Consolidative radiotherapy for residual fluorodeoxyglucose activity on day +30 post CAR T-cell therapy in non-Hodgkin lymphoma.

Majority of non-Hodgkin lymphoma (NHL) patients who achieve partial response (PR) or stable disease (SD) to CAR T-cell therapy (CAR T) on day +30 progress and only 30% achieve spontaneous complete response (CR). This study is the first to evaluate the role of consolidative radiotherapy (cRT) for residual fluorodeoxyglucose (FDG) activity on day +30 post- CAR T in NHL. We retrospectively reviewed 61 patients with NHL who received CAR T and achieved PR or SD on day +30. Progression-free survival (PFS), overall survival (OS), and local relapse-free survival (LRFS) were assessed from CAR T infusion. cRT was defined as comprehensive - treated all FDG-avid sites - or focal. Following day +30 positron emission tomography scan, 45 patients were observed and 16 received cRT. Fifteen (33%) observed patients achieved spontaneous CR, and 27 (60%) progressed with all relapses involving initial sites of residual FDG activity. Ten (63%) cRT patients achieved CR, and four (25%) progressed with no relapses in the irradiated sites. The 2-year LRFS was 100% in the cRT sites and 31% in the observed sites (P<0.001). The 2-year PFS was 73% and 37% (P=0.025) and the 2-year OS was 78% and 43% (P=0.12) in the cRT and observation groups, respectively. Patients receiving comprehensive cRT (n=13) had superior 2- year PFS (83% vs. 37%; P=0.008) and 2-year OS (86% vs. 43%; P=0.047) compared to observed or focal cRT patients (n=48). NHL patients with residual FDG activity following CAR T are at high risk of local progression. cRT for residual FDG activity on day +30 post-CAR T appears to alter the pattern of relapse and improve LRFS and PFS.

OB Nest randomized controlled trial: a cost comparison of reduced visit compared to traditional prenatal care.

BACKGROUND: Traditional prenatal care includes up to 13 in person office visits, and the cost of this care is not well-described. Alternative models are being explored to better meet the needs of patients and providers. OB Nest is a telemedicine-enhanced program with a reduced frequency of in-person prenatal visits. The cost implications of connected care services added to prenatal care packages are unclear. METHODS: Using data from the OB Nest randomized, controlled trial we analyzed the provider and staff time associated with prenatal care in the traditional and OB Nest models. Fewer visits were required for OB Nest, but given the compensatory increase in connected care activity and supplies, the actual cost difference is not known. Nursing and provider staff time was prospectively recorded for all patients enrolled in the OB Nest clinical trial. Published 2015 national wages for healthcare workers were used to calculate the actual labor cost of providing either traditional or OB Nest prenatal care in 2015 US dollars. Overhead expenses and opportunity costs were not considered. RESULTS: Total provider cost was decreased caring for the OB Nest participants, but nursing cost was increased. OB Nest care required an average of 160.8 (+/- 45.0) minutes provider time and 237 (+/- 25.1) minutes nursing time, compared to 215.0 (+/- 71.6) and 99.6 (+/- 29.7) minutes for traditional prenatal care (P < 0.01). This translated into decreased provider cost and increased nursing cost (P < 0.01). Supply costs increased, travel costs declined, and overhead costs declined in the OB Nest model. CONCLUSIONS: In this trial, labor cost for OB Nest prenatal care was 34% higher than for traditional prenatal care. The increased cost is largely attributable to additional nursing connected care time, and in some practice settings may be offset by decreased overhead costs and increased provider billing opportunities. Future efforts will be focused on development of digital solutions for some routine nursing tasks to decrease the overall cost of the model. TRIAL REGISTRATIONS: ClinicalTrials.gov Identifier: NCT02082275 .

Evaluating resilience as a predictor of outcomes in lung transplant candidates.

