Emily C. Liang, MD

All Publications

• Early neurologic response predicts outcomes after anakinra for immune effector cell-associated neurotoxicity syndrome BLOOD ADVANCES Liang, E. C., Kungwankiattichai, S., Wu, X., Voutsinas, J., Macero, D., Khouderchah, C., Qiao, Y., Jeon, Y., Basom, R., Huang, J. J., Portuguese, A. J., Kimble, E. L., Hirayama, A., Shadman, M., Chen, A. I., Desai, A., Hayes-Lattin, B., Meyers, G., Bastola, S., Rai, M., Leonard, J., Trussell, J., Stomberg, C., Spurgeon, S. E., Okada, C., Shree, T., Silbermann, R., Medvedova, E., Ratterree, B., Bixler, R., Williamson, S., Phan, C., Ahrenkiel, R., Wu, Q., Maziarz, R. T., Gauthier, J. 2026; 10 (15): 5264-5275

  Abstract

  Anakinra is increasingly used for corticosteroid-refractory and/or severe immune effector cell-associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor (CAR) T-cell therapy; however, robust data on its efficacy and predictors of response are lacking. We evaluated the outcomes of 101 patients treated with anakinra for ICANS (corticosteroid-refractory, n = 90) and investigated factors associated with anakinra efficacy. The median time to ICANS resolution from anakinra initiation was 8 days, and the 28-day cumulative incidences of ICANS resolution and treatment-related mortality (TRM) were 86% and 13%, respectively. Anakinra treatment failure occurred in 28%. The day +28 antitumor response rate was 91% (complete response, 47%). Significant neurologic improvement (SNI; ≥2-grade improvement in ICANS) occurred in 43% of patients within 72 hours after anakinra initiation. Achieving 72-hour SNI was associated with faster time to ICANS resolution (median, 3 vs 9 days; P< .001) and hospital discharge (28-day cumulative incidence, 93% vs 53%; P< .001), lower 2-week cumulative exposure to dexamethasone (120 vs 190 mg; P = .029) and anakinra (3650 vs 6600 mg; P = .059), lower TRM (28-day cumulative incidence, 0% vs 21%; P = .011), and a trend toward superior overall survival (28 days, 98% vs 74%; P = .094). In multivariable analysis, older age, CAR T-cell product type, and higher day 0 C-reactive protein were independently associated with lower odds of 72-hour SNI. Our study benchmarks key clinical outcomes after anakinra treatment for ICANS; 72-hour SNI may provide a practical clinical decision point to identify patients who may require additional treatment strategies.

  View details for DOI 10.1182/bloodadvances.2026020103

  View details for Web of Science ID 001842244800001

  View details for PubMedID 42530978

  View details for PubMedCentralID PMC13449367

• Coordinated expansion of CD163+ monocytes and immature CD177+ neutrophils marks severe neurotoxicity after CD19 CAR T cell therapy. bioRxiv : the preprint server for biology Chour, T., Poole, N., MacMillan, H. R., Burleigh, K., Glass, D. R., Liang, E. C., Basom, R., Webb-Robertson, B. M., Stratton, K., Gratz, D., Long, A. N., Elz, A. E., Huang, J. J., Hirayama, A. V., Riddell, S. R., Gauthier, J., Gustafson, H. H., Newell, E. W., Simon, S. 2026

  Abstract

  Immune effector cell-associated neurotoxicity syndrome (ICANS) is a major complication after CAR T cell therapy, but its underlying mechanisms remain poorly understood. We performed longitudinal immune profiling of paired whole blood and serum samples from patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) treated with CD19 CAR T cells. At peak neurotoxicity, high-dimensional mass cytometry and serum proteomics identified the expansion of CD163+ monocytes and immature CD10lowCD101low neutrophils correlated with elevated serum ST2 and IL-2RA concentrations. Integrative immune module analysis identified these features among the strongest predictors of ICANS severity. Independent single-cell transcriptomic profiling validated the emergence of immunoregulatory CD163+ monocytes and identified CD177 as a biomarker of ICANS-associated immature neutrophils. Together, these findings reveal a coordinated myeloid inflammatory network associated with ICANS and nominate candidate biomarkers and therapeutic targets for improving the safety of CAR T cell therapy.

  View details for DOI 10.64898/2026.07.07.737099

  View details for PubMedID 42465399

  View details for PubMedCentralID PMC13371044

• A novel dose-dense strategy for CD19-directed CAR T-cell therapy is associated with durable responses without increased toxicity in patients with B-cell non-Hodgkin lymphoma. Haematologica Ortiz-Maldonado, V., Liang, E. C., Huang, J. J., Jeon, Y., Hirayama, A. V., Kimble, E. L., Portuguese, A. J., Khouderchah, C., Braathen, K., Torkelson, A., Kirchmeier, D., Shadman, M., Maloney, D. G., Riddell, S. R., Turtle, C. J., Gauthier, J. 2026

  Abstract

  CD19-directed chimeric antigen receptor (CAR) T-cell therapy induces durable remissions in only 30-40% of patients with relapsed or refractory (R/R) B-cell non- Hodgkin lymphoma (B-NHL), highlighting a major need to improve outcomes. In dose-escalation studies, higher CAR T-cell doses improved tumor control but caused prohibitive toxicities. Having established the maximum tolerated JCAR014 dose in patients with B-NHL at 2 x 106 CAR+ cells/kg, we hypothesized that a second infusion at day 14 ("dose-dense") at the same dose and without repeat lymphodepletion, would be safe and enhance antitumor efficacy. We report outcomes from the pilot dose-dense cohort of a phase 1/2 trial (ClinicalTrials.gov identifier: NCT01865617) with 8-year follow-up. Two CAR T-cell products, each containing 2 x 106 CAR+ cells/kg, were manufactured for all 20 treated patients; 17 received both infusions. Any-grade cytokine release syndrome (CRS) and neurotoxicity (NT) occurred in 10 (59%) and 3 (18%) of dose-dense patients, respectively, and-except for one grade 2 CRS-events followed the first infusion only. Despite no additional lymphodepletion, CAR T-cell re-expansion after the second infusion occurred in 16 (94%) patients. By Lugano criteria, overall and complete response rates were 47% (8/17) and 41% (7/17), respectively. Among responders, the 8-year durationof- response rate was 63% (95% CI: 37-100), comparing favorably with the 26% (95% CI: 14-48) observed in patients treated with a single infusion. In conclusion, early redosing on day 14 was feasible, safe and led to durable responses in patients with R/R B-NHL.

  View details for DOI 10.3324/haematol.2025.300321

  View details for PubMedID 42389828

• Fear of Cancer Recurrence in Hematopoietic Cell Transplantation Survivors. Transplantation and cellular therapy Liang, E. C., Shen, M. J., Salit, R. B., Onstad, L., Vo, P., Oshima, M. U., Boiko, J. R., Lee, C. J., Carpenter, P. A., Gauthier, J., Simard, S., Lee, S. J. 2026; 32 (7): 895.e1-895.e8

  Abstract

  Fear of cancer recurrence (FCR) is a significant challenge faced by hematopoietic cell transplantation (HCT) survivors, yet it remains insufficiently characterized in this group, limiting the ability to develop interventions to reduce FCR. We aimed to determine the prevalence and correlates of clinically significant levels of FCR (csFCR) in a large cohort of long-term HCT survivors at a major cancer center. From July 1, 2023 through June 30, 2024, survivors who underwent HCT >1 year ago at Fred Hutch Cancer Center received an annual patient recovery questionnaire (PRQ) and FCR module that included Patient-Reported Outcomes Measurement Information System (PROMIS) instruments, the FCR Inventory-Short Form (FCRI-SF), and questions regarding adherence to healthcare maintenance and cancer screening. csFCR was defined as a score ≥16 on the FCRI-SF. We determined predictors of csFCR using logistic regression and compared PROs, healthcare maintenance, and cancer screening by presence of csFCR. Of 4514 participants, 1501 (33%) completed the PRQ and FCR module, and 513 (34%) reported csFCR. In univariate logistic regression, younger age at survey completion, shorter time from HCT, diagnosis, intermediate or high pre-HCT disease risk, current receipt of maintenance therapy, and history of post-HCT relapse were significantly associated with higher odds of csFCR. In multivariable logistic regression, younger age at survey completion, shorter time from HCT, and history of post-HCT relapse remained independently associated with higher odds of csFCR. Survivors with csFCR reported lower PROMIS physical and psychosocial function, greater anxiety before hematology/oncology appointments, and greater need for, yet reduced access to, psychological care. Rates of cancer screening did not differ significantly by presence of csFCR. HCT survivorship programs should integrate psychosocial support to address FCR and determine whether targeted interventions can mitigate FCR and improve quality of life.

  View details for DOI 10.1016/j.jtct.2026.03.022

  View details for PubMedID 41881346

  View details for PubMedCentralID PMC13108230

• Incidence and Risk Factors for CNS Relapse in Adult ALL after Allogeneic Hematopoietic Cell Transplantation. Blood advances Le, C. T., Zhang, A., Vyas, R. D., Otani, J., Russell, K., Cassaday, R. D., Muffly, L. S., Liang, E. C. 2026

  Abstract

  Relapse in the central nervous system (CNS) is a devastating outcome in acute lymphoblastic leukemia (ALL). Allogeneic hematopoietic cell transplantation (HCT) in ALL is reserved for patients with high-risk and/or relapsed/refractory disease. However, there is a paucity of data describing the incidence and factors associated with post-HCT CNS relapse in the modern era. In this multicenter retrospective study of adults with ALL who underwent first HCT between 2011 and 2021 at Stanford Health Care (SHC) or University of Washington/Fred Hutch Cancer Center (UW/FH), we aimed to describe the incidence of post-HCT CNS relapse, factors associated with post-HCT CNS relapse, and the impact of CNS relapse on overall survival (OS). A total of 636 patients were included. The 1- and 3-year cumulative incidences of CNS relapse after HCT were 3% and 6%, respectively. Absence of CNS involvement prior to HCT, pre-HCT MRD negativity, and receipt of TBI-based conditioning were significantly associated with decreased risk of post-HCT CNS relapse. These three characteristics defined a composite low-risk group that was associated with lower risk of post-HCT relapse [HR = 0.31 (95% CI, 0.15-0.68), p = 0.0032]. Post-HCT CNS relapse was significantly associated with shorter overall survival [HR 7.33 (95% CI, 5.12-10.49), p < 0.0001]; worse outcomes were seen with earlier post-HCT CNS relapse. Future studies will be needed to assess if this low-risk group may benefit from de-escalation of CNS-directed interventions during HCT.

  View details for DOI 10.1182/bloodadvances.2026020594

  View details for PubMedID 42348785

• Active Extramedullary Disease Predicts ICANS and Early ICAHT after CAR-T Therapy in Multiple Myeloma Transplantation and Cellular Therapy ( vol 31 , S409 , 2025) TRANSPLANTATION AND CELLULAR THERAPY Portuguese, A. J., Liang, E. C., Huang, J. J., Iovino, L., Wuliji, N., Dima, D., Banerjee, R., Kwok, M. L., Cicero, K. I., Shadman, M., Cowan, A. J., Gauthier, J. 2026; 32 (5): 630

  View details for DOI 10.1016/j.jtct.2025.03.009

  View details for Web of Science ID 001780337400001

• A Practical Guide to Competing Risk Analysis for Transplant and Cell Therapy Research. Transplantation and cellular therapy Vaquera-Alfaro, H. A., Jeon, Y., Wu, Q. V., Liang, E. C., Portuguese, A., Gómez-De León, A., Valdespino-Valdes, J., Gauthier, J. 2026; 32 (4): 489-500

  Abstract

  Competing risks are common in hematopoietic cell transplantation (HCT) and immune effector cell (IEC) therapy research. Competing risks refer to events that cannot co-occur and complicate time-to-event analyses. The typical example of competing risk in the context of HCT and IEC research is treatment-related mortality, which competes with disease relapse. In this primer, we first aim to introduce - in a clinician-friendly fashion - the core concepts underlying the statistical modelling of competing risks. Next, we propose a practical, step-by-step guide to analyze time-to-event outcomes in the context of competing risks using the open access R environment. Relevant R packages are introduced, enabling the generation of publication-ready tables and figures. We hope our manuscript will encourage more robust analyses in the fields of HCT and IEC therapy when competing risks are at play.

  View details for DOI 10.1016/j.jtct.2025.11.003

  View details for PubMedID 41205872

  View details for PubMedCentralID PMC12818700

• Real-world outcomes with elranatamab in multiple myeloma: a multicenter analysis from the U.S. Multiple Myeloma Immunotherapy Consortium. Blood cancer journal Portuguese, A. J., Davis, J. A., Raza, S., Castaneda Puglianini, O., Freeman, C., Alsina, M., Wright, C., Blue, B. J., Baz, R. C., Shain, K. H., Goel, U., Khouri, J., Anwer, F., Ali, H. M., Pasvolsky, O., Gaballa, M., Patel, K., Garcia-Pleitez, H., Mikulski, D., Fogel, L., Zolotov, E., Sannareddy, A., Afrough, A., Anderson, L. D., Julian, K., Dima, D., Banerjee, R., Liang, E. C., Cassano Cassano, R., Herr, M. M., Hassan, H., Shune, L., Kort, J., Midha, S., Nadeem, O., Sidana, S., Lin, Y., Locke, F. L., Hansen, D. K., Sborov, D., Biran, N., Grajales-Cruz, A. 2026

  Abstract

  Elranatamab, a BCMA-CD3 bispecific antibody, has demonstrated robust activity in relapsed/refractory multiple myeloma (RRMM), but real-world outcomes remain poorly defined. We conducted a multicenter retrospective study of 130 patients treated with commercial elranatamab across nine U.S. academic centers. The cohort was heavily pretreated (91% triple-class refractory, 49% penta-refractory), with 49% previously exposed to BCMA-targeted therapies. Only 22% would have met eligibility for MagnetisMM-3 cohort A. The overall response rate (ORR) was 65%, including ≥CR in 36%. Median progression-free survival (PFS) and overall survival (OS) were 4.3 and 14.6 months, respectively, shorter than MagnetisMM-3. Elevated LDH and low hemoglobin independently predicted poor outcomes and were incorporated into the novel ALPS (Anemia-LDH Prognostic System) score, which stratified patients into distinct risk groups for ORR, OS, PFS, and duration of response. Prior BCMA exposure reduced depth of response, with inferior OS observed in those treated within one year of prior therapy. Infections occurred in 38% of patients. Intravenous immunoglobulin supplementation, modeled as a time-dependent covariate, was associated with improved infection-free survival and PFS. While the incidence of CRS was modestly lower than in MagnetisMM-3, ICANS occurred more frequently in this real-world cohort. These findings highlight the efficacy, limitations, and supportive care needs of elranatamab in a frailer, more heterogeneous real-world RRMM population.

