American Society For Transplantation And Cellular Therapy Research Articles

Impact of Allogeneic Stem Cell Transplant on Safety and Outcomes of Chimeric Antigen Receptor T Cell (CAR-T) Therapy in Patients with Multiple Myeloma (MM).

Background: Allogeneic stem cell transplantation (allo-SCT) has seen limited use in treating multiple myeloma (MM), despite its potential to offer long-term survival or even cure through the graft-versus-myeloma effect. Its limited application is largely due to concerns over serious complications like infections and graft-versus-host disease (GVHD). The possibility of GVHD exacerbation when CAR-T cells are administered to patients previously treated with allo-SCT remains a topic of concern. Ciltacabtagene autoleucel (Cilta-cel) and idecabtagene vicleucel (Ide-cel) are CAR-T therapies that have been FDA-approved for relapsed/refractory (R/R) MM. A recent study using data from the CARTITUDE-1 trial has shown promising safety and efficacy of Cilta-Cel in patients with a prior history of allo-SCT. This report outlines our real-world experience with CAR-T treatment in such patients. The objective of this study is to assess the safety and effectiveness of CAR-T therapy in R/R MM patients who have previously undergone allo-SCT. Methods: We conducted a retrospective analysis of adult patients (18-70 years old) with R/R MM treated with CAR-T therapy as part of an institutional IRB-approved protocol. Data were collected on safety and efficacy outcomes from the institution's records. Adverse events (AEs) were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Efficacy metrics included overall response rate (ORR) and progression-free survival (PFS), analyzed through the Kaplan-Meier method, with PFS defined as the time from CAR-T initiation to disease progression or death. Results: Of the 56 patients treated with CAR-T therapy, 8 (14.3%) had previously undergone allo-SCT. These patients had a median of seven prior therapy lines (LOTs), compared to five LOTs in the non-allo-SCT group (p = 0.04). CAR-T infusion occurred a median of 98.8 months after allo-SCT, with a range from 57.9 months to 178.5 months. CRS occurred in 87.5% of the allo-SCT group versus 77.1% in the non-allo-SCT group (p = 0.48). One patient in the allo-SCT group developed hemophagocytic lymphohistiocytosis (HLH), requiring anakinra. At a median follow-up of 4.8 months, the ORR was 87.5% in the allo-SCT group versus 75% in the non-allo-SCT group (p = 0.4). Median PFS had not been reached for the allo-SCT group at the time of analysis compared to 11.9 months in the non-allo-SCT group (p = 0.5). No treatment-related mortality or acute GVHD was noted in the allo-SCT cohort. Conclusions: The study suggests that prior allo-SCT does not adversely affect the safety or efficacy of CAR-T therapy in patients with R/R MM. These findings highlight the need for further investigations with larger patient samples and longer follow-up to better understand the interaction between allo-SCT and CAR-T therapy.

Proceedings of the 2024 Third Annual ASTCT-NMDP ACCESS Initiative Workshop

The Third Annual Workshop of the American Society for Transplantation and Cellular Therapy (ASTCT) and National Marrow Donor Program (NMDP) ACCESS Initiative occurred on July 23 and 24, 2024. Content from the workshop is provided to inform the hematopoietic cell transplantation (HCT) and cellular therapy (CT) ecosystem about progress and direction of the collaborative. Highlights from the meeting are reviewed, including the inaugural Corporate Roundtable and Advocacy Day, new partnerships with non-profit organizations, and updates on projects from the Awareness, Poverty and Race and Ethnicity Inequity Committees. In addition, the Junior Faculty and Trainee Immersion Program-sponsored efforts in workforce diversity and physician advocacy are also presented. Lastly, continued education was provided on patient and caregiver participation as well as community engagement. As it enters its third year, the ASTCT-NMDP ACCESS Initiative will transition from foundation-building as a grass roots collaborative to intentional impact in reducing barriers and improving outcome disparities for all patients in need of HCT/CT. Enthusiasm for and participation in the ACCESS Initiative remain high and both are needed to sustain progress in achieving its goal in enabling all patients in need to receive HCT/CT.

ASTCT Committee on Practice Guidelines Survey on Evaluation and Management of Relapsed/Refractory Multiple Myeloma after Failure of Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor T cell therapy (CAR-T) has revolutionized the management of relapsed and/or refractory multiple myeloma (RRMM). However, CAR-T treatment failure is not uncommon and remains a major therapeutic challenge. There is substantial variability across transplantation and cellular therapy programs in assessing and managing post-CAR-T failures in patients with RRMM. The American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines conducted an online cross-sectional survey between September 2023 and December 2023 to determine myeloma, transplantation, and cellular therapy physicians' practice patterns for the surveillance, diagnosis, and management of CAR-T failure. The intent of this survey was to understand clinical practice patterns and identify areas for further investigation. Email surveys were sent to 1311 ASTCT physician members, of whom 80 (6.1%) completed the survey. The respondents were 58% white and 66% male, and 51% had >10 years of clinical experience. Most (89%) respondents were affiliated with a university/teaching center, and 56% had a myeloma-focused transplantation and/or cellular therapy practice. Post-CAR-T surveillance laboratory studies were commonly done every 4 weeks, and surveillance bone marrow biopsies and/or imaging surveillance were most commonly done at 3 months. Sixty-four percent of the respondents would often or always consider biopsy or imaging to confirm relapse. The most popular post-CAR-T failure rescue regimen was GPRC5D-directed immunotherapy (30%) for relapses occurring ≤3 months and BCMA-directed bispecific therapies (32.5%) for relapse at >3 months. Forty-one percent of the respondents endorsed post-CAR-T prolonged cytopenia as being "often" or "always" a barrier to next-line therapy; 53% had offered stem cell boost as a mitigation approach. Substantial across-center variation in practice patterns raises the need for collaborative studies and expert clinical recommendations to describe best practices for post-CAR-T disease surveillance, optimal workup for treatment failure, and choice of rescue therapies.

Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on behalf of the EBMT, ASTCT, CIBMTR, and APBMT

Despite emergence of novel therapies to treat hematologic malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an essential treatment modality capable of curing these diseases. Allo-HCT has been also shown to be curative in benign hematologic disorders such as aplastic anemia, sickle cell disease, and thalassemia, among others. Recently, the American Society for Transplantation and Cellular Therapy (ASTCT) published standardized definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism. To attempt broader international consensus, a panel of adult and pediatric physician transplant experts was assembled from European Society for Blood and Marrow Transplantation (EBMT), ASTCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), and Asia-Pacific Blood and Marrow Transplantation (APBMT). Consensus was defined as ≥70% of voting members strongly agreeing or somewhat agreeing with a definition. With few exceptions, there was a consensus to endorse the prior ASTCT definitions. Importantly, we revised existing EBMT and CIBMTR data collection forms to align with these harmonized definitions that will facilitate research and international collaboration among transplant researchers and across transplant registries.

Prospective Clinical and Biomarker Validation of the ASTCT Consensus Definition for Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

Introduction: Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications post-hematopoietic cell transplantation (HCT). Diagnosing TA-TMA is challenging due to non-standardized criteria. The American Society for Transplantation and Cellular Therapy (ASTCT) has proposed new consensus diagnostic criteria for standard risk (ASTCT-SR) and high risk (ASTCT-HR) but their correlation with older criteria based on microangiopathic hemolytic anemia (MAHA) or diagnostic complement biomarkers used in previous TA-TMA studies, such as levels of the terminal complement activation product sC5b-9 and the alternative complement pathway activation product Factor Ba, is unknown. Using data and samples from an ongoing prospective pediatric cohort study, we compared the two definitions and their associations with biomarkers. Methods: Patients aged 0 to 18 years who underwent first allogeneic HCT 2021-2023 at Texas Children's Hospital were included in the clinical and biomarker study. Those who did not have at least 100-day post-HCT event-free follow-up were excluded. Two different definitions for TA-TMA were applied. Clinical TMA (cTMA) was diagnosed if a patient 1) met 4/4 concurrent criteria of MAHA (schistocytosis, thrombocytopenia, anemia, and elevated lactate dehydrogenase (LDH)) at least twice in 14 days and 2) clinically adjudicated to exclude known mimics or alternative causes of TMA. In contrast, ASTCT-HR TMA was diagnosed if a patient 1) met 4/7 non-concurrent criteria (schistocytosis, thrombocytopenia, anemia, elevated LDH, elevated blood pressure, elevated urinary protein excretion, and elevated sC5b9) at least twice in 14 days and 2) had evidence of LDH >2x normal, proteinuria ≥1 mg/mg, elevated sC5b9, acute graft-versus-host disease, active bacterial/viral infection, or end-organ damage. Cumulative incidence of TA-TMA was assessed by the competing risk method. Overall survival was compared by the Kaplan Meier estimator and log-rank test. Biomarker levels for samples collected at day 15 (+/- 14 days) were compared using the t-test. Results: A total of 32 patients met the inclusion criteria. The median age was 5.7 years (range 1.1-18.8) and most were White (68.8%) and Hispanic (56.2%). Malignant disease was the indication for HCT in 50% of patients. While the classic MAHA-based cTMA definition had an incidence of 12.7%, the newly proposed ASTCT-HR definition doubled it to 28.5% by day-100 (Figure 1). In contrast to patients with concordant TA-TMA diagnosis (+/+) who had significantly worse post-transplant survival (p=0.0047) compared with those with concordant non-TMA (-/-), those reclassified as TA-TMA by the new definition only (-/+) had an unexpectedly good prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Longitudinal biomarker analysis was conducted on 29 patients. The highest average plasma levels of sC5b-9 and Ba during the first 100 days were observed in patients meeting both cTMA and ASTCT-HR criteria (+/+). When focused on early biomarkers measured around day 15, sC5b-9 (P=0.041) and Ba (P=0.004) were significantly elevated in the doubly positive TMA group (+/+) vs. non-TMA group (-/-) (Figure 2). We did not observe significant differences for ASTCT-HR singly positive (-/+) vs. non-TMA group (-/-). Conclusions: In the current prospective clinical and biomarker study, the recently proposed ASTCT-HR definition was more sensitive but less prognostic than the traditional cTMA definition for TA-TMA. Patients who solely met the ASTCT-HR diagnostic criteria but not the cTMA criteria had benign complement biomarker profiles and excellent survival prognosis without TMA-directed therapy. While clinicians need to be vigilant for this infrequent yet potentially severe complications, it is crucial that diagnostic criteria accurately identify affected patients given the expense and potential complications of treatment. We recommend ongoing validations of the new consensus diagnostic criteria from other prospective cohort studies with larger sample sizes and extended follow-up.

Real-World Outcomes of CD19CAR T Cell Therapy in Adult Patients with Relapsed Refractory Transformed Indolent Lymphoma