BACKGROUND: Resilience represents the capacity to adapt to adversity. Resilience can improve following behavioral interventions. We examined lung transplant candidates' resilience as a novel predictor using the Connor-Davidson Resilience Scale (RISC-10). METHODS: Waitlisted candidates at six centers were mailed questionnaires from 9/16/2015 to 10/1/2019. Follow-up surveys were collected annually and post-transplant. Outcomes were recorded through February 17, 2020. Primary outcome was pre-transplant death/delisting. Analyses included t test or chi-square for group comparisons, Pearson's correlation coefficients for strength of relationships, and Cox proportional-hazard models to evaluate associations with outcomes, adjusting for age, sex, and mood. RESULTS: Participation was 55.3% (N = 199). Baseline RISC-10 averaged 32.0 ± 5.6 and did not differ by demographics, primary transplant diagnosis, or disease severity markers. RISC-10 did not correlate to the commonly utilized Psychosocial Assessment of Candidates for Transplant [PACT] or Stanford Integrated Psychosocial Assessment for Transplantation [SIPAT] tools. Scores < 26.3 (representing > 1 standard deviation below population average) occurred in 16% and were associated with pre-transplant death or delisting, adjusted Hazard Ratio of 2.60 (95% Confidence Interval 1.23-5.77; P = .01). CONCLUSION: One in six lung candidates had low resilience, predicting increased pre-transplant death/delisting. RISC-10 did not correlate with PACT or SIPAT; resilience may represent a novel risk factor.

A Retrospective Review of Neonatal Sepsis among GBS-Colonized Women Undergoing Planned Cesarean Section after Labor Onset or Rupture of Membranes.

Background: Sepsis is a leading cause of mortality and morbidity in neonates, with group B streptococcus (GBS) remaining the most frequent pathogen isolated from term infants. Surveillance data showed that the majority of cases of early-onset GBS disease were neonates born to women who either received no or suboptimal intrapartum antibiotic prophylaxis with a notable portion of those women having a missed opportunity to receive ≥4 hours of chemoprophylaxis. Women planning delivery by cesarean section who present in labor or rupture of membranes prior to their scheduled surgery are unlikely to receive optimal GBS chemoprophylaxis and thus their neonates are at risk of having sepsis. Materials and Methods. A retrospective cohort study of women-infant dyads was extracted from the Consortium on Safe Labor dataset. Women who had an unlabored cesarean section at ≥37 + 0 week gestation were selected and divided into four groups based on GBS status and timing of cesarean section with respect to onset of labor or rupture of membranes. The rate of neonatal sepsis and the patterns of intrapartum antibiotic chemoprophylaxis were determined. Results: The sepsis rate (4.5%) among neonates of GBS-colonized women having their unlabored cesarean section after onset of labor or rupture of membranes was significantly higher than that in any other group in this study. In this group, 9.4% of women received chemoprophylaxis for ≥4 hours, while 31% had a missed opportunity to receive ≥4 hours of chemoprophylaxis. Conclusion: This study suggests that neonates of GBS-colonized women having a planned cesarean section after onset of labor or rupture of membranes are at increased risk of having a sepsis diagnosis. This finding suggest the need for additional studies to assess the risk of sepsis among neonates of women in this group.

Not All Cellular Rejections Are the Same: Differences in Early and Late Hepatic Allograft Rejection.

