Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA-directed therapy with eculizumab, a complement C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the MASP-2 effector enzyme of the lectin pathway, has been studied in adults with TA-TMA as first-line therapy with a response rate of 61%. Although there are limited data on narsoplimab use as a second-line agent in children, we hypothesized, that complement pathways proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children. In this single-center study, children were enrolled on single-patient, Institutional Review Board-approved compassionate use protocols for narsoplimab treatment. Clinical complement lab tests were obtained at the discretion of the treating physician, although all patients were also offered participation in a companion biomarker study. Research blood samples were obtained at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first narsoplimab dose. Single ELISA kits were used to measure markers of complement activation according to the manufacture's instructions. Five children with rTA-TMA received narsoplimab; 3 were in multiorgan failure and 2 had worsening multiorgan dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS; n = 3), viral infection (n = 3), and steroid-refractory stage 4 lower gut grade IV acute graft-versus-host disease (aGVHD, n = 3). Two infants with concurrent SOS and no aGVHD had resolution of organ dysfunction; 1 also developed transfusion-independence (complete response), and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence but had no improvement in organ manifestations (partial response), and 2 patients treated late in the course of disease had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to provide additional research blood samples. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with subsequent declines in Ba, Bb, C3a, and C5a and increases in C3 in both clinical and research lab tests. Otherwise, there was no clear pattern of other complement markers, including MASP-2 levels, after therapy. In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefited from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid-refractory aGVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful for monitoring lectin pathway activation and inhibition.

[Use of isoflurane as treatment for super-refractory status epilepticus]. / Uso de isoflurano como tratamiento del estado epiléptico superrefractario.

INTRODUCTION: Super-refractory status epilepticus (SRSE) is a neurological condition with an important morbidity and mortality rate, for which few therapeutic options are available. Inhalation sedation with isoflurane is currently a compassionate-use treatment in Spanish intensive care units. Little has been written about its usefulness in the treatment of refractory and super-refractory status epilepticus, but it appears to be a useful and safe therapeutic alternative for this condition. CASE REPORTS: This article reviews three cases of SRSE treated with isoflurane. The capacity of isoflurane to control seizures was assessed by electroencephalographic monitoring. Other variables assessed were time to seizure control, survival, functional outcome and occurrence of complications secondary to isoflurane. In the three cases reviewed, isoflurane proved to be effective for seizure control in patients affected by SRSE. Seizure control was accomplished quickly and the minimum dose required to obtain a burst-suppression pattern was titrated easily and rapidly. Despite controlling epilepsy, high mortality was observed (66.66%). This is explained by both the mortality of SRSE and the underlying pathologies of the patients who died. The use of isoflurane did not give rise to any complications. CONCLUSION: With the results obtained, it is feasible to think that the use of isoflurane is not related to lesions in the central nervous system reported in other articles, and this treatment can be considered effective and safe for the control of SRSE.

TITLE: Uso de isoflurano como tratamiento del estado epiléptico superrefractario.Introducción. El estado epiléptico superrefractario (EESR) es una entidad neurológica con una importante morbimortalidad, en la que se dispone de pocas opciones terapéuticas. La sedación inhalatoria con isoflurano es un tratamiento de uso compasivo actualmente en las unidades de cuidados intensivos españolas. Existe poca documentación sobre su utilidad en el tratamiento del estado epiléptico refractario y superrefractario, pero parece ser una alternativa terapéutica útil y segura para esta patología. Casos clínicos. Este artículo es una revisión de tres casos de EESR tratados con isoflurano. Se evaluó el control de las crisis epilépticas por isoflurano mediante monitorización electroencefalográfica. Otras variables evaluadas han sido el tiempo transcurrido hasta el control de las crisis, la supervivencia, el resultado funcional y la aparición de complicaciones secundarias al isoflurano. En los tres casos revisados, el isoflurano se mostró efectivo para el control de las crisis epilépticas en pacientes afectados por EESR. El control de las crisis epilépticas se logró rápidamente, y se pudo titular fácil y rápidamente la mínima dosis que obtenía el patrón burst-suppression. A pesar del control de la epilepsia, se objetivó una elevada mortalidad (66,66%). Esto se explica tanto por la mortalidad del EESR como por las patologías subyacentes de los pacientes fallecidos. El uso de isoflurano no presentó complicaciones. Conclusión. Con los resultados obtenidos, es factible pensar que el uso de isoflurano no se relaciona con las lesiones en el sistema nervioso central descritas en otros artículos, y se puede considerar que este tratamiento es efectivo y seguro para el control del EESR.

