FDA Approval Summary: Ciltacabtagene Autoleucel for Relapsed or Refractory Multiple Myeloma.

In February 2022, the U.S. Food and Drug Administration approved ciltacabtagene autoleucel, a chimeric antigen receptor (CAR) T cell therapy targeting the B-cell maturation antigen (BCMA), for adult patients with relapsed/refractory multiple myeloma (RRMM) after ≥4 lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Approval was based on overall response rate (ORR), complete response (CR) rate and duration of response (DOR) in 97 adult patients in a single-arm, open-label, multicenter phase 2 trial (CARTITUDE-1 [NCT03548207]). Patients received a single infusion of ciltacabtagene autoleucel, preceded by lymphodepleting chemotherapy. Of the 97 patients evaluable, ORR was 97.9% (95% CI: 92.7, 99.7) with stringent CR rate of 78.4% (95% CI: 68.8, 86.1). After median follow-up of 18 months, median DOR was 21.8 months (95% CI: 21.8, not estimable [NE]) in responders (PR or better) and NE (95% CI: 21.8 months, NE) in patients who achieved stringent CR. Serious adverse reactions occurred in 55% of 97 patients evaluated for safety. Grade 3 or higher cytokine release syndrome and neurologic toxicities occurred in 5% and 11%, respectively, leading to a Risk Evaluation and Mitigation Strategy. Neurologic toxicities included immune effector cell associated neurologic syndrome (ICANS) typically seen with CAR-T products, Parkinsonism, peripheral neuropathy, cranial nerve palsies and Guillain-Barre Syndrome (GBS). One fatal case of hemophagocytic lymphohistiocytosis/macrophage activation syndrome occurred. Prolonged and recurrent grade 3 or 4 cytopenias occurred; a single patient required hematopoietic stem cell rescue.

Cardiac Vagal Nerve Activity Increases During Exercise to Enhance Coronary Blood Flow.

BACKGROUND: The phrase complete vagal withdrawal is often used when discussing autonomic control of the heart during exercise. However, more recent studies have challenged this assumption. We hypothesized that cardiac vagal activity increases during exercise and maintains cardiac function via transmitters other than acetylcholine. METHODS: Chronic direct recordings of cardiac vagal nerve activity, cardiac output, coronary artery blood flow, and heart rate were recorded in conscious adult sheep during whole-body treadmill exercise. Cardiac innervation of the left cardiac vagal branch was confirmed with lipophilic tracer dyes (DiO). Sheep were exercised with pharmacological blockers of acetylcholine (atropine, 250 mg), VIP (vasoactive intestinal peptide; [4Cl-D-Phe6,Leu17]VIP 25 µg), or saline control, randomized on different days. In a subset of sheep, the left cardiac vagal branch was denervated. RESULTS: Neural innervation from the cardiac vagal branch is seen at major cardiac ganglionic plexi, and within the fat pads associated with the coronary arteries. Directly recorded cardiac vagal nerve activity increased during exercise. Left cardiac vagal branch denervation attenuated the maximum changes in coronary artery blood flow (maximum exercise, control: 63.5±5.9 mL/min, n=8; cardiac vagal denervated: 32.7±5.6 mL/min, n=6, P=2.5×10-7), cardiac output, and heart rate during exercise. Atropine did not affect any cardiac parameters during exercise, but VIP antagonism significantly reduced coronary artery blood flow during exercise to a similar level to vagal denervation. CONCLUSIONS: Our study demonstrates that cardiac vagal nerve activity actually increases and is crucial for maintaining cardiac function during exercise. Furthermore, our findings show the dynamic modulation of coronary artery blood flow during exercise is mediated by VIP.

Impact of radiographer immediate reporting of X-rays of the chest from general practice on the lung cancer pathway (radioX): a randomised controlled trial.