T cell-mediated rejection (TCMR) is common after liver transplantation (LT), and it is often thought to have a minimum impact on outcomes. Because alloimmune response changes over time, we investigated the role of the timing of TCMR on patient and allograft survival and examined the risk factors for early and late TCMR. We reviewed protocol liver biopsies for 787 consecutive LT recipients with an 8.6-year follow-up. The incidence of early TCMR (≤6 weeks after LT) was 33.5% with nonalcoholic steatohepatitis patients having the lowest incidence. Younger recipient age (P < 0.01), number of human leukocyte antigen mismatches (P < 0.01), and use of deceased donor allografts (P = 0.01) were associated with increased risk of early TCMR, which had no impact on allograft (hazard ratio [HR], 1.02; 95% CI, 0.79-1.32; P = 0.89) or overall survival (HR, 1.03; 95% CI, 0.78-1.34; P = 0.86). Late TCMR (>6 weeks after LT) was less common (17.7%) and was associated with different risk factors. The majority of late TCMR (56.2%) episodes had no antecedent early TCMR, although moderate-to-severe early TCMR (HR, 2.85; 95% CI, 1.55-5.23; P < 0.01) and steroid resistance (HR, 3.62; 95% CI, 1.87-6.99; P < 0.01) were associated with late TCMR. Late TCMR increased risk of mortality (HR, 1.89; 95% CI, 1.35-2.65; P = 0.001) and graft loss (HR, 1.71; 95% CI, 1.23-2.37; P = 0.001). Thus, these data suggest that the timing and histologic grade of TCMR determine its impact on patient and allograft survival. Early mild TCMR episodes after LT do not adversely impact patient or allograft survival provided that they are adequately treated. The occurrence of late TCMR carries deleterious effects with increased longterm risk of graft loss and decreased survival. Patients with moderate-to-severe early TCMR are at an increased risk for late TCMR and warrant closer clinical follow-up.

Liver transplantation after share 35: Impact on pretransplant and posttransplant costs and mortality.

Share 35 was implemented in 2013 to direct livers to the most urgent candidates by prioritizing Model for End-Stage Liver Disease (MELD) ≥ 35 patients. We aim to evaluate this policy's impact on costs and mortality. Our study includes 834 wait-listed patients and 338 patients who received deceased donor, solitary liver transplants at Mayo Clinic between January 2010 and December 2014. Of these patients, 101 (30%) underwent transplantation after Share 35. After Share 35, 29 (28.7%) MELD ≥ 35 patients received transplants, as opposed to 46 (19.4%) in the pre-Share 35 era (P = 0.06). No significant difference in 90-day wait-list mortality (P = 0.29) nor 365-day posttransplant mortality (P = 0.68) was found between patients transplanted before or after Share 35. Mean costs were $3,049 (P = 0.30), $5226 (P = 0.18), and $10,826 (P = 0.03) lower post-Share 35 for the 30-, 90-, and 365-day pretransplant periods, and mean costs were $5010 (P = 0.41) and $5859 (P = 0.57) higher, and $9145 (P = 0.54) lower post-Share 35 for the 30-, 90-, and 365-day posttransplant periods. In conclusion, the added cost of transplanting more MELD ≥ 35 patients may be offset by pretransplant care cost reduction. Despite shifting organs to critically ill patients, Share 35 has not impacted mortality significantly. Liver Transplantation 23:11-18 2017 AASLD.

Pre-transplant wasting (as measured by muscle index) is a novel prognostic indicator in lung transplantation.

BACKGROUND: Frailty in non-transplant populations increases morbidity and mortality. Muscle wasting is an important frailty characteristic. Low body mass index is used to measure wasting, but can over- or underestimate muscle mass. Computed tomography (CT) software can directly measure muscle mass. It is unknown if muscle wasting is important in lung transplantation. AIM AND METHODS: The aim of this single-center, retrospective cohort study was to determine whether pre-transplant low muscle mass (as measured by CT using Slice-O-matic software at L2-L3 interspace) was associated with post-transplantation mortality, hospital and intensive care unit length of stay (LOS), duration of mechanical ventilation, or primary graft dysfunction. Lung transplant recipients from 2000 to 2012 with a CT scan less than six months prior to transplant were included. Univariate, multivariate, and Kaplan-Meier analyses were conducted. RESULTS: Thirty-six patients were included. Those with low muscle index (lower 25th percentile) had a worse survival (hazard ratio = 3.83; 95% confidence interval 1.42-10.3; p = 0.007) and longer hospital LOS by an estimated 7.2 d (p = 0.01) when adjusted for age and sex as compared to those with higher muscle index. CONCLUSION: Low muscle index at lung transplantation is associated with worse survival and increased hospital LOS.

