Publications by authors named "Christina Bachmeier"

14 Publications

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Chimeric Antigen Receptor T Cell Therapy: A Comprehensive Review of Clinical Efficacy, Toxicity, and Best Practices for Outpatient Administration.

Transplant Cell Ther 2021 Jan 20. Epub 2021 Jan 20.

Division of Pharmacy, University of Kansas Cancer Center, Westwood, Kansas. Electronic address:

Chimeric antigen receptor T cell (CAR-T) therapy has been integrated into treatment algorithms for acute leukemia and lymphoma, and the number of clinical trials in both hematologic and solid tumor malignancies for new products and potential indications continues to grow. The clinical toxicities of CAR-T therapy include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which often warrant inpatient admission for close monitoring and treatment. Consequently, many centers have built processes around administration of these cells in the inpatient setting. As new products gain Food and Drug Administration approval with more manageable toxicity profiles, and as institutions gain experience with the management of these toxicities, outpatient administration and monitoring should be expected. In addition, payer reimbursements for inpatient treatment have left the sustainability of inpatient CAR-T therapy in jeopardy, especially for centers whose payer mix includes a high proportion of Medicare patients. This has the serious potential to limit access to care. As use of CAR-T therapy continues to expand, changes in payment models, care settings, or both are needed to ensure the sustainability of safe, efficient, and cost-effective treatment. This review outlines the efficacy and toxicity of currently approved products as well as best practices to optimize the management of CAR-T therapy in the outpatient setting.
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http://dx.doi.org/10.1016/j.jtct.2021.01.014DOI Listing
January 2021

Incidence and Management of Effusions Before and After CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Large B Cell Lymphoma.

Transplant Cell Ther 2021 Mar 27;27(3):242.e1-242.e6. Epub 2020 Dec 27.

Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida; Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, Florida. Electronic address:

In patients with lymphoma, third-space fluid accumulations may develop or worsen during cytokine release syndrome (CRS) associated with chimeric antigen receptor (CAR) T cell therapy. Pre-existing symptomatic pleural effusions were excluded by the ZUMA-1 trial of axicabtagene ciloleucel for large B cell lymphoma (LBCL) and variants. The incidence and management of effusions during CAR T cell therapy for LBCL are unknown. We performed a single-center retrospective study evaluating 148 patients receiving CD19-directed CAR T cell therapy for LBCL between May 2015 and September 2019. We retrospectively identified patients who had radiographic pleural, pericardial, or peritoneal effusions that were present prior to the time of CAR T infusion (pre-CAR T) or that newly developed during the first 30 days after CAR T-cell infusion (post-CAR T). Of 148 patients, 19 patients had a pre-CAR T effusion, 17 patients without pre-existing effusion developed a new infusion after CAR T, and 112 patients had no effusions. Comparing pre-CAR T effusions to new effusions post-CAR T, pre-CAR T effusions were more often malignant (84% versus 12%), persistent beyond 30 days (95% versus 18%), and required interventional drainage after CAR T infusion (79% versus 0%). Compared to patients with no effusion, patients with pre-CAR T therapy effusions had a higher frequency of high-risk baseline characteristics, such as bulky disease and high International Prognostic Index. Similarly, patients with pre-CAR T therapy effusions had a higher rate of toxicity with grade 3 or higher CRS occurring in 32% of patients. On multivariate analysis adjusting for age, Eastern Cooperative Oncology Group status, bulky disease, albumin, and lactate dehydrogenase, a pre-CAR T therapy effusion was associated with reduced overall survival (hazard ratio, 2.34; 95% confidence interval, 1.09 to 5.03; P = .03). Moreover, there was higher non-relapse mortality (11% versus 1%; P = .005). Post-CAR T effusions were not associated with significant difference in survival. Effusions commonly complicate CAR T cell therapy for lymphoma. Malignant effusions that occur prior to CAR T therapy are frequently persistent and require therapeutic intervention, and patients have a higher rate of toxicity and death. Effusions that newly occur after CAR T therapy can generally be managed medically and tend not to persist.
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http://dx.doi.org/10.1016/j.jtct.2020.12.025DOI Listing
March 2021

Acute patient-reported outcomes in B-cell malignancies treated with axicabtagene ciloleucel.

