declaration of Helsinki.

Estimation of Postinfusion Resource Use and Total Costs of Care for Patients with R/R Follicular Lymphoma (FL) Receiving Lisocabtagene Maraleucel (liso-cel) in the TRANSCEND FL Study

Background: Liso-cel, an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells, has previously demonstrated clinically meaningful responses in patients with R/R FL in the global phase 2 TRANSCEND FL study (NCT04245839). Limited evidence is published on estimates of health care resource utilization (HCRU) and cost of postinfusion care among patients with large B-cell lymphoma (LBCL) treated with liso-cel (Palomba ML, et al. Leuk Lymphoma 2021), and no evidence is currently available for patients with R/R FL. This analysis evaluated postinfusion HCRU and estimated cost of care across a 6-month period among patients treated with liso-cel in the TRANSCEND FL study. Methods: In this retrospective analysis, patient-level HCRU data from the TRANSCEND FL study database, including hospitalizations and length of hospital stay (LOS) for the entire hospitalization period postinfusion (standard inpatient [IP] and ICU days), diagnostics (eg, laboratory work and imaging), procedures (eg, dialysis and intubation), and medications (eg, oncology supportive care, prophylactics, and other AE management), were analyzed from the day of liso-cel infusion through 6 months of follow-up. Postinfusion costs (not including the cost of liso-cel) were estimated using a microcosting methodology in which HCRU in the 6-month period was identified and unit costs sourced from public databases or literature (adjusted to 2023 US dollars [USD] using the Consumer Price Index) were applied to each HCRU. Facility costs were sourced from the Healthcare Cost and Utilization Project National Inpatient Sample (2020) databases (Dasta JF, et al. Crit Care Med 2005), and the US Centers for Medicare and Medicaid Services (CMS) Hospital Outpatient Prospective Payment System (OPPS; 2023). Diagnostic and procedure costs were obtained from the CMS OPPS (2023), clinical laboratory fee schedule (2023), physician fee schedule (2023), durable medical fee schedule (2023), and Dasta 2005. Medication cost data were obtained from IBM ® Micromedex ® RED BOOK ® (2023) using wholesale acquisition cost and were uniformly applied across sites of care. Average total cost by month after liso-cel infusion was calculated among patients with ongoing status in that month. Patients censored due to data cutoff were excluded. Results: A total of 130 patients were treated with liso-cel in the TRANSCEND FL study, primarily in the fourth-line setting (45.4%). These patients had a median (range) age of 60 (23‒80) years and were predominantly male (83/130 [63.8%]) and White (69/130 [53.1%]); 45 (34.6%) had unknown race. Among patients who received liso-cel infusions, the estimated mean 6-month postinfusion total cost of care was $89,516 (Figure 1). Most 6-month costs ($77,088 [86.1%]) were incurred in Month 1 after infusion and were primarily driven by facility costs ($66,683 [74.5%]), namely standard IP hospitalization and ICU stays. HCRU and LOS (including standard IP hospitalization and ICU days) are shown in Table 1. Almost all patients were hospitalized in the standard IP setting (128/130 [98.5%]). Few patients were admitted to the ICU (4/130 [3.1%]), and 3/130 (2.3%) had an emergency department visit. Median (range) hospitalization time was 14 (3‒45) days for standard IP and 5 (3‒7) days for ICU stays. Some patients received corticosteroids (30/130 [23.1%]) or tocilizumab (31/130 [23.8%]), and few required intravenous immunoglobulin (11/130 [8.5%]), vasopressors (4/130 [3.1%]), lumbar puncture (2/130 [1.5%]), or mechanical ventilation (1/130 [0.8%]). No patients received dialysis. Conclusions: The majority of costs in the 6-month period after liso-cel infusion among patients with R/R FL in the TRANSCEND FL study were incurred in Month 1 and were facility related (IP and ICU hospitalizations and LOS). These findings, consistent with those previously reported for patients with LBCL treated with liso-cel, support that a single infusion of liso-cel is associated with significantly less HCRU and costs after the initial treatment period in the first month.

Development of Oral Azacitidine with Cedazuridine for Myelodysplastic Syndrome (MDS) and Myeloproliferative Neoplasms (MPN) Including CMML (Chronic Myelomonocytic Leukemia) By Targeting Pharmacokinetic AUC Equivalence Vs Subcutaneous Azacitidine

Introduction/ Background: Hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DEC) are FDA-approved for patients with MDS/CMML and acute myeloid leukemia (AML). Treatment is generally administered parenterally as a daily injection or infusion over 5-7 days per four-week cycle. The oral fixed-dose combination of decitabine with cedazuridine, ASTX727, was approved by regulators in the USA and Canada for patients with MDS and CMML based upon the demonstration of biologically equivalent pharmacokinetics (PK) area under the curve (AUC) vs IV decitabine. ASTX030 is a combination of AZA and cedazuridine (CED), a cytidine deaminase inhibitor (CDAi), which enables oral AZA to achieve systemic AUC similar to that of parenteral (subcutaneous) AZA. Development and approval of an oral AZA providing equivalent PK exposure to the parenteral therapy has the potential to markedly reduce the treatment burden associated with parenteral treatment. This Phase I trial is designed to determine the dose combination for oral AZA plus CED to replicate SC AZA AUC exposures in subjects with MDS and MDS/MPN, including CMML. Methods: Adult patients with confirmed MDS, CMML, and other MDS/MPN or AML who are candidates to receive benefit from single agent AZA were enrolled in this open label Phase 1 trial. In addition to assessing safety and efficacy of each combination, the primary PK endpoint was to achieve oral AZA PK AUC 0-24 equivalence versus subcutaneous AZA (at the approved dose of 75 mg/m 2 over the span of 7 days). In the first cycle, patients received oral AZA alone on Day -3, followed by SC AZA at 75 mg/m 2 on Day 1. Subsequently, oral ASTX030 (combination of AZA with CED) was given at varying dose combinations of AZA and CED for each cohort. After cycle 1, patients received oral ASTX030 on Days 1-7 for each 28-day cycle. Dose levels for cohorts in escalation were determined by the data safety and review committee based on safety and PK results. Pharmacodynamic (PD) impact was assessed by changes in LINE-1 DNA methylation in peripheral blood cells. Clinical response assessments were based upon International Working Group (IWG) 2006 criteria for MDS patients and IWG 2015 criteria for MDS/MPN and CMML patients. Results: As of 05 JUL 2023, 65 patients were treated across 8 different dose combinations, with ≥6 patients per cohort. The median age was 72 years old (range 26-87), 36.9% (n=24) were female, 6.2% (n=4), had previously received HMA treatment (unlimited). Of the enrolled patients, 69% (n=45) had MDS, 25%(n=16) had CMML, and 6% (n=4) had MDS/MPN (other). Evaluated dose levels for AZA ranged from 60-136mg and CED dose ranged from 20-100 mg. In cohorts 1-2, tablet formulation was tested first (AZA ranging 80-100mg with CED ranging 80-100mg). Starting with cohort 3, capsule formulation was introduced for AZA to optimize the interaction effect of CDA inhibition by CED. In both tablet and capsule formulation, grade ≥3 AE's (regardless of causality) were observed in 75.9% of patients. The most common Grade ≥3 AE's regardless of relation to drug were leukopenia (25%), thrombocytopenia (20%), and anemia (20%). Gastrointestinal toxicity were similar (for example, nausea 70% ASTX030 vs 71% SC AZA) to those reported for SC AZA (VIDAZA USPI)). No dose limiting toxicity was observed in any of the cohorts. The CED dose of 20 mg resulted in ~100% bioavailability for AZA, suggesting inhibition in a linear range. LINE-1 demethylation results were similar to those reported historically with SC AZA. Although a clinical response comparable to SC AZA was observed, the immature nature of the data requires continued analysis to yield results on treatment efficacy. Conclusion: ASTX030 successfully achieved the primary endpoint of PK equivalence versus SC AZA based on total cycle AUC. The dose combinations evaluated were well tolerated, and the safety profile similar to that of SC AZA, with no unique AE's. LINE-1 demethylation and clinical response confirm the clinical activity of ASTX030. Phase 1B dose expansion for the ASTX030 study at the recommended dose combination of 144mg AZA with 20mg CED will begin soon to confirm PK equivalence for this dose level. An orally bioequivalent AZA based HMA offers significant opportunity for novel combinations and improved convenience for patients with high grade myeloid malignancy.