Epidemiology of invasive fungal infections in lung transplant recipients on long-term azole antifungal prophylaxis.

Lung transplant recipients (LTR) at our institution receive prolonged and mostly lifelong azole antifungal (AF) prophylaxis. The impact of this prophylactic strategy on the epidemiology and outcome of invasive fungal infections (IFI) is unknown. This was a single-center, retrospective cohort study. We reviewed the medical records of all adult LTR from January 2002 to December 2011. Overall, 16.5% (15 of 91) of patients who underwent lung transplantation during this time period developed IFI. Nineteen IFI episodes were identified (eight proven, 11 probable), 89% (17 of 19) of which developed during AF prophylaxis. LTR with idiopathic pulmonary fibrosis were more likely to develop IFI (HR: 4.29; 95% CI: 1.15-15.91; p = 0.03). A higher hazard of mortality was observed among those who developed IFI, although this was not statistically significant (hazard ratio [HR]: 1.71; 95% confidence interval [CI] [0.58-4.05]; p = 0.27). Aspergillus fumigatus was the most common cause of IFI (45%), with pulmonary parenchyma being the most common site of infection. None of our patients developed disseminated invasive aspergillosis, cryptococcal or endemic fungal infections. IFI continue to occur in LTR, and the eradication of IFI appears to be challenging even with prolonged prophylaxis. Azole resistance is uncommon despite prolonged AF exposure.

Quantifying the importance of disease burden on perceived general health and depressive symptoms in patients within the Mayo Clinic Biobank.

BACKGROUND: Deficits in health-related quality of life (HRQOL) may be associated with worse patient experiences, outcomes and even survival. While there exists evidence to identify risk factors associated with deficits in HRQOL among patients with individual medical conditions such as cancer, it is less well established in more general populations without attention to specific illnesses. This study used patients with a wide range of medical conditions to identify contributors with the greatest influence on HRQOL deficits. METHODS: Self-perceived general health and depressive symptoms were assessed using data from 21,736 Mayo Clinic Biobank (MCB) participants. Each domain was dichotomized into categories related to poor health: deficit (poor/fair for general health and ≥3 for PHQ-2 depressive symptoms) or non-deficit. Logistic regression models were used to test the association of commonly collected demographic characteristics and disease burden with each HRQOL domain, adjusting for age and gender. Gradient boosting machine (GBM) models were applied to quantify the relative influence of contributors on each HRQOL domain. RESULTS: The prevalence of participants with a deficit was 9.5 % for perception of general health and 4.6 % for depressive symptoms. For both groups, disease burden had the strongest influence for deficit in HRQOL (63 % for general health and 42 % for depressive symptoms). For depressive symptoms, age was equally influential. The prevalence of a deficit in general health increased slightly with age for males, but remained stable across age for females. Deficit in depressive symptoms was inversely associated with age. For both HRQOL domains, risk of a deficit was associated with higher disease burden, lower levels of education, no alcohol consumption, smoking, and obesity. Subjects with deficits were less likely to report that they were currently working for pay than those without a deficit; this association was stronger among males than females. CONCLUSIONS: Comorbid health burden has the strongest influence on deficits in self-perceived general health, while demographic factors show relatively minimal impact. For depressive symptoms, both age and comorbid health burden were equally important, with decreasing deficits in depressive symptoms with increasing age. For interpreting patient-reported metrics and comparison, one must account for comorbid health burden.

Identifying the presence of clinically significant hepatic involvement in hereditary haemorrhagic telangiectasia using a simple clinical scoring index.

