Search

BACKGROUND: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. METHODS: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×10⁶ CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. RESULTS: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). CONCLUSIONS: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

PURPOSE: Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS: Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS: Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION: In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

Introduction: Poisoning is an increasingly important cause of injury in the United States. In 2009 poison centers received 2,479,355 exposure reports, underscoring the role of poison centers in intentional and unintentional injury prevention. Antiretroviral (ARV) agents are commonly prescribed drugs known to cause toxicity, yet the frequency of these incidents is unknown. The objectives of this study were to quantify the number of reported cases of toxicity secondary to ARV agents at a regional poison center, and to describe the circumstances and clinical manifestations of these poisonings.Methods: We conducted a retrospective review of poison center records between December 1, 2001, and January 7, 2010.Results: One hundred sixty-two exposures to ARV agents were reported to the poison center, of which 30% were intentional and 70% were unintentional. Three patients developed major toxicity and no deaths occurred. The remaining patients developed moderate and minor effects as defined by poison center guidelines.Conclusion: ARV drug toxicity appears to be infrequently reported to the poison center. Fatal and major toxicities are uncommon, and intentional overdoses are associated with a more serious toxicity. Educational efforts should encourage clinicians to report toxicities related to the use of ARV agents to poison centers in order to better study this problem. [West J Emerg Med. 2011;12(3):293-295.]

Orofacial pain is a worldwide pain problem, with many patients unable to find appropriate diagnosis and treatment. Orofacial pain includes pain arising from the odontogenic and nonodontogenic structures in the head and neck region. Dental clinicians need to have a thorough knowledge and skill to diagnose, manage, and treat patients with odontogenic pain or refer patients for treatment of nonodontogenic pain to specialists such as orofacial pain specialists, neurologists, otolaryngologists, and rheumatologists. More often, dental practitioners diagnose patients with a temporomandibular disorder (TMD), and when treatment is ineffective, term it "atypical facial pain." The first requirement for effective treatment is an accurate diagnosis. Dental clinicians must be aware of giant cell arteritis (GCA), a chronic large-vessel vasculitis, primarily affecting adults over the age of 50 years, as it frequently mimics and is misdiagnosed as TMD. GCA is associated with loss of vision, and stroke and can be a life-threatening disorder. Therefore, diagnostic testing for GCA and differential diagnosis should be common knowledge in the armamentarium of all dental clinicians. Historically, temporal artery biopsy was considered the definitive diagnostic test for GCA. Temporal artery ultrasound (TAUSG), a safe and noninvasive imaging modality, has replaced the previous diagnostic gold standard for GCA, the temporal artery biopsy, owing to its enhanced diagnostic capabilities and safety profile. The present case report describes a patient with GCA, and the role TAUSG played in the diagnosis. Case report: A 72-year-old woman presented with left-sided facial pain, jaw claudication, dysesthesia of the tongue, and episodic loss of vision of 2 years' duration. She was diagnosed with and treated for a myriad of dental conditions including endodontia and temporomandibular joint therapy with no benefit. A thorough history and physical examination, combined with serologic analysis, led to the diagnosis of GCA and TAUSG, which confirmed the diagnosis. Conclusion: This report underscores the responsibility of differential diagnosis and early recognition of GCA facilitated by TAUSG in optimizing treatment outcomes as a viable, noninvasive diagnostic tool. [ABSTRACT FROM AUTHOR]

BackgroundBrexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care.MethodsAdults with R/R B-ALL received a single infusion of KTE-X19 (1 × 106 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3.ResultsAfter 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively.ConclusionsThese data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population.Trial registrationNCT02614066.