Introduction Transformation of indolent lymphomas to diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes, particularly for patients (pts) with relapsed or refractory (r/r) disease. While chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of r/r DLBCL and is approved for transformed indolent lymphoma (TIL), patients with TIL were largely underrepresented in the pivotal trials leading to the approval of CD19CAR T. In this study, we evaluate the safety and efficacy of standard of care (SOC) CD19CAR T in TIL relative to de novo DLBCL (dDLBCL). Methods We performed a multi-center retrospective study to evaluate safety and efficacy of SOC CD19CAR T in adults with r/r TIL and dDLBCL treated at 5 centers. Eligibility criteria included age ≥ 18 years old, diagnosis of DLBCL (de novo or transformed), r/r disease, and receipt of SOC CD19CAR T. Pts who received CAR T on clinical trials were excluded. We defined TIL as DLBCL transformed from follicular lymphoma (FL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM). Pts with Richter's syndrome were excluded. Safety endpoints: incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Response was assessed using 2014 Lugano Criteria. Efficacy endpoints include best overall response rate (ORR) (proportion of patients achieving a complete or partial response), complete response (CR) rate, progression/relapse-free survival (PFS) and overall survival (OS). Results A total of 788 pts were included (212 (27%) TIL, 576 (73%) dDLBCL) with the CAR T infusion date ranging from 12/2017 to 03/2023. In the TIL cohort, 192 (91%) pts transformed from FL, 14 (7%) MZL, 5 (2%) WM, and 1 indolent lymphoma NOS. In TIL and dDLBCL cohorts, respectively, the median age at infusion was 64 (range 33-85)/64 (21-85) yrs, 37%/36% were female, pts received a median of 3 (range: 1-11)/ 3 (1-13) prior lines of therapy, and 11%/13% had ECOG ≥2 at time of lymphodepletion. In TIL cohort, 44 (21%) pts received prior stem cell transplantation (41 autologous, 3 allogeneic, and none both), while in dDLBCL cohort, 135 (23%) received prior SCT (122 autologous, 9 allogeneic, and 4 both). In TIL and dDLBCL cohorts, 76%/73% received axicabtagene ciloleucel, 17%/18% tisagenlecleucel, and 7%/10% lisocabtagene maraleucel, respectively. Similar toxicities were observed in both cohorts. Any grade CRS/grade ≥ 3 CRS were observed in 76% (95% CI: 70-82%)/ 5% (3-9%) of TIL pts and 81% (78-84%)/ 6% (4-8%) of dDLBCL pts, respectively. Any grade ICANS/grade ≥ 3 ICANS rate were observed in 37% (95%CI: 31-44%)/ 16% (11-21%) of TIL pts and 49% (45-53%)/ 23% (20-27%) of dDLBCL pts, respectively. In TIL and dDLBCL cohorts, respectively, 49%/59% of pts received tocilizumab for CRS and 41%/51% received steroids for CRS or ICANS. Efficacy outcomes were comparable. The best ORR/ CR rate were 78% (95%CI: 72-83%)/ 63% (56-70%) in the TIL cohort and 77% (73-80%)/ 55% (51-59%) in the dDLBCL cohort. Among responders, the median time from infusion to best response was 33 days (IQR: 29-69) and 34 days (IQR: 29-85), respectively. With a median overall follow-up of 13.4 (0.03-63.1) months (mons), the median PFS was 11.2 mons (95%CI: 6.3-20.8) in the TIL and 7.9 mons (95%CI: 6.1-12.2) in the dDLBCL cohort, with a 24-month PFS of 39.4% (95%CI: 32.2-46.5%) and 39.7% (95%CI: 35.5-44.0%) respectively (logrank p=0.45). Median OS was 41.7 mons (95%CI: 24.9-not reached) and 29.7 mons (95%CI: 22.1-not reached) with a 24-month OS of 57.8% (95%CI: 50.1-64.7%) and 53.2% (95%CI: 48.4-57.7%) in TIL and dDLBCL cohorts, respectively (logrank p=0.49). There was no statistically significant difference between the survival outcomes of the TIL and dDLBCL cohorts. 41% (86/212) and 42% (241/576) pts died in the TIL and dDLBCL cohorts respectively, with similar rates of CAR T cell related deaths (9.3% vs 7.1%). Conclusion This study represents the largest evaluation to date of outcomes of CD19CAR T in TIL. The results indicate that CD19CAR T is tolerable and active in pts with r/r TIL with safety and efficacy outcomes similar to that observed in pts with dDLBCL. Our findings suggest CD19CAR T cell therapy may be able to overcome the historically poor prognosis associated with r/r TIL.

Modified Endothelial Activation and Stress Index (mEASIX) Score and Immune Effector Cell Associated Haematotoxicity (ICAHT) Following Varnimcabtagene Autoleucel (IMN-003A), a CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy, in the Phase-2 Study (IMAGINE)

Background: Varnimcabtagene autoleucel (IMN-003A) is an anti-CD19 CAR-T cell immunotherapy for patients (pts) with relapsed refractory B cell malignancies (RR BCM) in first-in-India Industry Phase 2 IMAGINE study, administered in a fractionated (10%/30%/60%) infusion protocol. Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are commonly associated adverse events with CAR-T cell therapy. The modified Endothelial Activation and Stress Index (mEASIX) score [lactate dehydrogenase (LDH) (U/L) × CRP (mg/dL) / platelets (PLT) (10 9 cells/L)] is a prognostic predictor of outcomes for patients in post-allogeneic transplant setting. Elevated LDH and low PLT levels have been associated with severe ICANS, and high IL-6 level is a recognized marker for CRS. Immune Effector Cell Associated Hemato-Toxicity (ICAHT) represents the most common toxicity after CAR-T cell therapy. CAR-HEMATOTOX score is used to risk stratify patients for cytopenia. This abstract reviews the mEASIX score and ICAHT for pts in the IMAGINE study, prognostic value of mEASIX for CRS, ICANS and responses, and correlation of ICAHT score with outcomes. Methods: mEASIX scores were calculated for each pt at lymphodepletion (LD), D0, D+1 and D+4. CRS and ICANS were graded as per American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Pts were monitored for ICAHT post CAR-T infusion and risk stratified using CAR-HEMATOTOX score. ICAHT was graded using CTCAE v5.0. Appropriate statistical tools were used for analysis. Results: Twenty-four RR BCM pts (12 B-ALL; 12 B-NHL) were treated with var-cel in this study. Overall response rate (ORR) was 91.7% (22/24) at D+28 (B-ALL 91.7%; B-NHL 91.7%) and 80.9% (17/21) at D+90 (B-ALL 80%; B-NHL 81.8%). AESIs reported were CRS (Grade [G] 1 62.5%; G3+ 4.2%; overall 66.7%); ICANS (G1 4.2%; G3+ 0%; overall 4.2%); neutropenia (G3+ 91.7%; overall 100%); anemia (G3+ 29.2%; overall 95.8%); and thrombocytopenia (G3+ 20.8%; overall 91.7%). CRS median onset was D+5 and duration 3 days. No G3+ ICANS was reported. Treatment related mortality was 4.2% (n=1/24, CRS); 3 pts died of disease progression. The mEASIX score at LD, D0, D+1 and D+4 and its correlation with CRS, ICANS and responses is shown in Table 1. At D+1, mEASIX score <1 was predictive for responses (entire cohort, p=0.05; OR 15.0). At D+4, mEASIX score >1 was nearing statistical significance (p=0.07) for CRS (all grades; OR 6.0). However, mEASIX score at other timepoints was not predictive for CRS, ICANS or responses. The incidence of ICAHT was 100% (all grades; n=24), 100% neutropenia (G3+ 91.7%); 95.8% (n=23) anemia (G3+ 29.2%) and 91.7% (n=22) thrombocytopenia (G3+ 20.8%). The median time (range) to resolution of anemia, neutropenia and thrombocytopenia was 90 (11-270), 17.5 (1-181) and 9 (1-181) days respectively. Classical, biphasic and prolonged cytopenia pattern was seen for Neutropenia in 6, 2 and 16 pts respectively; for Anemia in 2, 0 and 21 patients respectively and for Thrombocytopenia in 4, 1 and 17 patients respectively. Overall, all patients, except two, were pancytopenic during their treatment course. Figure 1 shows the temporal course of var-cel mediated haematotoxicity (ICAHT). Two pts (8.3%) each received red cells, platelets, G-CSF and romiplostim; majority did not need supportive treatment. CAR-HEMATOTOX score was low risk in 18 pts and high risk in 6 pts. There was no statistical correlation between low risk (18 pts) and high risk (6 pts) with responses (17 pts, p=0.92) or with relapse / disease progression (9 pts, p=0.21). Conclusions: This is the first-in-India industry study evaluating mEASIX and ICAHT in patients treated with CAR-T cell therapy. mEASIX score <1 was predictive of responses at D+1 and score >1 at D+4 was mildly predictive of CRS. All patients developed ICAHT but only a small number of patients needed supportive treatment. Overall, var-cel was well tolerated with manageable cytopenia. The CAR-HEMATOTOX score was not predictive of relapse / disease progression in the IMAGINE study. mEASIX score may be used as an early predictor of CRS for permissive use of Tocilizumab before onset of severe symptoms. The ICAHT profile was heterogeneous, probably reflective of hematopoietic reserve, lines of treatment and downstream immune responses. The predictive role of mEASIX score and ICAHT profile in a real-world setting needs further study.

