Therapy In Recipients Research Articles

Procalcitonin as a biomarker for predicting bacterial infection in chimeric antigen receptor T-cell therapy recipients.

It is unknown whether serum procalcitonin (PCT) concentration monitoring can differentiate between bacterial infection or cytokine release syndrome (CRS) when chimeric antigen receptor T-cell (CAR-T) recipients present with a constellation of signs and symptoms that may represent both complications. The objective of the study was to assess the utility of serum PCT concentrations as a biomarker of bacterial infection in CAR-T recipients. This single-center, retrospective, medical record review evaluated patients prescribed CAR-T therapy until death or 30 days after infusion. Logistic regression modeling determined the association between elevated serum PCT concentrations within 48 h of fever onset and microbiologically confirmed infection. Secondary outcomes included clinically suspected infection, CAR-T toxicity rates, and broad-spectrum antibiotic usage. Predictive performance of PCT was assessed by area under the receiver operating characteristic curve (AUC). The 98 included patients were a median age of 63 (IQR: 55-69) years old, 47 (48%) were male, and 87 (89%) were Caucasian. Baseline demographics and clinical characteristics were similar between patients with and without a bacterial infection. Serum PCT >0.4 ng/mL within 48 h of fever was significantly associated with a microbiologically confirmed bacterial infection (OR: 2.75 [95% CI: 1.02-7.39], p= 0.045). Median PCT values in patients with and without confirmed infections were 0.40 ng/mL (IQR: 0.26, 0.74) and 0.26 ng/mL (IQR: 0.13, 0.47), respectively. The AUC for PCT to predict bacterial infection was 0.62 (95% CI 0.48-0.76). All patients experienced CRS of some grade, with no difference in CRS severity based on elevated PCT. Broad-spectrum antibiotics were used for a median of 45% and 23% of days in those with and without confirmed infection, respectively (p= 0.075). Elevated serum PCT concentrations above 0.4ng/mL at time of first fever after CAR-T infusion was significantly associated with confirmed bacterial infection. Furthermore, rigorous, prospective studies should validate our findings and evaluate serial PCT measurements to optimize antimicrobial use after CAR-T therapy.

443 - Efficacy of Tixagevimab-Cilgavimab in Preventing Sars-Cov-2 in Hematopoietic Stem Cell Transplant and Chimeric Antigen Receptor T-Cell Therapy Recipients

443 - Efficacy of Tixagevimab-Cilgavimab in Preventing Sars-Cov-2 in Hematopoietic Stem Cell Transplant and Chimeric Antigen Receptor T-Cell Therapy Recipients

431 - Lessons Learned from COVID-19 Pandemic: Outcomes after Sars-Cov-2 Infection in Hematopoietic Cell Transplant and Cell Therapy Recipients

431 - Lessons Learned from COVID-19 Pandemic: Outcomes after Sars-Cov-2 Infection in Hematopoietic Cell Transplant and Cell Therapy Recipients

451 - Evusheld™ Pre-Exposure COVID-19 Prophylaxis in Pediatric Hematopoietic Stem Cell Transplant (HSCT) and Cellular Therapy Recipients: A Single Institution Retrospective Series

451 - Evusheld™ Pre-Exposure COVID-19 Prophylaxis in Pediatric Hematopoietic Stem Cell Transplant (HSCT) and Cellular Therapy Recipients: A Single Institution Retrospective Series

A retrospective analysis of the incidence of severe adverse events among recipients of chiropractic spinal manipulative therapy

This study examined the incidence and severity of adverse events (AEs) of patients receiving chiropractic spinal manipulative therapy (SMT), with the hypothesis that < 1 per 100,000 SMT sessions results in a grade ≥ 3 (severe) AE. A secondary objective was to examine independent predictors of grade ≥ 3 AEs. We identified patients with SMT-related AEs from January 2017 through August 2022 across 30 chiropractic clinics in Hong Kong. AE data were extracted from a complaint log, including solicited patient surveys, complaints, and clinician reports, and corroborated by medical records. AEs were independently graded 1–5 based on severity (1-mild, 2-moderate, 3-severe, 4-life-threatening, 5-death). Among 960,140 SMT sessions for 54,846 patients, 39 AEs were identified, two were grade 3, both of which were rib fractures occurring in women age > 60 with osteoporosis, while none were grade ≥ 4, yielding an incidence of grade ≥ 3 AEs of 0.21 per 100,000 SMT sessions (95% CI 0.00, 0.56 per 100,000). There were no AEs related to stroke or cauda equina syndrome. The sample size was insufficient to identify predictors of grade ≥ 3 AEs using multiple logistic regression. In this study, severe SMT-related AEs were reassuringly very rare.

Anti-HLA antibodies in recipients of CD19 versus BCMA-targeted CAR T-cell therapy

Antibodies against foreign human leukocyte antigen (HLA) molecules are barriers to successful organ transplantation. B cell–depleting treatments are used to reduce anti-HLA antibodies but have limited efficacy. We hypothesized that the primary source for anti-HLA antibodies is long-lived plasma cells, which are ineffectively targeted by B cell depletion. To study this, we screened for anti-HLA antibodies in a prospectively enrolled cohort of 49 patients who received chimeric antigen receptor T-cell therapy (CARTx), targeting naïve and memory B cells (CD19-targeted, n = 21) or plasma cells (BCMA-targeted, n = 28) for hematologic malignancies. Longitudinal samples were collected before and up to 1 year after CARTx. All individuals were in sustained remission. We identified 4 participants with anti-HLA antibodies before CD19-CARTx. Despite B cell depletion, anti-HLA antibodies and calculated panel reactive antibody scores were stable for 1 year after CD19-CARTx. Only 1 BCMA-CARTx recipient had pre-CARTx low-level anti-HLA antibodies, with no follow-up samples available. These data implicate CD19neg long-lived plasma cells as an important source for anti-HLA antibodies, a model supported by infrequent HLA sensitization in BCMA-CARTx subjects receiving previous plasma cell–targeted therapies. Thus, plasma cell–targeted therapies may be more effective against HLA antibodies, thereby enabling improved access to organ transplantation and rejection management.