The National Optimal Lung Cancer Pathway recommends rapid progression from abnormal chest X-rays (CXRs) to CT. The impact of the more rapid reporting on the whole pathway is unknown. The aim of this study was to determine the impact of immediate reporting of CXRs requested by primary care by radiographers on the time to diagnosis of lung cancer. METHOD: People referred for CXR from primary care to a single acute district general hospital in London attended sessions that were prerandomised to either immediate radiographer (IR) reporting or standard radiographer (SR) reporting within 24 hours. CXRs were subsequently reported by radiologists blind to the radiographer reports to test the reliability of the radiographer report. Radiographer and local radiologist discordant cases were reviewed by thoracic radiologists, blinded to reporter. RESULTS: 8682 CXRs were performed between 21 June 2017 and 4 August 2018, 4096 (47.2%) for IR and 4586 (52.8%) for SR. Lung cancer was diagnosed in 49, with 27 (55.1%) for IR. The median time from CXR to diagnosis of lung cancer for IR was 32 days (IQR 19, 70) compared with 63 days (IQR 29, 78) for SR (p=0.03).8258 CXRs (95.1%) were reported by both radiographers and local radiologists. In the 1361 (16.5%) with discordance, the reviewing thoracic radiologists were equally likely to agree with local radiologist and radiographer reports. CONCLUSIONS: Immediate reporting of CXRs from primary care reduces time to diagnosis of lung cancer by half, likely due to rapid progress to CT. Radiographer reports are comparable to local radiologist reports for accuracy. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN21818068. Registered on 20 June 2017.

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project.

The Chimeric Antigen Receptor (CAR) T Cell Safety Database Project explored the use of cross-study safety data to identify risk factors associated with severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) after CAR T cell administration. Sponsors voluntarily submitted data for 1,926 subjects from 17 phases 1 and 2 studies (six acute lymphocytic leukemia [ALL], five non-Hodgkin's lymphoma [NHL], and six multiple myeloma [MM] studies). Subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR T cells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. Use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. Although this exploratory study was limited by unadjusted cross-study comparisons, it independently reproduced known risk factors for CAR T cell toxicity. Findings provide stakeholders in the CAR T cell clinical development community information on safety trends for consideration in early phase clinical trial design, as well as avenues for additional research.

Role of the angiotensin type 1 receptor in modulating the carotid chemoreflex in an ovine model of renovascular hypertension.

OBJECTIVE: The carotid body has been implicated as an important mediator and putative target for hypertension. Previous studies have indicated an important role for angiotensin II in mediating carotid body function via angiotensin type-1 receptors (AT1R); however, their role in modulating carotid body function during hypertension is unclear. METHODS: Using a large preclinical ovine model of renovascular hypertension, we hypothesized that acute AT1R blockade would lower blood pressure and decrease carotid body-mediated increases in arterial pressure. Adult ewes underwent either unilateral renal artery clipping or sham surgery. Two weeks later, flow probes were placed around the contralateral renal and common carotid arteries. RESULTS: In both hypertensive and sham animals, carotid body stimulation using potassium cyanide caused dose-dependent increases in mean arterial pressure but a reduction in renal vascular conductance. These responses were not different between groups. Infusion of angiotensin II led to an increase in arterial pressure and reduction in renal blood flow. The sensitivity of the renal vasculature to angiotensin II was significantly attenuated in hypertension compared with the sham animals. Systemic inhibition of the AT1R did not alter blood pressure in either group. Interestingly carotid body-evoked arterial pressure responses were attenuated by AT1R blockade in renovascular hypertension but not in shams. CONCLUSION: Taken together, our findings indicate a decrease in vascular reactivity of the non-clipped kidney to angiotensin II in hypertension. The CB-evoked increase in blood pressure in hypertension is mediated in part, by the AT1R. These findings indicate a differential role of the AT1R in the carotid body versus the renal vasculature.

Summary of US Food and Drug Administration Chimeric Antigen Receptor (CAR) T-Cell Biologics License Application Approvals From a Statistical Perspective.

The approval of tisagenlecleucel and axicabtagene ciloleucel in 2017 marked a milestone in the development of oncology therapies. Since 2017, the breakthrough in treatment or even cure of previously intractable diseases represented by this new class of cancer treatments has continued with subsequent chimeric antigen receptor T (CAR T)-cell approvals. To date, the US Food and Drug Administration has approved five autologous CAR T-cell products for seven indications. A feature of autologous CAR T-cell products that differentiates them from traditional oncology drugs is that they need to be manufactured specifically for each patient. This feature has implications in study design, statistical analyses, and interpretation of study results. In this article, we share our experiences in the statistical review of CAR T-cell products and provide considerations for the design and statistical analyses of CAR T-cell trials. We also describe how the newly adopted estimand framework for clinical trials can help clarify nuanced issues in CAR T-cell trial design.

FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Follicular Lymphoma.

In March 2021, the U.S. Food and Drug Administration granted accelerated approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor T-cell therapy, for the treatment of adult patients with relapsed or refractory follicular lymphoma (r/r FL) after at least 2 lines of systemic therapy. Approval was based on ZUMA-5, a single-arm, open-label, multicenter trial that evaluated a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine, in this population. Efficacy was based on objective response rate (ORR) and duration of response (DOR) as determined by an independent review committee. Among 81 patients in the primary efficacy analysis, having a median of 3 (range 2-9) prior lines of systemic therapy, the ORR was 91% (95% confidence interval [CI]: 83-96) with a complete remission (CR) rate of 60% and a median time-to-response of 1 month. The median DOR was not reached, and the 1-year rate of continued remission was 76% (95% CI: 64-85). For all leukapheresed patients with FL in this trial (n = 123), the ORR was 89% (95% CI: 83-94) with a CR rate of 62%. Among 146 patients with indolent lymphoma evaluated for safety, cytokine release syndrome occurred in 84% (Grade ≥3, 8%) and neurological toxicities occurred in 77% (Grade ≥3, 21%), leading to implementation of a risk evaluation and mitigation strategy. Serious adverse reactions occurred in 48%. Post-marketing studies will further evaluate clinical benefit in patients with r/r FL and long-term safety.

Need for aligning the definition and reporting of cytokine release syndrome (CRS) in immuno-oncology clinical trials.

As cancer immunotherapies continue to expand across all areas of oncology, it is imperative to establish a standardized approach for defining and capturing clinically important toxicities, such as cytokine release syndrome (CRS). In this paper, we provide considerations for categorizing the variety of adverse events that may accompany CRS and for recognizing that presentations of CRS may differ among various immunotherapies (e.g., monoclonal antibodies, CAR T cell therapies and T cell engagers, which can include bispecific antibodies and other constructs). The goals of this paper are to ensure accurate and consistent identification of CRS in patients receiving immunotherapies in clinical studies to aid in reporting; enable more precise evaluation of the therapeutic risk-benefit profile and cross-study analyses; support evidence-based monitoring and management of important toxicities related to cancer immunotherapies; and improve patient care and outcomes. These efforts will become more important as the number and variety of molecular targets for immunotherapies broaden and as therapies with novel mechanisms continue to be developed.

Evolving Techniques in RSI: Can the Choice of Induction Agent Matter in Securing a Definitive Airway in Emergency Settings?

How to cite this article: George B, Joachim N. Evolving Techniques in RSI: Can the Choice of Induction Agent Matter in Securing a Definitive Airway in Emergency Settings? Indian J Crit Care Med 2022;26(1):15-17.

FDA Approval Summary: Idecabtagene Vicleucel for Relapsed or Refractory Multiple Myeloma.

In March 2021, the FDA approved idecabtagene vicleucel, a chimeric antigen receptor T-cell therapy targeting the B-cell maturation antigen (BCMA), for adult patients with relapsed/refractory multiple myeloma (RRMM) after ≥4 lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 mAb. Approval was based on overall response rate (ORR), complete response (CR) rate, and duration of response (DOR) in 100 adult patients with RRMM treated with idecabtagene vicleucel in a single-arm trial. Patients received a single infusion of idecabtagene vicleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine. Of the 100 patients in the efficacy evaluable population, ORR was 72% [95% confidence interval (CI), 62-81] with stringent CR rate of 28% (95% CI, 19-38). After median follow-up of 10.7 months, median DOR was 11 months (95% CI, 10.3-11.4) in responders (partial response or better) and 19 months [95% CI, 11.4 months, not estimable (NE)] in patients who achieved stringent CR. Serious adverse reactions occurred in 67% of 127 patients evaluated for safety. Grade 3 or higher cytokine release syndrome and neurologic toxicities occurred in 9% and 4%, respectively, leading to a Risk Evaluation and Mitigation Strategy. Hemophagocytic lymphohistiocytosis/macrophage activation syndrome occurred in 4%, with two fatalities. Prolonged cytopenia requiring hematopoietic rescue occurred in 2% (3/127), with two fatalities.