  View details for DOI 10.1038/s41408-026-01477-z

  View details for PubMedID 41896552

• Comprehensive Benchmarking of Outcomes after Anakinra Treatment for Refractory Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Kungwankiattichai, S., Liang, E. C., Wu, X., Voutsinas, J. M., Macero, D. C., Jeon, Y., Qiao, Y., Huang, J. J., Portuguese, A. J., Kimble, E. L., Hirayama, A., Shadman, M., Chen, A., Desai, A., Hayes-Lattin, B., Meyers, G., Bastola, S., Rai, M., Leonard, J. T., Trussell, J., Stomberg, C., Spurgeon, S. E. F., Okada, C., Shree, T., Silbermann, R. W., Medvedova, E., Ratterree, B., Bixler, R., Williamson, S., Wu, Q., Maziarz, R. T., Gauthier, J. ELSEVIER SCIENCE INC. 2026: S13-S14

  View details for Web of Science ID 001697336900014

• Fear of Cancer Recurrence in Hematopoietic Cell Transplantation Survivors Liang, E. C., Carpenter, P. A., Lee, C. J., Onstad, L., Oshima, M., Salit, R. B., Vo, P., Boiko, J. R., Simard, S., Gauthier, J., Lee, S. J. ELSEVIER SCIENCE INC. 2026

  View details for Web of Science ID 001695027500048

• Outcomes of Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS) in Patients Receiving Frontline Anakinra and Corticosteroids Liang, E. C., Macero, D. C., Khouderchah, C., Voutsinas, J. M., Basom, R., Jeon, Y., Wu, X., Huang, J. J., Portuguese, A. J., Wuliji, N., Iovino, L., Mazziotta, F., Kopmar, N. E., Shah, E. E., Markey, K., Kimble, E. L., V. Hirayama, A., Chapuis, A. G., Cassaday, R. D., Otegbeye, F., Biernacki, M., Till, B. G., Warren, E. H., Milano, F., Shadman, M., Wu, Q., Gauthier, J. ELSEVIER SCIENCE INC. 2026

  View details for Web of Science ID 001708751400029

• Peripheral HLA-DR plus Neutrophils, CD163+Monocytes and Inflammatory Serum Cytokines Coincide with Severe Immune Effector Cell-Associated Neurotoxicity at Peak Toxicity Onset in CD19 CART cell Therapy Chour, T., Poole, N., MacMillan, H., Burleigh, K., Glass, D., Webb-Robertson, B., Liang, E. C., Huang, J. J., Hirayama, A., Stratton, K., Riddell, S. R., Gauthier, J., Gustafson, H. H., Newell, E. W., Simon, S. ELSEVIER SCIENCE INC. 2026

  View details for Web of Science ID 001708751400064

• ALC Kinetics Velocity and Acceleration Are Early Predictors of Non-Icans Neurotoxicities after Cilta-Cel Treatment Jeon, Y., Wu, X., Khouderchah, C., Liang, E. C., Portuguese, A. J., Huang, J. J., Kimble, E. L., Hirayama, A., Shadman, M., Dima, D., Banerjee, R., Fong, L., Vicky, Q., Durbin, M., Gauthier, J. ELSEVIER SCIENCE INC. 2026

  View details for Web of Science ID 001708753600007

• NEMO: A Novel Prognostic Model of Non-Icans Neurotoxicities Associated with Ciltacabtagene Autoleucel Jeon, Y., Wu, X., Khouderchah, C., Liang, E. C., Portuguese, A. J., Huang, J. J., Kimble, E. L., Hirayama, A., Shadman, M., Cowan, A. J., Dima, D., Banerjee, R., Dhodapkar, M., Fong, L., Wu, Q., Durbin, M., Gauthier, J. ELSEVIER SCIENCE INC. 2026: S12-S13

  View details for Web of Science ID 001697336900013

• Prior transplantation and idecabtagene vicleucel in multiple myeloma: a secondary analysis of CIBMTR data. Blood Banerjee, R., Khouderchah, C., Akhtar, O. S., Liang, E. C., Gauthier, J., Dhodapkar, M. V., Portuguese, A. J. 2026; 147 (3): 312-315

  Abstract

  Recent analyses have suggested a possible negative impact of prior autologous stem cell transplantation on outcomes with idecabtagene vicleucel (ide-cel) chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma. Our registry-based analysis of >800 ide-cel recipients did not identify any such association.

  View details for DOI 10.1182/blood.2025031426

  View details for PubMedID 41284631

  View details for PubMedCentralID PMC13437223

• Time-Series Clustering Captures Patterns of Early Immune Effector Cell-Associated Hematotoxicity That Are Predictable Using Tree-Based Models. JCO clinical cancer informatics Liang, E. C., Jeon, Y., Qiao, Y., Wu, X., Huang, J. J., Portuguese, A. J., Basom, R., Torkelson, A., Kirchmeier, D., Braathen, K., Cowan, A. J., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E. L., Wu, Q., Gauthier, J. 2026; 10: e2500148

  Abstract

  Immune effector cell-associated hematotoxicity (ICAHT) is a major cause of nonrelapse mortality after chimeric antigen receptor (CAR) T-cell therapy. We hypothesized that unsupervised time-series clustering could better identify archetypal patterns of early hematotoxicity compared to the early ICAHT (eICAHT) grading system.We applied unsupervised k-means time-series clustering based on Euclidean distances to longitudinal absolute neutrophil count (ANC) data from days +0 through +30 post-CAR T-cell infusion in 691 patients treated at our center (training set: n = 483, 70%; test set: n = 208, 30%).Within our training set, we identified an optimal cluster solution based on four ANC recovery clusters, which were labeled as very good, good, poor, and very poor. We trained a random forest (RF) model including the top five most important features (day +3, +4, +5, +26, and +27 ANC values) to predict the cluster assignments. Within our test set, we applied the RF model to predict cluster assignments. Compared with the eICAHT criteria, the RF-predicted clusters were more compact and better separated (Dunn index: 0.078 v 0.034; average silhouette width: 0.12 v 0.010). In addition, the RF model identified patients in the good recovery cluster with intermediate overall survival (hazard ratio [HR], 1.70 [95% CI, 1.05 to 2.74]; P = .029; reference, very good), which was not captured by grade 2 eICAHT (HR, 1.37 [95% CI, 0.80 to 2.35]; P = .25; reference, grade 0-1).Unsupervised time-series clustering identified distinct and clinically relevant patterns of hematotoxicity after CAR T-cell therapy. We trained and tested an RF model that accurately predicted cluster assignments using only five features. Predictions can be generated using our online web application.

  View details for DOI 10.1200/CCI-25-00148

  View details for PubMedID 41534004

  View details for PubMedCentralID PMC12810859

• Eomesodermin+ CD4+ T cells are critical for curative immunotherapy outcomes. Immunity Zhang, P., Haeseleer, F., Waltner, O. G., Gartlan, K. H., Bhise, S. S., Minnie, S. A., Adams, R. C., Yeh, A. C., Ensbey, K. S., Legg, S. R., Sekiguchi, T., Atilla, E., Nemychenkov, N. S., Nelson, E. L., Joshi, T., Liang, E. C., Hirayama, A. V., Abe, K., Koyama, M., Clouston, A. D., Gauthier, J., Furlan, S. N., Hill, G. R. 2025; 58 (12): 3024-3039.e7

  Abstract

  Interleukin 10 (IL-10)-producing CD4+ type-1 regulatory T cells (Tr1) promote immune tolerance during chronic infection, autoimmunity, and transplantation. However, specific Eomesodermin (Eomes)-dependent stages of Tr1 differentiation and function remain unclear. Using preclinical models of bone marrow transplantation (BMT), we demonstrated a Tr1 differentiation trajectory in vivo from Eomes+IL-10- to Eomes+IL-10+ subsets with the acquisition of cytokine, cytolytic, and exhaustion features. The Eomes+CD4+ fraction represented the dominant cytotoxic subset after BMT, mediating graft-versus-leukemia effects while limiting inflammation. In CD19-targeted chimeric antigen receptor (CAR) T cell immunotherapy, Eomes drove the same CD4+ Tr1 phenotype that controlled cytolysis, while mitigating immune toxicity and promoting persistence. In individuals with high-grade B cell lymphomas that had long-term disease control after receiving commercial CD19-targeted CAR T cells, Eomes+ Tr1 cells represented a stable population comprising 40%-80% of the CD4+ CAR T cell population. Hence, Eomes controls both regulatory and cytotoxic programs in CD4+ T cells, essential for curative immunotherapy outcomes.

  View details for DOI 10.1016/j.immuni.2025.09.004

  View details for PubMedID 41043413

• Real-world outcomes with elranatamab in multiple myeloma: A multi-center analysis from the United States multiple myeloma immunotherapy consortium Portuguese, A., Davis, J., Raza, S., Puglianini, O., Freeman, C., Alsina, M., Wright, C., Goel, U., Khouri, J., Anwer, F., Ali, H. M., Pasvolsky, O., Gaballa, M., Patel, K., Pleitez, H., Mikulski, D., Fogel, L., Zolotov, E., Sannareddy, A., Afrough, A., Anderson, L., Julian, K., Dima, D., Banerjee, R., Liang, E., Cassano, R., Herr, M., Hassan, H., Shune, L., Kort, J., Midha, S., Nadeem, O., Sidana, S., Lin, Y., Locke, F., Hansen, D., Sborov, D., Biran, N., Grajales-Cruz, A. ELSEVIER. 2025: 136-137

  View details for DOI 10.1182/blood-2025-136

  View details for Web of Science ID 001660470700037

• High-dose anakinra to treat refractory immune effector cell-associated neurotoxicity syndrome in CAR T-cell therapy recipients Liang, E., Kungwankiattichai, S., Wu, X., Voutsinas, J., Macero, D., Jeon, Y., Qiao, Y., Huang, J., Portuguese, A., Mazziotta, F., Kopmar, N., Shah, E., Markey, K., Kimble, E., Hirayama, A., Chapuis, A., Cassaday, R., Till, B., Warren, E., Milano, F., Shadman, M., Chen, A., Desai, A., Hayes-Lattin, B., Meyers, G., Bastola, S., Rai, M., Leonard, J., Trussell, J., Stomberg, C., Spurgeon, S., Okada, C., Shree, T., Silbermann, R., Medvedova, E., Ratterree, B., Bixler, R., Williamson, S., Wu, Q., Gauthier, J., Maziarz, R. ELSEVIER. 2025: 928-929

  View details for DOI 10.1182/blood-2025-928

  View details for Web of Science ID 001659053400029

• Independent assessment of ALC thresholds currently in use to predict motor/neurocognitive toxicities (MNTs) after treatment with ciltacabtagene autoleucel Jeon, Y., Wu, X., Khouderchah, C., Liang, E., Portuguese, A., Huang, J., Kimble, E., Hirayama, A., Shadman, M., Cowan, A., Dima, D., Banerjee, R., Dhodapkar, M., Fong, L., Wu, Q., Durbin, M., Gauthier, J. ELSEVIER. 2025: 4147-4148

  View details for DOI 10.1182/blood-2025-4147

  View details for Web of Science ID 001663417500046

• Impact of Gamma-Secretase Inhibition on Outcomes Following BCMA CAR-T Therapy in Multiple Myeloma: A Comparison of Two Phase 1 Trials. Transplantation and cellular therapy Portuguese, A. J., Tuazon, S. A., Pont, M. J., Cole, G. O., Sather, B. D., Song, X., Thomas, S., Wood, B. L., Blake, M., Works, M. G., Shadman, M., Liang, E. C., Wu, V. Q., Voutsinas, J. M., Gooley, T. A., Turtle, C. J., Till, B. G., Coffey, D. G., Maloney, D. G., Libby, E. N., Chapuis, A. G., Milano, F., Riddell, S. R., Green, D. J., Cowan, A. J. 2025; 31 (12): 1002.e1-1002.e9