Donor-Derived Infection's Prevention and Control in Kidney Transplantation

The study aimed to summarize the experience of donor selection and recipient therapy in the face of potential donor-derived infections and improve the quality of donor organ utilization, which would help reduce the risk of infection after recipient operation and decrease the risk of loss or even death of recipient kidney transplantation. In this study, 132 kidneys from 70 donors and their recipients who underwent surgery between July 2017 and January 2021 were studied to perform a retrospective analysis of their etiologic examination results and treatment process. In the 70 donors, only 25 had negative etiologic examination results, accounting for 35.71%. Among the 132 recipients, 31.82% had positive culture results, 3 (2.27%) experienced donor-derived infections, and one died. Although infection in the donor before the donation is quite common, the incidence of donor-derived infections is relatively low. The targeted and preventive application of adequate sensitive antibiotics in the whole course of therapy was the cornerstone for treating recipients at potential risk of potential donor-derived infection. The changes in infection indicators in the recipient should be closely monitored, which would guide medication adjustments timely. These measures could, to a great degree, ensure the prognosis of the recipient, in turn reducing the adverse events caused by donor-derived infections.

From Alpha to Omicron: anatomy of the SARS-CoV-2 pandemic in an outpatient haemodialysis unit in Johannesburg, South Africa

Background Recipients of kidney replacement therapy are more susceptible to severe disease and mortality from SARS-CoV-2 infection. We evaluated disease kinetics and clinical outcomes across four COVID-19 outbreak waves in the haemodialysis unit of a tertiary-level hospital in South Africa.

SARS-CoV-2 infections in pediatric and young adult recipients of chimeric antigen receptor T-cell therapy: an international registry report

BackgroundImmunocompromised patients are at increased risk of SARS-CoV-2 infections. Patients undergoing chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory B-cell malignancies are uniquely immunosuppressed due to CAR T-mediated B-cell aplasia...

Neuropsychiatric disorders in adults undergoing chimeric antigen receptor T cells therapy for aggressive lymphomas and acute lymphoblastic leukemia

ObjectiveTo evaluate risk factors for neuropsychiatric disorders (NPD) in recipients of CART therapy. MethodsPatients ≥ 18 years with acute lymphoblastic leukemia (ALL), and aggressive B-cell lymphomas who received CART in 2018 were evaluated. Patients with and without NPD were compared. ResultsNPD was diagnosed in 31.2% of patients. Compared to patients without NPD, patients with NPD were likely to be females (P = 0.035) and have ALL (P = 0.039). NPD was significantly associated with female gender (OR = 2.03) and diagnosis of ALL (OR = 2.76). No association between NPD and outcomes. ConclusionsFemale gender and ALL were risk factors for NPD.

Abstract B087: Disparities in pediatric patients receiving proton therapy during the COVID-19 pandemic - A single institutional experience

Abstract Introduction: Our institution cares for a largely underserved urban population, treating about 120 children annually with radiation therapy; roughly 10% are referred for proton therapy elsewhere. COVID-19 led to some decreases in medical care due to uncertainties regarding the state of public health. The purpose of this study is to evaluate existing socioeconomic disparities using the University of Wisconsin Area Deprivation Index (ADI) and whether the pandemic impacted this referral pattern. Methods: Over the last twenty years, approximately 2,275 children have presented to our institution for radiation treatment. A retrospective chart review was conducted and a patient database of demographic and clinical information was created. We used demographic data to obtain the ADI, and compared relative disparity rankings between proton therapy recipients and a random sample of patients from the 25 most common zip codes (representative of over 20% of the total cohort). We compared the number of patients treated only at the closest proton facility before and after the onset of the pandemic. Results: The demographic make-up of our patient population is approximately 53.7% Latino, 22.6% White, 9.5% African American, 9.2% Asian, and 5% Other. Of these patients, about 500 had diagnoses typically referred for proton therapy (such as brain tumors, neuroblastoma, sarcomas, and Hodgkin lymphoma). At baseline, we found a statistically significant difference in the median state ADI decile of 3 and 7 for protons and photons, respectively, reflecting lower socioeconomic disadvantage in the proton group. There was a difference in the median household income (based on zip code) of $102,028 and $70,479 between the proton and photon groups (p &amp;lt; 0.0001). There was also a difference in median household income of $57,871 and $76,808 between Latino and Non-Latino patients (p &amp;lt; 0.0001). Demographic data for the proton therapy cohort showed that 46.2% of these patients were White, 15.4% were Latino, 15.4% were African American, 7.7% were Asian, and 15.4% were Other. At the closest proton facility, between 2014-2019, 16 of our patients received radiation therapy. Since the beginning of pandemic associated restrictions in March 2020, 19 patients have received proton therapy at this center. Conclusions: Disparities preventing patients from receiving proton therapy have been described. Our work adds granular census block data and uses the ADI which takes into account median family income, unemployment rate, households without access to a vehicle, English language proficiency and more. Those with lower ADI risk rankings were overrepresented in the proton therapy group. Despite the pandemic and added referral challenges, the number of patients able to receive proton therapy did not decrease which we hypothesize may be due to many factors, including the unanticipated flexibility of remote work amongst those with lower ADI rankings. Latinos were least likely to have proton therapy, and further research is needed to ameliorate the disparities and barriers to care which they face. Citation Format: Samuel P. McKinnon, Zara I. Kazmierczak, Arthur J. Olch, Daniel Roh, Ethan Nguyen, Kristen Pang, Iain J. MacEwan, Kenneth K. Wong. Disparities in pediatric patients receiving proton therapy during the COVID-19 pandemic - A single institutional experience [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B087.