Left Atrial Enlargement on Non-Gated CT Is Associated with Large Vessel Occlusion in Acute Ischaemic Stroke.

BACKGROUND: Recent reports have suggested that atrial fibrillation (AF) is more prevalent in the large vessel occlusion (LVO) subgroup of acute ischaemic stroke patients. Given the association between left atrial enlargement (LAE) and AF, we sought to evaluate the feasibility of assessing LAE on non-gated CT and its association with LVO in the hyperacute stroke setting. METHODS: We analysed our prospectively collected database that included all stroke patients referred for consideration of endovascular treatment between April 14, 2020, and May 21, 2020. During this period, a CT chest was included in our regional stroke protocol to aid triage of patients suspected for COVID-19 from which cardiac measurements were obtained. Patients were dichotomized into LVO and no-LVO groups, and LA measurements were trichotomized into normal, borderline, and enlarged. Univariate analyses were performed between groups. RESULTS: Of the included 38 patients, 21 were categorized as LVO and 17 as no LVO. There was a statistically significant association between LAE and LVO (p = 0.028). No significant difference was demonstrated between groups for the baseline AF and other clinical characteristics, except for baseline NIHSS (p = 0.0005). There was excellent inter- and intra-rater reliability (ICC = 0.969) for LA measurements. CONCLUSION: Our study provides preliminary data to suggest LAE is more prevalent in the LVO stroke subgroup at presentation and can be reliably assessed on non-gated CT in the hyperacute setting. These findings have potential implications for stratifying secondary management and may prompt a more rigorous pursuit of occult AF or other cardiac causes of stroke.

Intracranial baroreflex is attenuated in an ovine model of renovascular hypertension.

We have previously shown that elevations in intracranial pressure (ICP) within physiological ranges in normotensive animals increase arterial pressure; termed the intracranial baroreflex. Hypertension is associated with alterations in reflexes which maintain arterial pressure however, whether the intracranial baroreflex is altered is not known. Hence, in the present study, we tested the hypothesis that in hypertension, physiological increases in ICP would not be accompanied with an increase in arterial pressure. Renovascular hypertension was associated with no change in heart rate, renal blood flow or ICP levels compared to the normotensive group. ICV infusion of saline produced a ramped increase in ICP of 20 ± 1 mmHg. This was accompanied by an increase in arterial pressure (16 ± 2 mmHg) and a significant decrease in renal vascular conductance. ICV infusion of saline in the hypertensive group also increased ICP (19 ± 2 mmHg). However, the increase in arterial pressure was significantly attenuated in the hypertensive group (5 ± 2 mmHg). Ganglionic blockade abolished the increase in arterial pressure in both groups to increased ICP. Our data indicates that physiological increases in ICP lead to increases in arterial pressure in normotensive animals but this is severely attenuated in renovascular hypertension.

FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-cell Lymphoma.

In October 2017, the FDA granted regular approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Efficacy was based on complete remission (CR) rate and duration of response (DOR) in 101 adult patients with relapsed or refractory large B-cell lymphoma (median 3 prior systemic regimens) treated on a single-arm trial. Patients received a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine. The objective response rate per independent review committee was 72% [95% confidence interval (CI), 62-81], with a CR rate of 51% (95% CI, 41-62). With a median follow-up of 7.9 months, the median DOR was not reached in patients achieving CR (95% CI, 8.1 months; not estimable, NE), whereas patients with partial remission had an estimated median DOR of 2.1 months (95% CI, 1.3-5.3). Among 108 patients evaluated for safety, serious adverse reactions occurred in 52%. Cytokine release syndrome and neurologic toxicities occurred in 94% and 87% of patients, respectively, leading to implementation of a risk evaluation and mitigation strategy.

FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia.

