Subsequent Malignancies after CD19-Targeted Chimeric Antigen Receptor T cells in Patients with Lymphoma.

Chimeric antigen receptor (CAR) T cells are an established treatment for B cell non-Hodgkin lymphomas (B-NHL). With the remarkable success in improving survival, understanding the late effects of CAR T cell therapy is becoming more relevant. The aim of this study is to determine the incidence of subsequent malignancies in adult patients with B-NHL. We retrospectively studied 355 patients from two different medical centers treated with four different CAR T cell products from 2016 to 2022. The overall cumulative incidence for subsequent malignancies at 36 months was 14% (95% CI: 9.2%, 19%). Subsequent malignancies were grouped into three primary categories: solid tumor, hematologic malignancy, and dermatologic malignancy with cumulative incidences at 36 months of 6.1% (95% CI: 3.1%-10%), 4.5% (95% CI: 2.1%-8.1%) and 4.2% (95% CI: 2.1%-7.5%) respectively. Notably, no cases of T cell malignancies were observed. In univariable analysis, increasing age was associated with higher risk for subsequent malignancy. While the overall benefits of CAR T products continue to outweigh their potential risks, more studies and longer follow ups are needed to further demonstrate the risks, patterns, and molecular pathways that lead to the development of subsequent malignancies.

Anti-CD19 chimeric antigen receptor T-cell therapy has less efficacy in Richter transformation than in de novo large B-cell lymphoma and transformed low-grade B-cell lymphoma.

The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL.

Atrial arrhythmias following CAR-chimeric antigen receptor T-cell therapy: Incidence, risk factors and biomarker profile.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain.

Conventional and novel [18F]FDG PET/CT features as predictors of CAR-T cell therapy outcome in large B-cell lymphoma.

Relapse and toxicity limit the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL), yet biomarkers that predict outcomes and toxicity are lacking. We examined radiomic features extracted from pre-CAR-T 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scans (n = 341) of 180 patients (121 male; median age, 66 years). Three conventional (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG]) and 116 novel radiomic features were assessed, along with inflammatory markers, toxicities, and outcomes. At both pre-apheresis and pre-infusion time points, conventional PET features of disease correlated with elevated inflammatory markers. At pre-infusion, MTV was associated with grade ≥ 2 cytokine release syndrome (odds ratio [OR] for 100 mL increase: 1.08 [95% confidence interval (CI), 1.01-1.20], P = 0.031), and SUVmax was associated with failure to achieve complete response (CR) (OR 1.72 [95% CI, 1.24-2.43], P < 0.001). Higher pre-apheresis and pre-infusion MTV values were associated with shorter progression-free survival (PFS) (HR for 10-unit increase: 1.11 [95% CI, 1.05-1.17], P < 0.001; 1.04 [95% CI, 1.02-1.07], P < 0.001) and shorter overall survival (HR for 100-unit increase: 1.14 [95% CI, 1.07-1.21], P < 0.001; 1.04 [95% CI, 1.02-1.06], P < 0.001). A combined MTV and LDH measure stratified patients into high and low PFS risk groups. Multiple pre-infusion novel radiomic features were associated with CR. These quantitative conventional [18F]FDG PET/CT features obtained before CAR-T cell infusion, which were correlated with inflammation markers, may provide prognostic biomarkers for CAR-T therapy efficacy and toxicity. The use of conventional and novel radiomic features may thus help identify high-risk patients for earlier interventions.

Modeling Tumor Growth Using Partly Conditional Survival Models: A Case Study in Colorectal Cancer.

PURPOSE: There are multiple approaches to modeling the relationship between longitudinal tumor measurements obtained from serial imaging and overall survival. Many require strong assumptions that are untestable and debatable. We illustrate how to apply a novel, more flexible approach, the partly conditional (PC) survival model, using images acquired during a phase III, randomized clinical trial in colorectal cancer as an example. METHODS: PC survival approaches were used to model longitudinal volumetric computed tomography data of 1,025 patients in the completed VELOUR trial, which evaluated adding aflibercept to infusional fluorouracil, leucovorin, and irinotecan for treating metastatic colorectal cancer. PC survival modeling is a semiparametric approach to estimating associations of longitudinal measurements with time-to-event outcomes. Overall survival was our outcome. Covariates included baseline tumor burden, change in tumor burden from baseline to each follow-up time, and treatment. Both unstratified and time-stratified models were investigated. RESULTS: Without making assumptions about the distribution of the tumor growth process, we characterized associations between the change in tumor burden and survival. This change was significantly associated with survival (hazard ratio [HR], 1.04; 95% CI, 1.02 to 1.05; P < .001), suggesting that aflibercept works at least in part by altering the tumor growth trajectory. We also found baseline tumor size prognostic for survival even when accounting for the change in tumor burden over time (HR, 1.02; 95% CI, 1.01 to 1.02; P < .001). CONCLUSION: The PC modeling approach offers flexible characterization of associations between longitudinal covariates, such as serially assessed tumor burden, and survival time. It can be applied to a variety of data of this nature and used as clinical trials are ongoing to incorporate new disease assessment information as it is accumulated, as indicated by an example from colorectal cancer.