Outcomes and Management of Sars-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation (HCT) and CAR-T Therapy

HCT or CAR-T therapy recipients who develop COVID-19 have decreased overall survival (68% Sharma et al. Lancet Haematol. 2021), likely due to disease-inherent and therapy-related immunodeficiency. The development of specific COVID therapies and vaccination during the pandemic has changed the prevention and management of COVID-19 infection. Nevertheless, with the appearance of new SARS-CoV2 variants and omicron, in particular, questions about the severity of disease in high-risk patients are yet to be defined. Methods We included retrospectively 218 adult HCT/CAR-T recipients diagnosed with presumed COVID-19 omicron variant at Memorial Sloan Kettering Cancer Center (MSK), New York, between December 2021 and February 2022. Data were analyzed using SPSS version 26 (IBM, Armonk, NY). Results Among 218 patients, 107 received an autologous HCT, 92 allogeneic HCT, and 19 CAR-T. The median age was 58 years (range, 21 to 87), and 56% were male. The median time from HCT/CAR-T to SARS-CoV2 infection was 44 months (range, 0.1 to 272 months), and 27 patients (12%) acquired SARS-CoV2 within the first 100 days post-HCT/CAR-T. The primary hematologic diagnoses were plasma cell (37%), myeloid (37%), and lymphoid (26%) malignancies. Myeloablative conditioning was performed in 90 patients (41%). In the alloHCT recipients, 17 donors (18%) were matched related, 51 (55%) matched unrelated, 19 (21%) umbilical cord blood, and 5 (6%) haploidentical. 31% patients had 2 or more comorbidities and 9% received IVIG for hypogammaglobulinemia within the prior month. Of note, 40% of the patients were on active cancer therapy (maintenance or treatment) at the time of COVID-19 infection, and 47% of the alloHCT recipients were on GVHD immunosuppressive treatment. Characteristics of COVID-19 omicron variant infection are shown in Table1. Specific COVID-19 treatment was administered in 111 patients (51%) and included MoAbs in 63 patients (56.7%), sotrovimab being the most frequently used (n=55, 87 %), remdesivir (n= 23, 21%), and other antivirals (n= 15, 14%). Risk factors for admission were presence of > 3 comorbidities (HR, 6.2; 95% CI 2.3-16.3, p= 0.000), progression of disease (POD) (HR, 3.8; 95% CI 1.6-8.9, p= 0.002,) and CAR-T therapy (HR 4.5; 95% CI 1.4-14.1p= 0.008). Regarding vaccination status, 84% (n= 183) of the cohort was vaccinated with mRNA Covid-19 vaccines, with 42% of patients having 1 booster before COVID19 infection. Interestingly, only 15/35 (42%) of the booster patients with measured serologic response showed SARS-CoV-19 Antibodies value> 2500 BAU/I. Nineteen patients showed low titer COVID-19 antibodies (<2500 BAU/I) testing after COVID-19 infection: 3 patients died (2 for POD, 1 for COVID), 3 were not vaccinated, 1 patient had to be revaccinated after HCT, and 6 patients were administered tixagevimab/cilgavimab for future prophylaxis. Persistent/Long COVID were present in 8 (3.5%) patients, showing fatigue and URI symptoms 5/8 (62%) had a previous admission for COVID-19 infection and 5/8 (62%) had a negative spike antibody titer before infection. The median duration of viral shedding (positive SARS-CoV-2 PCR) was 11 weeks (range, 3.2 to 19.1 weeks). After a median follow up of 4 months (range, 0 to 8 months), 21 patients (9.6%) had recurrent COVID infection, and two of them died. The overall mortality rate was 10% in all patients (22/218 patients), with 2.5% (6/22) attributable to COVID. Other causes of death were progressive disease (n=13), sepsis (n=1), and hepatic VOD (n=1). Comparing our omicron cohort with the initial 77 HCT & CAR-T patients infected with first wave COVID-19 in March 2020 at our institution, overall survival at 30 days was 94% vs 78% (p=0.010) (Figure 1). Conclusions In our cohort, mortality attributable to the COVID-19 omicron variant was low (2.5%), and only 19% required admission. Risk factors for admission were presence of 3 or more comorbidities, POD at time of COVID infection, and CAR-T therapy. Altogether our date confirms enhanced overall survival (94%) in HCT, and CART recipients infected with the omicron variant of SARS-CoV2 as compared to prior waves of the COVID-19 pandemic. Access to SARS-COV-2 specific treatments and the higher incidence of vaccination in this cohort appear to be key factors to successfully managing patients in order to reduce COVID-19 mortality. Pre-exposure prophylaxis became available later and is also likely important. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Monoclonal Protein at Diagnosis on Outcomes in Patients with Marginal Zone Lymphoma: A Multicenter Cohort Study