Comparison of Fludarabine/Cyclophosphamide Vs Bendamustine As Lymphodepleting Regimen for CAR-T: A Safety and Efficacy Analysis in Patients with Relapsed/ Refractory Multiple Myeloma

Background Two commercially available anti-BCMA chimeric antigen receptor T-cell therapies (CAR-T) are approved by FDA for use in patients with relapsed multiple myeloma (RRMM). Lymphodepletion (LD) with fludarabine in combination with cyclophosphamide (Flu/Cy) is used as a standard regimen sequentially prior to CAR-T. Due to a national shortage with regards to availability of fludarabine, bendamustine (B) has emerged as a possible alternative regimen for LD. We evaluated the impact of bendamustine as an alternative lymphodepleting regimen to Flu/Cy on safety and efficacy profile of CAR-T therapy in patients with relapsed multiple myeloma. Patients and methods We conducted a single center, retrospective, IRB-approved study for patients with RRMM who received LD with B and FC at Hackensack University Medical Center (HUMC). Efficacy outcomes included overall response rates (ORR), Progression free survival (PFS) and Overall survival (OS). Response to CAR-T was assessed by the treating physician per International Myeloma Working Group (IMWG) criteria. Safety outcomes included the incidence and severity of adverse events (AEs). AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE 5.0). Cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) were graded as per the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Results We identified 53 patients with RRMM who received anti-BCMA CAR-T therapy between 6/2021 and 6/2023, who had a follow-up of at least 30 days following infusion. Due to shortage of fludarabine, the majority of pts (67.9%) received LD with B. Baseline characteristics are described in table 1. The median age of the entire cohort was 69.6 years, not significantly different between the B vs FC group. There were no statistically significant differences between the two groups with respect to the baseline characteristics except more pts were male in the B group (66.7% vs 32.1%, p=0.03) and the type of CAR-T product received. No significant differences were found with regards to the safety profile; however, the ORR were found to be higher in the FC group compared to the B group (88.2% vs 69.4%) although not statistically significant (p=0.1). Median PFS (mPFS) was shorted in the B group compared with the FC group (7.7 months vs 13.1 months) respectively (p=0.0047). Median OS (mOS) was not reached in the FC group, whereas it was 12.4 months in the B group, p=0.5. Conclusions LD with B was not found to have any significant impact on the CRS or ICANS, however a lower ORR (although not statistically significant) was found. mPFS was shorter for the B group compared to the FC group which was a statistically significant finding. Although the follow-up is short, our experience suggests that the use of B as LD may have a negative impact on outcomes of pts receiving CAR-T therapy for RRMM.

Primary Analysis of Varnimcabtagene Autoleucel (IMN-003A) in Phase 2 Study (IMAGINE), a First-in-India Industry CD19-Directed CAR-T Cell Therapy for Patients with Relapsed Refractory B Cell Malignancies