Cancer Med 2021 03 28;10(6):1936-1943. Epub 2021 Feb 28.

Moffitt Cancer Center, Department of Health Outcomes and Behavior, Tampa, FL, USA.

Chimeric antigen receptor T-cell therapy with axicabtagene ciloleucel (axi-cel) has considerably improved survival in adults with relapsed/refractory large B-cell lymphoma. This study reports patient-reported outcomes (PROs) such as quality of life (QOL) and toxicity in the first 90 days after treatment. Hematologic cancer patients treated with axi-cel (N = 103, mean age = 61, 39% female) completed SF-36 or PROMIS-29 QOL questionnaires prior to treatment and 90 days after. PRO-Common Terminology Criteria for Adverse Events toxicity items were completed by patients at baseline and 14, 30, 60, and 90 days after treatment. Mixed models examined change in PROs over time. From preinfusion to 90 days later, patients reported improvements in physical functioning, pain, and fatigue (ps < 0.01), but worsening of anxiety (p = 0.02). Patient-reported toxicities worsened by day 14 with improvement thereafter. The five most severe symptoms at day 14 included fatigue, decreased appetite, dry mouth, diarrhea frequency, and problems with concentration. Results indicate improvement in some domains of QOL over time with transient patient-reported toxicities.
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http://dx.doi.org/10.1002/cam4.3664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957158PMC
March 2021

Regulatory challenges and considerations for the clinical application of CAR T cell therapy.

Expert Opin Biol Ther 2021 May 24;21(5):549-552. Epub 2021 Feb 24.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA.

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http://dx.doi.org/10.1080/14712598.2021.1887130DOI Listing
May 2021

Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma.

Blood 2021 May;137(19):2621-2633

Department of Blood and Marrow Transplant and Cellular Immunotherapy.

Axicabtagene ciloleucel (axi-cel) is a chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory large B-cell lymphoma (LBCL). This study evaluated whether immune dysregulation, present before CAR T-cell therapy, was associated with treatment failure. Tumor expression of interferon (IFN) signaling, high blood levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and high blood interleukin-6 and ferritin levels were each associated with a lack of durable response. Similar to other cancers, we found that in LBCL tumors, IFN signaling is associated with the expression of multiple checkpoint ligands, including programmed cell death-ligand 1, and these were higher in patients who lacked durable responses to CAR-T therapy. Moreover, tumor IFN signaling and blood M-MDSCs associated with decreased axi-cel expansion. Finally, patients with high tumor burden had higher immune dysregulation with increased serum inflammatory markers and tumor IFN signaling. These data support that immune dysregulation in LBCL promotes axi-cel resistance via multiple mechanistic programs: insufficient axi-cel expansion associated with both circulating M-MDSC and tumor IFN signaling, which also gives rise to expression of immune checkpoint ligands.
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http://dx.doi.org/10.1182/blood.2020007445DOI Listing
May 2021

High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma.

Blood Adv 2020 07;4(14):3268-3276

Department of Blood and Marrow Transplant and Cellular Immunotherapy, and.