Exploring the Relationship Between Health-Illness Transition Experiences and Distress Among Patients With Pancreatic Cancer.

OBJECTIVES: To explore the correlation between health-illness transition (HIT) experiences and distress among patients with pancreatic cancer. SAMPLE & SETTING: 55 patients with a diagnosis of pancreatic cancer receiving chemotherapy at a tertiary cancer center in New York. METHODS & VARIABLES: A prospective correlational study was performed to explore the frequency, extent, and management of HITs. HITs were evaluated using the Measurement of Transitions in Cancer Scale, and distress was measured with the National Comprehensive Cancer Network Distress Thermometer. RESULTS: All patients experienced at least one HIT. The extent of HITs decreased over time. Patients reported that they managed HITs moderately well. There was a significant correlation between unmanaged HITs and distress. As distress increased, the extent of the physical and emotional HITs increased and management worsened. IMPLICATIONS FOR NURSING: HITs are ubiquitous among patients diagnosed with pancreatic cancer. Associated distress inhibits management. Nurses are well suited to assess for potential HITs and to support self-management of HITs.

Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma.

Fludarabine is one of the most common agents given for lymphodepletion before CD19 chimeric antigen receptor T cells, but its optimal therapeutic intensity is unknown. Using data from a multicenter consortium, we estimated fludarabine exposure (area under the curve [AUC]) using a population pharmacokinetic (PK) model in 199 adult patients with aggressive B-cell non-Hodgkin lymphomas who received commercial axicabtagene ciloleucel (Axi-cel). We evaluated the association of estimated fludarabine AUC with key outcomes, aiming to find an AUC that optimized efficacy and tolerability. We identified low (<18 mg × hour/L [mgh/L]), optimal (18-20 mgh/L), and high (>20 mgh/L) AUC groups for analyses; the 6-month cumulative incidences of relapse/progression of disease (relapse/POD) by AUC groups were 54% (45%-62%), 28% (15%-44%), and 30% (14%-47%), respectively; and the 1-year progression-free survival (PFS) rates were 39% (31%-48%), 66% (52%-84%), and 46% (30%-70%) and the overall survival (OS) rates were 58% (50%-67%), 77% (64%-92%), and 66% (50%-87%), respectively. In multivariable analyses compared with low AUC, an optimal AUC was associated with the highest PFS (hazard ratio [HR], 0.52; 0.3-0.91; P = .02) and lowest risk of relapse/POD (HR, 0.46; 0.25-0.84; P = .01) without an increased risk of any-grade cytokine release syndrome (HR, 1.1; 0.7-1.6; P = .8) or and immune effector cell-associated neurotoxicity syndrome (ICANS) (HR, 1.36; 0.83-2.3; P = .2). A high AUC was associated with the greatest risk of any-grade ICANS (HR, 1.9; 1.1-3.2; P = .02). Although the main cause of death in all groups was relapse/POD, nonrelapse-related deaths, including 3 deaths from ICANS, were more frequent in the high AUC group. These findings suggest that PK-directed fludarabine dosing to achieve an optimal AUC may result in improved outcomes for patients receiving axi-cel.

Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma.

Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57-69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6-11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10-4.72]), lack of response to CAR-T (2.33 [1.02-5.29]), age >65 years (HR 2.65 [1.49-4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61-5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.

Open-label pilot study of romiplostim for thrombocytopenia after autologous hematopoietic cell transplantation.