Background: Varnimcabtagene autoleucel (IMN-003A) is an autologous second-generation CAR-T cell product with a 4-1BB co-stimulatory domain and a non-FMC63 based murine single chain variable fragment targeting CD19 (A3B1 binder), manufactured in India. Preclinical and Phase 1 study was conducted at HCB / IDIBAPS Spain. Here, we present the primary analysis of IMAGINE, a Phase 2, multicenter, single-arm study of var-cel for patients in India with relapsed/refractory B cell malignancies (RR BCM) (CTRI/2022/03/041162). Methods: Patients (pts) aged 3 to 45 years (B-ALL) and ≥ 18 years (B-NHL) with RR BCM were eligible if they had measurable disease, as assessed by lymphoid blasts (B-ALL) or metabolic tumour bulk (B-NHL), received ≥1 prior regimen, refractory to the last line of treatment with good performance status (ECOG 0 to 1). Bridging therapy was allowed after apheresis. Cyclophosphamide (300 mg/m 2) and fludarabine (30 mg/m 2) on days -5 to -3 were used as preparative lymphodepletion regimen. The target dose was 1x10 6/kg CAR+ cells (B-ALL) and 5x10 6/kg CAR+ cells (B-NHL) (overall range 0.1x10 6 to 5x10 6) and was administered in a fractionated manner (10%/30%/60%) over 3 days with at least 24h between infusions. Primary objectives were overall response rate (ORR: CR + CRi in B-ALL and CR + PR in B-NHL) at day +90 after first infusion, and safety. Response was assessed as per NCCN (B-ALL) and IWG (B-NHL) criteria; bone marrow minimal residual disease (MRD) for B-ALL was analyzed by flow cytometry at 10 -4 sensitivity and PET-CT for B-NHL. Adverse events (AEs) were graded using CTCAE v5.0. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Results: At data cut-off, of 25 pts enrolled (median age 31 yrs, range 3 - 66) with RR BCM [n=13 B-ALL, median blasts 0.34% (range 0.01 - 27.2); n=12 B-NHL, median TMTV 67.9 ml (range 27.1 - 1177), median SPD 3846 mm 2 (range 1001 to 35849], 24 pts received var-cel (1 withdrawal) with majority of infusions on Days 0, +3, +7 and 12 pts (50%) needed bridging therapy. Median CAR-T cell manufacturing time was 14 days (range 10 - 27) with 100% manufacturing success. Median follow-up after IMN-003A administration was 205 days (range 12 - 434). Overall response rate (ORR) was 91.7% (22/24) at D+28 (B-ALL 91.7%, MRD neg 83.3% (n=10/12); B-NHL 91.7%, CR 66.7%) and 80.9% (17/21) at D+90 [B-ALL 80%, MRD neg 80% (n=8/10); B-NHL 81.8% (9/11), CR 63.6%]. One B-NHL pt in PR at D+28 achieved CR at D+90. Three pts relapsed by D+90. Of MRD evaluable pts, response was 100% at day+28 (n=11/11) and 88.9% at D+90 (n=8/9). Median time to first response was 28 days. Median progression free survival (PFS, range 12-NR), duration of response (DOR, range 0-NR) and overall survival (OS) were not reached (range 12-NR). AESIs reported were CRS (Grade [G] 1 62.5%; G3+ 4.2%; overall 66.7%); ICANS (G1 4.2%; G3+ 0%; overall 4.2%); neutropenia (G3+ 91.7%; overall 100%); anemia (G3+ 29.2%; overall 95.8%); and thrombocytopenia (G3+ 20.8%; overall 91.7%). CRS median onset was D+5 and duration 3 days. No G3+ ICANS was reported. Tocilizumab, steroids and anakinra usage was in 37.5% (n=9/24, majority for persistent G1 CRS), 8.3% and 4.2% respectively. Treatment related mortality was 4.2% (n=1/24); 3 pts died of disease progression. IMN-003A cells demonstrated peak expansion on D+10 (range 7 - 28 days). 79.2% at D+28 and 29.2% at D+90 had measurable CAR+ T cells in peripheral blood; median D+28 (range D+10 - NR). Updated results will be presented in the meeting. Conclusions: Varnimcabtagene autoleucel (IMN-003A), a First-In-India Industry CD19-directed CAR-T Cell Therapy for RR BCM, has demonstrated manageable safety profile and durable efficacy outcomes with deep responses including absence of severe neurotoxicity. This offers a significant benefit over standard treatment options for patients with RR BCM.

A Pro-Inflammatory State and Peak Cytokines Are Associated with Toxicity and Early Responses in Real-World Multiple Myeloma Patients Treated with Idecabtagene Vicleucel

Introduction. Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor T-cell therapy (CAR-T) approved for patients with triple-class exposed relapsed/refractory multiple myeloma (TCE RRMM) (Munshi NC, et al. N Engl J Med 2021;384:705-716). Treatment-related toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are prevalent and common to all CAR T-cell therapies. We examined the association of serum cytokines and pre-CAR-T bone marrow composition with toxicity and early response among patients with TCE RRMM treated with ide-cel. Methods. Patients treated with commercial ide-cel at H. Lee Moffitt Cancer Center between May 5 th, 2021 to May 18 th, 2023, and that consented to a biospecimen collection protocol, were included. Serum cytokine levels (GM-CSF, IL2, IL6, IL15, IFNγ, Angiopoietin 1&2 [ANG1, ANG2] and TNFα) were measured at apheresis, pre-lymphodepleting (LD) chemotherapy (day -6), infusion (D0) and at least weekly until day 28 using the Ella system (ProteinSimple). Inflammatory markers (C-reactive protein [CRP], ferritin, and albumin) at pre-LD were measured in the clinical laboratory. Marrow biopsy plasma cell burden (PCB) and marrow aspirate immune cell phenotyping of T cells, myeloid cells, and natural killer (NK) cells by flow cytometry were calculated prior to LD. High PCB was considered ≥50% CD138+ plasma cells. CRS and ICANS were graded per the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria. Patient characteristics, cytokines, and other biomarkers were examined by any grade and ≥ grade 2 CRS and ICANS and day 90 (D90) response using Wilcoxon rank sum or chi-square tests. Results. 86 patients were included, and 30 (35%) were analyzed by flow cytometry. Patient characteristics included a median age of 66 years (range, 43-83), 30% high PCB, 33% high-risk cytogenetics, and a median of 6 prior lines of therapy (range 4-13). Any grade CRS occurred in 80% of the patients, ≥ grade 2 CRS in 19%, any grade ICANS in 14%, and ≥ grade 2 ICANS in 10%. Tocilizumab was administered to 65%, 29% received steroids, and 2% received anakinra. At D90, 52/78 (67%) had achieved ≥ partial response (PR) and 26/78 (33%) had either stable disease (SD), progressive disease (PD) or had died. Three deaths occurred by D90 and were attributed to complications of myeloma progression. Older patients (≥ 65 years) were more likely to develop any grade CRS (p=0.04) and ICANS (p=0.047), and those requiring bridging chemotherapy were more likely to develop ICANS (p=0.025). High PCB was not associated with CRS or ICANS, but was associated with T cell exhaustion and increased CD56 dim NK-cells (p<0.05, Figure A). At apheresis, patients with higher TNFα levels were more likely to develop ICANS (p=0.004), but no other cytokines were associated with toxicity at this timepoint, although patients with CRS and ICANS had numerically higher IL-6. At LD, elevated ratio of ANG2/ANG1 (p=0.029), IL-15 (p=0.019), and high CRP/low albumin ratio (p=0.007) were observed for patients that developed ICANS. Higher peak cytokines, ferritin, and CRP were associated with any grade CRS (p<0.05), and higher peak IL6 was associated with grade ≥ 2 CRS (p=0.03). Patients that developed any grade ICANS had higher peak IL6, IL15, ANG2 /ANG1 ratio, ferritin, and CRP (p<0.05), and these associations persisted for IL15, ANG2/ANG1 ratio, ferritin, and CRP for grade ≥ 2 ICANS (p<0.05). Achievement of ≥PR at D90 was associated with higher peak levels of GM-CSF, IL2, IFNγ, and TNFα (p<0.05, Figure B). Conclusion. In this analysis of real-world TCE RRMM patients treated with commercial ide-cel, inflammatory markers, pre-treatment marrow plasma cell burden, and immune cell subsets were associated with treatment-related toxicities and early responses. These findings provide insights into potential avenues for toxicity prevention and therapeutic optimization in high-risk patients. Additional studies in a larger patient cohort are warranted to understand the complex relationships between inflammation, immunity, toxicity, and efficacy among TCE RRMM patients treated with ide-cel.