High metabolic tumor volume (MTV) predicts worse outcomes in lymphoma treated with chemotherapy. However, it is unknown if this holds for patients treated with axicabtagene ciloleucel (axi-cel), an anti-CD19 targeted chimeric antigen receptor T-cell therapy. The primary objective of this retrospective study was to investigate the relationship between MTV and survival (overall survival [OS] and progression-free survival [PFS]) in patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axi-cel. Secondary objectives included finding the association of MTV with response rates and toxicity. The MTV values on baseline positron emission tomography of 96 patients were calculated via manual methodology using commercial software. Based on a median MTV cutoff value of 147.5 mL in the first cohort (n = 48), patients were divided into high and low MTV groups. Median follow-up for survivors was 24.98 months (range, 10.59-51.02 months). Patients with low MTV had significantly superior OS (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.10-0.66) and PFS (HR, 0.40; 95% CI, 0.18-0.89). Results were successfully validated in a second cohort of 48 patients with a median follow-up for survivors of 12.03 months (range, 0.89-25.74 months). Patients with low MTV were found to have superior OS (HR, 0.14; 95% CI, 0.05-0.42) and PFS (HR, 0.29; 95% CI, 0.12-0.69). In conclusion, baseline MTV is associated with OS and PFS in axi-cel recipients with LBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020001900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391155PMC
July 2020

Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel.

Clin Cancer Res 2020 09 15;26(18):4823-4831. Epub 2020 Jul 15.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Purpose: One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).

Experimental Design: Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.

Results: We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.

Conclusions: These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501265PMC
September 2020

Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma.

Haematologica 2021 Apr 1;106(4):978-986. Epub 2021 Apr 1.

Dept. of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, USA.

CD19 CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with >= grade 3 neutropenia seen in 21/70 (30-0%) patients at day 30 and persisting in 3/31 (9-7%) patients at 1 year. B cells were undetectable in 30/34 (88-2%) patients at day 30, but were detected in 11/19 (57-9%) at 1 year. Median IgG levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/μl at 1 year after axi-cel (n=19, range 33 - 269). In total, 23/85 (27-1%) patients received IVIG after axi-cel, and 34/85 (40-0%) received G-CSF. Infections in the first 30 days occurred in 31/85 (36-5%) patients, of which 11/85 (12-9%) required intravenous antibiotics or hospitalization ("severe") and were associated with cytokine release syndrome (CRS), neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, 7 severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T cell immunosuppression without severe infection.
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http://dx.doi.org/10.3324/haematol.2019.238634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017820PMC
April 2021

Haemophagocytic lymphohistiocytosis has variable time to onset following CD19 chimeric antigen receptor T cell therapy.

Br J Haematol 2019 10 13;187(2):e35-e38. Epub 2019 Aug 13.

Department of Blood & Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA.

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http://dx.doi.org/10.1111/bjh.16155DOI Listing
October 2019

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products.

Ther Adv Hematol 2019 15;10:2040620719841581. Epub 2019 Apr 15.

Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cell has changed the treatment landscape of B-cell non-Hodgkin's lymphoma (NHL), especially for aggressive B-cell lymphomas. Single-center and multicenter clinical trials with anti-CD19 CAR T-cell therapy have shown great activity and long-term remissions in poor-risk diffuse large B-cell lymphoma (DLBCL) when no other effective treatment options are available. Two CAR T-cell products [axicabtagene ciloleucel (axi-cel) and tisagenlecleucel] have obtained US Food and Drug Administration approval for the treatment of refractory DLBCL after two lines of therapy. A third product, liso-cel, is currently being evaluated in clinical trials and preliminary results appear very promising. CAR T-cell-related toxicity with cytokine-release syndrome and neurotoxicity remain important potential complications of this therapy. Here, we review the s biology, structure, clinical trial results and toxicity of two commercially approved CAR T-cell products and others currently being studied in multicenter clinical trials in B-cell NHLs.
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http://dx.doi.org/10.1177/2040620719841581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466472PMC
April 2019

Mechanisms and Management of Chimeric Antigen Receptor T-Cell Therapy-Related Toxicities.

BioDrugs 2019 Feb;33(1):45-60

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, 12902 Magnolia Drive, FOB-3, Tampa, FL, 33612, USA.