BACKGROUND & AIMS: Though hepatic involvement is common in patients with hereditary haemorrhagic telangiectasia (HHT), symptomatic liver disease is rare but potentially fatal without liver transplantation. Factors associated with clinically significant liver disease in patients with HHT are unknown. METHODS: In this prospective cohort study, we included consecutive patients from 2001 to 2011 with definite HHT, who underwent systematic protocol screening including contrast-enhanced hepatic CT and/or abdominal ultrasound. Using a multivariable logistic regression model, we developed a simple clinical scoring index to identify the presence of symptomatic liver disease (cardiac failure, portal hypertension, or biliary disease) or 'at-risk' liver disease (asymptomatic patients, with hepatic bruit, abnormal liver biochemistry, or elevated cardiac index). RESULTS: Of 316 patients with definite HHT, 171 patients (54.1%; age 53.4 ± 15.2 y, 101 females) had hepatic involvement on imaging. Twenty-nine patients had symptomatic liver disease (22 patients with high-output heart failure); 45 patients were 'at-risk' for liver disease. Using multivariable logistic regression analysis, we derived a score using age, gender, hemoglobin and alkaline phosphatase at presentation which could accurately distinguish patients with clinically significant liver involvement from patients with no or incidental liver lesions (c-statistic=0.80). A score <3 indicated low risk (<5%) and score >6 indicated high risk (>80%) of harboring clinically significant liver disease in HHT. CONCLUSIONS: A simple scoring system can distinguish patients at low, moderate, and high risk of harboring clinically significant liver disease. With validation, this score may be used to identify patients for individualized screening and enrollment in clinical trials.

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

BACKGROUND: 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. OBJECTIVE: The objective of the study was to assess the utility of serum PCT concentrations as a biomarker of bacterial infection in CAR-T recipients. STUDY DESIGN: 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). RESULTS: 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). CONCLUSION: Elevated serum PCT concentrations above 0.4 ng/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.

Prognostic value of early bone marrow MRD status in CAR-T therapy for myeloma.

Bone marrow (BM) assessment of minimal residual disease (MRD) is prognostic for survival in multiple myeloma (MM). BM is still hypocellular at month 1 post CAR-T, thus the value of MRD negative (MRDneg) status at this timepoint is unclear. We examined the impact of month 1 BM MRD status in MM patients who received CART at Mayo Clinic between 8/2016 and 6/2021. Among 60 patients, 78% were BM-MRDneg at month 1; and 85% (40/47) of these patients also had decreased to less than normal level of both involved and uninvolved free light chain (FLC < NL). Patients who achieved CR/sCR had higher rates of month 1 BM-MRDneg and FLC < NL. The rate of sustained BM-MRDneg was 40% (19/47). Rate of conversion from MRDpos to MRDneg was 5%(1/20). At month 1, 38%(18/47) of the BM-MRDneg were hypocellular. Recovery to normal cellularity was observed in 50%(7/14) with a median time to normalization at 12 months (range: 3-Not reached). Compared to Month 1 BM-MRDpos patients, patients who were BM-MRDneg had longer PFS irrespective of BM cellularity [PFS: 2.9 months (95% CI, 1.2-NR) vs. 17.5 months (95% CI, 10.4-NR), p < 0.0001]. Month 1 BM-MRDneg and FLC below normal were associated with prolonged survival. Our data support the continued evaluation of BM early post-CART infusion as a prognostic tool.

Metabolic PET/CT analysis of aggressive Non-Hodgkin lymphoma prior to Axicabtagene Ciloleucel CAR-T infusion: predictors of progressive disease, survival, and toxicity.

PET/CT is used to evaluate relapsed/refractory non-Hodgkin lymphoma (NHL) prior to chimeric antigen receptor T-cell (CAR-T) infusion at two time points: pre-leukapheresis (pre-leuk) and pre-lymphodepletion chemotherapy (pre-LD). We hypothesized that changes in PET/CT between these time points predict outcomes after CAR-T. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and other metrics were calculated from pre-leuk and pre-LD PET/CT scans in patients with NHL who received axicabtagene ciloleucel, and assessed for association with outcomes. Sixty-nine patients were analyzed. While single time point PET/CT characteristics were not associated with risk of PD or death, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p < 0.05 for all). LASSO analysis identified increasing extranodal MTV and increasing TLG of the largest lesion as strong predictors of death (AUC 0.74). Greater pre-LD total MTV was associated with higher risk of grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS) (p = 0.042). Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of progression and death. A two variable risk score stratifies prognosis prior to CAR-T infusion and may inform risk-adapted strategies.