Prospective Clinical and Biomarker Validation of the American Society for Transplantation and Cellular Therapy Consensus Definition for Transplantation-Associated Thrombotic Microangiopathy

Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications after allogeneic hematopoietic cell transplantation (allo-HCT). Diagnosing TA-TMA is challenging because of the lack of standardized criteria. In this study, we aimed to evaluate the new TA-TMA consensus definition from the American Society for Transplantation and Cellular Therapy (ASTCT) panel as part of an ongoing prospective pediatric cohort study, and also to compare the impact and outcomes of using the current definition of clinical TMA (cTMA) versus the new consensus definition. We included patients age 0 to 18 years who underwent their first allo-HCT between May 2021 and January 2023 at Texas Children's Hospital. We compared the incidence, biomarkers, and outcomes of TA-TMA applying the previous and recently proposed screening algorithms and definitions. Whereas use of the classic microangiopathic hemolytic anemia (MAHA)-based cTMA definition led to an incidence of 12.7% by day 100 post-transplantation, the ASTCT-HR definition doubled the incidence to 28.5% by day 100. In contrast to patients with a concordant diagnosis (+/+), who had significantly worse post-transplantation survival, those reclassified as TA-TMA only by the new definition (-/+) had a significantly different prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Furthermore, biomarkers of the terminal and alternative complement pathways (sC5b9 and Ba, respectively) were significantly elevated compared with non-TMA patients around day 15 in the concordant group (+/+) but not in the discordant group (-/+). The recently proposed ASTCT consensus TA-TMA diagnosis is more sensitive and allows earlier recognition of manifestation that requires closer clinical monitoring but risks overdiagnosis and overtreatment. We recommend additional prospective validation.

Assessing Medicaid Coverage for Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy: A Project from the American Society for Transplantation and Cellular Therapy and the National Marrow Donor Program ACCESS Initiative

The American Society for Transplantation and Cellular Therapy (ASTCT) and the National Marrow Donor Program (NMDP) formed the ACCESS Initiative to address and reduce barriers to hematopoietic cell transplantation (HCT) and cellular therapy (CT) to ensure equal access and outcomes for all patients in need. The 3 committees, addressing awareness, poverty, and racial and ethnic inequity, defined pilot projects focusing on addressing relevant barriers to HCT/CT. Because many socioeconomically disadvantaged HCT/CT recipients receive care through state Medicaid programs, the Poverty Committee conducted a Medicaid scan of all 50 US states with the following objectives: to define beneficiary coverage for allogeneic and autologous HCT and chimeric antigen receptor (CAR) T cell therapy; to define support for travel, temporary lodging, and meals for both beneficiaries and caregivers; and to determine search and cell acquisition payment procedures. Here we summarize the results of the Medicaid scan and highlight significant variations and gaps in coverage for HCT/CT recipients. We also provide an initial roadmap for addressing gaps in Medicaid support for HCT and CAR-T therapy recipients.

The Transplantation Ecosystem: A New Concept to Improve Access and Outcomes for Older Allogeneic Hematopoietic Cell Transplantation Patients

Allogeneic hematopoietic cell transplantation (HCT) is increasingly offered to older adults with hematologic malignancies, even though nonrelapse mortality remains a major concern in older patients owing to more comorbidities and greater frailty compared with their younger counterparts. The importance of patient fitness, a well-matched donor, and disease control to the success of allogeneic HCT have been well documented; however, these factors fail to account for the impact of the complex transplantation ecosystem (TE) that older adult HCT candidates must navigate. We propose a definition of the TE modeled after the social determinants of health. Furthermore, we outline a research agenda aimed at increasing understanding of the roles of individual social determinants of transplantation health in the larger ecosystem and how they may benefit or harm older adult HCT candidates. Herein we define the TE and its individual tenets, the social determinants of transplantation health. We review the available literature while incorporating the expertise of the membership of the American Society for Transplantation and Cellular Therapy (ASTCT) Special Interest Group for Aging. The membership of the ASTCT Special Interest Group for Aging identify knowledge gaps and strategies to address them for each of the described social determinants of transplantation health. The ecosystem is an essential but underappreciated pillar for transplant access and success. We put forth this novel research agenda seeking to gain a better understanding of the complexity of HCT in older adults and develop strategies to improve access to HCT, survival, and quality of life.