Introduction Marginal zone lymphoma (MZL) is an indolent B-cell non-Hodgkin lymphoma that includes 3 subtypes: extranodal marginal zone lymphoma (EMZL) of the mucosa-associated lymphatic tissue (MALT), splenic MZL (SMZL), and nodal MZL (NMZL). Outside of case reports and small case series, the relevance of monoclonal protein (M-protein) in patients with MZL at diagnosis is largely unknown. Hence, we sought to evaluate the impact of M-protein at diagnosis on outcomes in patients with MZL. Methods This multicenter, retrospective cohort study of MZL patients treated at 8 US medical centers included patients who were ≥18 years old, diagnosed with MZL from 2010-2020, and had information on M-protein at diagnosis. Patients who were on observation or received antibiotics only were excluded. Patients were grouped according to the presence or absence of M-protein detectable by serum protein electrophoresis or immunofixation. The primary endpoint was progression-free survival (PFS). Secondary endpoints were time from diagnosis to systemic therapy, cumulative incidence of relapse in stage 1 disease after local treatment (surgery or radiation therapy), and cumulative incidence of transformation in M-protein versus no M-protein groups. PFS was defined as the time from the start of first-line therapy until lymphoma relapse/progression or death from any cause, censoring at the last clinical assessment. Results Among 501 eligible patients with newly diagnosed MZL, 152 (30%) had detectable M-protein at diagnosis and 349 (70%) did not. Among those with M-protein, 59% (n=90) had IgM, 29% (n=44) had IgG, 3% (n=4) had both IgM and IgG, and 9% (n=14) had non-IgM/non-IgG M-protein and light chains. Patients in the M-protein group had a higher median age (66 vs 61 years), more advanced stage disease (76% vs 53%), lower albumin (27% vs 15%), and were more likely to receive R-chemotherapy (39% vs 23%) compared to no M-protein group. The median PFS was 3.2 years (95%CI=2.1-5.6) in the M-protein group compared to 6.6 years (95%CI=5.4-NR) in the no M-protein group (log-rank p<0.001; Figure 1) with a 3-year and 5-year PFS rates of 51% and 44% in the M-protein gp versus 74% and 59% in the no M-protein groups. In order to determine if the M-protein was independently associated with PFS, we performed Cox regression analysis in only those who received systemic therapy at diagnosis (n=377). After adjusting for factors associated with PFS in univariate analysis (age, MZL subtype, ECOG PS, albumin level, LDH>ULN, and first-line treatment regimen), M-protein remained associated with significantly inferior PFS (HR=1.80, 95%CI=1.24-2.62, p=0.002) in the multivariable analysis. There was no difference in PFS based on the type of M-protein at diagnosis (IgM vs IgG, p=0.88). M-protein group treated with rituximab monotherapy had significantly shorter PFS compared to no M-protein group (1.9 years versus 4.3 years, p<0.001, Figure 2), however, there was no significant difference in PFS among patients treated with bendamustine and rituximab (BR, 6.1 years versus NR, p=0.14). In the EMZL subset (n=101) treated with local therapy (surgery or radiation), PFS did not significantly differ by presence/absence of M-protein at diagnosis (p=0.53). There was no difference in the time from diagnosis to systemic therapy initiation between the M-protein and no M-protein groups with % of patients who started treatment at 1, 3, and 5 years being 89% vs 86%, 96% vs 94%, and 99% vs 98%, respectively (p=0.21). The cumulative incidence of relapse in stage 1 disease (n=144) among the recipients of local therapy was not significantly different between the M-protein and no M-protein groups (p=0.10). The cumulative incidence of transformation was significantly higher in the M-protein group compared to no M-protein group with 3-, 5-, and 10-year rate of transformation being 5.6% vs 0.6%, 8.9% vs 1.3%, and 14% vs 1.3%, respectively (p=0.001). Conclusions In this study (to our knowledge, the largest to date) of the prognostic relevance of M-protein in MZL, we found that M-protein at diagnosis was associated with shorter PFS and a higher risk of histologic transformation. Because the PFS difference was not observed after BR, immunochemotherapy may be a preferred approach over rituximab monotherapy in this group and needs to be explored further. M-protein in stage 1 EMZL was not associated with shorter PFS after standard local therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Feasibility of Patient-Reported Outcome Assessment in the Acute Phase after CAR T-Cell Therapy in Lymphoid Malignancies: A Pilot Study

