scholarly journals Extracorporeal Membrane Oxygenation Candidacy in Pediatric Patients Treated With Hematopoietic Stem Cell Transplant and Chimeric Antigen Receptor T-Cell Therapy: An International Survey

2021 ◽  
Vol 11 ◽  
Author(s):  
Saad Ghafoor ◽  
Kimberly Fan ◽  
Matteo Di Nardo ◽  
Aimee C. Talleur ◽  
Arun Saini ◽  
...  
Keyword(s):  
Decision Making ◽  
Critical Care ◽  
T Cell ◽  
North America ◽  
Extracorporeal Membrane Oxygenation ◽  
Chimeric Antigen Receptor ◽  
Pediatric Patients ◽  
Cell Transplant ◽  
Pediatric Critical Care ◽  
Car T

IntroductionPediatric patients who undergo hematopoietic cell transplant (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy are at high risk for complications leading to organ failure and the need for critical care resources. Extracorporeal membrane oxygenation (ECMO) is a supportive modality that is used for cardiac and respiratory failure refractory to conventional therapies. While the use of ECMO is increasing for patients who receive HCT, candidacy for these patients remains controversial. We therefore surveyed pediatric critical care and HCT providers across North America and Europe to evaluate current provider opinions and decision-making and institutional practices regarding ECMO use for patients treated with HCT or CAR-T.MethodsAn electronic twenty-eight question survey was distributed to pediatric critical care and HCT providers practicing in North America (United States and Canada) and Europe through the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and individual emails. Responses to the survey were recorded in a REDCap® database.ResultsTwo-hundred and ten participants completed the survey. Of these, 159 (76%) identified themselves as pediatric critical care physicians and 47 (22%) as pediatric HCT physicians or oncologists. The majority (99.5%) of survey respondents stated that they would consider patients treated with HCT or CAR-T therapy as candidates for ECMO support. However, pediatric critical care physicians identified more absolute and relative contraindications for ECMO than non-pediatric critical care physicians. While only 0.5% of respondents reported that they consider HCT as an absolute contraindication for ECMO, 6% of respondents stated that ECMO is contraindicated in HCT patients within their institution and only 23% have an institutional protocol or policy to guide the evaluation for ECMO candidacy of these patients. Almost half (49.1%) of respondents would accept a survival to hospital discharge of 20-30% for pediatric HCT patients requiring ECMO as adequate.ConclusionsECMO use for pediatric patients treated with HCT and CAR-T therapy is generally acceptable amongst physicians. However, there are differences in the evaluation and decision-making regarding ECMO candidacy amongst providers across medical specialties and institutions. Therefore, multidisciplinary collaboration is an essential component in establishing practice guidelines and advancing ECMO outcomes for these patients.

OP206 Expert Elicitation Of Probabilistic Distributions to Inform Survival Modelling of CD19 Chimeric Antigen Receptor T-Cell Therapies

2020 ◽  
Vol 36 (S1) ◽  
pp. 3-3
Author(s):  
Niamh Carey ◽  
Conor Hickey ◽  
Laura Mc Cullagh ◽  
Michael Barry
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Expert Elicitation ◽  
Cell Transplant ◽  
Major Advance ◽  
Cell Therapies ◽  
Risk Of Death ◽  
Car T Cell ◽  
Car T

IntroductionIn 2018, the National Centre for Pharmacoeconomics (NCPE) was commissioned to conduct a health technology assessment (HTA) of one of the first commercially available chimeric antigen receptor (CAR) T-cell therapies, tisagenlecleucel. CAR T-cells are a major advance in personalized cancer treatment, demonstrating promising outcomes in relapsed/refractory pediatric acute lymphoblastic leukemia (pALL). However, the results are based on short-term follow up, limiting their value in predicting long-term survival and leading to uncertainty about the most appropriate survival modeling method to employ. This study aimed to address these limitations by means of expert elicitation.MethodsAn expert elicitation method, the histogram technique, was employed. A predefined discrete numerical scale was presented in Microsoft Excel® and the expert was asked to place twenty crosses on a frequency chart. These crosses represented the expert's beliefs about the distribution of particular quantities. Each cross represented five percent of the probabilistic distribution. Individual distributions were then aggregated across experts using linear pooling.ResultsA total of seventeen experts were invited to take part; eight agreed to participate and five completed the exercise. Three experts did not consider tisagenlecleucel to be a “curative” therapy because patients had a higher risk of death, compared with the age- and sex-matched general population. The aggregated distributions indicated the five-year overall survival rate to be thirty-three percent (95% CI 8.65–56.88) in patients who do not receive a subsequent stem cell transplant and twenty percent (95% CI 2.38 -52.04) in those who do.ConclusionsThe results of this study will be used to calibrate CD19 CAR T-cell therapy survival estimates presented in HTA submissions to the NCPE to ensure more robust assessments. They will also be used to inform the construction of a de novo cost-utility model for examining the cost effectiveness of CD19 CAR T-cell therapies for relapsed/refractory pALL in the Irish healthcare setting.