Inflammatory Marker Levels, Age, Race and Prior Treatment Burden Independently Predict Delayed Hematologic Recovery after BCMA-Directed CART Therapy in Multiple Myeloma

Inflammatory Marker Levels, Age, Race and Prior Treatment Burden Independently Predict Delayed Hematologic Recovery After BCMA-directed CART Therapy in Multiple Myeloma Introduction: With the advent of two approved anti-BCMA products and several additional investigational cellular therapies, the use of BCMA-directed chimeric antigen receptor T-cell therapy (CART) is expanding for the treatment of multiple myeloma (MM). Prolonged cytopenias have been observed in a subset of CART recipients across products. The etiology and natural history of these cytopenias has not been thoroughly evaluated in the literature. We present a comprehensive multivariable model of hematologic recovery post-CART in an analysis of 140 MM CART recipients from a large academic center. Methods: We retrospectively reviewed electronic health record data for relapsed/refractory MM patients from our institution who received a BCMA-directed CART product between 2017 & 2022. For each patient, all available lab values of hemoglobin (Hgb), platelet count (Plt) and absolute neutrophil count (ANC) were recorded and graded according to CTCAE v5.0 criteria. Missing lab values were linearly interpolated between available measurements. We defined time to recovery for each blood count as the number of days from CART infusion (day 0) until the first day of a 30-day-long period without any grade 3 or 4 (G3/4) values. Time to recovery from any G3/4 myeloid cytopenia (i.e., anemia, thrombocytopenia, and neutropenia) was also calculated. Next, we classified patients according to the CAR-HEMATOTOX scoring system (Rejeski et al, ASH 2022), a tool which incorporates baseline blood counts and inflammatory parameters such as C-reactive protein and ferritin prior to lymphodepletion to predict the risk of post-CART hematotoxicity. Kaplan-Meier curves were generated treating recovery from G3/4 cytopenia as the ‘event’ and censoring patients at the time of PD. A Cox proportional hazards model was used for multivariate analysis. Results: A total of 140 MM patients who received a BCMA-directed CART product at ISMMS were included in the study. 107 patients (76%) received CART as part of a clinical trial and 33 (24%) commercially. Median age at CART infusion was 62 (range 35-83) and median number of prior lines of therapy was 5 (range 1-18). 102/140 patients (73%) were previously treated with high-dose melphalan and autologous stem cell transplantation, of which 23 had more than one prior transplant. Median CAR-HEMATOTOX score was 1 (range 0-6), with 45 patients (33%) classified as HT high (higher inflammatory marker levels prior to lymphodepletion) and 91 (67%) as HT low (lower inflammatory marker levels). Median time to recovery from G3/4 anemia, thrombocytopenia, neutropenia, and any myeloid cytopenia were as follows: 11.5 days, 10 days, 32 days and 40 days, respectively. After censoring 28 patients who had PD before day +120, 112/140 patients (80%) remained evaluable at that time point, of which 105 (94%) had achieved recovery from G3/4 anemia, 94 (84%) from G3/4 thrombocytopenia, 99 (88%) from G3/4 neutropenia, and 88 (79%) from any G3/4 myeloid cytopenia. Four variables were significantly associated with delayed recovery from any G3/4 myeloid cytopenia as compared to others: HT high score (median 63 vs 31 days, p<0.01, Fig. 1A), age at CART infusion ≥50 (42 vs 29 days, p<0.01, Fig. 1B), ≥3 prior lines of therapy (44 vs 14 days, p<0.01, Fig. 1C), and Black race (68 vs 35 days, p=0.02, Fig. 1D). In a multivariate Cox proportional hazards model, all four variables maintained their significance in predicting delayed hematologic recovery after CART. Conclusion: Systemic inflammation and reduced bone marrow reserve due to aging and/or prior therapies were independently associated with delayed recovery from G3/4 myeloid cytopenias in a large, single-center cohort of MM patients treated with BCMA-directed CART therapy. Our study reinforces the predictive capability of CAR-HEMATOTOX in assessing the risk of delayed hematologic recovery after CART. However, we suggest that this tool could be further refined for MM by factoring in variables such as patient age, race, and number of prior lines of therapy.

Population pharmacokinetic modeling and target attainment analyses of rezafungin for the treatment of candidemia and invasive candidiasis.

Rezafungin is a chemically and metabolically stable echinocandin with a longer half-life than other echinocandins, allowing for a once-weekly intravenous infusion versus a daily infusion. Rezafungin is approved in the US for the treatment of candidemia and/or invasive candidiasis and is in development for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in immunosuppressed patients. A population pharmacokinetic (PPK) model was developed using data from five Phase 1, one Phase 2, and one Phase 3 study. The model found to best describe the available data was a three-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V23), intercompartmental clearance 1, and intercompartmental clearance 2. The variability model included correlated interindividual variability in CL, V1, and V23 and a proportional residual variability model. The following statistically significant covariates were identified: albumin concentrations on V23; body surface area (BSA) on CL, V1, and V23; and disease state on CL and V1. Disease states were defined as patients from the Phase 2 and Phase 3 studies and hepatically impaired subjects. Covariates of BSA, disease state, or albumin, included in the final model, were not associated with clinically meaningful changes in PK, nor were any other patient factors, indicating that a common dose regimen is adequate for all adult patients. Target attainment simulations were performed to estimate the probability of achieving PK/pharmacodynamic targets across the range of minimum inhibitory concentration values for six species of Candida.

Delivery of Care for Pediatric Patients Receiving Blinatumomab: A Children's Oncology Group Study.