Introduction: Although acute toxicities of chimeric antigen receptor T-cell (CAR T-cell) therapies are well described, there is a paucity of data on patient-reported outcomes (PROs) in the acute phase after CAR T-cell infusion. We performed a prospective pilot study to assess the feasibility of measuring PROs and trajectory of health-related quality of life (HRQoL) in the first 3 months after CAR T-cell therapy in lymphoid malignancies. Methods: We enrolled patients with aggressive B-cell non-Hodgkin lymphoma receiving CD-19 directed CAR T-cell therapy. PROs were assessed using 2 instruments: PROMIS-29 v2.0 (7 domains and 29 items) and FACT-Lym (6 domains and 48 items). PROs were assessed at the following time-points: baseline/prior to lymphodepleting chemotherapy, day#0 (day of CAR T-cell infusion [before infusion]), and post-CAR days 7 (±3), 14 (±3), 21 (±3), 28 (±3), 60 (±10), and 90 (±10). The primary endpoint was compliance rate of PRO instruments at each time-point. The key secondary endpoint was trajectory of QoL domains, as measured by PROMIS-29 and FACT-Lym. The raw score of each PROMIS-29 domain was converted to standardized T-score, which has a mean of 50 (±10) for general US population and a minimal clinically important difference (MCID) of 5 . Results: A total of 23 patients were enrolled, among which 3 died prior to baseline PRO assessment. In 20 evaluable patients, median age was 66 years (range, 50-78) and all had ECOG performance status 0 or 1. The CAR T product was tisa-cel in 11, axi-cel in 9, and experimental in 1 patient. Two patients died during the study period, one at day#35 and one at day#89 after CAR T-cell infusion. Proportion of patients with any missing PROMIS data increased from 0% at baseline to the highest of 50% at day#14 post CAR (p-value for trend=0.0001), and subsequently decreased to 22% at day 90 (p-value for trend [day#14 vs 90]=0.01) (Figure 1a). Proportion of patients with any missing FACT-Lym increased from 15% at baseline to the highest of 50% at day#14/21, and then decreased to 22.2% at day#90. The three domains of PROMIS-29 that showed significant change over time were physical function, fatigue, and satisfaction with social role (Figure 1b). The physical function T-score (46.5 [baseline]-->38.8 [day#21]-->43.6 [day#90]) and satisfaction with social role T-score (50.2 [baseline]-->43.0 [day#21]-->49.3 [day#90]) significantly decreased from baseline to day#21, and then significantly increased from day#21 to day#90, with fatigue T-score showing a significant increase-decrease pattern (50.6-->55.9-->49.1, at respective time-points). There were no significant difference between baseline and post-CAR day#90 for all three scores. There was also no significant change in pain over time, both by PROMIS pain interference domain and pain intensity item. The only FACT-Lym domain that showed significant change over time was Functional Well-Being (FWB). It decreased from baseline to day#21 (LS-mean 0.37 to 0.30, p=0.04 , and significantly increased from day#21 to day#90 (0.30 to 0.38, p=0.03). Conclusion: Our study adds novel data on feasibility of using PROMIS-29 for PRO assessment in CAR T-cell therapy recipients. The rate of missing data with both PROMIS-29 and FACT-Lym was greatest at day#14 and day#21 post-CAR, which correlated with a drop in HRQoL. Notably, PROMIS-29 demonstrated significant variability in PROs in the domains of physical function, fatigue, and satisfaction with social roles, whereas only one FACT-Lym domain (functional wellbeing) showed significant variability. Future clinical trials of CAR T-cell therapy should incorporate CMS-recommended PROMIS-29 for PRO assessment to reduce heterogeneity and enable comparison across products and trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Examination of Disparities in Access to Chimeric Antigen Receptor (CAR) T Cell Therapies in Medicare Patients (Pts) with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) Who Had Failed at Least 2 Prior Lines of Therapy (LOT)

Background: The Medicare population, representing older pts with multiple comorbidities, has been successfully treated with CAR T cell therapy. However, prior research suggests that access to this therapy offering possible durable, long-term responses could be limited and subject to health disparities based on socioeconomic status, age, or other pt characteristics (Ahmed et al. Transplant Cell Ther. 2022). Prior research focused on examining determinants of access to CAR T cell therapy relative to a heterogeneous group of pts with respect to treatment history (ie, 0-3 prior lines, etc) or subsequent management (ie, active or maintenance therapy or no additional treatment). The current study examines and contextualizes determinants of receipt of CAR T cell therapy and disparities in access among pts with R/R DLBCL enrolled in a Medicare plan who failed ≥ 2 prior LOTs and were actively treated with ≥ 3 LOTs. Methods: This retrospective cohort study used the Medicare Limited Data Set (LDS) administrative claims data (from 01/01/2017 to 03/31/2021) containing 100% final action claims submitted for fee-for-service (FFS) Medicare beneficiaries. Claims data were linked to publicly available US census county-level measures of the Area Deprivation Index (ADI) 2019 as well as predisposing, enabling, and need contextual characteristics from the Area Health Resource Files from 2019 to 2020 to measure socioeconomic disadvantage. Pts with newly diagnosed DLBCL (ICD-10-CM: C83.3X) continuously enrolled for ≥ 6 months before diagnosis (baseline period) and who received rituximab (RTX)-based therapy during follow-up were included. DLBCL treatments received by pts were identified using ICD-10 procedure and HCPCS codes; Medicare Part D prescription drug claims were not available. Pts had to have received ≥ 2 prior LOTs after DLBCL diagnosis and initiated a subsequent LOT consistent with NCCN guidelines. Those with prior diagnoses of other non-Hodgkin lymphomas or hematologic cancers were excluded, except for primary mediastinal large B-cell lymphoma, chronic lymphocytic leukemia, and follicular lymphoma. The association between receiving CAR T cell therapy and key patient and county of residence characteristics was assessed using multivariate logistic regression models. Results: A total of 15,472 Medicare pts with DLBCL received RTX at any point during follow-up. Of those, 266 pts had 2 prior LOTs, RTX in combination with another chemotherapy as first line, and a third or later LOT that was an active comparator of interest (104 pts received CAR T cell therapy vs 162 pts who did not). Among pts who did not receive CAR T cell therapy, the distribution of third LOTs included stem cell transplant (27.8%), polatuzumab-based therapy (26.5%), and various salvage combinations of RTX with chemotherapy (45.7%). More CAR T cell therapy recipients were evaluated for clinical trial participation over the study period versus nonrecipients (37.5% vs 11.1%, respectively). In unadjusted analysis, those ≥ 76 y old were numerically associated with lower odds of receiving CAR T cell therapy vs those 66-75 y, but the difference was not statistically significant (OR = 0.501, P = 0.06). In multivariate adjusted analysis restricted to 209 pts excluding those who were evaluated for clinical trial participation (65 pts received CAR T cell therapy vs 144 pts who did not), CAR T cell therapy recipients were less likely to be female (odds ratio [OR] = 0.463, P = 0.04), have Charlson Comorbidity Index (CCI) score ≥ 3 (OR = 0.451, P = 0.04), or be residents of the South (OR = 0.284, P = 0.02) (Table). There was no association of ADI and receipt of CAR T cell therapy. Conclusions: Pts with R/R DLBCL on Medicare FFS who received CAR T cell therapy were less fragile, with a CCI < 3, and more likely to experience advanced LOTs. Despite the small sample size of this study, the findings suggest that access to CAR T cell therapy should be particularly improved in female pts and pts living in the South, possibly due to geographical limitations of CAR T centers and a high population of socioeconomically disadvantaged racial minorities. Given the demonstrated durable benefit in pts with R/R DLBCL, increased adoption of CAR T cell therapy can have a significant impact on pts’ lives and improve their health outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Performance of Glomerular Filtration Rate Estimating Equations in Cancer Patients Evaluated for Chimeric Antigen Receptor T-Cell Therapy