Tisagenlecleucel (Kymriah; Novartis Pharmaceuticals) is a CD19-directed genetically modified autologous T-cell immunotherapy. On August 30, 2017, the FDA approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR, and minimal residual disease (MRD) <0.01% in a cohort of 63 children and young adults with relapsed or refractory ALL treated on a single-arm trial (CCTL019B2202). Treatment consisted of fludarabine and cyclophosphamide followed 2 to 14 days later by a single dose of tisagenlecleucel. The CR rate was 63% (95% confidence interval, 50%-75%), and all CRs had MRD <0.01%. With a median follow-up of 4.8 months, the median duration of response was not reached. Cytokine release syndrome (79%) and neurologic events (65%) were serious toxicities reported in the trial. With implementation of a Risk Evaluation and Mitigation Strategy, the benefit-risk profile was considered acceptable for this patient population with such resistant ALL. A study of safety with 15 years of follow-up is required as a condition of the approval.See related commentary by Geyer, p. 1133.

Regulation of biologic oncology products in the FDA׳s Center for Biologics Evaluation and Research.

In the United States, cancer vaccines and immunotherapies, including cell and gene therapies and peptides and proteins used as therapeutic vaccines, are regulated by the Food and Drug Administration's Center for Biologics Evaluation and Research in the Office of Cellular, Tissue, and Gene Therapies (OCTGT). Center for Biologics Evaluation and Research has licensed two immunotherapy products for urologic indications: bacillus Calmette-Guérin for superficial bladder cancer and sipuleucel-T for advanced prostate cancer. OCTGT places a high priority on scientific and regulatory activities that promote the development of safe and effective cancer therapy products. OCTGT has published guidance documents and developed innovative tools that are designed to aid the rapid development of biologic products for patient use. The success of immunotherapeutic products for urologic malignancies stands as an example for ongoing and future therapeutic research and discovery.

Tension colothorax causing cardiac tamponade: A life-threatening complication following transhiatal oesophagectomy.

Postoperative diaphragmatic hernia following transhiatal oesophagectomy is a rare but potentially life threatening complication. We describe a case of a 65 year old patient who developed diaphragmatic hernia following oesophagectomy and presented with cardio pulmonary compromise. During surgery, haemodynamic instability continued despite fluid resuscitation and noradrenaline infusion. An immediate improvement in the haemodynamics and reduction in airway pressure occurred on reduction of the herniated colon from the thoracic cavity. This can be explained by tension colothorax causing collapse of the underlying lung and cardiac tamponade. It is a surgical emergency requiring urgent decompression for resuscitation. The etiology, clinical presentation, pathophysiology and preventive measures are discussed.

Aortic valve calcification - a commonly observed but frequently ignored finding during CT scanning of the chest.

AIM: To describe the frequency and severity of Aortic valve calcification (AVC) in an unselected cohort of patients undergoing chest CT scanning and to assess the frequency with which AVC was being reported in the radiology reports. METHODS AND RESULTS: Consecutive CT scan images of the chest and the radiological reports (December 2009 to May 2010) were reviewed at the district general hospital (DGH). AVC on CT scan was visually graded on a scale ranging from 0 to IV (0 = no calcification, IV = severe calcification). Total of 416 (232 male; 184 female) CT chest scans [Contrast enhanced 302 (72%), unenhanced 114 (28%)] were reviewed. Mean age was 70.55 ± 11.48 years. AVC in CT scans was identified in 95 of the 416 patients (22.83%). AVC classification was as follows: Grade I: 60 (63.15%), Grade II: 22 (23.15%), Grade III: 9 (9.47%), Grade IV: 4 (4.21%). Only one CT report mentioned AVC. Only 31 of 95 AVC had Transthoracic echocardiogram (TTE). The interval time between CT scan and TTE was variable. CONCLUSION: Aortic valve calcification in CT chest scans is a common finding and studies have shown that it is strongly related to the presence and severity of aortic valve disease. As CT scans are considered as a valuable additional screening tool for detection of aortic stenosis, AVC should always be commented upon in the radiology reports. Furthermore, patients with at least Grade III and IV AVC should be sent for TTE.