Blinatumomab is an immunotherapy agent used in pediatric oncology for the treatment of B-lineage acute lymphoblastic leukemia. Administration of blinatumomab, via continuous 28-day infusion cycles, can present multiple decision points and challenges related to patient care. Nurses are at the forefront of coordinating and delivering care for patients receiving blinatumomab. To describe the current state of practice across Children's Oncology Group (COG) member institutions regarding blinatumomab administration in both inpatient and home/outpatient settings. Between August and December 2021, a cross-sectional survey was used to determine current institutional practices related to blinatumomab administration. A single targeted respondent who was actively engaged in coordinating blinatumomab administration completed the survey on behalf of each COG institution. Survey participation rate was 78% (150/192). During the first 28-day blinatumomab cycle, 71 institutions (53%) reported patient hospital stays between 73 hours and 7 days; 42 (31%) reported hospital stays ≤72 hours, and only 12 (9%) reported hospitalization for the full 28-day infusion. Small- to medium-size institutions were more likely to report longer hospitalizations ( P = .03). Most blinatumomab administration occurred in the outpatient setting, with low rates of unplanned clinic/emergency room visits. The majority of COG institutions have navigated the complex coordination of care required for children to receive blinatumomab at home. Wide variations in practice were noted across institutions. This study describes current institutional practices surrounding administration of 28-day blinatumomab infusions in children with leukemia and offers a starting point for institutional benchmarking and standardization of practice.

465. Use of Monoclonal Antibodies for COVID-19 in Solid Organ Transplant Recipients: A Single-Center Experience

Abstract Background The use of coronavirus disease 2019 (COVID-19) monoclonal antibody (mAb) treatment in solid organ transplant (SOT) patients have been shown to reduce the rates of hospitalization, Emergency Department (ED) visits, and mortality in previous studies. However, most of these studies provide little or no data in minority patients, specifically Hispanic patients, a group that has been associated with worse outcomes with COVID-19. Our study describes the use of COVID-19 mAbs in the SOT recipients at our institution, where a majority of patients are of Hispanic ethnicity. Methods We performed a retrospective chart review of all adult SOT patients who received COVID-19 mAbs from December 2020 to December 2022. Results We identified 54 patients who were SOT recipients. The mean age was 46.3 (IQR 33-59), and 30 (55.6%) were male. Of the 54 patients, 34 (63.0%) identified as Hispanic, 17 (31.5%) as White, 2 (3.7%) as Asian, and 1 (1.9%) as Black. There were 23 (42.6%) heart, 22 kidney (40.7%), 6 liver (11.1%), 2 (3.7%) combined kidney and liver, and 1 (1.9%) combined kidney and pancreas recipients. There were four mAbs available during the study period. Of the 54 SOT recipients, 16 (29.6%) received casirivimab/imdevimab, 5 (9.3%) received bamlanivimab, 19 (35.2%) received bebtelovimab, and 14 (25.9%) received sotrovimab. Average time from symptom onset to receipt of infusion was 4 (IQR 1-5) days. The 30-day hospitalization rate due to COVID-19 from time of diagnosis in our cohort was 5.6%. There were 3 (5.6%) patients who visited the ED due to COVID-19 within 30 days of diagnosis and there were no deaths due to COVID-19 within 30 days of diagnosis. When comparing between the Hispanic and non-Hispanic groups in our cohort, the 30-day hospitalization rate due to COVID-19 from time of diagnosis was not statistically significant (5.6% vs 0, p=0.29). There was one patient who had an infusion reaction and 3 patients who developed allograft rejection within 90 days of mAb infusion. Conclusion In our small cohort of SOT recipients, the majority of which are Hispanic, use of COVID-19 mAbs had low rate of poor outcomes and adverse events. There was no statistically significant difference in hospitalization rate following mAb infusions between the Hispanic and non-Hispanic SOT recipients in our group. Disclosures All Authors: No reported disclosures

Determinants of bleeding before and during immune tolerance in 222 boys with severe hemophilia A and inhibitors >5 BU

AbstractPrevention of bleeding and its consequences is the main goal of hemophilia treatment and determines treatment choices for patients who develop inhibitors. To assess bleeding before and during immune tolerance induction (ITI) and its association with ITI regimen and inhibitor titer, we selected and analyzed data on patients receiving high-titer inhibitors from the international prospective PedNet cohort study. In total, 222 patients with severe hemophilia A and inhibitor titers of >5 Bethesda units (BU) were followed from the first positive to the first negative inhibitor result (median overall follow-up, 1.7 years). Mean annual (joint) bleeding rates (AJBR) and 95% confidence intervals (CIs) were compared according to treatment and inhibitor titer using multivariable negative binomial regression. Before ITI, 115 patients showed an ABR of 6.1 (5.0-7.4) and an AJBR 2.6 (2.1-3.2). Bleeding was independent of inhibitor titer. During ITI, 202 patients had an ABR of 4.4 (3.9-5.1) and an AJBR of 1.7 (1.5-2.0). AJBR during ITI increased with inhibitor titer (hazard ratio [HR] for ≥200 BU vs 5 to 39 BU [4.9; CI, 3.2-7.4]) and decreased with daily ITI infusions (HR, 0.4; CI, 0.3-0.6) or activated prothrombin complex concentrate prophylaxis (HR, 0.4; CI, 0.2-0.8), whereas ITI dose and recombinant activated factor VII prophylaxis did not independently affect bleeding. These data provide evidence for a protective effect of repeated FVIII infusions (ITI) on bleeding in patients who have developed inhibitors; these data should be used to plan ITI and/or serve as a comparator for prophylaxis with nonreplacement therapy.

A Real-World Single-Center Report on the Effectiveness and Safety of Blinatumomab Treatment on Pediatric Acute Lymphoblastic Leukemia in China