  Abstract

  BCMA-directed chimeric antigen receptor (CAR)-T cell therapy represents a major therapeutic breakthrough for relapsed/refractory multiple myeloma (RRMM), offering deep and durable responses in heavily pretreated patients. However, a subset of patients experiences early relapse or fail to respond, highlighting the need for strategies to enhance efficacy. Gamma-secretase inhibitors (GSIs) have been shown to increase surface BCMA expression on malignant plasma cells and may potentiate the activity of BCMA CAR-T cells, particularly in patients with low baseline BCMA antigen density. Two contemporaneous phase 1 trials (FH9952 and FH9762) evaluated the fully human BCMA-targeted CAR-T product FCARH143, with FH9952 incorporating GSI co-administration.To determine whether GSI use improves clinical outcomes following FCARH143 CAR-T therapy in RRMM, with particular focus on overall survival (OS), progression-free survival (PFS), and subgroup differences based on prior BCMA-targeted therapy and baseline tumor BCMA levels.This retrospective analysis compared outcomes from two single-arm, single-center phase 1 trials of the fully human BCMA-targeted CAR-T cell product FCARH143 in RRMM: FH9952 (n = 18), which incorporated the GSI crenigacestat, and FH9762 (n = 25), which did not. Both studies had extended follow-up beyond previously published reports. Eligible patients had measurable RRMM with ≥10% bone marrow plasma cell involvement and confirmed BCMA expression. BCMA-naïve patients were defined as those without prior exposure to BCMA-targeted therapies (e.g., BCMA CAR-T, bispecific antibodies, or antibody-drug conjugates); BCMA-exposed patients had received at least one such therapy. All participants received lymphodepletion with fludarabine and cyclophosphamide followed by infusion of FCARH143. In FH9952, crenigacestat (25 mg orally, three times weekly) was administered from day 0 through day +18. Outcomes included response rates, adverse events, OS, and PFS. Cox proportional hazards models were used for survival analysis.With extended follow-up (median 5.8 years), the overall cohort (n = 43) had a median OS of 2.7 years (95% CI 1.9-4.8) and median PFS of 1.1 years (95% CI 0.72-2.2). Baseline characteristics were generally similar, though BCMA-exposed status was more frequent in FH9952 (39% versus 8%). Rates of cytokine release syndrome, immune effector cell-associated neurotoxicity, and early immune effector cell-associated hematotoxicity were comparable between trials. Among BCMA-naïve patients (n = 34), GSI use was associated with improved OS (not reached versus 2.3 years; adjusted HR 0.30, 95% CI 0.10-0.88, P = .028) and a trend toward improved PFS (2.6 versus 1.3 years; adjusted HR 0.47, 95% CI 0.22-1.04, P = .062). No benefit was observed among BCMA-exposed patients. Exploratory spline modeling suggested GSI mitigated the adverse impact of low tumor BCMA levels, with inferior outcomes at low BCMA expression observed only in the non-GSI cohort.Co-administration of a GSI with BCMA CAR-T therapy was associated with improved survival in BCMA-naïve RRMM patients, particularly those with low baseline tumor BCMA levels. These findings suggest GSI modulation of BCMA surface expression may enhance CAR-T efficacy in select patients and support further prospective investigation.

  View details for DOI 10.1016/j.jtct.2025.09.003

  View details for PubMedID 40930223

• Extramedullary disease is associated with severe toxicities following B-cell maturation antigen CAR T-cell therapy in multiple myeloma. Haematologica Portuguese, A. J., Liang, E. C., Huang, J. J., Jeon, Y., Dima, D., Banerjee, R., Kwok, M., Cicero, K. I., Hirayama, A. V., Basom, R., Khouderchah, C., Shadman, M., Fong, L., Cowan, A. J., Gauthier, J. 2025; 110 (12): 3065-3077

  Abstract

  Extramedullary disease (EMD) in multiple myeloma (MM) is associated with poor outcomes following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T therapy, yet its impact on treatment-related toxicity remains unclear. This study evaluates the impact of active EMD on toxicity, efficacy, and survival in patients with MM treated with idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel). We conducted a retrospective cohort study of all patients with MM who received ide-cel (N=32) or cilta-cel (N=76) as standard-of-care therapy at our institution from August 2021 to October 2024. EMD was defined as the presence of soft tissue masses in extraosseous locations, and outcomes were compared based on EMD status. Among 108 patients, 26 (24%) had EMD. Patients with EMD experienced higher rates of grade (G)1+ (38% vs. 17%; P=0.022) and G3+ immune effector cell-associated neurotoxicity syndrome (19% vs. 1.2%; P=0.003), as well as G1+ (96% vs. 78%; P=0.041) and G3+ early immune effector cell-associated hematoxicity (31% vs. 0; P<0.001). Patients with EMD had more prolonged severe neutropenia (median: 7 vs. 2 days; P<0.001), greater cefepime use (median 10 vs. 6 doses; P=0.039), and higher rates of bacteremia (15% vs. 2.4%; P=0.029). In terms of efficacy, patients with EMD had lower complete response rates (20% vs. 59%; P<0.001), shorter median progression-free survival (7.6 vs. 24.6 months; P<0.001), and shorter median overall survival (20 months vs. not reached; P<0.001; 1-year estimates, 53% vs. 96%) and higher 1-year non-relapse mortality (21% vs. 2.5%; P=0.003). EMD is associated with increased toxicity, delayed hematologic recovery, more infectious complications, and reduced survival in patients with MM receiving CAR T therapy.

  View details for DOI 10.3324/haematol.2025.287985

  View details for PubMedID 40534492

  View details for PubMedCentralID PMC12666262

• Identifying high-risk profiles and adverse prognoses in relapsed/refractory multiple myeloma treated with bispecific antibodies: A real-world analysis of 943 treatment initiations Zanwar, S., Pasvolsky, O., Hansen, D., Goel, U., Afrough, A., Rana, M., Portuguese, A., Davis, J., Sborov, D., Bal, S., Janakiram, M., Shune, L., Ferreri, C., Biran, N., Herr, M., Hassan, H., Grajales-Cruz, A., Khouri, J., Corraes, A., Kort, J., Atrash, S., Puglianini, O., Baz, R., Cassano, R., Liang, E., Zolotov, E., Ali, H. M., Varga, C., Richards, T., Hosoya, H., Gaballa, M., Dillard, C., Fortuna, G., Lee, L., Julian, K., Green, K., Sannareddy, A., Anderson, L., Alsina, M., Raza, S., Dima, D., Mikkilineni, L., Anwer, F., Banerjee, R., Krishnan, A., Locke, F., Voorhees, P., Kumar, S., Sidana, S., Patel, K., Dhakal, B., Lin, Y., Costa, L. ELSEVIER. 2025: 4069-4070

  View details for DOI 10.1182/blood-2025-4069

  View details for Web of Science ID 001663433200019

• Incidence and risk factors for CNS relapse in adult ALL after allogeneic hematopoietic cell transplant Le, C., Zhang, A., Vyas, R., Otani, J., Russell, K., Cassaday, R. D., Muffly, L., Liang, E. ELSEVIER. 2025: 6038-6039

  View details for DOI 10.1182/blood-2025-6038

  View details for Web of Science ID 001671394700038

• Correlates of organ damage in patients with advanced systemic mastocytosis enrolled in clinical trials of avapritinib. Blood neoplasia Liang, E. C., Perkins, C., Lu, R., Shi, H., Dimitrijević, S., Abuel, J., Langford, C., Abidi, P., Fechter, L., Shomali, W., Gotlib, J. 2025; 2 (4): 100127

  Abstract

  Organ damage in patients with advanced systemic mastocytosis (AdvSM) at the time of enrollment in clinical trials of KIT inhibitors has not been well characterized. We describe the spectrum and clinicopathologic correlates of organ damage as defined by World Health Organization (WHO) and modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (mIWG) criteria among patients with AdvSM enrolled in the phase 1 and 2 trials of the KIT D816V inhibitor avapritinib (n = 174; systemic mastocytosis [SM] with an associated hematologic neoplasm [SM-AHN], 68%; aggressive SM and mast cell leukemia [MCL], both 16%). Notably, 47% of patients received previous midostaurin. Patients with SM-AHN had the highest absolute monocyte and eosinophil counts, whereas those with MCL had the highest serum tryptase level, bone marrow (BM) mast cell burden, and spleen/liver volumes. Treatment-naïve patients were more likely to fulfill WHO and mIWG criteria for hepatic organ damage. The presence of tier 1 SRSF2, ASXL1, and/or RUNX1 mutations was associated with older age, shorter interval between diagnosis and enrollment, and fewer number of previous therapies, including midostaurin. AdvSM subtype, the presence and number of additional comutated genes beyond KIT D816V, BM mast cell burden, and KIT D816V variant allele fraction were associated with the presence and/or number of WHO/mIWG organ damage findings. Our study provides a snapshot of the correlates of organ damage in patients enrolled in clinical trials of avapritinib and identifies a key association between molecular profile and burden of organ damage.

  View details for DOI 10.1016/j.bneo.2025.100127

  View details for PubMedID 41424934

  View details for PubMedCentralID PMC12711656

• Opportunities to Improve Antibiotic Stewardship, and Identification of Blood Biomarkers Associated with Bacteremia Following CAR-T Cell Therapy. Transplantation and cellular therapy Ng, S. K., Flaherty, P. W., Ancheta, M., Tindbaek, K. A., Sekhon, M. K., Huang, J. J., Portuguese, A. J., Albittar, A., Kopmar, N. E., Cowan, A. J., Shadman, M., Hirayama, A. V., Till, B. G., Cassaday, R. D., Turtle, C. J., Liu, C., Xie, H., Leisenring, W. M., Gauthier, J., Liang, E. C., Hill, J. A. 2025; 31 (10): 838.e1-838.e16

  Abstract

  Cytokine release syndrome (CRS) is frequent after chimeric antigen receptor T-cell therapy (CAR-T). CRS and bacteremia share clinical features, making it difficult to distinguish between the two and deliver targeted treatment. As a result, most patients with CRS receive empiric broad-spectrum antibiotics that may adversely impact long-term outcomes. The objectives of this study were to identify blood biomarkers that distinguish between CRS and bacteremia in the first month after CAR-T. We also describe the utilization of empiric antibiotics to identify opportunities for improved antimicrobial stewardship. We identified patients who received CAR-T for hematologic malignancies between July 2013 and April 2024. We calculated the cumulative incidences of CRS and bacteremia within 30 days post-CAR-T. In a matched case control analysis, where three patients with CRS and no bacteremia (controls) were matched to each patient with bacteremia (cases), we described the clinical characteristics of CRS, bacteremia, and antibiotic exposure. We then assessed the levels and kinetics of six biomarkers (C-reactive protein [CRP], interleukin-6, ferritin, fibrinogen, lactate dehydrogenase, and D-dimer) for their ability to discriminate between bacteremia and CRS using Mann-Whitney U tests and generalized estimating equation (GEE) models. Among 694 CAR-T recipients, 517 (75%; 95% confidence interval [CI], 71%-78%) developed CRS. Bacteremia occurred in 19 patients with a cumulative incidence of 2.7% (95% CI, 1.7%-4.2%) within 30 days and 1.4% (95% CI, 0.7%-2.6%) within 14 days of CAR-T. The median time from blood culture to a positive result was one day (interquartile range [IQR], 1-1). Among the 57 matched controls, CRS occurred a median of four days (IQR, 1-5) post-CAR-T, all were hospitalized for fevers, and 92% of CRS events were treated with empiric antibiotics for a median of seven days (IQR, 5-8). As a result, for every patient with bacteremia treated with antibiotics within the first 14 days, an estimated 52 patients with CRS and no serious bacterial infection received empiric antibiotics. The levels and kinetics of biomarkers were similar among cases and controls within 14 days after CAR-T. Beyond day +14, CRP, D-dimer, and ferritin levels were significantly higher among patients with bacteremia and distinguished cases from controls with moderate discrimination (area under the curve of 0.77, 0.77, and 0.81, respectively). In addition, increasing CRP and fibrinogen ≥14 days post-CAR-T were significantly associated with bacteremia (odds ratio [OR], 1.46; 95% CI, 1.07-2.01 and OR, 4.32; 95% CI, 1.28-14.61 per 0.25 log10 increase in biomarker level per day, respectively). We demonstrate that most CAR-T recipients who developed CRS received empiric broad-spectrum antibiotics, but bacteremia was rare. Although blood biomarkers were unable to distinguish between CRS and bacteremia early after CAR-T, higher CRP, D-dimer, and ferritin and rising levels of CRP and fibrinogen ≥14 days post-CAR-T were associated with bacteremia and can facilitate earlier targeted interventions. These data highlight opportunities for improved antibiotic stewardship in the context of CRS, which is critical given the association between broad-spectrum antibiotic exposure, gut microbiome dysbiosis, and worse outcomes after CAR-T.

  View details for DOI 10.1016/j.jtct.2025.07.022

  View details for PubMedID 40752589

• Real-world comparison of lisocabtagene maraleucel and axicabtagene ciloleucel in large B-cell lymphoma: an inverse probability of treatment weighting analysis with 3-year follow-up. Haematologica Portuguese, A. J., Huang, J. J., Jeon, Y., Taheri, M., Albittar, A., Liang, E. C., Hirayama, A. V., Kimble, E. L., Iovino, L., Poh, C., Gopal, A. K., Shadman, M., Till, B. G., Milano, F., Chapuis, A. G., Otegbeye, F., Cassaday, R. D., Basom, R. S., Wu, Q. V., Maloney, D. G., Gauthier, J. 2025; 110 (9): 2040-2054

  Abstract

  Lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) are Food and Drug Administration- and European Medicines Agency-approved chimeric antigen receptor (CAR) T-cell therapies for relapsed/refractory large B-cell lymphoma (LBCL). However, comparative real-world analyses of their efficacy and toxicity with extended follow-up are lacking. We conducted a retrospective study of 160 LBCL patients treated at the Fred Hutchinson Cancer Center with commercial liso- cel or axi-cel per standard of care. Using inverse probability of treatment weighting (IPTW) to mitigate treatment allocation bias and multivariable adjustments to minimize other sources of confounding, we assessed the impact of CAR T-cell product type on outcomes. Axi-cel was associated with significantly higher rates of cytokine release syndrome (CRS; grade [G]1+: adjusted odds ratio [aOR] =4.27; P=0.004; G2+: aOR=2.88; P=0.006), immune effector cell-associated neurotoxicity syndrome (ICANS; G1+: aOR=2.10; P=0.048), and immune effector cell-associated hematotoxicity (ICAHT; G1+: aOR=8.09; P<0.001; G2+: aOR=3.86; P=0.001). Axi-cel was also associated with more frequent use of supportive care measures, such as tocilizumab (aOR=2.50; P=0.017), dexamethasone (aOR=2.77; P=0.007), and cefepime (aOR=3.37; P=0.001). We could not confirm statistically significant differences in the response rates and survival outcomes after liso-cel versus axi-cel (complete response: aOR=1.12; P=0.8; overall survival: adjusted hazard ratio [aHR] =1.34; P=0.3; progression-free survival: aHR=0.97; P=0.9; duration of response: aHR=0.89; P=0.7; cumulative incidence of relapse: aHR=0.92; P=0.8). In summary, although axicel was associated with greater toxicity requiring more intensive management, the response rates and survival outcomes were comparable between axi-cel and liso-cel.