Don't Put the CART Before the Horse: The Role of Radiation Therapy in Peri-CAR T-cell Therapy for Aggressive B-cell Non-Hodgkin Lymphoma.

PURPOSE: The optimal approach to incorporate radiation therapy (RT) in conjunction with chimeric antigen receptor (CAR) T-cell therapy (CART) for relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (bNHL) remains unclear. This study documented the RT local control rate among patients who received bridging radiation therapy (BRT) before CART and compares it with those who received salvage radiation therapy (SRT) after CART. This article further reports on a promising way to use SRT for post-CART disease and identifies predictors for RT in-field recurrence. METHODS AND MATERIALS: We retrospectively reviewed 83 patients with r/r bNHL who received CART and RT, either as BRT pre-CART infusion (n = 35) or as SRT post-CART infusion (n = 48), between 2018 and 2021. RT was defined as comprehensive (compRT; ie, treated all sites of active disease) or focal (focRT). Limited disease was defined as disease amenable to compRT, involving <5 active disease sites. RESULTS: At time of RT, patients who received BRT before CART had bulkier disease sites (median diameter, 8.7 vs 5.5 cm; P = .01) and were treated to significantly lower doses (median equivalent 2-Gy dose, 23.3 vs 34.5 Gy; P = .002), compared with SRT post-CART. Among 124 total irradiated sites identified, 8 of 59 (13%) bridged sites and 21 of 65 (32%) salvaged sites experienced in-field recurrence, translating to 1-year local control rates (LC) of 84% and 62%, respectively (P = .009). Patients with limited post-CART disease (n = 37) who received compSRT (n = 26) had better overall survival (51% vs 12%; P = .028), freedom from subsequent progression (31% vs 0%; P < .001), and freedom from subsequent event (19% vs 0%; P = .011) compared with patients with limited disease who received focSRT (n = 11). CONCLUSIONS: BRT followed by CART appears to be associated with improved LC compared with SRT in r/r bNHL. Nonetheless, SRT offers a promising salvage intervention for limited (<5 sites) relapsed post-CART disease if given comprehensively.

Incidence and Risk Factors for Acute Kidney Injury After Chimeric Antigen Receptor T-Cell Therapy.

OBJECTIVE: To evaluate the association of baseline and postinfusion patient characteristics with acute kidney injury (AKI) in the month after chimeric antigen receptor T-cell (CAR-T) therapy. METHODS: We retrospectively reviewed records of 83 patients with non-Hodgkin lymphoma undergoing CAR-T therapy (axicabtagene ciloleucel) between June 2016 and November 2020. Patients were followed up to 1 month after treatment. Post-CAR-T AKI was defined as a more than 1.5-fold increase in serum creatinine concentration from baseline (on the day of CAR-T infusion) at any time up to 1 month after CAR-T therapy. RESULTS: Of 83 patients, 14 (17%) developed AKI during follow-up. At 1 month after CAR-T infusion, 10 of 14 (71%) AKI events had resolved. Lower baseline estimated glomerular filtration rate, use of intravenous contrast material, tumor lysis prophylaxis, higher peak uric acid and creatine kinase levels during follow-up, and change in lactate dehydrogenase from baseline to peak level within 1 month after initiation of CAR-T therapy were significantly associated with AKI incidence during follow-up. Incidence of AKI was also higher in patients who received higher doses of corticosteroids and tocilizumab. CONCLUSION: Acute kidney injury occurred in approximately 1 in 6 patients who received axicabtagene ciloleucel for non-Hodgkin lymphoma. Patients with high tumor burden receiving higher total doses of corticosteroids or tocilizumab should be closely monitored for development of AKI. Lower baseline kidney function at CAR-T initiation, exposure to contrast material, and progressive increase in levels of tumor lysis markers (uric acid, lactate dehydrogenase, creatine kinase) after CAR-T infusion may predict risk of AKI during the 1 month after infusion.