There are no standard treatments to prevent or hasten the recovery from severe conditioning-regimen-induced thrombocytopenia occurring after autologous hematopoietic cell transplantation (auto-HCT). We conducted an open-label, single-arm pilot study of romiplostim, a thrombopoietin receptor agonist, to enhance platelet recovery in patients with multiple myeloma or lymphoma undergoing auto-HCT. All patients were treated weekly with romiplostim starting day +1 after auto-HCT until the platelet count was >50 × 109/L without transfusion. Compared with contemporary retrospective data from romiplostim-naïve patients (N = 853), romiplostim-treated patients (N = 59) had a similar median number of days of grade 4 thrombocytopenia or days requiring transfusions, time to platelet engraftment, and number of platelets transfusions during the auto-HCT. However, romiplostim-treated patients had enhanced platelet recovery to normal values beginning at approximately day +15. In matched cohort multivariable analyses, romiplostim treatment was associated with higher platelet counts by an average of 40 × 109/L (95% confidence interval (CI) (14, 67), P = .003) and 118 × 109/L (95% CI [84, 152], P<.001) at days +21 and +30, respectively, compared with those of no romiplostim. Only 1 adverse event was deemed possibly attributable to romiplostim: a low-risk pulmonary embolism in a patient with multiple myeloma. In conclusion, romiplostim showed promising activity and safety after auto-HCT, but the improvement in platelet counts occurred later than the goal of shortening the duration and depth of the platelet nadir. This trial was registered at www.clinicaltrials.gov (#NCT04478123).

Allogeneic Hematopoietic Cell Transplantation after Chimeric Antigen Receptor T Cell Therapy in Large B Cell Lymphoma.

Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy has transformed the care of patients with relapsed/refractory large B cell lymphoma (LBCL). However, approximately 60% of CAR-T recipients ultimately will experience disease recurrence or progression. Salvage therapies after CAR-T treatment failures are of limited efficacy and have a short duration of response. The objective of the present study was to evaluate the role of allogeneic hematopoietic cell transplantation (allo-HCT) after CAR-T therapy in LBCL patients. This was a multicenter observational study reporting the outcome of 39 adult LBCL patients who underwent allo-HCT following anti-CD19 CAR-T therapy. The median patient age was 47 years (range, 20 to 68 years). HLA-matched sibling, HLA-matched unrelated, and alternative donors were used in 36%, 36%, and 28% of transplantations, respectively. Conditioning regimens were primarily of low or intermediate intensity. Disease status at allo-HCT was complete response in 41%, partial response in 38%, and progressive disease in 21%. Allo-HCT was performed at a median of 127 days (range, 82 to 206 days) after CAR-T therapy. A high incidence of hepatic toxicity (28%), including sinusoidal obstruction syndrome (15.4%; 95% confidence interval; [CI], 6.2% to 28.5%), was observed. The 1-year cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) was 38.5% (95% CI, 23.2% to 53.6%) and 15.4% (95% CI, 6.1% to 28.5%), respectively. The 2-year cumulative incidence of moderate-severe chronic GVHD was 11.1% (95% CI, 3.3% to 24.3%). Overall, 2-year nonrelapse mortality and relapse/progression incidence were 26% (95% CI, 13% to 41%) and 43% (95% CI, 27% to 59%), respectively. With a median follow-up of 32 months, the 2-year overall survival (OS) and progression-free survival (PFS) were 45% (95% CI, 31% to 66%) and 31% (95% CI, 19% to 50%), respectively. In multivariable analyses, pre-HCT elevated lactate dehydrogenase level and transformed lymphoma were predictive of OS and PFS, respectively. Our data suggest that allo-HCT after anti-CD19 CAR-T treatment failure is feasible with a relatively promising efficacy but possibly high toxicity rate.

Low toxicity and excellent outcomes in patients with DLBCL without residual lymphoma at the time of CD19 CAR T-cell therapy.

CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), inducing sustained remissions in these patients. However, CAR T cells can result in significant toxicities. Preinfusion disease burden is associated with toxicities and outcomes after CAR T-cell therapy. We identified 33 patients with R/R DLBCL treated at 8 academic centers who had no detectable disease at the time of CAR T-cell therapy. The median time from leukapheresis to CAR T-cell infusion was 48 (19-193) days. Nine patients received axicabtagene ciloleucel, and 24 received tisagenlecleucel. There was no severe (grade ≥3) cytokine release syndrome, and only 1 patient developed severe neurotoxicity (grade 4). After a median follow-up of 16 months, 13 patients relapsed (39.4%) and 6 died (18.1%). One-year event-free survival and overall survival were 59.6% and 81.3%, respectively. Our findings suggest that, in patients with R/R DLBCL who have an indication for CAR T-cell therapy, treating patients in complete remission at the time of infusion is feasible, safe, and associated with favorable disease control. Further exploration in a larger clinical trial setting is warranted.

Tumor volume as a predictor of cell free DNA mutation detection in advanced non-small cell lung cancer.