  View details for DOI 10.3324/haematol.2024.287010

  View details for PubMedID 40079097

  View details for PubMedCentralID PMC12399936

• Real-world performance of the CALGB 10403 regimen in young adults in the United States. Blood neoplasia DaSilva, B., Darwin, A., Zhang, A., Vyas, R. D., Russell, K., Gilbert, J. S., Tan, V., Feldt, S., Johnston, H., Liang, E. C., DuVall, A. S., Liedtke, M., Stock, W., Cassaday, R. D., Schwartz, M., Leonard, J. T., Muffly, L. S., Luskin, M. R. 2025; 2 (3): 100111

  Abstract

  The Cancer and Leukemia Group B 10403 (C10403) trial prospectively demonstrated the safety and efficacy of administering an asparaginase-containing pediatric regimen for the treatment of adolescents and young adults (AYAs) with acute lymphoblastic leukemia. Since its implementation as standard of care, it is unknown how the C10403 regimen performs beyond the clinical trial setting. To bridge this knowledge gap, we designed a multicenter retrospective cohort study to examine the safety, efficacy, and challenges of completing C10403 in the "real world." From October 2012 through June 2020, a total of 139 patients began induction as per the C10403 regimen across 6 US academic cancer centers. The median age was 26 years (range, 17-39), 69% were male, 55% were non-Hispanic White, and 27% were Hispanic. Among them, 122 patients (88%) achieved complete remission or complete remission with incomplete count recovery (CR/CRi) with C10403, 48 (35%) completed maintenance therapy, and 47 (34%) changed postremission regimens while in CR/CRi. The 3-year event-free survival (EFS) was 66% (95% confidence interval [CI], 55-74), and the 3-year overall survival (OS) was 81% (95% CI, 74-87). Four deaths occurred while on C10403 treatment: 1 during induction; and 3 later in the treatment course. The most common grade 3 or 4 adverse events during induction included alanine aminotransferase elevation (22%) and sepsis (14%). B-cell immunophenotype (hazard ratio [HR], 2.45; 95% CI, 1.09-5.48), Philadelphia chromosome-like genetics (HR, 3.05; 95% CI, 1.25-7.44), and Hispanic ethnicity (HR, 2.00; 95% CI, 1.06-3.78) were associated with worse EFS in univariate analyses. Overall, these real-world results are comparable to those of the C10403 trial. Further improvements are needed to enhance outcomes and regimen tolerability in the AYA population.

  View details for DOI 10.1016/j.bneo.2025.100111

  View details for PubMedID 40792014

  View details for PubMedCentralID PMC12335966

• A phase 1 trial of fully human BCMA CAR-T therapy for relapsed/refractory multiple myeloma with 5-year follow-up. Blood Tuazon, S. A., Portuguese, A. J., Pont, M. J., Cowan, A. J., Cole, G. O., Sather, B. D., Song, X., Thomas, S., Wood, B. L., Blake, M., Works, M. G., Shadman, M., Liang, E. C., Wu, Q. V., Voutsinas, J. M., Gooley, T. A., Turtle, C. J., Till, B. G., Coffey, D. G., Maloney, D. G., Riddell, S. R., Green, D. J. 2025; 146 (5): 535-545

  Abstract

  FCARH143, an autologous B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell (CAR-T) therapy, which incorporates a fully human BCMA-specific single chain variable fragment and 4-1BB costimulatory domain, was evaluated in a phase 1 trial for relapsed/refractory multiple myeloma (RRMM). Patients were stratified by bone marrow plasma cell involvement (10%-30% or >30%) and received lymphodepleting chemotherapy followed by escalating CAR-T doses (50 × 106 to 450 × 106). The primary end point was safety; secondary end points were overall response rate (ORR), duration of response, and progression-free survival (PFS). Among 28 enrolled patients, all underwent leukapheresis and successful CAR-T manufacturing, although 3 (11%) did not proceed to infusion. The 25 treated patients (median age, 64 years) had a median of 8 prior therapies, 80% were triple-class refractory, and 44% had extramedullary disease. Cytokine release syndrome occurred in 84% (8% grade 3-4 and no grade 5), and neurotoxicity in 24% (12% grade 3 and no grade 4-5). No treatment-related deaths occurred. At a median follow-up of 67.3 months, treated patients had an ORR of 100%, including a stringent complete response in 64%. Median PFS and overall survival (OS) were 15.5 and 32.1 months, respectively. In an intention-to-treat analysis (median follow-up, 69.6 months), the ORR was 89.3%, and OS was 30.2 months. FCARH143 demonstrated potent antimyeloma activity, with a 100% response rate and manageable toxicity, independent of disease burden or cytogenetic risk. Further evaluation in high-risk RRMM is warranted. This trial was registered at www.clinicaltrials.gov as #NCT03338972.

  View details for DOI 10.1182/blood.2024027681

  View details for PubMedID 40198877

  View details for PubMedCentralID PMC12782959

• Phase 1 study of CD19 CAR T-cell therapy harboring a fully human scFv in CAR-naïve adult patients with B-ALL. Blood advances Gauthier, J., Liang, E. C., Huang, J. J., Kimble, E. L., Hirayama, A. V., Fiorenza, S., Voutsinas, J. M., Wu, Q. V., Jaeger-Ruckstuhl, C. A., Pender, B. S., Kirchmeier, D. R., Torkelson, A., Braathen, K., Basom, R., Shadman, M., Kopmar, N. E., Cassaday, R. D., Riddell, S. R., Maloney, D. G., Turtle, C. J. 2025; 9 (8): 1861-1872

  Abstract

  CD19-directed chimeric antigen receptor-engineered (CAR) T-cell therapy elicits high response rates but fails to induce durable responses in most adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). In a previous clinical trial, we observed anti-CAR immune responses associated with impaired in vivo CAR T-cell expansion after second infusions. Because these CD8+ T-cell responses were predominantly directed at peptides derived from the murine single-chain variable fragment (scFv) in the CAR, we conducted a clinical trial investigating the safety and efficacy of CD19 CAR T-cells engineered with a CAR incorporating a fully human scFv (JCAR021) in adults with R/R B-ALL (NCT03103971). Twenty-three patients received lymphodepletion chemotherapy and JCAR021 infusion. Nineteen patients developed cytokine release syndrome (any grade, 83%; grade 2, 61%) and 12 developed neurotoxicity (52%; grade ≥3, 35%). The overall response and complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 82% and 64%, respectively. We observed measurable residual disease-negative bone marrow (BM) responses in 82% of those with BM disease and extramedullary responses by positron emission tomography-computed tomography in 79% (CR, 50%) of those with measurable fluorodeoxyglucose-avid disease. The median duration of remission (DOR) was 10 months with a 4-year DOR probability of 29%. Four patients underwent allogeneic hematopoietic cell transplantation while in CR/CRi after JCAR021. Durable remissions were observed in patients with low BM disease burden. In contrast, the DOR was limited in those with high BM burden. We observed similar outcomes in CAR-naïve adult patients with B-ALL receiving CD19 CAR T cells expressing a fully human or murine scFv-containing CAR. This trial was registered at www.ClinicalTrials.gov as #NCT03103971.

  View details for DOI 10.1182/bloodadvances.2024015314

  View details for PubMedID 39820359

  View details for PubMedCentralID PMC12008683

• Development and validation of predictive models of early immune effector cell-associated hematotoxicity. Blood advances Liang, E. C., Huang, J. J., Portuguese, A. J., Ortiz-Maldonado, V., Albittar, A., Wuliji, N., Basom, R., Jeon, Y., Wu, Q., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Sorror, M., Hill, J. A., Kopmar, N. E., Banerjee, R., Cowan, A. J., Green, D., Gopal, A. K., Poh, C., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E. L., Iovino, L., Chapuis, A. G., Otegbeye, F., Cassaday, R. D., Milano, F., Turtle, C. J., Maloney, D. G., Gauthier, J. 2025; 9 (3): 606-616

  Abstract

  Immune effector cell-associated hematotoxicity (ICAHT) is associated with morbidity and mortality after chimeric antigen receptor (CAR) T-cell therapy. To date, the factors associated with ICAHT are poorly characterized, and there is no validated predictive model of ICAHT as defined by current consensus criteria. Therefore, we performed comprehensive univariate analyses to identify factors associated with severe (grade 3-4) early ICAHT (eICAHT) in 691 patients who received commercial or investigational CAR T-cell therapy for hematologic malignancies. In univariate logistic regression, preinfusion factors associated with severe eICAHT included disease type (acute lymphoblastic leukemia), prelymphodepletion (pre-LD) blood counts including absolute neutrophil count (ANC), lactate dehydrogenase (LDH), and inflammatory (C-reactive protein [CRP], ferritin, and interleukin-6 [IL-6]) and coagulopathy biomarkers (D-dimer). Postinfusion laboratory markers associated with severe eICAHT included early and peak levels of inflammatory biomarkers (CRP, ferritin, and IL-6), coagulopathy biomarkers (D-dimer), peak cytokine release syndrome grade, and peak neurotoxicity grade. We trained (n = 483) and validated (n = 208) 2 eICAHT prediction models (eIPMs): eIPMPre including preinfusion factors only (disease type and pre-LD ANC, platelet count, LDH, and ferritin) and eIPMPost containing both preinfusion (disease type and pre-LD ANC, platelet count, and LDH) and early postinfusion (day +3 ferritin) factors. Both models generated calibrated predictions and high discrimination (area under the receiver operating characteristic curve in test set, 0.87 for eIPMPre and 0.88 for eIPMPost), with higher net benefit in decision curve analysis for eIPMPost. Individualized predictions of severe eICAHT can be generated from both eIPMs using our online tool (available at https://eipm.fredhutch.org).

  View details for DOI 10.1182/bloodadvances.2024014455

  View details for PubMedID 39626349

  View details for PubMedCentralID PMC11847049

• Correction: Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity. Bone marrow transplantation Liang, E. C., Rejeski, K., Fei, T., Albittar, A., Huang, J. J., Portuguese, A. J., Wu, Q., Raj, S., Subklewe, M., Shouval, R., Gauthier, J. 2025; 60 (2): 254

  View details for DOI 10.1038/s41409-024-02453-6

  View details for PubMedID 39533017

• Autoimmune Outcomes in Patients with Concurrent Autoimmune Disease Receiving CD19 CAR T-Cell Therapy for Lymphoma Huang, J. J., Singh, N., Shadman, M., Basom, R. S., Kalus, A., Portuguese, A. J., Liang, E. C., Wuliji, N., Hirayama, A., Chapuis, A. G., Otegbeye, F., Milano, F., Cassaday, R. D., Gopal, A. K., Till, B. G., Warren, E. H., Gauthier, J., Fong, L., Maloney, D. G. ELSEVIER. 2024: 7132-7133

  View details for DOI 10.1182/blood-2024-201809

  View details for Web of Science ID 001411014600006

• INCIDENCES AND FACTORS ASSOCIATED WITH EARLY HEMATOTOXICITY AFTER CAR T-CELL THERAPY ASSESSED BY EHA/EBMT ICAHT CRITERIA Liang, E., Albittar, A., Portuguese, A., Huang, J., Wuliji, N., Wu, Q., Reyes, J., Pin, N., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Hill, J., Kopmar, N., Banerjee, R., Cowan, A., Green, D., Gopal, A., Poh, C., Shadman, M., Hirayama, A., Till, B., Kimble, E., Iovino, L., Chapuis, A., Otegbeye, F., Cassaday, R., Milano, F., Turtle, C., Maloney, D., Gauthier, J. SPRINGERNATURE. 2024: 202-204

  View details for Web of Science ID 001365375001090

• MACHINE-LEARNING-BASED CLUSTERING TO REFINE THE EHA/ EBMT IMMUNE EFFECTOR CELL-ASSOCIATED HEMATOTOXICITY GRADING CRITERIA Liang, E., Albittar, A., Portuguese, A., Huang, J., Wuliji, N., Wu, Q., Reyes, J., Pin, N., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Hill, J., Kopmar, N., Banerjee, R., Cowan, A., Green, D., Gopal, A., Poh, C., Shadman, M., Hirayama, A., Till, B., Kimble, E., Iovino, L., Chapuis, A., Otegbeye, F., Cassaday, R., Milano, F., Turtle, C., Maloney, D., Gauthier, J. SPRINGERNATURE. 2024: 45-46

  View details for Web of Science ID 001365375000044

• T-CELL LARGE GRANULAR LYMPHOCYTE POPULATION INVOLVING CHIMERIC ANTIGEN RECEPTOR-MODIFIED T (CAR T) CELLS IN PATIENTS WITH CYTOPENIA AFTER CD19-TARGETED CAR T-CELL THERAPY: CASE SERIES Albittar, A., Torabi, A., Liang, E., Portuguese, A., Huang, J., Yeung, C., Kimble, E., Kirchmeier, D., Torkelson, A., Chutnik, A., Cassaday, R., Chapuis, A., Kiem, H., Milano, F., Otegbeye, F., Shadman, M., Till, B., Maloney, D., Turtle, C., Gauthier, J., Hirayama, A. SPRINGERNATURE. 2024: 230-231

  View details for Web of Science ID 001365375001126

• AUTOMATED GRADING OF IMMUNE EFFECTOR CELL-ASSOCIATED HEMATOTOXICITY Liang, E., Rejeski, K., Raj, S., Albittar, A., Huang, J., Portuguese, A., Wuliji, N., Wu, Q., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Hill, J., Kopmar, N., Banerjee, R., Cowan, A., Poh, C., Shadman, M., Hirayama, A., Kimble, E., Iovino, L., Shouval, R., Gauthier, J. SPRINGERNATURE. 2024: 206-207

  View details for Web of Science ID 001365375001093

• Human herpesvirus 6 reactivation and disease are infrequent in chimeric antigen receptor T-cell therapy recipients. Blood Kampouri, E., Krantz, E. M., Xie, H., Ibrahimi, S. S., Kiem, E. S., Sekhon, M. K., Liang, E. C., Cowan, A. J., Portuguese, A., Green, D. J., Albittar, A., Huang, J. J., Gauthier, J., Pérez-Osorio, A. C., Jerome, K. R., Zerr, D. M., Boeckh, M. J., Hill, J. A. 2024; 144 (5): 490-495

  Abstract

  Human herpesvirus 6B (HHV-6B) reactivation and disease are increasingly reported after chimeric antigen receptor (CAR) T-cell therapy (CARTx). HHV-6 reactivation in the CAR T-cell product was recently reported, raising questions about product and patient management. Because of overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide 2 lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks after infusion, HHV-6B reactivation occurred in 8 of 89 participants; 3 had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval [CI], 2.2-12.5). HHV-6B detection was low level (median peak, 435 copies per mL; interquartile range, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in the blood and/or cerebrospinal fluid (CSF) within 12 weeks after infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing, with detection in 1. Among 34 patients with CSF HHV-6 testing, 1 patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.