162 - Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplant Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation (EBMT), American Society for Transplantation and Cellular Therapy (ASTCT), Asia-Pacific Blood and Marrow Transplantation Group (APBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR)

162 - Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplant Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation (EBMT), American Society for Transplantation and Cellular Therapy (ASTCT), Asia-Pacific Blood and Marrow Transplantation Group (APBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR)

Paving the Road for Chimeric Antigen Receptor T Cells: American Society for Transplantation and Cellular Therapy 80/20 Task Force Consensus on Challenges and Solutions to Improving Efficiency of Clinical Center Certification and Maintenance of Operations for Commercially Approved Immune Effector Cell Therapies

As the number and type of regulatory authority-approved cellular therapies grow, clinical treatment centers face a heavy burden of duplicative documentation around initial qualification, ongoing auditing, and reporting, with overlapping requirements from each manufacturer to ensure safe use of their specific product, which in the United States are stipulated under individual Food and Drug Administration (FDA) Biologic License Applications. The American Society for Transplantation and Cellular Therapy (ASTCT) convened the 80/20 Task Force to consider challenges and potential solutions to these issues. The Task Force proposed that 80% of manufacturers' requirements for onboarding and ongoing operations of commercially available products could be standardized and streamlined. Task Force members interviewed dozens of stakeholders, including clinicians at large academic medical centers already using commercial and investigational immune effector cell (IEC) products, regulators, members of accrediting bodies and professional cellular therapy societies, and manufacturers of IEC therapies for oncologic indications. In November 2021, the Task Force organized and led virtual discussions in a public forum and at a private ASTCT 80/20 Workshop at the online AcCELLerate Forum, a cellular-therapy stakeholders' meeting organized by the ASTCT, National Marrow Donor Program (NMDP), and Center for International Blood and Marrow Transplant Research (CIBMTR). At the workshop, approximately 60 stakeholders worked to identify and prioritize common challenges in onboarding and maintenance of operations at clinical sites for commercial FDA-approved and future IEC therapies and ways to streamline the process. It was agreed that standardization would improve efficiency of onboarding, allowing more cost-effective, sustainable growth of approved IEC therapies at treatment centers, and facilitate wider access while maintaining safety and clinical success. This early but extensive survey of stakeholders resulted in 5 overarching suggestions for both established and emerging treatment centers: (1) eliminate duplication in accreditation and auditing of clinical sites; (2) define expectations for the education about and management of CAR-T therapy toxicities to potentially replace product-specific REMS programs; (3) streamline current REMS education, testing, and data reporting; (4) standardize information technology (IT) platforms supporting enrollment, clinical site-manufacturer communication, and logistics of maintaining chain of identity/chain of custody across multiple transportation steps; and (5) encourage the use of universal nomenclature by cell therapy manufacturers. Future discussions need to engage a broader range of stakeholders, including administrators, pharmacists, nurses, data coordinators, surgeons, pathologists, and those developing promising cellular therapies for solid tumors, as well as teams from smaller academic or community cancer center settings. Continued collaboration with stakeholders outside of clinical sites will include accrediting bodies/auditors, established and emerging cell therapy companies, software developers, professional societies, and the patients who receive these therapies. Active dialog with government regulators remains essential. Such joint efforts are critical as the number of IEC therapies for myriad oncologic and nononcologic indications grows.

Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations

Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations

Role of Autologous Stem Cell Transplantation in Patients with Peripheral T-Cell Lymphoma in the First Complete or Partial Remission: A Propensity Score-Matched Analysis

Background Consolidation with autologous stem cell transplantation (ASCT) was recommended for most responders to the initial peripheral T-cell lymphoma (PTCL) treatment. Evidence came primarily from retrospective studies affected by a selection bias between patients allocated to receive ASCT or not and a few prospective studies with no control groups (d'Amore F,2012; Ellin F, 2014). The National Comprehensive Cancer Network and the American Society for Transplantation and Cellular Therapy (ASTCT) recommend ASCT for patients with first-time complete remission (CR1). The European Society of Medical Oncology (ESMO) guidelines suggest that patients with first-time partial remission (PR1) could also be considered for ASCT (d'Amore F, 2015). However, the role of ASCT in patients with PTCL after CR1 or PR1 remains controversial. The COMPLETE study showed an insignificant tendency for better survival following ASCT in the PTCL with CR1 group (Park SI, 2016). The LYSA multicenter study investigated the effect of ASCT in patients with CR1 or PR1. Neither propensity score matching (PSM) nor Cox multivariate analysis supported the advantage of ASCT in upfront consolidation (Fossard G, 2018). However, well-designed randomized controlled trials to investigate the precise effect of ASCT in the front-line setting are lacking. Therefore, we aimed to investigate the efficacy of ASCT for PTCL with CR1 and PR1 by PSM analysis. Methods We pre-screened 8 826 patients with lymphoma admitted to Peking University, Cancer Hospital & Institute from January 1996 to November 2020. Patients with mature T/NK cell lymphomas were selected (n = 1 136). We excluded patients with NK/TCL or missing clinical data. Response assessment to the initial treatment was evaluated by 18F-FDG positron emission tomography/computed tomography (PET/CT) or CT using the Lugano criteria. We identified 685 patients with PTCL, of which 622 achieved CR1 or PR1. PSM was used to balance clinical indicators between the ASCT and non-ASCT groups. The primary endpoints were event-free survival (EFS) and overall survival (OS). Results Among the 622 patients who underwent initial therapy, 272 (43.7%) achieved CR1, and 147 (23.6%) achieved PR1 after the treatment. After excluding 5 patients with subsequent unknown schemes following the initial treatment, 414 were included in the final analysis (ASCT, n = 73; non-ASCT, n = 341). With a median follow-up of 5.7 years for the entire cohort, long-term survival in the ASCT group was better than in the non-ASCT group (median EFS, 8.1 vs. 2.8 years, P = 0.002; median OS, 14.9 vs. 10.2 years; P = 0.007). The 5-year EFS and OS were 66.7% (95% CI, 56.0-79.4%) and 74.7% (95% CI, 64.1-87.0%) in patients with ASCT consolidation, and 26.6% (95% CI, 23.0-30.8%) and 43.6% (95% CI, 39.2-48.4%) in patients without ASCT. After PSM, the ASCT and non-ASCT groups were similar in their disease subtypes, LDH level, Ann Abor stage, and the response to the initial treatment. The survival advantage for ASCT (n = 46), as a consolidation procedure, over non-ASCT (n = 84; median EFS. 8.1 vs 2.7 years, P = 0.007; median OS, not reached vs 7.7 years; P = 0.022; Figure 1) was maintained even after PSM. For the entire cohort, ASCT was associated with better long-term survival than non-ASCT [hazard ratio (HR) for EFS, 0.46 (95% CI, 0.28-0.76), P = 0.003; HR for OS, 0.50 (95% CI, 0.31-0.84), P = 0.008)]. Subgroup analysis showed that patients at a higher risk based on International Prognostic Index (IPI) stratifications and advanced stages might benefit significantly from ASCT. Patients with angioimmunoblastic T-cell lymphoma (AITL) in the ASCT group appeared to show better survival than those in the non-ASCT group (EFS: HR, 0.26; 95% CI, 0.10-0.66; P = 0.005; OS: HR, 0.29; 95% CI, 0.12-0.74; P = 0.009). However, ASCT endowed no survival advantage for other PTCL subtypes. Conclusion ASCT could improve the long-term survival of responders to the initial treatment among patients with PTCL, especially those with AITL. However, the specific population that could benefit most from up-front ASCT needs to be characterized further. Figure 1. EFS (A) and OS (B) after propensity score matching in the ASCT and non-ASCT groups Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The ASTCT-NMDP ACCESS Initiative: A Collaboration to Address and Sustain Equal Outcomes for All across the Hematopoietic Cell Transplantation and Cellular Therapy Ecosystem

