scholarly journals Risk factors associated with durable progression-free survival in relapsed or refractory multiple myeloma patients treated with anti-BCMA CAR-T cell therapy

2021 ◽  
pp. clincanres.2031.2021
Author(s):  
Mingming Zhang ◽  
Linghui Zhou ◽  
Houli Zhao ◽  
Yanlei Zhang ◽  
Guoqing Wei ◽  
...  
Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3010-3010
Author(s):  
Aditi Sharma ◽  
Vijendra Singh ◽  
Abhinav Deol

Abstract Background: CAR (chimeric antigen receptor) T-cell therapy is a novel form of immunotherapy that utilizes genetically altered autologous T cells to target cancer cells. Since the first FDA (Food and Drug Administration) approval in August 2017, several CAR T-cell products have been approved for the treatment of various malignancies. Due to the recent approval, large-scale epidemiologic data are lacking. This study aims to characterize the epidemiology of hospitalizations for CAR T-cell therapy, readmissions, and factors associated with all-cause-30-day readmission. Methods: We performed a retrospective cohort study using the Nationwide Readmissions Database (NRD) for 2017 & 2018 to identify hospitalizations with CAR T-cell therapy administration utilizing the ICD-10-PCS (International Classification of Diseases, Tenth Revision, Procedure Coding System) codes XW033C3 & XW043C3. These admissions were further categorized into non-Hodgkin's lymphoma, leukemia, and multiple myeloma. Descriptive analysis was performed to compare demographics, hospital characteristics, various comorbid conditions, and complications between these groups. We identified primary diagnoses at readmission and all-cause 30-day readmission rate after excluding index admissions from December and deaths during index admissions. Multivariable logistic regression was used to elucidate factors associated with all-cause-30-day readmission. The analysis was carried out to produce national estimates after applying weights, and the methodology provided by the HCUP (Healthcare Cost and Utilization Project) was utilized. Results: Out of 1,322 CAR T-cell therapy admissions in 2017-2018, 909 had a diagnosis of non-Hodgkin's lymphoma, 154 had multiple myeloma, and 128 had leukemia. The median age of those with leukemia was lowest at 26 (10-42) years, followed by multiple myeloma and non-Hodgkin's at 59 (57-61) years and 63 (61-64) years, respectively (p<0.001). The majority of CAR T-cell recipients were males (63%), admitted to teaching hospitals (97.96%), had private insurance (53.01%), and belonged to the highest income communities (34.95%). The median length of stay was longest for leukemia, followed by multiple myeloma and non-Hodgkin's (18 days vs. 16 days vs. 15 days; p<0.001). Median hospital charges were highest for non-Hodgkin's, followed by leukemia and multiple myeloma ($702,484 vs. $313,366 vs. $185,854; p<0.001). Overall mortality during index hospitalization was 2.98%. The complete baseline characters are described in table 1. A total of 316 hospitalizations (25%) were readmitted within 30 days. The median time to readmission was 9 days, the median length of stay during readmission was 5 days, and crude in-hospital mortality during readmission was 3%. Readmission incurred an additional median hospital charge of $58,568. The top five diagnoses at readmission were malignancy & therapy-related (23%), sepsis or infection (19%), neurologic events (19%), neutropenia or pancytopenia (13%), and fever or hypotension (8%) (figure1). On multivariable logistic regression for predictors of 30-day readmission, admission to public hospital (aOR {adjusted odds ratio} 2.01, p 0.027), transfer to a skilled nursing facility or intermediate care facility at discharge (aOR 2.59, p 0.001), and chronic renal disease (aOR 1.47 p 0.027) were associated with higher odds of readmission. Admission to a large metro hospital (aOR 0.63 p 0.047) and teaching hospital (aOR 0.59 p 0.012) were associated with reduced odds of readmission (figure2). Conclusion: As CAR T-cell therapy has recently been added to the cancer treatment arsenal, we describe that it is associated with strikingly high hospital charges, and a quarter of recipients are readmitted within the first 30 days. Figure 1 Figure 1. Disclosures Deol: Kite, a Gilead Company: Consultancy.


Hemato ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 660-671
Author(s):  
Juan Luis Reguera-Ortega ◽  
Estefanía García-Guerrero ◽  
Jose Antonio Pérez-Simón

Current data on CAR-T cell-based therapy is really promising in multiple myeloma, especially in terms of response. In heavily pretreated patients, who have already received proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies, current trials report an overall response rate ranging from 81 to 97% and 45 to 67% of complete remission rates. Data are less encouraging in terms of duration of response, although most recent trials have shown significant improvements in terms of event-free survival, with medians ranging from 8 to 14 months and up to 77% progression-free survival at 12 months with an acceptable toxicity profile. These data will be consolidated in future years and will provide new evidence on the best timing for CAR-T cell therapy. Moreover, new CAR-T designs are underway and will challenge the current results.