Vaccine titers in lymphoma patients receiving chimeric antigen receptor T-cell therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7555-7555
Author(s):  
Radhika Bansal ◽  
Paschalis Vergidis ◽  
Pritish Tosh ◽  
John W. Wilson ◽  
Matthew Hathcock ◽  
...  
Keyword(s):  
T Cell ◽  
Hepatitis B ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Aggressive Lymphoma ◽  
Cell Transplant ◽  
T Cell Therapy ◽  
Car T ◽  
The Impact

7555 Background: While CAR-T therapy is not myelo-ablative, patients with aggressive lymphoma treated with CD19 chimeric antigen receptor T cell therapy (CAR-T) are lymphodepleted and have prolonged B cell aplasia. The impact of CAR-T on immunologic protection from vaccine-preventable diseases (and thus the need to revaccinate) is not known. We report the vaccine titers of patients treated with axicabtagene ciloleucel (axi-cel) at Mayo Clinic. Methods: Retrospective chart review of adult lymphoma patients who received axi-cel from 9/2018 to 9/2020 for anti-viral and anti-bacterial titers prior to CAR-T infusion and at month 3 (MO3) post CAR-T. Results: Prior to CAR-T therapy, positive titer rate was highest for tetanus and lowest for Strep pneumoniae (Strep PNA) (Table). Similar trends were seen whether patients had stem cell transplant (ASCT) within 2 years of CAR-T (i.e. within immunization timeframe post ASCT) or not (Table). Compared to patients who had ASCT, those who did not had higher rate of positive titer for Strep PNA and lower rate for hepatitis B, Mumps, and VZV. The same trend for sero-positive rate were observed at MO3 post CAR-T. Patients with IgG<400 mg/dl received IVIG supplement for prophylaxis. Among the 23 patients who received IVIG, variable rate of conversion from negative to positive titers were seen for measles (1/2, 50%), mumps (2/3, 67%), rubella (2/3, 67%), varicella-zoster (VZV, 3/3, 100%), hepatitis A (6/6, 100%), hepatitis B (6/7, 86%) and Strep PNA (0/10, 0%). For patients who did not receive IVIG prophylaxis, there was one loss of seropositivity for Strep PNA (1/4, 25%). Conclusions: The presence of protective vaccine titers is variable for patients receiving CAR-T, regardless of recent ASCT. The loss of protective titers post CART was low. IVIG variably impacted vaccine titer status. Immunization remains important for patients with ASCT prior to CART, without completion of post ASCT immunization protocol. Further study is needed to inform the need for immunization and optimal timing post CART.[Table: see text]

scholarly journals Autologous Transplant versus Chimeric Antigen Receptor T-cell Therapy for Relapsed DLBCL in Partial Remission

Blood ◽  
2021 ◽  
Author(s):  
Mazyar Shadman ◽  
Marcelo C. Pasquini ◽  
Kwang Woo Ahn ◽  
Yue Chen ◽  
Cameron J. Turtle ◽  
...  
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Salvage Therapy ◽  
Partial Remission ◽  
Antigen Receptor ◽  
B Cell Lymphoma ◽  
Progression Rate ◽  
Cell Transplant ◽  
Car T ◽  
Multivariable Regression

The relative efficacy of autologous hematopoietic cell transplant (auto-HCT) versus chimeric antigen receptor T-cell (CAR-T) therapy in diffuse large B-cell lymphoma (DLBCL) patients who achieve a partial remission (PR) after salvage chemotherapy is not known. Using the Center for International Blood & Marrow Transplant Research registry database, we identified adult DLBCL patients who received either an auto-HCT (2013-2019) or CAR-T treatment with axicabtagene ciloleucel (2018-2019) while in a PR by CT or PET scan. We compared the clinical outcomes between the two cohorts using univariable and multivariable regression models after adjustment for relevant baseline and clinical factors. In the univariable analysis, the 2-year progression-free survival (52% vs. 42% ; p=0.1) and the rate of 100-day non-relapse mortality (4% vs. 2% ; p=0.3) were not different between the 2 cohorts but consolidation with auto-HCT was associated with a lower rate of relapse/progression (40% vs. 53% ; p=0.05) and a superior overall survival (OS) (69% vs. 47% ; p=0.004) at 2-years. In the multivariable regression analysis, treatment with auto-HCT was associated with a significantly lower risk of relapse/progression rate (HR=1.49; p=0.01) and a superior OS (HR=1.63; p=0.008). In patients with DLBCL in a PR after salvage therapy, treatment with auto-HCT was associated with a lower incidence of relapse and a superior OS compared with CAR-T. These data support the role of auto-HCT as the standard-of-care in transplant-eligible patients with relapsed DLBCL in PR after salvage therapy.