Chimeric antigen receptor T-cell (CAR-T) therapy has proven to be a very effective cancer immunotherapy. Axicabtagene ciloleucel and tisagenlecleucel are the first-in-class anti-CD19 CAR-T currently available for relapsed/refractory adult large B-cell lymphoma. Tisagenlecleucel is also available for pediatric and young adult (up to age 25 years) patients with relapsed/refractory B-acute lymphoblastic leukemia. Cytokine release syndrome (CRS) and CAR-T-associated encephalopathy syndrome (neurotoxicity) are the most common adverse effects associated with CAR-T therapy. They can lead to significant morbidity and preclude widespread use of this treatment modality. Treatment-related deaths from severe CRS and cerebral edema have been reported. There is a significant heterogeneity in the side-effect profile of different CAR-T products under investigation and there is a need to develop standardized guidelines for toxicity grading and management. Here, we summarize the current literature on pathogenesis, clinical presentation, and management of CRS and neurotoxicity. The different grading systems of CRS and management protocols used in different trials have made it difficult to compare the outcomes of different CAR-T therapies. Several prevention strategies such as predictive biomarkers of CRS and neurotoxicity and modified CAR-T with 'built-in' safety mechanisms are being studied, with the potential to greatly expand the safety and applicability of CAR-T treatment across various malignancies.
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http://dx.doi.org/10.1007/s40259-018-0324-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733400PMC
February 2019

Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin's lymphoma.

Ther Clin Risk Manag 2018 31;14:1007-1017. Epub 2018 May 31.

Department of Oncologic Sciences, University of South Florida, Tampa, FL, USA.

Adoptive T-cell immunotherapy is a rapidly growing field and is shifting the paradigm of clinical cancer treatment. Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell therapy that was initially developed at the National Cancer Institute and has recently been commercially approved by the US Food and Drug Administration for relapsed or refractory aggressive non-Hodgkin's lymphomas including diffuse large B-cell lymphoma and its variants. The ZUMA-1 Phase I and II clinical trials formed the basis of the US Food and Drug Administration approval of this product, and we discuss the particulars of the clinical trials and the pharmacology of axi-cel. In addition, we review the CD19 chimeric antigen receptor T-specific toxicities of cytokine release syndrome and neurotoxicity, which remain the challenges to the safe delivery of this important therapy for aggressive B-cell lymphomas with poor prognosis.
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http://dx.doi.org/10.2147/TCRM.S145039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987753PMC
May 2018

Association of time to antibiotics and clinical outcomes in adult hematologic malignancy patients with febrile neutropenia.

J Oncol Pharm Pract 2017 Jun 11;23(4):278-283. Epub 2017 Jan 11.

5 College of Pharmacy, University of Kentucky, Lexington, KY, USA.

Objective The objective of this study was to determine the clinical impact of time to antibiotic administration in adult inpatients who have hematologic malignancies and develop febrile neutropenia. Methods A retrospective chart review was conducted to screen for all febrile neutropenia events amongst adult hematologic malignancy patients between 1 January 2010 and 1 September 2014. All included patients were admitted to the hospital at the time of fever onset, having been admitted for a diagnosis other than febrile neutropenia. Descriptive statistics and logistic generalized estimated equations were used to analyze the data. Results Two hundred forty-four neutropenic fever events met inclusion criteria. Thirty-five events (14.34%) led to negative clinical outcomes (in-hospital mortality, intensive care unit transfer, or vasopressor requirement), with an in-house mortality rate of 7.4%. The time to antibiotics ranged from 10 min to 1495 min. The median time to antibiotics in the events that led to negative outcomes was 120 min compared to 102 min in the events that did not lead to the negative outcome ( p = 0.93). Conditional order sets were used to order empiric antibiotics in 176 events (72.1%) and significantly reduced time to antibiotics from 287 min to 143 min ( p = 0.0019). Conclusion Prolonged time to antibiotic administration in hematologic malignancy patients who develop neutropenic fever was not shown to be associated with negative clinical outcomes.
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http://dx.doi.org/10.1177/1078155216687150DOI Listing
June 2017