  View details for DOI 10.1182/blood.2024024145

  View details for PubMedID 38635788

  View details for PubMedCentralID PMC11406171

• Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity. Bone marrow transplantation Liang, E. C., Rejeski, K., Fei, T., Albittar, A., Huang, J. J., Portuguese, A. J., Wu, Q., Raj, S., Subklewe, M., Shouval, R., Gauthier, J. 2024; 59 (7): 910-917

  Abstract

  Hematologic toxicity frequently complicates chimeric antigen receptor (CAR) T-cell therapy, resulting in significant morbidity and mortality. In an effort to standardize reporting, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) devised the immune effector cell-associated hematotoxicity (ICAHT) grading system, distinguishing between early (day 0-30) and late (after day +30) events based on neutropenia depth and duration. However, manual implementation of ICAHT grading criteria is time-consuming and susceptible to subjectivity and error. To address these challenges, we introduce a novel computational approach, utilizing the R programming language, to automate early and late ICAHT grading. Given the complexities of early ICAHT grading, we benchmarked our approach both manually and computationally in two independent cohorts totaling 1251 patients. Our computational approach offers significant implications by streamlining grading processes, reducing manual time and effort, and promoting standardization across varied clinical settings. We provide this tool to the scientific community alongside a comprehensive implementation guide, fostering its widespread adoption and enhancing reporting consistency for ICAHT.

  View details for DOI 10.1038/s41409-024-02278-3

  View details for PubMedID 38627450

  View details for PubMedCentralID PMC11380036

• Early prediction of severe ICANS after standard-of-care CD19 CAR T-cell therapy using gradient-boosted classification trees Huang, J., Liang, E. C., Albittar, A., Portuguese, A., Wuliji, N., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E., Iovino, L., Chapuis, A., Otegbeye, F., Cassaday, R., Milano, F., Maloney, D. G., Gauthier, J. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557401683

• Improving the ICAHT grading criteria using time-series clustering Liang, E. C., Albittar, A., Portuguese, A., Huang, J., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Hill, J. A., Kopmar, N., Banerjee, R., Cowan, A., Poh, C., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E., Iovino, L., Cassaday, R., Gauthier, J. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557401668

• Predictors of severe hematotoxicity after CAR T-cell therapy Liang, E. C., Albittar, A., Portuguese, A., Huang, J., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Hill, J. A., Kopmar, N., Banerjee, R., Cowan, A., Poh, C., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E., Iovino, L., Cassaday, R., Gauthier, J. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557401673

• How I Use Next Generation Sequencing-MRD to Plan Approach and Prevent Relapse after HCT for Children and Adults with ALL. Blood Muffly, L., Liang, E. C., Dolan, J. G., Pulsipher, M. A. 2024

  Abstract

  Measurable residual disease (MRD) evaluation by multiparameter flow cytometry (MFC) or quantitative PCR methods is an established standard of care for assessing risk of relapse prior to or after hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL). Next generation sequencing (NGS)-MRD has emerged as a highly effective approach that allows detection of lymphoblasts at a level of fewer than 1 in 106 nucleated cells, increasing sensitivity of ALL detection by 2-3 logs. Early studies have shown superior results compared with MFC and suggest that NGS-MRD may allow determination of patients in whom reduced toxicity transplant preparative approaches could be deployed without sacrificing outcomes. Many centers/study groups have implemented immune modulation approaches based on MRD measurements that have resulted in improved outcomes. Challenges remain with NGS-MRD, as it is not commercially available in many countries and interpretation of results can be complex. Through patient case review, discussion of relevant studies, and detailed expert opinion we share our approach to NGS-MRD testing prior to and after HCT in pediatric and adult ALL. Improved pre-HCT risk classification and post-HCT monitoring for relapse in bone marrow and less invasive peripheral blood monitoring by NGS-MRD may lead to alternative approaches to prevent relapse in patients undergoing this challenging procedure.

  View details for DOI 10.1182/blood.2023023699

  View details for PubMedID 38728375

• Managing side effects: guidance for use of immunotherapies in multiple myeloma. Hematology. American Society of Hematology. Education Program Liang, E. C., Sidana, S. 2023; 2023 (1): 348-356

  Abstract

  Chimeric antigen receptor T-cell therapy and bispecific T-cell recruiting antibodies have transformed the treatment landscape for relapsed/refractory multiple myeloma, with B-cell maturation antigen being the most common target and other targets in clinical development. However, these therapies are associated with unique and severe toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity, cytopenias, and infection. In addition, immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS), which exhibits overlap between CRS and HLH, can be challenging to diagnose and treat. In this review, we provide an overview of toxicities associated with novel immunotherapies for treatment of multiple myeloma and describe management recommendations. The pathophysiology and risk factors behind these toxicities are not yet comprehensively understood. Based on consensus recommendations, treatment for CRS consists of tocilizumab and steroids, while treatment for ICANS includes steroids and anakinra in severe cases. Management of cytopenias and infection is similar to post-hematopoietic cell transplantation principles with antimicrobial prophylaxis, growth factor support, immunoglobulin replacement, and vaccinations. In contrast, effective treatments for delayed neurotoxicity and IEC-HS are lacking, although steroids and anakinra are commonly used. Management of all these toxicities should include a broad differential and multidisciplinary collaboration with infectious diseases, neurology, and/or critical care providers.

  View details for DOI 10.1182/hematology.2023000435

  View details for PubMedID 38066898

• Phase I/II Study to Evaluate the Safety, Feasibility, and Efficacy of FP-1201 (Intravenous Interferon-Beta-1a) to Prevent Toxicities after CD19-Directed CAR T-Cell Therapy: Trial in Progress Liang, E. C., Kimble, E. L., Albittar, A., Huang, J. J., Portuguese, A. J., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Simon, S., Chour, T., Newell, E. W., Banerjee, R., Maloney, D. G., Spicer, A., Jalkanen, J., Hirayama, A. V., Gauthier, J. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-173152

  View details for Web of Science ID 001159900800061

• Lisocabtagene Maraleucel Versus Axicabtagene Ciloleucel: Efficacy and Toxicity in a RealWorld Setting Portuguese, A. J., Albittar, A., Liang, E. C., Huang, J. J., Hirayama, A. V., Kimble, E. L., Iovino, L., Poh, C., Gopal, A. K., Shadman, M., Till, B. G., Kiem, H., Milano, F., Chapuis, A. G., Otegbeye, F., Cassaday, R. D., Maloney, D. G., Gauthier, J. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-172978

  View details for Web of Science ID 001159306708104

• Machine Learning-Based Time-Series Clustering Identifies Archetypal Trajectories of Hematotoxicity after CAR T-Cell Therapy Liang, E. C., Albittar, A., Portuguese, A. J., Huang, J. J., Wu, Q., De Los Reyes, J., Pin, N., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Hill, J. A., Banerjee, R., Cowan, A. J., Green, D. J., Gopal, A. K., Poh, C., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E. L., Iovino, L., Chapuis, A. G., Otegbeye, F., Cassaday, R. D., Milano, F., Maloney, D. G., Gauthier, J. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-174106

  View details for Web of Science ID 001159306708116

• Day+3/Day 0 Ferritin Ratio: A Simple Point-of-Care Index Predictive of Severe Immune Effector Cell-Associated Neurotoxicity Syndrome after CD19 CAR T-Cell Therapy Huang, J. J., Liang, E. C., Albittar, A., Portuguese, A. J., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E. L., Iovino, L., Chapuis, A. G., Otegbeye, F., Cassaday, R. D., Milano, F., Turtle, C. J., Maloney, D. G., Gauthier, J. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-182597

  View details for Web of Science ID 001159740304106

• Phase 2 Study of Anakinra to Prevent CRS and Neurotoxicity after Treatment with Lisocabtagene Maraleucel: Planned Interim Analysis Liang, E. C., Albittar, A., Portuguese, A. J., Huang, J. J., Wu, Q., Reyes, J., Pin, N., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Simon, S., Chour, T., Newell, E. W., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E. L., Iovino, L., Chapuis, A. G., Otegbeye, F., Cassaday, R. D., Milano, F., Maloney, D. G., Gauthier, J. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-172695

  View details for Web of Science ID 001159900806217

• Phase 2 Study of CD19 CAR T Cells with a Fully Human Binder for Large B-Cell Lymphoma in Relapse or Progression after a Murine Binder-Bearing CD19 CAR T-Cell Therapy Gauthier, J., Huang, J. J., Jaeger-Ruckstuhl, C., Liang, E. C., Albittar, A., Portuguese, A. J., Wu, Q., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E. L., Iovino, L., Chapuis, A. G., Otegbeye, F., Cassaday, R. D., Milano, F., Poh, C., Gopal, A. K., Riddell, S. R., Maloney, D. G., Turtle, C. J. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-181273

  View details for Web of Science ID 001159900806229

• Phase 2 Study of CD19 CAR T Cells with a Fully Human Binder for Large B-Cell Lymphoma in Relapse or Progression after a Murine Binder-Bearing CD19 CAR T-Cell Therapy Gauthier, J., Huang, J. J., Jaeger-Ruckstuhl, C., Liang, E. C., Albittar, A., Portuguese, A. J., Wu, Q., Torkelson, A., Kirchmeier, D., Chutnik, A., Pender, B., Shadman, M., Hirayama, A. V., Till, B. G., Kimble, E. L., Iovino, L., Chapuis, A. G., Otegbeye, F., Cassaday, R. D., Milano, F., Poh, C., Gopal, A. K., Riddell, S. R., Maloney, D. G., Turtle, C. J. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-181273

  View details for Web of Science ID 001159900806229

• Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL. Blood advances Liang, E. C., Albittar, A., Huang, J. J., Hirayama, A. V., Kimble, E. L., Portuguese, A. J., Chapuis, A., Shadman, M., Till, B. G., Cassaday, R. D., Milano, F., Kiem, H. P., Riddell, S. R., Turtle, C. J., Maloney, D. G., Gauthier, J. 2023; 7 (22): 6990-7005

  Abstract

  High response rates have been reported after CD19-targeted chimeric antigen receptor-modified (CD19 CAR) T-cell therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), yet the factors associated with duration of response in this setting are poorly characterized. We analyzed long-term outcomes in 47 patients with R/R CLL and/or Richter transformation treated on our phase 1/2 clinical trial of CD19 CAR T-cell therapy with an updated median follow-up of 79.6 months. Median progression-free survival (PFS) was 8.9 months, and the 6-year PFS was 17.8%. Maximum standardized uptake value (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.07-1.23; P < .001) and bulky disease (≥5 cm; HR, 2.12; 95% CI, 1.06-4.26; P = .034) before lymphodepletion were associated with shorter PFS. Day +28 complete response by positron emission tomography-computed tomography (HR, 0.13; 95% CI, 0.04-0.40; P < .001), day +28 measurable residual disease (MRD) negativity by multiparameter flow cytometry (HR, 0.08; 95% CI, 0.03-0.22; P < .001), day +28 MRD negativity by next-generation sequencing (HR, 0.21; 95% CI, 0.08-0.51; P < .001), higher peak CD8+ CAR T-cell expansion (HR, 0.49; 95% CI; 0.36-0.68; P < .001), higher peak CD4+ CAR T-cell expansion (HR, 0.47; 95% CI; 0.33-0.69; P < .001), and longer CAR T-cell persistence (HR, 0.56; 95% CI, 0.44-0.72; P < .001) were associated with longer PFS. The 6-year duration of response and overall survival were 26.4% and 31.2%, respectively. CD19 CAR T-cell therapy achieved durable responses with curative potential in a subset of patients with R/R CLL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