Chimeric Antigen Receptor (CAR) T Cells Targeting the CD19 Antigen for the Treatment of Pediatric Relapsed B Cell ALL

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3716-3716 ◽  
Author(s):  
Kevin J. Curran ◽  
Isabelle Riviere ◽  
Rachel Kobos ◽  
Nancy A. Kernan ◽  
Farid Boulad ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Complete Remission ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Pediatric Patients ◽  
Elevated Serum ◽  
Car T Cells ◽  
Car T

Abstract T cells can be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). CAR T cells targeting the CD19 antigen is a novel therapeutic approach for patients with relapsed B cell acute lymphoblastic leukemia (B-ALL). We have previously demonstrated that CAR T cells have a significant clinical benefit in adult patients with relapsed B-ALL. The primary objective of this study (NCT01860937) is to extend the use and test the safety of CD19 specific CAR T cells in children with relapsed CD19+ B-ALL. To date, 11 pediatric patients with very high risk (VHR) or relapsed B-ALL have been enrolled on protocol with a median age of 13 years (range 2-23 years) at time of T cell collection. We have treated 4 pediatric patients with relapsed B-ALL (ages 13, 14, 19, and 22 years) using patient derived T cells expressing a CD19 specific CAR (19-28z). Complete response (complete remission or complete remission with incomplete count recovery) occurred in 2/4 (50%) patients. Severe cytokine release syndrome (sCRS) defined by fever for ≥3 consecutive days, elevated serum cytokine levels, and one clinical sign of toxicity (hypotension, hypoxia, neurologic disorder including altered mental status, obtundation, and/or seizure) occurred in both patients who responded to CAR T cells. Morphologic disease (≥5% bone marrow blasts) at time of treatment was present in three patients including both patients with sCRS. Systemic immunosuppressants (corticosteroids or anti-IL6 receptor antibody tocilizumab) abrogated clinical symptoms of sCRS. Elevated serum cytokines of IFN-g (>20 fold), fractalkine (>20 fold), Flt-3L (>55 fold), IL-5 (>15 fold), IL-6 (>100 fold), and IL-10 (>15 fold) were demonstrated in patients with sCRS. Monitoring of bone marrow demonstrated peak 19-28z CAR T-cell detection within 1-2 weeks following infusion with gradual contracture over 2-3 months. These early results demonstrate the feasibility and significant clinical impact of this approach in patients with relapsed B-ALL. To more rapidly generate statistically relevant data, demonstrate the “exportability” of this technology between academic institutions, and offer this therapeutic option to a broader number of pediatric patients with chemo-refractory B-ALL our trial will expand into a phase I multicenter clinical trial with a collaborating institution. Subsequent cohorts of patients will receive 19-28z CAR T cells and will be evaluated for toxicity, persistence of CAR T cells, and for anti-leukemic efficacy. Disclosures Off Label Use: CAR T cells for relapsed B-ALL. Riviere:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other. Boulad:Genzyme Sanofi: Trials partially funded by Genzyme Sanofi Other. Sadelain:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other. Brentjens:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other.

The pharmacist’s role in chimeric antigen receptor T cell therapy

2020 ◽  
Vol 26 (7) ◽  
pp. 1725-1731
Author(s):  
Jennifer P Booth ◽  
Carolyn L Kusoski ◽  
Julie M Kennerly-Shah
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Cell Transplant ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

The emergence and efficacy of chimeric antigen receptor (CAR) T cell therapy in previously incurable malignancies represents a promising paradigm shift in cancer care. However, it is not without significant clinical, operational, and financial considerations. Pharmacists should be prepared to fulfill the various roles in CAR T cell therapy provision including: policy development; electronic medical record build; patient and staff education; patient selection; procurement, storage, and handling; medication administration and supportive care; management of adverse reactions; and quality tracking. Our commentary provides an overview of the opportunities for pharmacy involvement in the implementation and maintenance of a CAR T cell therapy program with an emphasis on the importance of pharmacy involvement as part of a multidisciplinary approach to care. Although some institutions have dedicated a CAR T cell pharmacist to meet the demands of emerging CAR T cell therapy, we believe that clinical pharmacists practicing in hematopoietic stem cell transplant and hematology/oncology have the skills and training to fulfill the pharmacist’s role in CAR T cell therapy.

scholarly journals 1090. HHV-6 Encephalitis following Chimeric Antigen Receptor T-cell Therapy: Report of 2 Cases