“Presidential administration” has been discussed for the last twenty years. However, scholars have not considered whether courts are doing the same thing. Like presidents, courts may oversee the quality of administrative action under authority granted by the Constitution and legislation. And also, like presidents, courts make policy decisions in lieu of the agency that has been delegated policymaking power. This Article draws on case law and legal scholarship, as well as work from public administration and political science, to construct a paradigm of “judicial administration.” More specifically, it offers a history of and traces the tension between the “overseer” and “decider” approaches to judicial administration. In addition, it explains the implications of these approaches for the constitutionality and efficacy of judicial review today. First, this Article considers judicial administration as accomplished through the reinforcement of administrative procedure. These efforts were criticized as judicial policymaking by formalists. However, as this Article notes, these decisions focus on reconciling administrative action with constitutional, technical, and rule-of-law norms and are thus rooted in overseer impulses. In other words, the decider dimensions of even the most intrusive judicial review of agency process have been overstated. Second, and in contrast, this Article notes that the recent call to overturn Chevron constitutes uncritical advocacy for the decider approach to the judicial administration of statutory directives. In the past, courts have limited their role in the administration of legislation to that of overseer. However, today’s formalists seek to implement de novo review wholesale. This effort is, at its core, a push for courts to decide policy in lieu of the agencies to which Congress has delegated policymaking power or to which policymaking power belongs as a matter of executive authority. This may not trouble functionalists much. But it should trouble the very formalists who denounce Chevron. First, this evinces an inconsistency in their position, given that many have condemned what they identify as judicial policymaking in administrative process. More broadly, as in presidential administration, the decider approach to judicial administration runs the risk of treading on the legislature’s authority to make the law. To the extent this is the case, calls to dismantle the administrative state and instate the judiciary in its place are focused on reimbursing the wrong branch of government. For those interested in judicial intervention as a means of regulating the administrative state, including the exercise of presidential power, the overseer model of judicial administration is less likely to offend a formal conception of the separation of powers. Furthermore, longstanding paradigms of judiciary as overseer confront the pressing issues—namely, the denigration of administrative due process and corrosion of expertise in service of the President’s agenda—resulting from today’s unsupervised executive branch.

Context.--Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been incorporated into consensus criteria regarding treatment response, strategy, and clinical trial endpoints. clonoSEQ (a next-generation sequencing [NGS]-MRD assay) uses multiplex polymerase chain reaction and NGS to identify clonotypic rearrangements at the immunoglobulin (Ig) H, IgK, IgL, T-cell receptor (TCR)-[beta], and TCR-[gamma] loci, as well as translocated B-cell lymphoma 1/IgH and 2/IgH sequences for MRD assessment. Additionally, it can be used to confirm diagnoses of cutaneous T-cell lymphoma (CTCL). Objective.--To review the technical aspects of our experience using the clonoSEQ Assay in routine clinical practice. Design.--In this single-center experience, 390 patients with lymphoid and plasma cell malignancies were assessed with the NGS-MRD Assay at a central laboratory. Results.--Median time from arrival of the shipment to initiation of the assay (defined as captured in Adaptive's secure tracking system) was 2.1 hours. Overall, 317 patients had 1 or more samples submitted for sequence identification. Of these, 290 (91.5%) had trackable sequences identified. The median calibration rate of samples by malignancy (where n [greater than or equal to] 10 samples, excluding CTCL samples) was 88.1%, across a variety of fresh and archived sample sources (177 of 201 samples). TCR-[beta] and/ or TCR-[gamma] clonotypes were identified in 40 of 95 samples (42.1%) from 66 patients with suspected CTCL. Conclusions.--This NGS-MRD Assay is a valuable and sensitive tool for monitoring MRD in patients with plasma cell and lymphoid malignancies and assisting in the diagnosis of CTCL., In the past decade, the clinical utility of assessing measurable (minimal) residual disease (MRD) in patients with plasma cell and lymphoid malignancies has been recognized increasingly. (1) MRD has been [...]

Measurable residual disease (MRD) that persists after initial therapy is a powerful predictor of relapse and survival in acute lymphoblastic leukemia (ALL). However, the optimal use of this information to influence therapeutic decisions is controversial. Herein, we comprehensively review the role of MRD assessment in adults with ALL, including methods to quantify residual leukemia cells during remission, prognostic impact of MRD across ALL subtypes, and available therapeutic approaches to eradicate MRD. This review presents consensus statements and provides an evidence-based framework for practicing hematologists and oncologists to use MRD information to make rational treatment decisions in adult patients with ALL.

South Asians have the highest rates of premature atherosclerotic cardiovascular disease amongst all ethnic groups in the world; however this risk cannot be fully explained by traditional risk factors. Participants from the Mediators of Atherosclerosis in South Asians Living in America Study were included in this cross-sectional analysis. The purpose of this study was to investigate the association of psychosocial factors (including anger, anxiety, depressive symptoms, current and chronic stress, and everyday hassles) with carotid intima-media thickness (CIMT). Three multivariate models were examined to evaluate the association between the psychosocial factors and CIMT. Findings suggest that the impact of psychosocial factors on subclinical atherosclerosis is differential for South Asian men and women. For men, anxiety and depression were associated; while for women, stress was associated with common carotid intima media thickness, independent of traditional CVD risk factors, diet and physical activity.