  View details for DOI 10.1182/bloodadvances.2023011399

  View details for PubMedID 37774014

  View details for PubMedCentralID PMC10690558

• Retrospective Analysis of Adolescent Young Adult Patients with Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma Treated with the CALGB 10403 Regimen Since Completion of Trial Enrollment DaSilva, B., Vyas, R. D., Darwin, A., Russel, K., Gilbert, J., Tan, V., Darji, H., Miller, K., Liang, E. C., Raychaudhuri, S., Duvall, A. S., Liedtke, M., Stock, W., Cassaday, R., Schwartz, M., Leonard, J. T., Luskin, M. R., Muffly, L. S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-185176

  View details for Web of Science ID 001159740306286

• LISOCABTAGENE MARALEUCEL FOR RELAPSED OR REFRACTORY LARGE B-CELL LYMPHOMA: FEASIBILITY, SAFETY AND EFFICACY IN A REAL-WORLD SETTING Portuguese, A., Liang, E., Albittar, A., Hirayama, A., Till, B., Cassaday, R., Lynch, R., Poh, C., Milano, F., Chapuis, A., Kiem, H., Maloney, D. G., Gauthier, J. SPRINGERNATURE. 2023: 207-208

  View details for Web of Science ID 001110902800256

• FACTORS ASSOCIATED WITH DURATION OF RESPONSE AFTER CD19 CAR T-CELL THERAPY FOR RELAPSED/REFRACTORY CLL: 5-YEAR FOLLOW-UP UPDATE Liang, E., Hirayama, A., Kimble, E., Portuguese, A., Albittar, A., Chapuis, A., Shadman, M., Till, B., Cassaday, R., Milano, F., Kiem, H., Turtle, C., Maloney, D., Gauthier, J. SPRINGERNATURE. 2023: 12-14

  View details for Web of Science ID 001110902800003

• Association of Self-Reported COVID-19 Vaccination Status with COVID-19 Infection among Adult Long-Term Hematopoietic Cell Transplantation Survivors. Transplantation and cellular therapy Liang, E. C., Onstad, L. E., Carpenter, P., Pergam, S. A., Flowers, M. E., Lee, S. J., Liu, C. 2023; 29 (9): 584.e1-584.e9

  Abstract

  Hematopoietic cell transplantation (HCT) recipients experience significant morbidity and mortality from coronavirus disease 19 (COVID-19) infection. Data are limited regarding long-term HCT survivors' uptake of and experiences with COVID-19 vaccination and infection. This study aimed to characterize COVID-19 vaccination uptake, use of other prevention measures, and COVID-19 infection outcomes in adult HCT recipients at our institution. Between July 1, 2021, and June 30, 2022, long-term adult HCT survivors were surveyed regarding overall health, chronic graft-versus-host (cGVHD) status, and experiences with COVID-19 vaccinations, prevention measures, and infections. Patients reported COVID-19 vaccination status, vaccine-related adverse effects, use of nonpharmaceutical prevention measures, and infections. Comparisons by response and vaccination status were performed using the chi-square test and Fisher exact test for categorical variables and the Kruskal-Wallis test for continuous variables. Of 4758 adult HCT survivors who underwent HCT between 1971 and 2021 and consented to participate in annual surveys, 1719 (36%) completed the COVID-19 module, and 1598 of 1705 (94%) reported receiving ≥1 dose of COVID-19 vaccine. Severe vaccine-related adverse effects were infrequent (5%). Among respondents receiving an mRNA vaccine, completion of doses according to the Centers for Disease Control and Prevention's vaccine recommendations at the time of survey return was 2 doses in 675 of 759 (89%), 3 doses in 610 of 778 (78%), and 4 doses in 26 of 55 (47%). Two hundred fifty respondents (15%) reported COVID-19 infection; 25 (10%) required hospitalization. Vaccinated respondents reported significantly higher uptake of household vaccination (1284 of 1404 [91%] versus 18 of 88 [20%]; P < .001) and the use of nonpharmaceutical interventions (P < .001). Vaccinated respondents were significantly less likely to have contracted COVID-19 (85 of 1480 [6%] versus 130 of 190 [68%]; P < .001), as were their household members (149 of 1451 [10%] versus 85 of 185 [46%]; P < .001). Receipt of additional COVID-19 vaccine doses beyond the first dose was associated with a reduced risk of COVID-19 infection (odds ratio, .63; 95% confidence interval, .47 to .85; P = .002). Vaccination was well tolerated and associated with a lower risk of COVID-19 infection among HCT survivors and their household contacts. Vaccination and booster doses should be encouraged as part of a multifaceted approach in this high-risk population.

  View details for DOI 10.1016/j.jtct.2023.06.017

  View details for PubMedID 37394113

  View details for PubMedCentralID PMC10528463

• Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy. Transplantation and cellular therapy Gazeau, N., Liang, E. C., Wu, Q. V., Voutsinas, J. M., Barba, P., Iacoboni, G., Kwon, M., Ortega, J. L., López-Corral, L., Hernani, R., Ortiz-Maldonado, V., Martínez-Cibrian, N., Martinez, A. P., Maziarz, R. T., Williamson, S., Nemecek, E. R., Shadman, M., Cowan, A. J., Green, D. J., Kimble, E., Hirayama, A. V., Maloney, D. G., Turtle, C. J., Gauthier, J. 2023; 29 (7): 430-437

  Abstract

  Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n = 40) and grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n = 3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P = .069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P = .039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P = .02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings.

  View details for DOI 10.1016/j.jtct.2023.04.001

  View details for PubMedID 37031746

  View details for PubMedCentralID PMC10330552

• Next-Generation Sequencing-Based MRD in Adults with ALL Undergoing Hematopoietic Cell Transplantation. Blood advances Liang, E. C., Dekker, S. E., Sabile, J. M., Torelli, S., Zhang, A., Miller, K., Shiraz, P., Hayes-Lattin, B., Leonard, J. T., Muffly, L. 2023

  Abstract

  Measurable residual disease (MRD) is an adverse prognostic factor in adult acute lymphoblastic leukemia (ALL) patients undergoing hematopoietic cell transplantation (HCT). Next-generation sequencing (NGS) can detect MRD with a sensitivity of 10-6, but the prognostic value of NGS-based MRD in adult ALL patients undergoing HCT remains minimally studied. To evaluate the prognostic value of NGS-based MRD in adult ALL patients undergoing HCT. Patients with ALL aged ≥18 years old who underwent allogeneic HCT at Stanford University or Oregon Health & Science University between January 2014-April 2021 and who were evaluated for MRD using the NGS-based clonoSEQ assay were included in this study. MRD was assessed pre-HCT (MRDpre) and for up to 1 year post-HCT (MRDpost). Patients were followed for leukemia relapse and survival for up to 2 years post-HCT. 158 patients had a trackable clonotype for MRD monitoring. The cumulative incidence of relapse was increased at all levels of MRDpre, including in patients who had low MRDpre of <10-4 (HR 3.56, 95% CI, 1.39-9.15). In multivariable analysis, MRDpre level remained significantly prognostic; however, detectable MRDpost was the strongest predictor of relapse (HR 4.60, 95% CI, 3.01-7.02). In exploratory analyses limited to B-cell ALL patients, detection of post-HCT IgH MRD clonotypes, rather than non-IgH MRD clonotypes, were associated with relapse. In this analysis across two large transplant centers, we found that detection of MRD by NGS at a level of 10-6 offers significant prognostic value in adults with ALL undergoing HCT.

  View details for DOI 10.1182/bloodadvances.2023009856

  View details for PubMedID 37196642

• Corrigendum to "T cell senescence and impaired CMV-specific response are associated with infection risk in kidney transplant recipients" [Hum. Immunol. 83(4) (2022) 273-280]. Human immunology Pickering, H., Schaenman, J., Rossetti, M., Ahn, R., Sunga, G., Liang, E. C., Bunnapradist, S., Reed, E. F. 2022; 83 (12): 857

  View details for DOI 10.1016/j.humimm.2022.09.001

  View details for PubMedID 36192241

• Ultra-Sensitive Next-Generation Sequencing Establishes the Prognostic Value of Very Low MRD in Adults with Acute Lymphoblastic Leukemia Undergoing Hematopoietic Cell Transplantation Liang, E. C., Dekker, S. E., Sabile, J. M. G., Torelli, S., Zhang, A., Miller, K., Shiraz, P., Hayes-Lattin, B., Leonard, J., Muffly, L. AMER SOC HEMATOLOGY. 2022: 1732-1733

  View details for DOI 10.1182/blood-2022-157442

  View details for Web of Science ID 000893223201306

• Self-Reported Experiences of Adult Hematopoietic Cell Transplantation Survivors with COVID-19 Vaccination and Infection Liang, E. C., Onstad, L. E., Carpenter, P. A., Pergam, S. A., Lee, S. J., Liu, C. ELSEVIER. 2022

  View details for DOI 10.1182/blood-2022-157440

  View details for Web of Science ID 000893223200378

• Clinicopathologic and Molecular Correlates of Organ Damage Across the Spectrum of Advanced Systemic Mastocytosis Liang, E., Perkins, C., Lu, R., Shi, H., Dimitrijevic, S., Hoehn, G., Abuel, J., Langford, C., Abidi, P., Fechter, L., Shomali, W., Gotlib, J. CIG MEDIA GROUP, LP. 2022: S334

  View details for Web of Science ID 000897948100332

• Epidemiology of lower respiratory tract infections and community-acquired respiratory viruses in patients with bronchiolitis obliterans syndrome after hematopoietic cell transplant: a retrospective cohort study. Transplantation and cellular therapy Epstein, D. J., Liang, E. C., Sharifi, H., Lai, Y. K., Arai, S., Graber-Naidich, A., Sundaram, V., Nelson, J., Hsu, J. L. 2022

  Abstract

  Among 55 patients with bronchiolitis obliterans syndrome, 34 (61.8%) developed lower respiratory tract infections, which were associated with impaired lung function and a trend toward increased mortality. Rhinovirus/enterovirus and Pseudomonas aeruginosa infections predominated; 10 (18.2%) patients developed non-tuberculous mycobacterial infections.

  View details for DOI 10.1016/j.jtct.2022.07.016

  View details for PubMedID 35872303

• Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia in the Modern Era. Transplantation and cellular therapy Liang, E. C., Craig, J., Torelli, S., Cunanan, K., Iglesias, M., Arai, S., Frank, M. J., Johnston, L., Lowsky, R., Meyer, E. H., Miklos, D. B., Negrin, R., Rezvani, A., Shiraz, P., Shizuru, J., Sidana, S., Weng, W. K., Bharadwaj, S., Muffly, L. 2022

  Abstract

  Allogeneic hematopoietic cell transplantation (HCT) remains an important treatment for adults with acute lymphoblastic leukemia (ALL). We hypothesized that advances in ALL and transplantation have resulted in improved HCT outcomes in recent years.To evaluate the characteristics and outcomes of adult ALL patients undergoing allogeneic HCT over the last decade.Patients with ALL aged ≥18 years old who underwent allogeneic HCT at Stanford University between 2008 and 2019 were included in this study. Patients were divided into two Eras based on year of HCT: 2008-2013 (Earlier Era) and 2014-2019 (Later Era).A total of 285 patients were included: 119 patients underwent HCT in the Earlier Era and 166 in the Later Era. Patients transplanted in the Later Era were more likely to be Hispanic (38% vs. 21%) and to have HCT-Comorbidity Index of ≥ 3 (31% vs. 18%). Donor source for HCT also differed with an increase in the use of HLA-mismatched donor sources (38% vs. 24%), notably umbilical cord blood (UCB) in the Later Era (16% vs. 0%). Patients in the Later Era were less likely to undergo transplant with active disease (4% vs.16%); pre-HCT rates of measurable residual disease (MRD) were similar across the Eras (38% vs. 40%). In unadjusted analyses, overall survival (OS) improved across Eras, with 2-year estimates for the Later and Earlier Eras of 73% (95% CI, 66%-80%) vs. 55% (95% CI, 46%-64%), respectively. Multivariable analysis confirmed the association between Later Era and OS (HR = 0.52, 95% CI, 0.34-0.78). Finally, among patients relapsing after HCT (25% in Later Era and 33% in Earlier Era), the utilization of novel immunotherapies increased in the Later Era (44% vs. 3%), as did the median OS following post-HCT relapse (16 months vs. 8 months, p < 0.001).OS following HCT for adult ALL has improved in recent years. This is due, in part, to a significant improvement in the ability to effectively salvage adults with ALL relapsing after HCT.

  View details for DOI 10.1016/j.jtct.2022.05.010

  View details for PubMedID 35584783

• T cell senescence and impaired CMV-specific response are associated with infection risk in kidney transplant recipients. Human immunology Pickering, H., Schaenman, J., Rossetti, M., Ahn, R., Sunga, G., Liang, E. C., Bunnapradist, S., Reed, E. F. 2022; 83 (4): 273-280

  Abstract

  Older kidney transplant recipients demonstrate increased rates of infection, and lower rates of rejection, compared with younger kidney transplant recipients. However, the mechanism behind this observation remains unknown. To develop a multifaceted view of age-associated immune dysfunction, we determined the function and phenotype of T cells predisposing to vulnerability to infection on a molecular level. Overlapping peptide pools representing the dominant CMV antigens were used to stimulate PBMC collected from 51 kidney transplant recipients, using cytokine secretion to determine specificity and intensity of response. Staphylococcal endotoxin B (SEB) was analyzed in parallel. To define immune cell subsets, we used single cell RNA sequencing (scRNAseq) to evaluate cellular surface markers and gene expression. We found increased frequency of SEB- and CMV-specific T cells was associated with freedom from infection, especially in older patients. Spatialized t-SNE analysis revealed decreased frequency of naïve T cells, increased frequency of TEMRA cells, and decreased frequency of IFNγ secreting T cells in patients with infection. Application of scRNAseq analysis revealed increased frequency of terminally differentiated T cells expressing NK-associated receptors and inhibitory markers. These findings offer unique insight into the mechanism behind vulnerability to infection in the kidney transplant recipient, revealing a specific T cell subtype of impaired antigen response and terminal effector phenotype as markers of T cell senescence.