Background: Cell free DNA (cfDNA) is an exciting biomarker with applications across the cancer care continuum. Determinants of cfDNA shedding dynamics remain an active research area. We performed a detailed analysis of tumor volume and factors associated with detection of cfDNA mutations. Methods: Patients with advanced non-small cell lung cancers (NSCLCs) were prospectively enrolled on a plasma biomarker protocol. Next generation sequencing (NGS) was performed using a validated, bias-corrected, hybrid-capture panel assay of lung cancer-associated genes. Volume of tumor in different subsites and total tumor volume were determined through manual volume delineation using PET/CT and brain magnetic resonance imaging (MRI) imaging. The primary endpoint was detection of cfDNA mutation; secondary endpoints were overall survival (OS) and variant allele frequency (VAF). Results: There were 110 patients included, 78 of whom had at least one mutation detected. Median total tumor volume for the entire cohort, patients with mutation detected, and patients with no mutation detected were 66 mL (range, 2-1,383 mL), 76 mL (range, 5-1,383 mL), and 45 mL (range, 2-460 mL), respectively (P=0.002; mutation detected vs. not). The optimal total tumor volume threshold to predict increased probability of mutation detection was 65 mL (P=0.006). Total tumor volume greater than 65 mL was a significant predictor of mutation detection on multivariate analysis (OR: 4.30, P=0.003). Significant predictors of OS were age (HR: 1.04, P=0.002), detection of cfDNA mutation (HR: 2.11, P=0.024), and presence of bone metastases (HR: 1.66, P=0.047). Conclusions: Total tumor volume greater than 65 mL was associated with cfDNA mutation detection in patients with advanced NSCLC.

Evaluation of Melphalan Exposure in Lymphoma Patients Undergoing BEAM and Autologous Hematopoietic Cell Transplantation.

High-dose melphalan is one of the main cytotoxic DNA alkylating agents and is used in many transplantation conditioning regimens. Studies have shown a wide range of drug exposure when a traditional weight-based dose of melphalan is used. The optimal melphalan dose in BEAM (carmustine, etoposide, cytarabine, and melphalan), which results in maximum efficacy with acceptable toxicity, is unknown. In this pharmacokinetic (PK) analysis of 105 patients with lymphoma undergoing treatment with BEAM and autologous hematopoietic cell transplantation, we initially estimated melphalan exposure as area under the curve (AUC) by a noncompartmental analysis and subsequently compared it with a newly developed 2-compartment population-PK model. The 2 models correlated closely with each other. We found that the traditional fixed weight-based dosing of propylene glycol-free (captisol-enabled) melphalan in BEAM results in a wide variation in exposure as estimated by both models. Higher melphalan exposure was significantly associated with increased metabolic toxicities but did not seem to impact progression-free survival. Although our study suggests a melphalan AUC of 8 mg·h/L as a potential target in BEAM, larger prospective studies using personalized PK-directed melphalan dosing are needed to determine the optimal melphalan exposure in lymphomas.

Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers.

BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy.

PURPOSE: Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. MATERIALS AND METHODS: Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre-CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. RESULTS: We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type (P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. CONCLUSION: TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.

Pharmacoresistant seizures and IDH mutation in low-grade gliomas.

BACKGROUND: Many low-grade gliomas (LGG) harbor isocitrate dehydrogenase (IDH) mutations. Although IDH mutation is known to be epileptogenic, the rate of refractory seizures in LGG with IDH mutation vs wild-type had not been previously compared. We therefore compared seizure pharmacoresistance in IDH-mutated and wild-type LGGs. METHODS: Single-institution retrospective study of patients with histologic proven LGG, known IDH mutation status, seizures, and ≥2 neurology clinic encounters. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥2 changes in anti-epileptic drugs were considered pharmacoresistant. Incidence rates of pharmacoresistant seizures were estimated using competing risks methodology. RESULTS: Of 135 patients, 25 patients (19%) had LGGs classified as IDH wild-type. Of those with IDH mutation, 104 (94.5%) were IDH1 R132H; only 6 were IDH2 R172K. 120 patients (89%) had tumor resection, and 14 (10%) had biopsy. Initial post-surgical management included observation (64%), concurrent chemoradiation (23%), chemotherapy alone (9%), and radiotherapy alone (4%). Seizures became pharmacoresistant in 24 IDH-mutated patients (22%) and in 3 IDH wild-type patients (12%). The 4-year cumulative incidence of intractable seizures was 17.6% (95% CI: 10.6%-25.9%) in IDH-mutated and 11% (95% CI: 1.3%-32.6%) in IDH wild-type LGG (Gray's P-value = .26). CONCLUSIONS: 22% of the IDH-mutated patients developed pharmacoresistant seizures, compared to 12% of the IDH wild-type tumors. The likelihood of developing pharmacoresistant seizures in patients with LGG-related epilepsy is independent to IDH mutation status, however, IDH-mutated tumors were approximately twice as likely to experience LGG-related pharmacoresistant seizures.