Background: An accurate assessment of kidney function is necessary to evaluate candidates seeking chimeric antigen receptor T-cell (CAR-T) therapy.(Jain, et al, 2019, Yakoub-Agha, et al, 2019) Additionally, kidney function quantification is essential to selecting the appropriate dose for fludarabine-based lymphodepleting chemotherapy prior to CAR-T cell infusion in order to optimize outcomes.(Hirayama, et al, 2019) Treatment decisions are currently guided by a glomerular filtration rate (GFR) that is estimated using serum creatinine. However, estimated GFR (eGFR) utilizing cystatin C-based equations has been suggested to overcome the known limitations of creatinine-based eGFR in patients with cancer.(Kellum, et al, 2012, Hersh, et al, 1986) The accuracy and precision of these eGFR assessment strategies in potential CAR-T therapy recipients has not been explored, and the preferred method for quantifying GFR in this patient population remains unknown. Methods: This IRB-approved, single-center, observational study evaluated the performance of contemporary eGFR equations in any adult patient being evaluated for CAR-T therapy with a measured GFR (mGFR) by iothalamate clearance. Excluded individuals were those without a serum creatinine (SCr) and serum cystatin C (cysC) concentration performed within 14 days of the mGFR. Baseline characteristics and pertinent laboratory values were abstracted from the medical record. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, including the most recent iterations that were developed without the race parameter.(Levey, et al, 2009, Inker, et al, 2012, Inker, et al, 2021) Bias, accuracy (percentage of estimates within 10% and 30% of mGFR), and precision (SD of the difference between the eGFR and the mGFR) were assessed. The prediction of mGFR by each eGFR equation was assessed with scatterplots. Results: The 135 patients that were included had a median age of 63 (IQR: 56, 69) years and 77 (57%) were male. Two patients (1%) were African American and 123 (91%) were White. Relapsed lymphoma was the most common cancer diagnosis (n=94, 70%), followed by multiple myeloma (n=38, 28%) and acute lymphoblastic leukemia (n=3, 2%). Median mGFR was 73 ml/min/1.73m2 (IQR: 57, 92) with mGFR >60 ml/ml/1.73m2 in 95 (70%) patients. Table 1 summarizes baseline characteristics, laboratory values, and eGFR. The average absolute bias ranged from -10.1 to -0.1 ml/min/1.73m2 indicating that all equations underestimated mGFR to some degree. CKD-EPI 2021 SCr and CKD-EPI 2021 cysC+SCr had the least bias at -0.1 ml/min/1.73m2 and -4.0 ml/min/1.73m2, respectively. CKD-EPI 2021 cysC+SCr had the greatest accuracy within 10% of GFR and within 30% of mGFR. Additional bias, precision, and accuracy details of each estimating equation are summarized in table 1. The CKD-EPI 2012 cysC+SCr and the CKD-EPI 2021 cysC+SCr equations most closely correlated with mGFR in all patients (r=0.82 and 0.81, respectively). Correlation of measured glomerular filtration rate (GFR) with each of the GFR estimating equations is depicted in figure 1. Conclusion: CKD-EPI 2021 SCr and CKD-EPI 2021 cysC+SCr were the equations with the least bias. Contemporary eGFR equations had the greatest correlation with mGFR and seem acceptable when evaluating CAR-T therapy candidacy. Accuracy when dosing medications with a narrow therapeutic index, such as chemotherapy, is paramount, and all eGFR methods had limited accuracy within 10% of mGFR. Though the CKD-EPI 2021 cysC+SCr demonstrated the highest degree of accuracy within 10% of mGFR and within 30% of mGFR, iothalamate clearance should be the preferred method for kidney function assessment in patients seeking and receiving CAR-T therapy. Future research should investigate the impact of fludarabine dose selection on clinical outcomes of CAR-T recipients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lessons Learned from COVID-19 Pandemic: Outcomes after Sars-Cov-2 Infection in Hematopoietic Cell Transplant and Cell Therapy Recipients