2019 ◽  
Author(s):  
Gregory J. Kimmel ◽  
Frederick L. Locke ◽  
Philipp M. Altrock

ABSTRACTChimeric antigen receptor (CAR) T cell therapy is a remarkably effective immunotherapy that relies on in vivo expansion of engineered CAR T cells, after lymphodepletion by chemotherapy. The laws underlying this expansion and subsequent tumor eradication remain unknown. Still, about 60% of CAR T-treated patients are likely to progress; their tumors are not eradicated. Here we seek to understand and disentangle the multiple processes that contribute to CAR expansion and tumor eradication. We developed a mathematical model of T cell-tumor cell interactions, and demonstrate that CAR T cell expansion is shaped by immune reconstitution dynamics after lymphodepletion and predator prey-like dynamics. Our cell population model was parameterized using patient population-level data over time and recapitulates progression free survival. As an intrinsic property, we find that tumor eradication is a stochastic event. Our cell population-based approach renders CAR T cell therapy as an ecological dynamic process that drives tumors toward an extinction vortex. Even if a clinical event, such as progression, is likely, its timing can be highly variable. We predict how clinical interventions that increase CAR T memory populations could improve the likelihood of tumor eradication and improve progression free survival. Our model can be leveraged to propose new CAR composition and dosing strategies, assess the need for multiple doses, and identify patient populations most likely to benefit from CAR T with or without additional interventions.


2019 ◽  
Vol 61 (4) ◽  
pp. 940-943 ◽  
Author(s):  
George R. Nahas ◽  
Krishna V. Komanduri ◽  
Denise Pereira ◽  
Mark Goodman ◽  
Antonio M. Jimenez ◽  
...  

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3871-3871
Author(s):  
Linde Dekker ◽  
Friso Calkoen ◽  
Yilin Jiang ◽  
Hilly Blok ◽  
Maike Spoon ◽  
...  

Abstract The addition of fludarabine to cyclophosphamide as lymphodepleting regimen prior to adoptive transfer of CD19 chimeric antigen receptor (CAR) T cells significantly improves CAR T cell expansion and correlates with longer B cell aplasia and a decreased probability of developing a CD19+ relapse (Gardner, 2017). Dosing of fludarabine is currently based on body surface area. We previously showed that this leads to a highly variable plasma exposure that correlates with clinical outcome after allogeneic hematopoietic cell transplantation (Langenhorst, 2019). We therefore hypothesized that optimal exposure of fludarabine might be of clinical importance in the CD19 CAR T setting. An observational cohort analysis was conducted with data from 26 consecutive patients receiving tisagenlecleucel as treatment for refractory/relapsed B cell acute lymphoblastic leukemia (B-ALL; table 1). Prior to CAR T cell infusion, patients received fludarabine on 4 consecutive days at a daily dosage of 30 mg/m 2 and cyclophosphamide on 2 consecutive days at a daily dosage of 500 mg/m 2. Fludarabine concentrations were measured longitudinally after fludarabine infusion using a liquid chromatography mass spectrometry method. The total exposure (Area Under the Curve (AUC 0−∞)) was subsequently determined using a fludarabine population pharmacokinetic model (Langenhorst, 2019). The study was performed in accordance with the Declaration of Helsinki. The primary outcome parameter was leukemia free survival, defined as the time between CAR19 T cell infusion and the moment of measurable leukemic blasts (>5% or >0.01% by two subsequent measurements). The effect of fludarabine on leukemia free survival and the secondary outcome measures CD19+ relapse and B cell aplasia were explored using martingale residuals and further identified by fitting univariable Cox Proportional Hazards models. In addition, Kaplan Meier and cumulative incidence curves were plotted and compared with log-rank tests. To compare CAR T cell numbers over time in peripheral blood, the AUCs were computed and compared between exposure groups with the Mann-Whitney test. Analyses were performed using R4.03 with packages pknca, survival and survminer. The fludarabine AUC 0−∞ was highly variable, resulting in a large range of 8.7-21.8 mg*h/L. Exposure of fludarabine was shown to be a predictor for leukemia free survival, B cell aplasia, and CD19+ relapse following CAR T cell infusion. Minimal event probability was observed at a cumulative fludarabine exposure ≥14 mg*h/L and underexposure was therefore defined as an AUC 0−∞ <14 mg*h/L. In the underexposed group, leukemia free survival was lower (p<0.001; Figure 1A) and the occurrence of CD19+ relapse was higher (p<0.0001; figure 1B) compared to the group with an AUC 0−∞ ≥14 mg*h/L. Furthermore, the duration of B cell aplasia was shorter (p=0.009) and the AUCs of CAR T cell numbers lower (p=0.03) in the underexposed group. No significant differences in baseline characteristics were present between the two exposure groups. To our knowledge, this is the first study describing the effect of fludarabine exposure on outcome in a cohort of paediatric and young adults receiving CD19 CAR T cell therapy as treatment for B-ALL. These preliminary results suggest that optimizing fludarabine exposure may have a relevant impact on leukemia free survival following CAR T cell therapy. However, it should be noted that multivariate regression models are needed to show consistency of the relationship between fludarabine exposure and outcome. The limited number of patients did not allow for inclusion of potential covariates that may influence clinical outcome into the analysis. Therefore, our results need to be confirmed in a larger cohort. In conclusion, clinical outcome in patients receiving CAR19 T cell therapy might be improved by the optimization of fludarabine exposure in the lymphodepleting regimen. LD and FC contributed equally to this study. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


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