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S574-S574
Author(s):  
Melanie T Rebechi ◽  
Jacqueline Bork ◽  
David J Riedel
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Human Herpesvirus ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Cell Transplant ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T

Abstract Background Human herpesvirus 6 (HHV-6) is the most common cause of infectious encephalitis following hematopoietic stem cell transplant. Chimeric antigen receptor T-cell (CAR-T) therapy is a novel cancer-directed immunotherapy; chemotherapy conditioning for CAR-T results in prolonged, severe immunosuppression. HHV-6 encephalitis has not been reported in patients after CAR-T therapy. Methods We report 2 cases of HHV-6 encephalitis after CAR-T therapy. Results Case 1: A 69 year old man underwent CAR-T therapy after fludarabine/cyclophosphamide (Flu/Cy) conditioning for relapsed diffuse large B cell lymphoma (DLBCL). His course was complicated by cytokine release syndrome (CRS) requiring tocilizumab and neurotoxicity requiring high dose dexamethasone. On day 29 he was febrile to 39.3℃, confused, and had difficulty speaking. Mental status (MS) worsened, so LP and MRI of the brain were performed. HHV-6 CSF PCR was positive, and ganciclovir (GCV) was started. He improved gradually over 10 days. At follow up, he reported mild short term memory difficulty but no focal deficits. Case 2: A 57 year old man underwent CAR-T therapy after Flu/Cy conditioning for refractory DLBCL. His course was complicated by CRS requiring tocilizumab. On day 6, he had difficulty concentrating, slowed thinking, stuttering and repetitive speech. MS continued to worsen, and dexamethasone and siltuximab were given for CAR-T neurotoxicity. After 1 week he was following commands. By week 3 he remained intermittently confused and agitated, so MRI and LP were performed. HHV-6 PCR was positive in the CSF. He was started on GCV and improved gradually over the next 2 weeks but remained dysarthric with slowed speech. On day 55, HHV-6 remained detectable in CSF but not quantifiable and GCV was discontinued despite persistent cognitive deficits. Table 1: Demographics and clinical characteristics of 2 patients with HHV-6 encephalitis following CAR-T therapy Conclusion Diagnosing HHV-6 encephalitis can be challenging after CAR-T therapy because altered MS is often attributed to CAR-T associated neurotoxicity. It is important to maintain a high index of suspicion for infectious causes of altered MS after CAR-T therapy, including HHV-6 encephalitis, especially in patients treated with further immunosuppression for CRS and CAR-T related neurotoxicity. Disclosures All Authors: No reported disclosures

scholarly journals IMMU-02. CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL NEUROTOXICITY CORRELATES WITH PRETREATMENT AND ACUTE CSF NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii360-iii360
Author(s):  
Juliane Gust ◽  
Ashley Wilson ◽  
Olivia Finney ◽  
Kendra Jae Hartsuyker ◽  
Prabha Narayanaswamy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pediatric Patients ◽  
Cell Transplant ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Baseline Serum ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract OBJECTIVE Immunotherapy for hematologic malignancies with CD19-directed CAR T cells is complicated by neurotoxicity in approximately 40% of patients. We have previously reported evidence of glial injury in pediatric patients with CAR T neurotoxicity by elevated CSF levels of GFAP and S100b. We now hypothesize that NFL is also a useful biomarker of neuronal injury related to abnormal blood-brain-barrier and glial function. METHODS We used the Mesoscale Discovery platform to measure CSF and serum NFL levels in a consecutive cohort of 43 pediatric patients with B cell ALL who received CD19-directed CAR T cells. In addition, we will present expansion cohort measurements of NFL and GFAP (N=95). RESULTS CSF NFL levels prior to CAR T cell infusion positively correlated with the risk of subsequently developing severe neurotoxicity (no neurotoxicity, median 275pg/mL, mild 378pg/mL, severe 951pg/mL, P=0.0182 for severe vs none, P=0.0458 for severe vs mild). During neurotoxicity, mean CSF NFL levels increased to 1179pg/mL (mild neurotoxicity, P=0.0338) and 1345 pg/mL (severe neurotoxicity, P=0.0148), respectively. In serum, pretreatment NFL levels were highly abnormal in many patients (median 368pg/mL, range 10–56,321pg/mL; healthy control median 4pg/mL, range 1–7.5pg/mL). However, there was no correlation with neurotoxicity, history of CNS radiation, peripheral neuropathy, stem cell transplant, or number of prior chemotherapies. Day 7 serum NFL levels did not change significantly (median 439pg/mL, range 5–17,439pg/mL, P=0.3254). CONCLUSION We conclude that CSF NFL is promising biomarker of CAR T neurotoxicity risk and severity. The abnormal baseline serum NFL concentrations remain unexplained and require further study.

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