Background: Studies overseas have demonstrated blinatumomab benefits pediatric acute lymphoblastic leukemia (ALL), but the experience is limited in China. Methods: We retrospectively collected 28 pediatric ALL patients in our center who received blinatumomab treatment since August 2021. All patients were diagnosed with B-ALL with CD19 expression on cell surface. Patients were divided into three groups: clearance of minimal residual disease (MRD) in first complete remission (MC, 18/28), supplement therapy during chemotherapy intolerance (IC, 3/28) and reinduction therapy for refractory or relapsed ALL (RR, 7/28). Results: The age of 28 patients (16 males and 12 females) ranged from 0.6 to 16.4 years (median, 11.0 years). BCR::ABL1 fusion was found in 6 patients in MC group and 1 patient in RR group. The reasons for chemotherapy intolerance included pancreatitis, infection, and endocarditis. The median interphase from diagnosis to blinatumomab was 3.7 (range: 0.7 to 39.8) months, 1.4 (range: 1.1 to 16.8) months and 29.0 (range: 4.9 to 62.1) months in MC, IC and RR groups, respectively. Most patients accepted 14 to 28 days of uninterrupted infusion except 1 patient in MC group received 7 days treatment for economic issue and 2 patients in MC group discontinued therapy for severe reaction in 1 or 2 days. 7 patients received 1 to 3 more cycles of blinatumomab if MRD decreased after the first cycle. In MC group, the median MRD level in bone marrow before blinatumomab, detected by flow cytometry (FC) or by real time PCR (RT-PCR) if recurrent fusion genes were positive, was 0.145% (range: 0.01% to 4.00%). MRDs were turned negative in 13 patients (72.2%) by both FC and RT-PCR, while the MRDs in the other 5 patients with BCR::ABL1 fusion gene, of whom 3 were positive in both FC and RT-PCR and 2 were only positive in RT-PCR, wereturned negative in FC but still positive in RT-PCR. In terms of safety, one patient developed grade 4 immune effector cell associated neurotoxicity syndrome on the second day of infusion. The most common reaction was fever in 9 cases in cycle 1 (9/18). In IC group, all 3 patients with negative MRD before treatment maintained their negative status, with only fever occurring (3/3) during the early stage of infusion. In RR group, the median MRD level before treatment was 8.37% (range: 0.08% to 78.3%). 4 patients (57.1%) with lower MRD (0.08% to 8.37%) by FC before blinatumomab attained MRD negativity, while 3 patients (42.9%) with higher MRD (22.64% to 78.3%) failed. The patient with BCR::ABL1 fusion gene turned MRD negative by FC after blinatumomab, but remained positive by RT-PCR. Two patients (2/7) had cytokine release syndrome of grade 2, and 3 cases only had fever. No other severe or fetal adverse reactions were observed. Conclusions: Blinatumomab is an effective treatment for B-ALL MRD cleanup with a good safety profile. It may, however, not benefit patients with R/R B-ALL with high tumor loads before blinatumomab, and those who carry BCR::ABL1 fusion gene. Studies with a larger sample size are needed to confirm the results.

Patterns and Safety of Glucocorticosteroids Use Following CD19 CAR-T Cell Therapy for B-Cell Lymphoma

Introduction: CAR T-cell therapy is a well-established therapy for relapsed and/or refractory B cell non-Hodgkin's lymphomas (R/R B-NHL). However, CAR-T cell therapy may cause significant toxicities such as CRS and ICANS. Glucocorticosteroids play a pivotal role in managing these toxicities but can also suppress T cell function and may impede the persistence and effectiveness of CAR-T cells. The impact of glucocorticosteroids has resulted in conflicting conclusions in the literature. Objective: This single-center, retrospective, observational study aimed to compare the outcomes of patients with R/R B-NHL who received steroids to those who did not after CAR-T cell therapy. Methods: Patients' records were reviewed to identify any steroid administration within 30 days of CAR-T cell infusion. Patients receiving steroids within 7 days before CAR-T infusion were excluded to focus on CAR-T impact without confounding baseline steroid use. Information on the type of steroids, indication, timing and duration was collected. Steroids were expressed as dexamethasone equivalent. Steroids-associated variables were analyzed as both continuous and categorical variables, using median as the threshold. Cox regression models and Kaplan-Meier analysis was employed for PFS and OS estimation using steroids as a time-dependent covariate and a 30-day landmark analysis, with events as disease progression or death for PFS and death only for OS. Results: 292 patients with R/R B-NHL received commercial CAR-T cell therapy (48% axi-cel, 24% tisa-cel, 22% liso-cel, and 6% Brexu-cel), primarily for large B cell cell lymphoma (85%), mantle cell (11%) or follicular (4%) lymphoma. Only 49 of the 292 patients (17%) received steroids between the day of infusion (day 0) to 30 days after. The median cumulative dexamethasone-equivalent dose at 30 days was 60 mg (range: 1-1982), the median day from CAR-T cells infusion to steroids initiation was 7 days (range 0-26) and the median duration of corticosteroid use was 3 days (range, 1-27). Patients receiving steroids had a significantly higher number of lines of prior therapies (p=0.036), more stage 3-4 disease (p=0.027), and elevated pre-lymphodepletion LDH levels(p=0.004). However, there were no other significant differences, including CD19 CAR-T product type, between the groups. The rates of grade 2 or higher CRS and ICANS were documented in 42% and 18%, respectively. ICANS (47%), CRS (14%), or both (21%) were the leading indications for steroid administration. Other indications for administration of steroids were progression of disease (n=4), adrenal insufficency (n=3), graft vs host disease (n=1), and premedication with intravenous immune globulin (n=1). With a median follow-up of 20 months, median PFS and OS were 6.8 months (95% CI 6-11) and 27 months (95% CI 18-not reached), respectively. The use, duration, and cumulative dose of steroids, whether analyzed as continuous or categorial variables in univariable Cox regression models, were not associated with PFS and OS in a 30 landmark analysis ( Figure). The analysis of the adminstration of steroids as a time-dependent covariate did not show significant differences for either PFS or OS. Importantly, patients exposed to steroids were also not at increased risk for bloodstream infections (p=0.68). Conclusion: In this largest analysis to date on the impact of steroids on CAR-T outcomes, steroid exposure following CAR-T cell infusion was not associated with a greater likelihood of CAR-T cell therapy failure. Our results deviate from previous observations that associate using steroids with shorter PFS and OS (Starti et al, Blood 2021, Terao et al, JTCT 2023). The discrepancy is likely due to our study's exclusion of steroid use prior to CAR-T and statistical analysis. Overall, our findings suggest that steroid administration for CAR-T cell therapy toxicity management is safe and does not appear to have a negative impact on efficacy.

Exploring the Efficacy and Feasibility of Outpatient Blinatumomab Short Cycles in Pediatric Patients with Relapsed/Refractory B-ALL in LMIC: Preliminary Results