Should Postoperative Radiation for Long Bone Metastases Cover Part or All of the Orthopedic Hardware? Results of a Large Retrospective Analysis.

PURPOSE: For patients with long bone metastases who undergo orthopedic stabilization surgery followed by radiotherapy (RT), it is unclear what extent of hardware coverage by the radiation field is needed for optimal tumor control. METHODS AND MATERIALS: Long bone metastases treated with surgical intervention followed by radiation between August 2011 to May 2019 from a single institution were reviewed. Local recurrence, defined as any in-bone recurrence, was identified by chart review. Accompanying demographic and treatment characteristics were recorded. Statistical analysis to evaluate factors associated with tumor recurrence included univariate analysis, multivariate analysis, and propensity score matching. RESULTS: Among 138 patients with 145 long bone metastases undergoing postoperative RT with a median follow-up of 29.5 months, 36 bone metastases experienced a local recurrence. Most patients (92%) were treated with conventional RT and the median delivered dose was 30 Gy (interquarile range, 20-30 Gy). On univariate analysis, whole hardware RT field coverage and higher dose (biologically effective dose 10 ≥39 Gy) were associated with reduced local recurrence (0.44 hazard ratio [HR]; 95% confidence interval [CI], 0.22%-0.86%; P = .017; 0.5 HR; 95% CI, 0.26%-0.96%; P = .038, respectively). Covariates of time from surgery to RT start, histology of primary tumor (categorized as resistant vs sensitive), intramedullary hardware placement, reaming procedure, and margin status did not reach statistical significance. To adjust for confounding effects, we also conducted a propensity score matched analysis which confirmed that whole hardware coverage was statistically associated with a decreased risk of recurrence on the matched dataset (0.24 HR; 95% CI, 0.07%-0.84%; P = .026). CONCLUSIONS: In this analysis of mostly patients undergoing conventional radiation, coverage of the whole hardware was associated with reduced local recurrence for patients with long bone metastases, consistent with prior reports. Investigation of approaches to further reduce local recurrence, such as preoperative stereotactic radiation, may be warranted.

Modified EASIX predicts severe cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells.

Patients who develop chimeric antigen receptor (CAR) T-cell-related severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase [LDH; U/L] × creatinine [mg/dL]/platelets [PLTs; 109 cells/L]) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX [m-EASIX], which replaces creatinine with CRP [mg/dL]), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve [AUC] at lymphodepletion, 80.4%; at day -1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell-related toxicities.

Assessment of Frailty Can Guide Decision Making for Utilization of Sentinel Lymph Node Biopsy in Patients with Thick Melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is often omitted in selected patients with advanced primary melanoma, although the justification/criteria for omission have been debated. OBJECTIVE: We sought to determine whether assessment of frailty could serve as an objective marker to guide selection for SLNB in patients with advanced primary melanoma. METHODS: Patients presenting with clinical stage IIC (ulcerated, > 4 mm Breslow thickness) cutaneous melanoma from January 1999 through June 2019 were included. Frailty was assessed using the Memorial Sloan Kettering Frailty Index (MSK FI), a composite score of functional status and medical comorbidities. Five-year melanoma-specific survival (MSS) and overall survival (OS) were estimated using Cox regression, and predictors of OS were identified using competing risk models. RESULTS: MSS did not differ between patients who did (n = 451) or did not undergo SLNB (n = 179) [63.2% vs. 65.0%, p = 0.14]; however, omission of SLNB was associated with decreased 5-year OS (29% vs. 44%, p < 0.001). In a multivariable competing risk model, selection for SLNB omission was an independent predictor of death from non-melanoma causes (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2-2.3, p < 0.001). After incorporation of the MSK FI score into the multivariable model in this subset, MSK FI (HR 2.4, 95% CI 1.5-4.1, p < 0.001), but not SLNB omission, was an independent predictor of poorer OS. CONCLUSION: We observed worse OS in patients with thick melanoma selected not to undergo SLNB, which was attributed to death due to non-melanoma causes. Formal assessment of frailty may provide an objective prognostic measure to guide selective use of SLNB in these patients.