Metabolic characteristics and prognostic differentiation of aggressive lymphoma using one-month post-CAR-T FDG PET/CT.

BACKGROUND: F-18 fluorodeoxyglucose positron emission tomography computed tomography (PET/CT) is used to assess response of non-Hodgkin lymphoma (NHL) to chimeric antigen receptor T cell (CAR-T) therapy. We sought to describe metabolic and volumetric PET prognostic factors at one month post-CAR-T and identify which patients with partial response (PR) or stable disease (SD) are most likely to subsequently achieve complete response (CR), and which will develop progressive disease (PD) and death. METHODS: Sixty-nine patients with NHL received axicabtagene ciloleucel CAR-T therapy. One-month post-CAR-T infusion and PET/CT scans were segmented with a fixed absolute SUV maximum (SUVMax) threshold of 2.5 using a semiautomated workflow with manual modification to exclude physiologic uptake as needed. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUVMax, and other lesion characteristics were calculated and associated with risk of PD and death. RESULTS: Patients with total MTV > 180 cc, presence of bone or parenchymal disease, SUVMax > 10, single lesion TLG > 245 g, or > 2 total lesions had increased risk of death. Patients with total MTV > 55 cc, total TLG > 250 cc, SUV Max > 10, or > 2 total lesions had increased risk of PD. For the subset of 28 patients with PR/SD, higher SUVMax was associated with increased risk of subsequent PD and death. While 86% of patients who had SUVMax ≥ 10 eventually had PD (HR 3.63, 1.13-11.66, p = 0.03), only 36% of those with SUVMax < 10 had PD. CONCLUSIONS: Higher SUVMax at one month post-CAR-T is associated with higher risk of PD and death. SUVMax ≥ 10 may be useful in guiding early salvage treatment decisions in patients with SD/PR at one month.

Autologous Umbilical Cord Blood-Derived Mononuclear Cell Therapy Promotes Cardiac Proliferation and Adaptation in a Porcine Model of Right Ventricle Pressure Overload.

Congenital heart diseases, including single ventricle circulations, are clinically challenging due to chronic pressure overload and the inability of the myocardium to compensate for lifelong physiological demands. To determine the clinical relevance of autologous umbilical cord blood-derived mononuclear cells (UCB-MNCs) as a therapy to augment cardiac adaptation following surgical management of congenital heart disease, a validated model system of right ventricular pressure overload due to pulmonary artery banding (PAB) in juvenile pigs has been employed. PAB in a juvenile porcine model and intramyocardial delivery of UCB-MNCs was evaluated in three distinct 12-week studies utilizing serial cardiac imaging and end-of-study pathology evaluations. PAB reproducibly induced pressure overload leading to chronic right ventricular remodeling including significant myocardial fibrosis and elevation of heart failure biomarkers. High-dose UCB-MNCs (3 million/kg) delivered into the right ventricular myocardium did not cause any detectable safety issues in the context of arrhythmias or abnormal cardiac physiology. In addition, this high-dose treatment compared with placebo controls demonstrated that UCB-MNCs promoted a significant increase in Ki-67-positive cardiomyocytes coupled with an increase in the number of CD31+ endothelium. Furthermore, the incorporation of BrdU-labeled cells within the myocardium confirmed the biological potency of the high-dose UCB-MNC treatment. Finally, the cell-based treatment augmented the physiological adaptation compared with controls with a trend toward increased right ventricular mass within the 12 weeks of the follow-up period. Despite these adaptations, functional changes as measured by echocardiography and magnetic resonance imaging did not demonstrate differences between cohorts in this surgical model system. Therefore, this randomized, double-blinded, placebo-controlled pre-clinical trial establishes the safety of UCB-MNCs delivered via intramyocardial injections in a dysfunctional right ventricle and validates the induction of cardiac proliferation and angiogenesis as transient paracrine mechanisms that may be important to optimize long-term outcomes for surgically repaired congenital heart diseases.