CONCLUSIONS In low- and middle-income countries (LMIC) like Mexico, the treatment of patients with refractory or relapsed acute lymphoblastic leukemia (r/r ALL) represents a significant challenge due to limited access to immunotherapy and hematopoietic stem cell transplantation (HSCT). As a result, the one-year survival rate is reported to be less than 20%. The use of intensive chemotherapy has not improved survival in this group due to its high toxicity. Blinatumomab uses the patient's own cytotoxic T-cells to induce lysis of the leukemia cells expressing CD19 and has been established as a bridge therapy for transplant in patients with r/r B-ALL. The usual pattern of administration is a dose scaled up to complete a total of 28 days of infusion. According to various studies, it is considered appropriate to use repeated cycles of this antibody to achieve the desired response. However, there are also reports of patients achieving complete responses within the first 15 days of the cycle. The high costs of Blinatumomab's administration present a significant barrier to its use in LMIC. As a consequence, the application of prolonged or multiple cycles of the drug becomes unaffordable for a substantial portion of the global population. Demonstrate the safety and efficacy of utilizing short cycles of Blinatumomab (21 days) as a bridge therapy to HSCT in pediatric patients with r/r ALL to explore the potential cost-reduction benefits and increased access to this therapy in resource-limited settings. A pilot clinical trial was conducted. Pediatric patients (<16 y) diagnosed with r/r B- ALL between the years 2020-2022 were included. The usual Blinatumomab dosing regimen was adopted, but the total duration of the cycle was reduced. Continuous infusion was initiated at a dose of 5 mcg/m2/day for the first 7 days, followed by an increase to 15 mcg/m2/day for 14 days (21-day total treatment duration). To mitigate cytokine release syndrome (CRS) a single dose of dexamethasone was administered at the start of the infusion and after the dose escalation. The entire regimen was administered on an outpatient basis, with an infusion pump at home. Caregivers were instructed on the operation of the pump and detection of any signs of toxicity, with 24/7 contact with the medical team and the option to hospitalize if necessary. A total of 7 patients were included, and all of them received Blinatumomab in a single 21-day cycle. The median age was 5 years (15 mo- 13 y). The majority of patients were stratified as high-risk at the time of diagnosis (85.7%). Among the patients, 4 had relapsed ALL, while 3 had refractory disease. The median time from the initial diagnosis to the use of Blinatumomab was 16 months (ranging 7-29 mo), and the median number of treatment lines before Blinatumomab administration was 3 (ranging 2-4). The highest level of minimal residual disease (MRD) detected before the Blinatumomab treatment was 4.2% (by flow cytometry). Remarkably, all patients (100%, n=7) achieved a complete response, with MRD being negative for flow cytometry after the 21-day cycle of Blinatumomab. In 5 out of 7 patients, the administration of the drug was completely ambulatory. Only 2 patients experienced grade I CRS which was successfully managed with steroids. No adverse effects greater than grade 2 were reported, and no patient required support with transfusion therapy during or after the infusion. There were no reports of profound neutropenia, and no treatment-related deaths occurred. HSCT was conducted in all patients to consolidate the response, with 6 patients undergoing haploidentical and 1 patient undergoing identical allogeneic HSCT. At present, 5 out of 7 patients are alive and in complete remission. One patient died on day +51 post-HSCT due to pulmonary thromboembolism, and the second patient experienced relapse on day +395 post-HSCT and subsequently died on day +640 due to disease progression. The median overall survival at 3 years was 66.7%, with a median follow-up period of 21 months (4 -30mo). An alternative outpatient, low-toxicity and cost-effective treatment approach was implemented. The findings from this study could shed light on a promising strategy to improve the outcomes for patients with ALL patients with limited therapeutic options, particularly in the context of resource-constrained settings.

Easix Indices Predict CRS and Overall Survival in Adult CAR-T Cell Recipients

Background: Immunotherapy with Chimeric Antigen Receptor T cells (CAR-Τ) is worldwide commercially available for refractory B cell malignancies, with continuously expanding indications.Given that cytokine release syndrome (CRS) and neurotoxicity (ICANS) are encountered in many CAR-T recipients both in trials and real-world setting, novel predictive and prognostic markers are highly needed. Aim: To this end, we hypothesized that EASIX (Endothelial Activation and Stress Index) and the most recently described modified EASIX (mEASIX) would be associated with severe CRS, ICANS and/or Overall Survival (OS) in the real-world setting. Methods: We collected data from consecutive adult patients (pts) from six transplant centers in Greece. Tisagenlecleucel and axicabtagene ciloleucel were administered since 2020, and brexucabtagene autoleucel since 2022. All pts received lymphodepleting therapy before CAR-T cell infusion with combination of cyclophosphamide and fludarabine. For patient monitoring as well as for prophylaxis and treatment of side effects, the EBMT and MD Anderson guidelines were adopted. EASIX (lactate dehydrogenase [LDH; U/L] x creatinine [mg/dL]/platelet [PLT] count; 10 9/L]) and mEASIX (which replaces creatinine with CRP [mg/dL]) were calculated before lymphodepletion (baseline), at day of infusion (0), and day 14 (14). The following variables were analyzed: age, gender, disease type and phase, product type, time from collection to product arrival and to infusion, progression-free (PFS) and overall survival (OS), laboratory markers at pre-specified time-points (LDH, creatinine, platelets, ferritin, CRP). Data cut-off date was end of June 2023, with at least 1 month of follow-up post infusion. Multivariate models were not performed due to multicollinearity issues. Results: Ninety pts, aged 49 (18-75) years, received commercial CAR-T cell products (33 tisagenlecleucel, 37 axicabtagene ciloleucel, 11 brexucabtagene autoleucel) for refractory/relapsed DLBCL (56), PMBCL (5), TFL (8), B-ALL (10), or MCL (11) after a median of 3 (1-9) previous lines of treatment including autologous (n=13) or allogeneic (n=7) transplantation. Severe (grade 3-4) CRS and ICANS were noted in 21% and 39%, respectively. Severe CRS was associated with mEASIXbaseline (p=0.025), and CRPbaseline (p=0.001), EASIX14 and m-EASIX14 (p<0.001). Both mEASIXbaseline and m-EASIX14 were able to predict severe CRS in ROC curve (AUC=0.768, p=0.032 and AUC=0.712, p=0.027). Severe ICANS did not correlate with EASIX indices, except for a trend towards statistically significant association with EASIX14 (p=0.054). On the other hand, severe ICANS was associated with increased LDH at baseline (p=0.001). With a median follow-up of 6.6 (1-42) months, 1-year PFS and OS were 33.2% and 62.5% respectively. Baseline values of ferritin and LDH, CRP values at all time-points, EASIX14 and mEASIX14 were associated with OS. Both EASIX indices predicted death in ROC curves. Similarly, EASIX14 was associated with PFS. Conclusions: This multicenter study, based on real-world experience with CAR-T cell therapy, confirms the predictive value of EASIX and mEASIX not only for life-threatening complications but also for survival outcomes. The implementation of EASIX may therefore aid in the selection of patients who are candidates for interventions to mitigate untoward sequelae of CAR-T therapy.

Postinfusion Monitoring Health Care Resource Utilization and Costs By Site of Care Among Inpatients and Outpatients with Relapsed or Refractory Large B-Cell Lymphoma Who Received Second-Line Treatment with Lisocabtagene Maraleucel in the TRANSFORM and PILOT Clinical Trials