  View details for DOI 10.1016/j.humimm.2022.01.016

  View details for PubMedID 35190203

  View details for PubMedCentralID PMC9462879

• Correction to: Measurable residual disease status and FLT3 inhibitor therapy in patients with FLT3-ITD mutated AML following allogeneic hematopoietic cell transplantation. Bone marrow transplantation Liang, E. C., Chen, C., Lu, R., Mannis, G. N., Muffly, L. 2022

  View details for DOI 10.1038/s41409-022-01606-9

  View details for PubMedID 35169285

• Organ Damage at Initial Presentation across the Spectrum of Advanced Systemic Mastocytosis Variants Liang, E. C., Perkins, C., Lu, R., Abuel, J., Langford, C., DeVore, D., Fechter, L., Abidi, P., Shomali, W., Gotlib, J. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-145082

  View details for Web of Science ID 000736413902083

• Measurable Residual Disease Status and FLT3 Inhibitor Therapy in Patients with FLT3-ITD-Mutated AML Following Allogeneic Hematopoietic Cell Transplantation Liang, E. C., Chen, C., Lu, R., Mannis, G. N., Muffly, L. CIG MEDIA GROUP, LP. 2021: S278-S279

  View details for Web of Science ID 000691910500112

• Leukocyte transcriptome indicators of development of infection in kidney transplant recipients. Clinical transplantation Schaenman, J. M., Rossetti, M., Liang, E. C., Lum, E., Abdalla, B., Bunnapradist, S., Pham, P. T., Danovitch, G., Reed, E. F., Cole, S. W. 2021; 35 (4): e14252

  Abstract

  After kidney transplantation, infection and death are important clinical complications, especially for the growing numbers of older patients with limited resilience to withstand adverse events. Evaluation of changes in gene expression in immune cells can reveal the underlying mechanisms behind vulnerability to infection. A cohort of 60 kidney transplant recipients was evaluated. Gene expression in peripheral blood mononuclear cells 3 months after kidney transplantation was analyzed to compare differences between patients with infection and those who were infection-free in the first-year post-transplant. Pro-inflammatory genes such as IL1B, CCL4, and TNF were found to be downregulated in post-transplant PBMC from patients who developed infection. In contrast, genes involved in metabolism, HLA genes, and transcripts involved in type I interferon innate antiviral responses were found to be upregulated. Promoter-based bioinformatic analyses implicated increased activity of interferon regulatory factors, erythroid nuclear factor (E2), and CCAAT-enhancer-binding protein (C/EBP) in patients who developed infections. Differential patterns of gene expression were observed in patients who developed infection after kidney transplantation, with patterns distinct from changes associated with patient age, suggesting possible mechanisms behind vulnerability to infection. Assessment of gene expression in blood may offer an approach for patient risk stratification and monitoring after transplantation.

  View details for DOI 10.1111/ctr.14252

  View details for PubMedID 33570750

  View details for PubMedCentralID PMC9341289

• Use of Backup Stem Cells for Stem Cell Boost and Second Transplant in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation. Transplantation and cellular therapy Liang, E. C., Muffly, L. S., Shiraz, P., Shizuru, J. A., Johnston, L., Arai, S., Frank, M. J., Weng, W., Lowsky, R., Rezvani, A., Meyer, E. H., Negrin, R., Miklos, D. B., Sidana, S. 2021

  Abstract

  Autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient stem cells in case there is a need for stem cell boost for delayed/poor engraftment or for future second ASCT. However, collecting and storing backup stem cells in all patients requires significant resources and cost, and the rates of backup stem cell utilization are not well studied. We sought to examine the utilization of backup stem cells (BSCs) in patients with MM undergoing ASCT. Patients with MM aged ≥18 years old who underwent first ASCT at our institution from January 2010 through December 2015 and collected sufficient stem cells for at least 2 transplants were included in this single-center retrospective study. This timeframe was selected to allow for adequate follow-up. A total of 393 patients were included. The median age was 58 years (range, 25-73). After a median follow-up of 6 years, the median progression-free survival (PFS) of the cohort was 3 years. Sixty-one percent (n=240) of patients progressed or relapsed. Chemotherapy-based mobilization was used in almost all patients (98%). The median total CD34+ cells collected was 18.2*106/kg (range, 3.4-112.4). A median of 5.7*106 CD34+ cells/kg (range, 1.8-41.9) was infused during the first ASCT, and a median of 10.1*106 CD34+ cells/kg (range, 1.5-104.5) was cryopreserved for future use. Of the patients, 6.9% (n=27) used backup stem cells, with 2.3% (n=10) using them for stem cell boost, 4.6% (n=18) for a second salvage ASCT, including 1 patient for both stem cell boost and second ASCT. Rates of backup stem cell use among patients aged <60, 60-69, and ≥70 years were 7.8%, 5.7%, and 5.9%, respectively. There was a trend toward higher rates of backup stem cell use for second ASCT in patients who were younger, had suboptimal disease control at time of first ASCT, and longer PFS. The median dose of stem cell boost given was 5.6*106 CD34+ cells/kg (range, 1.9-20). The median time from stem cell boost to neutrophil, hemoglobin, and platelet engraftment was 4 (range, 2-11), 15 (range, 4-34), and 12 (range, 0-34) days, respectively. Lower CD34+ dose and older age at time of ASCT predicted need for stem cell boost. With new salvage therapies for relapsed MM, the rates of second ASCT are very low. The low rates of use suggest that institutional policies regarding universal BSC collection and long-term storage should be reassessed and individualized. However, need for stem cell boost in 2.3% of patients may present a challenge to that.

  View details for DOI 10.1016/j.jtct.2021.02.026

  View details for PubMedID 33775587

• Measurable residual disease status and FLT3 inhibitor therapy in patients with FLT3-ITD mutated AML following allogeneic hematopoietic cell transplantation. Bone marrow transplantation Liang, E. C., Chen, C., Lu, R., Mannis, G. N., Muffly, L. 2021

  Abstract

  Measurable residual disease (MRD) is associated with poor prognosis in acute myeloid leukemia (AML), even after allogeneic hematopoietic cell transplantation (HCT). New next-generation sequencing (NGS) methods have emerged as a highly sensitive and specific method to detect MRD. In addition to defining the role of post-HCT MRD monitoring in FLT3-ITD mutated AML, there is great interest in the optimal use of oral FLT3 tyrosine kinase inhibitors (FLT3 inhibitors) to maintain remission following HCT. In this study, we evaluated the clinical impact of sensitive FLT3 MRD testing early after HCT and maintenance FLT3 inhibitor use at our transplant center. We found that there was a trend towards inferior progression-free survival (PFS) for patients with early post-HCT MRD, but that overall survival (OS) was not significantly impacted by MRD. The use of maintenance FLT3 inhibitors led to a significantly superior PFS and OS in our cohort, and improved PFS and OS in both MRD-negative and MRD-positive patients. Altogether, our results demonstrate the prognostic significance of NGS-based MRD monitoring for FLT3-ITD and the ability of post-HCT maintenance therapy to prevent relapse and death in FLT3-ITD mutated AML.

  View details for DOI 10.1038/s41409-021-01475-8

  View details for PubMedID 34584238

• DNA Methylation Age Is More Closely Associated With Infection Risk Than Chronological Age in Kidney Transplant Recipients. Transplantation direct Schaenman, J., Zhou, X., Guo, R., Rossetti, M., Liang, E. C., Lum, E., Abdalla, B., Bunnapradist, S., Pham, P. T., Danovitch, G., Karlamangla, A., Reed, E., Horvath, S., Elashoff, D. 2020; 6 (8): e576

  Abstract

  Older kidney transplant recipients demonstrate increased rates of infection but decreased rates of rejection compared with younger recipients, suggesting that older transplant patients are functionally overimmunosuppressed. We hypothesized that this is a consequence of reduction in immunological activity due to biological aging and that an immune biological age, as determined by DNA methylation (DNAm), would be associated more strongly with incidence of infection than chronological age.DNAm analysis was performed on peripheral blood mononuclear cell collected from 60 kidney transplant recipients representing older (≥age 60 y) and younger (aged 30-59 y) patients 3 months after transplantation. DNAm age was calculated based on methylation status of a panel of CpG sites, which have been previously identified as indicative of biological age.Correlation was seen between chronological and DNAm age; however, there were many patients with significant differences (either acceleration or slowing) between DNAm age and chronological age. A statistically significant association was seen between increased DNAm age and incidence of infection in the first year after kidney transplantation, whereas no significant association was seen between chronological age and infection.Assessment of DNAm age holds promise as an approach for patient evaluation and individualization of immune suppression regimens. This analysis may provide insights into the immunological mechanism behind increased incidence of infection observed in older transplant patients. The ability to measure biological age would allow for patient risk stratification and individualization of immunosuppression, improving outcomes for the growing numbers of older patients undergoing kidney transplantation.

  View details for DOI 10.1097/TXD.0000000000001020

  View details for PubMedID 33134500

  View details for PubMedCentralID PMC7581059

• Utility of the AVISE Connective Tissue Disease test in predicting lupus diagnosis and progression. Lupus science & medicine Liang, E., Taylor, M., McMahon, M. 2020; 7 (1): e000345

  Abstract

  The AVISE Connective Tissue Disease (CTD) test uses autoantibody, erythrocyte-bound C4d (EC4d) and B-cell-bound C4d (BC4d) levels to aid in diagnoses of SLE, other CTDs and fibromyalgia. We evaluated the utility of the AVISE CTD test in predicting SLE disease development and damage progression.Patients who had undergone AVISE CTD testing were assessed for SLE diagnosis by the Systemic Lupus International Collaborating Clinics (SLICC) and American College of Rheumatology criteria and for SLE damage by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at the time of AVISE testing (t=0) and 2 years later (t=2).Among 117 patients without a previous diagnosis of SLE, 65% of patients who tested positive developed SLE at t=2, compared with 10.3% of patients who tested non-positive (p<0.0001). AVISE-positive patients fulfilled significantly more SLICC diagnostic criteria than AVISE-non-positive patients at both t=0 (3.8±2.1 vs 1.9±1.1, p=0.001) and t=2 (4.5±2.2 vs 2.1±1.2, p<0.0001). AVISE-positive patients also had had significantly higher SDI at t=2 (1.9±1.3 vs 1.03±1.3, p=0.01). BC4d levels correlated with the number of SLICC criteria at t=0 (r=0.33, p<0.0001) and t=2 (r=0.34, p<0.0001), as well as SDI at t=0 (r=0.25, p=0.003) and t=2 (r=0.26, p=0.002).The AVISE CTD test can aid in SLE evaluation by predicting SLE disease development and future damage progression.

  View details for DOI 10.1136/lupus-2019-000345

  View details for PubMedID 32231785

  View details for PubMedCentralID PMC7101049

• The Frailty Risk Score predicts length of stay and need for rehospitalization after kidney transplantation in a retrospective cohort: a pilot study PILOT AND FEASIBILITY STUDIES Schaenman, J., Castellon, L., Liang, E. C., Nanayakkara, D., Abdalla, B., Sarkisian, C., Goldwater, D. 2019; 5 (1): 144

  Abstract

  Frailty is a widely used measure in older patients as a predictor of poor outcomes after hospitalization and surgery. There is a growing body of data in kidney transplantation suggesting frailty can predict adverse outcomes. There is interest in using chart review measures of frailty and multimorbidity, as they may be equally predictive as physical measurement. This approach holds promise for patient evaluation, identifying candidates for prehabilitation, and targeting resources towards those anticipated to have an increased rate of clinical challenges after kidney transplantation. Frail patients who are often older may place a large resource and economic burden on transplant programs.We applied a previously published chart review-based approach in a retrospective, pilot study to calculate the Frailty Risk Score (FRS) utilizing a cohort of kidney transplant patients. We reviewed concurrent comorbidities using the Charlson comorbidity (CM) score to determine the feasibility and utility of applying this approach in transplant patients to predict post-transplant outcomes such as length of hospitalization and the need for rehospitalization.Sixty kidney transplant recipients were evaluated by chart review, 23 characterized as older (> = 60) and 37 younger (ages 30-59). Median FRS score was 3 (range 1-7). Higher FRS was significantly associated with increased patient age (high FRS 19% in younger patients, 43% in older patients). Increased CM score was also associated with increased patient age. Patients with a high FRS stayed in the hospital for an average of 8 days, compared with 5.7 days for a low FRS. Patients with high FRS were readmitted an average of 2.9 times compared with an average of 1.1 for those with a low FRS. FRS score remained significant for predicting outcomes after adjustment for patient age.Elevated FRS prior to transplantation was associated with increased hospital stay and the need for readmission in kidney transplant recipients. This analysis demonstrates the potential strength of chart review in evaluating frailty prior to transplantation, permitting risk stratification and targeting of resources for rehabilitation and close post-transplant monitoring. Frail patients may benefit from targeted "prehabilitation" to attenuate the associated adverse clinical outcomes.