Background: Coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic in March 2020. Over 500 million cases of SARS-CoV-2 have been reported worldwide, with over 90 million being in the US. More than 6 million lives, with over 1 million only from the US, have been claimed by the pandemic. Hematopoietic cell transplant (HCT) or chimeric antigen receptor-T (CART) cell therapy recipients have a higher risk of mortality with COVID-19. In this updated analysis, we investigated the outcomes after SARS-CoV-2 infection in HCT/CART recipients. Methods: We conducted a single-center prospective study, including all (n=196) adult HCT/CART recipients who were diagnosed with COVID-19 at the University of Kansas Medical Center from March 2020 to March 2022. Baseline and disease-related characteristics were ascertained from medical records. Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using the chi-square and t-test, were performed. Kaplan-Meier and cox regression analyses were conducted. Results: The study included 196 HCT/CART recipients who acquired SARS-CoV-2 infection, including allogeneic HCT (n=91, 46%), autologous HCT (n=89, 46%), and CART (n=16, 8%) recipients. The median age was 59.8 (21.9-79.5) years; 76.5% were Caucasians and 58% were males. The median time since HCT/CART to SARS-CoV-2 infection was 25.4 (0.2-201.9) months, and 12% of patients acquired SARS-CoV-2 within the first 100 days post-HCT/CAR-T. Plasma cell (37%), myeloid (34%), lymphoid (28%) or solid (1%) malignancies were primary diagnoses. Myeloablative conditioning was performed in 64% of patients. Donors were autologous (53%), matched sibling (12%), matched unrelated (21%), and haploidentical (14%). Prior acute graft-versus-host disease (GVHD), prior chronic GVHD, active GVHD, and current immunosuppressive therapy (IST) were noted in 20%, 26.5%, 23.5%, and 25.5% of patients respectively. Concurrent infections were observed in 12% of patients. COVID-19 severity was mild (n=136, 70%), moderate (n=24, 12%), severe (n=20, 10%) or critical/fatal (n=16, 8%). Clinical findings included pneumonia or abnormal chest imaging (31%), hypoxia (19%), intensive care unit admission (9%), and mechanical ventilation (6%). Therapies included remdesivir (31%), convalescent plasma (11%), dexamethasone (15%), monoclonal antibodies (32%), and tocilizumab/baricitinib (5%). At least one dose of SARS-CoV-2 vaccine was reported in 70% of patients (45% pre-COVID, 25% post-COVID) while 3% of patients had received pre-exposure prophylaxis. The median duration of viral shedding (positive SARS-CoV-2 PCR) was 6.5 (0.3-23.4) weeks. After a median follow-up of 5.4 (0.3-24.8) months, the mortality rate was 12% with COVID-specific mortality of 8%. Of allogeneic HCT patients, 18% (n=16) developed subsequent GVHD after COVID-19 requiring systemic steroids and additional immunosuppression. Eighty-four (43%) patients were diagnosed with COVID after Sep 2021 and had the lowest COVID-specific mortality (2% compared to 12.5% in preceding months of the pandemic). Significant predictors of COVID-19 mortality included allogeneic HCT (HR 3.7, 95% CI 1.2-11.6, p=0.023), COVID-19 within 100 days of HCT/CART (HR 4.8, 95% CI 1.7-13.2, p=0.002), COVID-19 diagnosis earlier in the pandemic (HR 5.2, 95% CI 1.1-24.4, p=0.037), prior acute GVHD (HR 3.2, 95% CI 1.2-8.5, p=0.022), active GVHD (HR 3.5, 95% CI 1.3-9.2, p=0.013), and concurrent IST (OR 7.0, 95% CI 2.4-20.1, p<0.001) while prior SARS-CoV-2 vaccination significantly reduced the COVID-19 mortality (HR 0.19, 95% CO 0.05-0.68, p=0.010). In 15 patients with available data, vaccination induced protective anti-spike protein antibody response (>100 U/mL) in 67% of patients with a median titer of 656 (9-688,000) U/mL after completion of the primary vaccination series. Conclusion: Hematopoietic stem cell transplant and CART cell therapy recipients have a higher risk of morbidity and mortality with SARS-CoV-2 infection. Our findings highlight factors associated with COVID-19 mortality in HCT/CAR-T recipients. In HCT/CART recipients, strict vigilance, infection prevention measures, vaccination prioritization, close monitoring, and early aggressive treatment interventions are suggested for COVID-19 and future emerging infectious diseases. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Vector Analysis of Multicentric Lymphoma in a Severe Hemophilia Α Dog after AAV Gene Therapy