Background:CAR T cell therapy administration is often in an inpatient (IP) setting due to the possibility of severe AEs after infusion. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + andCD4 + CAR + T cells. Outpatient (OP) administration of liso-cel is feasible given trial-demonstrated low rates of grade ≥ 3 AEs that require hospitalization, including cytokine release syndrome and neurological events (Bachier CR, et al. J Clin Oncol 2020). Follow-up care in the OP setting may differ from that in an IP setting and may offer an opportunity to reduce AE management-related health care resource utilization (HCRU) and costs; limited data is published on this topic. Thus, this study assessed postinfusion monitoring HCRU and costs by site of care (ie, IP/OP) among patients with R/R large B-cell lymphoma (LBCL) treated with liso-cel as second-line (2L) therapy in TRANSFORM (NCT03575351) and PILOT (NCT03483103) clinical trials. Methods: A microcosting methodology was used to assess postinfusion monitoring-related HCRU identified from pooled TRANSFORM and PILOT case report forms and to estimate associated costs (excluding liso-cel acquisition costs) by site of care using a 6-month time frame, beginning on the liso-cel infusion date. HCRU data were analyzed in the 6 months after infusion, including facility (eg, number of standard IP and ICU hospitalizations and length of stay [LOS]), procedures (eg, dialysis or intubation/mechanical ventilation), diagnostics (eg, imaging or laboratory tests), and medication use (eg, tocilizumab or corticosteroids). Unit costs were then applied to each HCRU. Unit costs were assessed from the health care system perspective, derived from publicly available databases (eg, United States [US] Centers for Medicare & Medicaid Services, Healthcare Cost and Utilization Project, and IBM ® Micromedex ® RED BOOK ®) or peer-reviewed literature, and adjusted to 2021 US dollars using the medical component of the Consumer Price Index. Patients were considered OP if discharged on the day of infusion or at the end of the observation period. Results: Among 150 patients treated with liso-cel, 111 (74%) were infused as IPs and 39 (26%) as OPs. Estimated median 6-month total postinfusion monitoring costs were $55,253 in the IP setting and $17,505 in the OP setting, reflecting a reduction of $37,748 for OP site of care (Figure). Among patients cared for in the OP setting who required subsequent hospitalization (19/39 [49%]), the median total LOS was 7 days shorter than patients cared for in the IP setting who required hospitalization (105/111 [95%]) (OP: 7 days [range, 1-33] vs IP: 14 days [range, 1-164]). Facility costs, especially hospitalizations, were the largest contributor to overall median 6-month costs in both the IP setting ($40,501; 73%) and the OP setting ($5697; 33%). The majority of total costs occurred in Month 1 postinfusion for patients in both settings. For patients receiving care in the IP setting, 78% ($42,864) of median costs were incurred within the first month after infusion; for OPs, 36% ($6295) of median costs were incurred within Month 1. Patients in the IP setting had higher rates of key HCRU than in the OP setting, respectively, for the following: standard IP hospitalizations (105/111 [95%] vs 19/39 [49%]), ICU admissions (10/111 [9%] vs 0/39 [0%]), any tocilizumab use (32/111 [29%] vs 5/39 [13%]), and any corticosteroid use (54/111 [49%] vs 17/39 [44%]). Patients in the OP setting had higher rates compared with the IP setting, respectively, for office visits (37/39 [95%] vs 87/111 [78%]) and intubation (2/39 [5%] vs 0/111 [0%]). Conclusions: Among patients with R/R LBCL treated with liso-cel in the 2L TRANSFORM and PILOT trials, estimated median 6-month postinfusion costs were 68% lower for patients cared for in the OP versus IP setting. These results are consistent with a previous analysis of patients treated with liso-cel in the third-line setting (Palomba ML, et al. Leuk Lymphoma 2021); and thus, further support that OP postinfusion monitoring and care may allow health care systems to optimize HCRU and costs for patients with LBCL who receive CAR T cell therapy.

Inflammatory Biomarkers and Outcomes in Multiple Myeloma Patients after CAR T-Cell Therapy

Introduction: CAR T-cell therapy is an effective tool for the treatment of multiple myeloma but produces a systemic inflammatory response which can manifest as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and other neurologic toxicities, and hyperferritinemia. Understanding the factors associated with these complications can help clinicians better evaluate their patients' candidacy for CAR T-cell therapy. In this study, we assessed whether baseline values of inflammatory biomarkers were associated with outcomes after CAR T-cell therapy. Methods: We retrospectively reviewed multiple myeloma patients who underwent CAR T-cell therapy with commercial products or on clinical trials at The Mount Sinai Hospital between 2017 and 2023. We gathered data on lab parameters that we felt were indicative of patients' baseline inflammatory status including C-reactive protein (CRP), ferritin, D-dimer, fibrinogen, absolute lymphocyte count (ALC), and absolute neutrophil count (ANC). Baseline data were collected prior to lymphodepletion. Outcomes of interest were occurrence and maximum grade of CRS and ICANS, occurrence of delayed neurotoxicity, attainment of peak ferritin ≥5000 within 30 days of infusion, progression-free survival (PFS), and overall survival (OS). Univariate logistic regression was used to assess the association between baseline labs and CRS, ICANS, delayed neurotoxicity, and peak ferritin ≥5000. Ordinal logistic regression was used to assess the baseline labs' association with maximum grade of CRS and ICANS, while proportional cox regression was used to assess their association with OS and PFS. The percentage of bone marrow plasma cells pre-CAR T, which we used as a surrogate for tumor burden, was included as a covariate on multivariable analyses. Results: A total of 101 patients treated with CAR T cells were included - 45 with ciltacabtagene autoleucel, 37 with idecabtagene vicleucel, and 19 with other products on clinical trials. Median age was 63 (range 37-82), median baseline marrow plasma cells percentage was 5% (range 0%-95%), and median follow-up was 11.9 months. Patients had a median (IQR) CRP of 4.0 mg/L (1.8, 11.8), ferritin of 174 ng/mL (68, 364), D-dimer of 0.6 mcg/L (0.4, 1.2), fibrinogen of 397.0 mg/dL (334.0, 477.5), ALC of 0.8 x10 3/µL (0.5, 1.1), and ANC of 2.7 x10 3/µL (1.9, 3.6). CRS occurred in 88.2% of patients (3.9% grade ≥3), ICANS in 15.7% (all grade <3), and delayed neurotoxicity in 5.9% (all grade <3). Increased baseline fibrinogen and ferritin were significantly associated with inferior OS even after adjusting for covariates (p-values 0.031 and 0.010, respectively). Every 143 mg/dL increase in fibrinogen increased the hazard of death by 83.7%, while every 500 ng/mL increase in ferritin increased the hazard of death by 27.5%. Patients with higher baseline CRP had a trend towards inferior OS (30.2% increased hazard of death per 20 mg/L CRP increase, p = 0.055). Baseline CRP, D-dimer, fibrinogen, ferritin, ALC, and ANC were not associated with PFS. Higher baseline ALC was associated with both increased odds of ICANS (110.2% increased odds of ICANS for every 0.5 x10 3/µL increase in ALC, p = 0.019 on multivariable analysis) and increased grade of ICANS (p = 0.023 on multivariable analysis). None of the assessed biomarkers were associated with peak ferritin ≥5000 (aside from baseline ferritin), occurrence of CRS, maximum grade of CRS, or delayed neurotoxicity. Conclusion: Although CAR T-cell therapy is a highly effective treatment option for patients with multiple myeloma, outcomes of infused patients can be highly variable. Serologic biomarkers like fibrinogen and ferritin are routinely assessed in patients undergoing CAR T-cell therapy and could offer value as predictors of outcomes. We found that higher fibrinogen and ferritin values at baseline were associated with inferior OS after CAR T-cell therapy, even after controlling for tumor burden. Higher baseline ALC was also associated with higher risk of ICANS and higher grade of ICANS, an important toxicity to consider for patients receiving CAR T. Baseline fibrinogen, ferritin, and ALC may be incorporated into assessments of the risk of CAR T-cell therapy for multiple myeloma patients.