  View details for DOI 10.1186/s40814-019-0534-2

  View details for Web of Science ID 000704684400001

  View details for PubMedID 31890257

  View details for PubMedCentralID PMC6905019

• Association of pro-inflammatory cytokines and monocyte subtypes in older and younger patients on clinical outcomes after mechanical circulatory support device implantation HUMAN IMMUNOLOGY Schaenman, J. M., Rossetti, M., Sidwell, T., Groysberg, V., Sunga, G., Liang, E., Vangala, S., Chang, E., Bakir, M., Bondar, G., Cadeiras, M., Kwon, M., Reed, E. F., Deng, M. 2019; 80 (2): 126-134

  Abstract

  Noninvasive immunologic analysis of peripheral blood holds promise for explaining the mechanism of development of adverse clinical outcomes, and may also become a method for patient risk stratification before or after mechanical circulatory support device (MCSD) implantation. Dysregulation of the innate immune system is associated with increased patient age but has yet to be evaluated in the older patient with advanced heart failure undergoing MCSD surgery. Patients pre- and post-MCSD implantation had peripheral blood mononuclear cells (PBMC) and serum isolated. Multiparameter flow cytometry was used to analyze markers of innate cell function, including monocyte subtypes. Multiplex cytokine analysis was performed. MELD-XI and SOFA scores were utilized as surrogate markers of outcomes. Increased levels of pro-inflammatory cytokines including IL-15, TNF-α, and IL-10 were associated with increased MELD-XI and SOFA scores. IL-8, TNF- α, and IL-10 were associated with risk of death after MCSD implantation, even with correction for patient age. Increased frequency of 'classical' monocytes (CD14 + CD16-) were associated with increased MELD-XI and SOFA scores. This suggests that inflammation and innate immune system activation contribute to progression to multiorgan system failure and death after MCSD surgery. Development of noninvasive monitoring of peripheral blood holds promise for biomarker development for candidate selection and patient risk stratification.

  View details for DOI 10.1016/j.humimm.2018.11.004

  View details for Web of Science ID 000459844700009

  View details for PubMedID 30445099

  View details for PubMedCentralID PMC7115755

• Increased T cell immunosenescence and accelerated maturation phenotypes Check for in older kidney transplant recipients HUMAN IMMUNOLOGY Schaenman, J. M., Rossetti, M., Sidwell, T., Groysberg, V., Sunga, G., Korin, Y., Liang, E., Zhou, X., Abdalla, B., Lum, E., Bunnapradist, S., Pham, T., Danovitch, G., Reed, E. F. 2018; 79 (9): 659-667

  Abstract

  Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens. We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4+ and CD8+ T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis. This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation.

  View details for DOI 10.1016/j.humimm.2018.06.006

  View details for Web of Science ID 000443531700004

  View details for PubMedID 29913200

  View details for PubMedCentralID PMC6429965

• T cell dysfunction and patient age are associated with poor outcomes after mechanical circulatory support device implantation HUMAN IMMUNOLOGY Schaenman, J. M., Rossetti, M., Korin, Y., Sidwell, T., Groysberg, V., Liang, E., Vangala, S., Wisniewski, N., Chang, E., Bakir, M., Bondar, G., Cadeiras, M., Kwon, M., Reed, E. F., Deng, M. 2018; 79 (4): 203-212

  Abstract

  Immunologic impairment may contribute to poor outcomes after implantation of mechanical circulatory support device (MCSD), with infection often as a terminal event. The study of immune dysfunction is of special relevance given the growing numbers of older patients with heart disease. The aim of the study was to define which immunologic characteristics are associated with development of adverse clinical outcomes after MCSD implantation. We isolated peripheral blood mononuclear cells (PBMC) from patients pre- and up to 20 days post-MCSD implantation and analyzed them by multiparameter flow cytometry for T cell dysfunction, including terminal differentiation, exhaustion, and senescence. We used MELD-XI and SOFA scores measured at each time point as surrogate markers of clinical outcome. Older patients demonstrated increased frequencies of terminally differentiated T cells as well as NKT cells. Increased frequency of terminally differentiated and immune senescent T cells were associated with worse clinical outcome as measured by MELD-XI and SOFA scores, and with progression to infection and death. In conclusion, our data suggest that T cell dysfunction, independently from age, is associated with poor outcomes after MCSD implantation, providing a potential immunologic mechanism behind patient vulnerability to multiorgan dysfunction and death. This noninvasive approach to PBMC evaluation holds promise for candidate evaluation and patient monitoring.

  View details for DOI 10.1016/j.humimm.2018.01.011

  View details for Web of Science ID 000430907000005

  View details for PubMedID 29409843

  View details for PubMedCentralID PMC6476571

• Differences in Proinflammatory Cytokines and Monocyte Subtypes in Older as Compared With Younger Kidney Transplant Recipients TRANSPLANTATION DIRECT Liang, E. C., Rossetti, M., Sidwell, T., Groysberg, V., Sunga, G., Korin, Y., Vangala, S., Abdalla, B., Lum, E., Bunnapradist, S., Phuong-Thu Pham, Danovitch, G., Reed, E. F., Schaenman, J. 2018; 4 (3)

  View details for DOI 10.1097/TXD.0000000000000762

  View details for Web of Science ID 000426558300002

• The newborn human NK cell repertoire is phenotypically formed but functionally reduced CYTOMETRY PART B-CLINICAL CYTOMETRY Strauss-Albee, D. M., Liang, E. C., Ranganath, T., Aziz, N., Blish, C. A. 2017; 92 (1): 33-41

  Abstract

  Infection is a leading cause of death worldwide in babies under 1 month of age. Better vaccines and therapeutics are desperately needed for this vulnerable population.Because newborns rely heavily on the innate immune system, we evaluated cell phenotype and function of some of the earliest cellular responders during infection, natural killer (NK) cells. We used mass cytometry to provide a comprehensive comparison of NK cells from umbilical cord blood and adult peripheral blood.In unsupervised analyses, including viSNE and principal component analysis, the structure of the cord blood and adult NK cell repertoires are highly similar, distinguishable mainly by maturity-related markers expressed on rare subpopulations of cells. However, in functional analyses, cord blood NK cells show reduced degranulation and cytokine production following target recognition, as well as antibody-dependent cell-mediated cytotoxicity and apoptosis induction in targets.These findings show that the structure of the NK cell repertoire is intact at birth, suggesting great potential for vaccine and therapeutic strategies targeting this cell population. © 2016 International Clinical Cytometry Society.

  View details for DOI 10.1002/cyto.b.21485

  View details for Web of Science ID 000394980300005

• The newborn human NK cell repertoire is phenotypically formed but functionally reduced. Cytometry. Part B, Clinical cytometry Strauss-Albee, D. M., Liang, E. C., Ranganath, T., Aziz, N., Blish, C. A. 2016

  Abstract

  Infection is a leading cause of death worldwide in babies under 1 month of age. Better vaccines and therapeutics are desperately needed for this vulnerable population.Because newborns rely heavily on the innate immune system, we evaluated cell phenotype and function of some of the earliest cellular responders during infection, natural killer (NK) cells. We used mass cytometry to provide a comprehensive comparison of NK cells from umbilical cord blood and adult peripheral blood.In unsupervised analyses, including viSNE and principal component analysis, the structure of the cord blood and adult NK cell repertoires are highly similar, distinguishable mainly by maturity-related markers expressed on rare subpopulations of cells. However, in functional analyses, cord blood NK cells show reduced degranulation and cytokine production following target recognition, as well as antibody-dependent cell-mediated cytotoxicity and apoptosis induction in targets.These findings show that the structure of the NK cell repertoire is intact at birth, suggesting great potential for vaccine and therapeutic strategies targeting this cell population. © 2016 International Clinical Cytometry Society.

  View details for DOI 10.1002/cyto.b.21485

  View details for PubMedID 27718327

• Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility. Science translational medicine Strauss-Albee, D. M., Fukuyama, J., Liang, E. C., Yao, Y., Jarrell, J. A., Drake, A. L., Kinuthia, J., Montgomery, R. R., John-Stewart, G., Holmes, S., Blish, C. A. 2015; 7 (297): 297ra115-?

  Abstract

  Innate natural killer (NK) cells are diverse at the single-cell level because of variegated expressions of activating and inhibitory receptors, yet the developmental roots and functional consequences of this diversity remain unknown. Because NK cells are critical for antiviral and antitumor responses, a better understanding of their diversity could lead to an improved ability to harness them therapeutically. We found that NK diversity is lower at birth than in adults. During an antiviral response to either HIV-1 or West Nile virus, NK diversity increases, resulting in terminal differentiation and cytokine production at the cost of cell division and degranulation. In African women matched for HIV-1 exposure risk, high NK diversity is associated with increased risk of HIV-1 acquisition. Existing diversity may therefore decrease the flexibility of the antiviral response. Collectively, the data reveal that human NK diversity is a previously undefined metric of immune history and function that may be clinically useful in forecasting the outcomes of infection and malignancy.

  View details for DOI 10.1126/scitranslmed.aac5722

  View details for PubMedID 26203083

• Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility SCIENCE TRANSLATIONAL MEDICINE Strauss-Albee, D. M., Fukuyama, J., Liang, E. C., Yao, Y., Jarrell, J. A., Drake, A. L., Kinuthia, J., Montgomery, R. R., John-Stewart, G., Holmes, S., Blish, C. A. 2015; 7 (297)

  Abstract

  Innate natural killer (NK) cells are diverse at the single-cell level because of variegated expressions of activating and inhibitory receptors, yet the developmental roots and functional consequences of this diversity remain unknown. Because NK cells are critical for antiviral and antitumor responses, a better understanding of their diversity could lead to an improved ability to harness them therapeutically. We found that NK diversity is lower at birth than in adults. During an antiviral response to either HIV-1 or West Nile virus, NK diversity increases, resulting in terminal differentiation and cytokine production at the cost of cell division and degranulation. In African women matched for HIV-1 exposure risk, high NK diversity is associated with increased risk of HIV-1 acquisition. Existing diversity may therefore decrease the flexibility of the antiviral response. Collectively, the data reveal that human NK diversity is a previously undefined metric of immune history and function that may be clinically useful in forecasting the outcomes of infection and malignancy.

  View details for DOI 10.1126/scitranslmed.aac5722

  View details for Web of Science ID 000358738700007

• Association between Latent Proviral Characteristics and Immune Activation in Antiretrovirus-Treated Human Immunodeficiency Virus Type 1-Infected Adults. Journal of virology Liang, E. C., Sceats, L., Bayless, N. L., Strauss-Albee, D. M., Kubo, J., Grant, P. M., Furman, D., Desai, M., Katzenstein, D. A., Davis, M. M., Zolopa, A. R., Blish, C. A. 2014; 88 (15): 8629-8639

  Abstract

  Generalized immune activation during HIV infection is associated with an increased risk of cardiovascular disease, neurocognitive disease, osteoporosis, metabolic disorders, and physical frailty. The mechanisms driving this immune activation are poorly understood, particularly for individuals effectively treated with antiretroviral medications. We hypothesized that viral characteristics such as sequence diversity may play a role in driving HIV-associated immune activation. We therefore sequenced proviral DNA isolated from peripheral blood mononuclear cells from HIV-infected individuals on fully suppressive antiretroviral therapy. We performed phylogenetic analyses, calculated viral diversity and divergence in the env and pol genes, and determined coreceptor tropism and the frequency of drug resistance mutations. Comprehensive immune profiling included quantification of immune cell subsets, plasma cytokine levels, and intracellular signaling responses in T cells, B cells, and monocytes. These antiretroviral therapy-treated HIV-infected individuals exhibited a wide range of diversity and divergence in both env and pol genes. However, proviral diversity and divergence in env and pol, coreceptor tropism, and the level of drug resistance did not significantly correlate with markers of immune activation. A clinical history of virologic failure was also not significantly associated with levels of immune activation, indicating that a history of virologic failure does not inexorably lead to increased immune activation as long as suppressive antiretroviral medications are provided. Overall, this study demonstrates that latent viral diversity is unlikely to be a major driver of persistent HIV-associated immune activation.Chronic immune activation, which is associated with cardiovascular disease, neurologic disease, and early aging, is likely to be a major driver of morbidity and mortality in HIV-infected individuals. Although treatment of HIV with antiretroviral medications decreases the level of immune activation, levels do not return to normal. The factors driving this persistent immune activation, particularly during effective treatment, are poorly understood. In this study, we investigated whether characteristics of the latent, integrated HIV provirus that persists during treatment are associated with immune activation. We found no relationship between latent viral characteristics and immune activation in treated individuals, indicating that qualities of the provirus are unlikely to be a major driver of persistent inflammation. We also found that individuals who had previously failed treatment but were currently effectively treated did not have significantly increased levels of immune activation, providing hope that past treatment failures do not have a lifelong "legacy" impact.

  View details for DOI 10.1128/JVI.01257-14

  View details for PubMedID 24850730

  View details for PubMedCentralID PMC4135944

• Lack of Proficiency in Musculoskeletal Medicine Among Emergency Medicine Physicians JOURNAL OF ORTHOPAEDIC TRAUMA Comer, G. C., Liang, E., Bishop, J. A. 2014; 28 (4): E85-E87

  Abstract

  Emergency medicine (EM) physicians are frequently responsible for evaluating and treating patients with urgent or emergent musculoskeletal conditions, so it is critical that they achieve a basic level of proficiency in musculoskeletal medicine. However, inadequacies in musculoskeletal education have previously been documented among medical students, residents, and attending physicians in a number of specialties. The goal of this study was to assess the proficiency with musculoskeletal medicine among EM physicians in particular.A validated musculoskeletal medicine competency examination was administered to the EM residents and faculty at a university-affiliated level 1 trauma center. Demographic data and satisfaction with musculoskeletal education were also surveyed.Twenty-three EM residents and 21 attending physicians completed the survey. Thirty-five percent of residents and 43% of attending physicians failed to demonstrate proficiency on the examination. Pass rates were not significantly different among junior residents, senior residents, or attending physicians. Twenty-three percent of respondents indicated that they were dissatisfied with their musculoskeletal education.Significant deficiencies in musculoskeletal education exist among EM physicians in training and attending staff. Given the frequency with which these physicians evaluate and treat acute musculoskeletal conditions, additional resources should be committed to their training.

  View details for DOI 10.1097/BOT.0b013e3182a66829

  View details for Web of Science ID 000333153200004

  View details for PubMedID 23899765