The American Society for Transplantation and Cellular Therapy (ASTCT) and the National Marrow Donor Program (NMDP) have formed the ACCESS Initiative to address and reduce barriers to hematopoietic cell transplantation (HCT) and cellular therapy (CT) in an effort to ensure equal access and outcomes for all patients in need. In addition to cellular therapy physicians, the initiative includes program administrators, health policy and health equity experts, health service researchers, participants from commercial payer organizations, and federal stakeholders. The inaugural ASTCT-NMDP ACCESS Workshop was held in Washington, DC on July 28 and 29, 2022, wherein committee members met to discuss and to define goals for 3 focus areas: awareness, poverty, and racial and ethnic inequity. This position paper reviews the mission, vision, and structure of the ACCESS Initiative and the proceedings from the inaugural workshop and provides an initial roadmap for the group's efforts at reducing access barriers and outcome disparities in HCT/CT.

Editorial introductions.

Current Opinion in Infectious Diseases was launched in 1988. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of infectious diseases is divided into 11 sections that are reviewed once a year. Each section is assigned to a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Genovefa A. PapanicolaouGenovefa A. PapanicolaouDr Genovefa A. Papanicolaou is the Director of Clinical Trials in the Infectious Disease Service at Memorial Sloan Kettering Cancer Center and Professor at Weill Cornell Medical College of Cornell University in New York, USA. Dr Papanicolaou is the current Chair of the Infectious Disease special Interest Group (ID-SIG) of the American Society for Transplantation and Cellular Therapy (ASTCT). Her research focuses on viral infections after stem cell transplantation and particularly cytomegalovirus (CMV). Her areas of interest are novel therapeutics, biomarkers and personalized infection management. Dionysios NeofytosDionysios NeofytosDionysios Neofytos is an Infectious Disease specialist with expertise in infectious disease complications in patients with hematologic malignancies and bone marrow and solid organ transplant recipients. Since the completion of his training in Infectious Diseases at Thomas Jefferson University Hospital in Philadelphia, PA, USA, in 2006 he has joined the Faculty and worked as an attending physician with the Transplant Infectious Disease Services at the Johns Hopkins University in Baltimore, MD, USA, and the Memorial Sloan Kettering Cancer Center in New York, NY, USA. Since 2016, he joined the Division f Infectious Diseases at the University Hospital of Geneva, in Geneva, Switzerland. His research and area of expertise are focusing on the epidemiology, diagnosis and management of viral and invasive fungal infections in immunocompromised hosts. Trish M. PerlTrish M. PerlTrish M. Perl, MD, MSc, is the H. Ben and Isabelle T. Decherd Chair in Internal Medicine (Infectious Diseases and Geographic Medicine) at UT Southwestern Medical Center in Dallas TX, USA. Dr Perl received her Medical Degree from the University of North Carolina (Chapel Hill), USA, and a Master of Science from McGill University in Montreal, Canada. She trained in Internal Medicine at the Royal Victoria Hospital and in Infectious Diseases and Clinical Epidemiology at the University of Iowa, USA. She rose through the ranks to Professor of Medicine at Johns Hopkins University School of Medicine, USA, and Epidemiology at the Bloomberg School of Public Health and is recognized globally for her innovation and research in healthcare associated infections, antimicrobial resistance, and their transmission and prevention. As the Hospital Epidemiologist at Johns Hopkins Hospital and Health System Epidemiologist, she developed extensive practical and research experience. Internationally, she has helped with outbreak management and mitigation including SARS, MERS CoV, Ebola and consults on guideline development and strategies to prevent emerging threats in healthcare. She is actively involved in monitoring the COVID-19 pandemic and supporting the national and local response.

Timing of Tocilizumab Administration Under the Guidance of IL-6 in CAR-T Therapy for R/R Acute Lymphoblastic Leukemia.

Chimeric antigen receptor T (CAR-T) cells targeting CD19 have achieved great clinical responses in patients with relapsed or refractory (R/R) acute B lymphoblastic leukemia. However, severe adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome restrict it to further application. Tocilizumab is the corner stone for the treatment of severe CRS. It has been used to treat mild CRS in recent years, whereas some statistical supports clarifying the suitable timing of its administration are lacking. Sixty-seven patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated with CD19-CART and enrolled in the study, of which 33 patients received Tocilizumab. Application of Tocilizumab in patients with grade 2 CRS in American Society for Transplantation and Cellular Therapy (ASTCT) criteria can significantly shorten the duration of CRS without affecting side effects and long-term efficacy. However, a number of patients still developed severe CRS with early use of Tocilizumab, indicating the significance of the introduction of clinical laboratories to assist medications. Statistically, patients with less than fourfold increase in IL-6 levels had a higher incidence of severe CRS after receiving Tocilizumab (37.5% versus. 0%, p=0.0125), which provided a basis for refining CRS intervention strategies under the guidance of IL-6.Clinical Trial Registration www.clinicaltrials.gov, NCT02965092 and NCT04008251