A Phase 1 Study of NKX101, a Chimeric Antigen Receptor Natural Killer (CAR-NK) Cell Therapy, with Fludarabine and Cytarabine in Patients with Acute Myeloid Leukemia

Introduction Relapsed or refractory (r/r) acute myeloid leukemia (AML) has a dismal prognosis. Treatment options are limited and include fludarabine (Flu) and cytarabine (Ara-C), +/- anthracyclines (e.g., FLAG-Ida). Recent progress has been limited to targeted therapies, which benefit only a subset of the population; efforts to develop cellular therapies have not been met with success. NKX101 is an NK cell therapy derived from healthy donors and engineered to express an NKG2D ligand-directed chimeric antigen receptor (CAR) to enhance killing of malignant cells, as well as a membrane bound form of interleukin (IL)-15 to promote persistence and activity. Because Ara-C is known to upregulate NKG2D ligand expression, use of Flu/Ara-C as an alternative to standard Flu/cyclophosphamide (Flu/Cy) for lymphodepletion (LD) was tested for NKX101. Methods Six patients with r/r AML were enrolled in this cohort of NKX101-101, a Phase 1 safety study. All patients had received at least one prior line of therapy, as well as approved targeted therapies for those with underlying genetic mutations. Patients received NKX101 at a dose of 1.5 billion (B) viable CAR+ cells/dose on Days 0, 7, and 14 after LD comprising Flu (30 mg/m2) and Ara-C (2 g/m2) each once daily for five days and 2 days of rest. Efficacy assessments were performed on Day 27 and included bone marrow aspiration and biopsy. Additional treatment cycles of LD and NKX101 were given to some patients to deepen or consolidate responses. Pharmacokinetic (PK) and cytokine sampling were performed throughout the treatment cycle(s). Results At baseline, five out of six patients had poor-risk genetic features, including TP53 mutation; the median bone marrow blast count was 35% (range: 20 - 86%). Patients had received a median of two prior lines of therapy, with all patients having previous venetoclax exposure (Table 1). All patients received at least three doses of NKX101 at 1.5 B cells/dose. There were no cases of cytokine release syndrome (CRS), immune cell associated neurotoxicity syndrome (ICANS), or graft-versus-host disease of any grade in any patients (Table 2). Myelosuppression and infection were the most common higher-grade toxicities. Four out of six patients had CR/CRi, with three out of six achieving CR. Three of these patients had no detectable MRD by flow, and one had 0.18% RUNX1-RUNX1T1 translocation via polymerase chain reaction testing on bone marrow. One subject was taken to consolidative hematopoietic cell transplant (HCT) and remains in CR. Another subject received a consolidative cycle of therapy and remains in CR. A third subject had three cycles of treatment with successive decrease in disease burden and remains in CRi. The fourth subject had CR after one cycle of treatment. PK profiling showed that NKX101 was consistently detected and correlated with infusion days (Figure 1). Cytokine data showed minimal post-infusion elevations above baseline; no association was observed between clinical response and elevation of serum cytokines (including IL-15, IL-6, IFNγ, IL-10, and IL-8). Data on the expression of NKG2D ligands (MICA, MICB, ULBP1, and ULBP3) in subject bone marrow samples were obtained via multiplex immunohistochemistry. This was evaluated as a composite H-score. Responders were split between those with relatively low ligand expression and those with higher ligand expression, suggesting that further factors may contribute to NK cell resistance. Conclusions Alternative LD with Flu/Ara-C followed by NKX101 shows promising early responses including MRD negativity in r/r AML. The toxicity profile of this regimen is manageable and was consistent with underlying AML and exposure to LD, without any events of CRS or ICANS. Expansion of enrollment and longer follow-up are needed. Despite being an allogeneic, non-HLA-matched cell product, NKX101 persisted for up to three weeks in PK testing. Directly comparing the data from patients treated with Flu/Cy with NKX101 versus Flu/Ara-C with NKX101 suggests that Flu/Ara-C can replace the Flu/Cy regimen common to CAR T cell therapy as LD without compromising overall NKX101 exposure.

Brexucabtagene Autoleucel in Adults with Relapsed/Refractory B-Cell ALL: Outcomes and Novel Insights from the Real-World Outcomes Collaborative of CAR T in Adult ALL (ROCCA)

Introduction In October 2021, brexucabtagene autoleucel (brexu-cel) received U.S. FDA approval as the first CAR T-cell therapy for adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) based on the 55-patient ZUMA-3 Phase II study. We subsequently established ROCCA and now report on the largest cohort of patients treated with commercial brexu-cel for r/r B-ALL to date. Methods Adults (18+) with r/r B-ALL infused with commercial brexu-cel across 25 U.S. institutions were included. ASTCT consensus criteria were used to score CRS and ICANS. Methodologies for assessing MRD (minimal threshold of 10 -4) included flow cytometry, NGS, or qPCR depending on institution practice. Duration of remission (DOR) was calculated from time of complete response (CR); progression-free survival (PFS) and overall survival (OS) were calculated from day of brexu-cel infusion and were not censored for hematopoietic cell transplant (HCT) or maintenance. All living patients were censored at the time of last follow-up prior to data lock, which occurred on June 30, 2023. Results Among 152 infused, the median age was 46 (range, 18-81), 57% were male, and 34% were Hispanic. Most (67%) had Ph- ALL, were heavily pre-treated (median 4 prior lines), and entered apheresis with high disease burden (57%). At time of apheresis, 23% of patients only had MRD+ disease and 15% were in complete molecular remission. While 82% developed CRS, the majority was grade 1-2, with 9% of the overall cohort experiencing grade 3-4 CRS. In contrast, 55% developed ICANS, with 32% of the entire cohort experiencing grade 3-4 ICANS. Eight patients (5%) died of toxicity/infection prior to D+28 response assessment. Among 133 patients with response assessment, 120 (90%) achieved morphologic CR, of whom 82% were MRD-, 15% were MRD+, and 3% MRD unknown. The median follow-up for survivors was 8.4 months; 45 patients have relapsed and 42 patients died. Median DOR was not reached. Median PFS and OS were 8.6 months and 15.6 months, respectively. Estimated PFS and OS of the entire cohort at 6-months were 61% (95% CI, 52-68) and 81% (95% CI, 73-87) and at 12-months were 47% (95% CI, 37-56) and 63% (95% CI, 53-72), respectively. We found no association between pre-CAR disease burden and post-CAR PFS/OS. However, patients with MRD- response to CAR had superior PFS relative to patients with MRD+ CR (median 14 months vs. 5 months, P=0.002). Forty-four patients received post-CAR consolidation/maintenance therapy while in CR: 25 allogeneic HCT, 15 TKI, 2 POMP, and 3 other/unknown. To examine the effect of consolidation/maintenance following brexu-cel, we performed a landmark analysis of PFS limited to patients alive and in CR at 2-months post-CAR infusion (N=113) and suggests superior PFS in patients receiving either HCT or other forms maintenance, relative to those receiving no further therapy following brexu-cel ( P=0.055). We then investigated post-CAR MRD-response in combination with receipt of post-CAR consolidation/maintenance and found that even among patients achieving MRD-negative response, post-CAR consolidation/maintenance led to superior PFS (Figure 1). Conclusions Among 152 adults treated with commercial brexu-cel for r/r B-ALL across 25 U.S. institutions, we found very high response rates (CR/CRi: 90%; 82% MRD-) consistent with the Zuma-3 data. While rates of severe CRS are low, grade 3-4 ICANS was observed in 32% of patients and warrants further investigation We demonstrate the prognostic impact of achieving an MRD-negative CR and an emerging role for consolidation/maintenance therapies to enhance the durability of response following brexu-cel in adults r/r B-ALL.