Background Adeno-associated viral (AAV) vector gene therapy for severe hemophilia A (HA) is approaching a clinical reality with multiple successful clinical trials. Despite this success, questions remain about the long-term safety of AAV vectors, especially regarding genomic integration and resulting oncogenesis. Studies of neonatal mice have demonstrated AAV integrations that drive hepatocellular carcinoma formation (Donsante et al. Science, 2007). Studies in HA canine models have also demonstrated AAV integrations and clonal expansion of hepatocytes with integrated vector genomes, but no evidence of tumor formation (Nguyen et al. Nat Biotechnol, 2021). Additionally, three tumors have been reported in AAV gene therapy recipients with HA or hemophilia B in clinical trials, without evidence of vector integrations driving oncogenesis. Though overall reassuring, these data highlight that the field needs to remain vigilant about the possibility of AAV integrations driving cancer development. Thus, the assessment of tumors in gene therapy recipients remains important for the AAV field. Aims To determine the role of AAV vector in the development of multicentric lymphoma in a severe HA dog that received liver-directed gene therapy. Methods Vector genome copy numbers in relevant tissues were determined by real-time PCR with primers situated in the 3'-end of the promoter and the 5'- end of the transgene. The vector copy number was calculated by comparing the analyte amplification signal against a standard curve of the plasmid DNA. Results A privately owned mixed-breed dog (PC9) with a history of recurrent spontaneous bleeding events presented with canine factor VIII (cFVIII) levels <1% normal, consistent with severe HA. At 9-months of age, he received liver-directed AAV8 gene therapy with a high-expressing canine factor FVIII (cFVIII-ΔF/V3) variant transgene at a dose of 6 x 1012 vg/kg via intravenous administration. Following gene therapy, his cFVIII levels increased to 2-3% normal and remained stable through duration of follow-up. His annualized bleeding rate decreased from 8 pre-gene therapy to 0 post-gene therapy. At 3.5 years after vector administration, PC9 was diagnosed with a widely disseminated cancer and euthanized due to complications of the disease. At autopsy, he was diagnosed with multicentric lymphoma involving peripheral and visceral lymph nodes, spleen, liver, and lungs. The average age of lymphoma diagnosis in dogs is between 6-9 years of age (Edwards et al. Vet Comp Oncol, 2003), so the development of cancer at an early age in a gene therapy recipient warranted additional study. Vector copy number analysis showed that the liver had the highest levels of AAV vector genomes, as expected. Liver samples showed a heterogenous distribution of vector genomes, consistent with previous studies of AAV8 transduction (Bell et al. Hum Gene Ther, 2011). Splenic samples also had a high level of AAV vector genomes, which again is consistent with known targeting of AAV8. Importantly, the lymph nodes had no detectable AAV vector genomes present, suggesting that vector integration could not contribute to lymphoma development. cFVIII levels remained stable before and after diagnosis of lymphoma, supporting lack of vector integration in the malignant cells. Conclusions AAV gene therapy resulted in a 100% reduction in the annualized bleeding rate in this pet dog with severe HA. Furthermore, the multicentric lymphoma that developed 3.5 years after liver-directed gene therapy is unlikely related to the AAV vector. We are unable to rule out other factors that may have contributed, including environmental influences or genetic predispositions for lymphoma. These results support the ongoing efforts to treat HA with AAV-based gene therapy and reinforce the safety profile of AAV vectors outside of a laboratory environment.

Epidemiology and Predictors of 30-Day Readmission in CAR-T Cell Therapy Recipients

The novel cellular immunotherapy using chimeric antigen receptor (CAR) T cells has transformed the management of several previously incurable hematologic malignancies. Since the first CAR-T cell product was approved by the Food and Drug Administration in 2017, five additional products have been approved for various hematologic malignancies. Although there is now more experience with outpatient administration, CAR-T therapy was initially delivered in an inpatient setting. The unique complications of cytokine release syndrome (CRS) and neurologic side effects (commonly known as immune effector cell-associated neurotoxicity syndrome [ICANS]), along with a higher risk for infection, increase the risk for hospital readmission. Given the recent approval of CAR-T therapy, large-scale epidemiologic data are lacking. The present study aimed to characterize the epidemiology of hospitalizations, readmissions, and factors associated with all-cause 30-day readmission post CAR-T therapy. This retrospective cohort study used the Nationwide Readmissions Database from 2017 to 2019 to identify hospitalizations for CAR-T therapy administration. A descriptive analysis was performed after categorizing these hospitalizations as non-Hodgkin lymphoma, multiple myeloma, or leukemia. The readmission rate was calculated, and etiologies of readmission were identified. A Cox proportional hazards model was used to elucidate factors associated with 30-day readmission. We also estimated the healthcare utilization related to readmissions, including total hospital charges and length of stay. The 2,964 CAR-T therapy-related admissions included 2,176 with a diagnosis of non-Hodgkin lymphoma, 344 with multiple myeloma, and 445 with leukemia. The median length of stay was 15 days. Most CAR-T therapy recipients were male (63.4%), admitted to a teaching hospital (99.2%); 49.3% had private insurance, and 33.2% belonged to the highest-income communities. CAR-T therapy was administered mostly in privately owned (89.5%) large-sized hospitals (74.4%) in large metropolitan regions (91.4%). Median total hospital charges were highest for non-Hodgkin lymphoma, followed by leukemia and multiple myeloma ($945,645 versus $265,034 versus $184,194; P < .001). All-cause mortality during index hospitalization was highest for leukemia at 8.6%, followed by 3.6% for non-Hodgkin lymphoma and 1.4% for multiple myeloma (P < .001). The 30-day all-cause readmission rate was 23.6%, and the median time to readmission was 7 days. The readmission rate was highest for leukemia, followed by non-Hodgkin lymphoma and multiple myeloma (34.2% versus 22.8% versus 15.7%; P < .001). Readmission incurred an additional median total hospital charge of $64,561. During readmission, median length of stay was 5 days, and in-hospital mortality was 4.9%. Top etiologies for readmission were cancer or treatment-related (22%), sepsis or infection (18%), neurologic events (15%), neutropenia or pancytopenia (11%), and fever, hypotension, or hypoxia (8%). On multivariable analysis, non-Hodgkin lymphoma and leukemia (compared with multiple myeloma), transfer to a facility at discharge, chronic renal disease, cerebrovascular disease, and noninvasive ventilation were associated with higher odds of readmission. In contrast, admission to a teaching hospital predicted lower odds of readmission. Almost a quarter of CAR-T therapy recipients are readmitted within the first 30 days resulting in additional economic burden and substantial healthcare utilization.

Progressive multifocal leukoencephalopathy in patients treated with chimeric antigen receptor T cells

Using 2 global postmarketing surveillance databases, Goldman and colleagues report that progressive multifocal leukoencephalopathy (PML), a viral disease associated with profound immunosuppression, occurs in approximately 0.9 cases per 1000 recipients of CD19-directed CAR T-cell therapy. The risk of PML appears higher with CAR T-cell therapy than other cancer therapies, but its precise role cannot be distinguished from antecedent therapies that these patients receive.