Effects of Idecabtagene Vicleucel (Ide-Cel) Versus Standard Regimens on Health-Related Quality of Life (HRQoL) in Patients with Triple-Class-Exposed (TCE) Relapsed/Refractory Multiple Myeloma (RRMM) Who Received at Least 3 Lines of Prior Antimyeloma Regimens in the KarMMa-3 Phase 3 Randomized Controlled Trial

Introduction: Patients with TCE RRMM have a high disease burden and often report worsening HRQoL with additional lines of therapy. The single-arm, phase 2 KarMMa study demonstrated that ide-cel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy, improved HRQoL from baseline in patients with TCE RRMM who had received ≥ 3 prior regimens (Delforge M, et al. Blood Adv 2022;6:1309-1318). Furthermore, in the phase 3 KarMMa-3 clinical trial (NCT03651128), ide-cel significantly improved progression-free survival and response compared with standard regimens in patients with TCE RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014). Here we assessed the comparative effects of ide-cel versus standard regimens on HRQoL in patients with TCE RRMM who had received 3-4 prior regimens including an immunomodulatory agent, a proteasome inhibitor, and daratumumab (an anti-CD38 monoclonal antibody) using data from the KarMMa-3 study. Methods: Patient-reported outcomes (PROs) were assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. The pre-specified primary domains of interest included EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D-5L visual analog scale (EQ-5D VAS). PROs were collected at screening (baseline), the day of ide-cel infusion (ide-cel) or first treatment dose (standard regimens), monthly from 2 to 28 months, and thereafter every 3 months. Comparisons were performed on least squares (LS) mean changes from baseline through 28 months between arms using constrained longitudinal data analysis (cLDA). Effect size was estimated by Hedges' g. The comparative effects of ide-cel versus standard regimens on time to confirmed improvement and time to confirmed deterioration (defined by prespecified change thresholds) were assessed via stratified Cox proportional hazards regression analyses. All P values are nominal and not adjusted for multiple testing. Statistical significance was set at P < 0.05. Results: Baseline characteristics were well balanced among the patients in the ide-cel arm (n = 167) and the standard regimen arm (n = 93), with a median age of 63 years and a median time of 4.7 years from RRMM diagnosis to study screening. Completion rates of HRQoL assessments were high over time for most visits (> 75%). At baseline, mean HRQoL domain scores were similar between arms. Overall LS mean changes from baseline to 28 months showed significant differences in favor of ide-cel versus standard regimens (nominal P < 0.05) for 11 domains (effect sizes of 0.26-0.82), and 7 (4 primary: global health status/QoL, cognitive functioning, pain, EQ-5D VAS; 3 secondary: dyspnea, insomnia, constipation) of them exceeded the prespecified MID thresholds (Table). Time to confirmed improvement was significantly shorter (nominal P < 0.05) in the ide-cel arm than in the standard regimen arm for 10 domains, including all primary domains except pain. Time to confirmed deterioration was longer in the ide-cel arm than the standard regimen arm for most domains, with significant differences in emotional functioning, cognitive functioning, and dyspnea (EORTC QLQ-C30). Finally, side effects of treatment favored the ide-cel versus standard regimen arm (EORTC QLQ-MY20) (Table). Conclusions: These patient-reported findings demonstrate that compared with standard regimens, treatment with ide-cel improved MM-relevant disease symptoms, functioning, and overall health status/HRQoL of patients with TCE RRMM in the KarMMa-3 trial. These data further substantiate the superior treatment outcomes of ide-cel over standard regimens in this patient population. Overall, treatment with ide-cel may help alleviate detriments to HRQoL in these patients with complex disease.

Bendamustine Versus Fludarabine and Cyclophosphamide for Lymphodepletion Prior to CAR-T Therapy

Background As CAR-T treatment volumes and approved indications rapidly expand, identifying optimal lymphodepleting chemotherapy (LDC) regimens is an urgent and unmet need. A combination of fludarabine and cyclophosphamide (flu/cy) is most commonly performed. However, an ongoing international fludarabine shortage1 has led to the use of bendamustine (benda), a potent lymphotoxin, as LDC, with initial reports suggesting similar efficacy with less toxicity2, 3. We performed a multi-center retrospective analysis of patients with non-Hodgkin lymphoma (NHL) who have received benda or flu/Cy LDC prior to infusion of FDA-approved CAR-T products across the Sarah Cannon Transplant and Cellular Therapy Network (SCTCTN). We hypothesized that, compared with flu/cy, benda is noninferior in terms of lymphodepletion, hematologic recovery, CAR-T response and toxicities, as well as resource utilization. Methods We retrospectively analyzed 215 NHL patients receiving benda (46) or flu/cy (169) LDC prior to commercial CAR-T from 2018-2023 in the SCTCTN CAR-T registry. Patients on clinical trials, who received CAR-T for other malignancies than NHL, or were within 30 days of CAR-T infusion were excluded. Absolute lymphocyte count (ALC), neutrophil, and platelet kinetics were measured. Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were graded according to consensus criteria of the American Society of Transplant and Cellular Therapy (ASTCT), and the occurrence, maximum grade, days to onset/resolution, and tocilizumab dosing were recorded. Overall survival (OS), progression free survival (PFS), and resource utilization (length of stay in hospital and ICU requirement) were recorded. Results Characteristics of patients receiving benda and flu/cy were matched in terms of age, gender, race, ethnicity, NHL subtype, performance status. Flu/cy and benda produced deep absolute lymphocyte count (ALC) nadirs by the date of CAR-T infusion (day 0) with subsequent partial recovery by day 30. Lymphodepletion nadir at day 0 was deeper [P<0.001] with flu/cy (ALC 0.03 K/uL, IQR range 0.01-0.05) than benda (ALC 0.21 K/uL, IQR range 0.1-0.3) but not at other time points. The kinetics of neutrophil and platelet recovery were similar between groups suggesting an equivalent extent of marrow suppression. Parameters of resource utilization such as inpatient hospitalization, length of stay, ICU utilization, and the use of tocilizumab were similar between flu/cy and benda recipients. Conclusion In a large cohort of real-world CAR-T recipients, benda produced efficient lymphodepletion and equivalent outcomes compared to traditional flu/cy. While flu/cy produces a deeper nadir than benda at day 0, this difference did not exert clinical relevance.