Clinical Experience of the PK Papyrus Covered Stent in Patients With Coronary Artery Perforations: Results From a Multi-Center Humanitarian Device Exemption Survey.

BACKGROUND/PURPOSE: The PK Papyrus covered coronary stent system (Biotronik AG, Bülach, Switzerland) is intended for treatment of coronary artery perforation (CAP) and is approved for use under a Humanitarian Device Exemption (HDE) in the United States (US). METHODS/MATERIALS: The retrospective data analysis includes cases reported from the US PK Papyrus HDE post-market surveillance clinical dataset with CAP cited as the reason for PK Papyrus stent use. RESULTS: From April 2019 to July 2021, PK Papyrus device registration forms citing CAP as the reason for use were received for 1094 cases from 335 US hospital programs. Ellis classification was assessed as: type III cavity spilling/IV, 11.0%; type III, 57.9%; type II, 23.8%; type I, 7.3%. Mechanisms of perforation included: balloon angioplasty (42.3%), stent placement (31.3%), atherectomy (13.9%), and guidewire (10.9%). The majority (72.6%) of cases involved single covered stent placement. Successful PK Papyrus delivery was reported in 97.7% of cases with successful perforation sealing in 92.1%. Emergency cardiac surgery and in-hospital death occurred in 6.3% and 12.4% of cases, respectively. Pericardiocentesis was performed in 30.2% of patients. Acute/subacute stent thrombosis occurred in 10 patients (1.1%). CONCLUSION: As the largest dataset of patients treated with a covered stent for CAP, these data provide significant insight into patient characteristics, procedural outcome, and in-hospital clinical events associated with this life-threatening complication. These results demonstrate that the PK Papyrus stent is a safe and effective method to seal CAP and with the potential to reduce high morbidity and mortality associated with this event.

Mesenchymal Stromal Cells for Treating Steroid-Resistant Acute and Chronic Graft Versus Host Disease: A Multicenter Compassionate Use Experience.

Graft versus host disease (GVHD) is a severe complication after allogenic hematopoietic cell transplantation (HSCT). Several clinical trials have reported the use of mesenchymal stromal cells (MSCs) for the treatment of GVHD. In March 2008, the Andalusian Health Care System launched a compassionate use program to treat steroid-resistant GVHD with MSC. Clinical-grade MSC were obtained under GMP conditions. MSC therapy was administered intravenously in four separate doses of 1 × 106 cells/kg. Sixty-two patients, 45 males (7 children) and 17 females (2 children), received the treatment. Patients had a median age of 39 years (range: 7-66) at the time of the allogenic HSCT. The overall response was achieved in 58.7% of patients with acute (a)GVHD. Two years' survival for aGVHD responders was 51.85%. The overall response for patients with chronic (c)GVHD was 65.50% and the 2-year survival rate for responders was 70%. Age at the time of HSCT was the only predictor found to be inversely correlated with survival in aGVHD. Regarding safety, four adverse events were reported, all recovered without sequelae. Thus, analysis of this compassionate use experience shows MSC to be an effective and safe therapeutic option for treating refractory GVHD, resulting in a significant proportion of patients responding to the therapy.

Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France.

OBJECTIVE: Ketoconazole (KTZ) is one of few available treatments for Cushing's syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ. DESIGN: An observational prospective French cohort study (Compassionate Use Programme (CUP)). METHODS: Enrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury. RESULTS: Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes. CONCLUSIONS: These findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ.

Long-term toxicity of bevacizumab therapy in neurofibromatosis 2 patients.

PURPOSE: Bevacizumab treatment is associated with tumor shrinkage and hearing improvement in about 50 % of neurofibromatosis 2 (NF2) patients with progressive vestibular schwannomas. Hypertension and proteinuria are common side effects of treatment. However, the long-term toxicity of bevacizumab in this population has not been reported. METHODS: We reviewed the medical records of all NF2 patients treated with compassionate care bevacizumab at our institution. Hypertension was defined as a systolic blood pressure ≥140 or a diastolic blood pressure ≥90. Proteinuria was measured by urine dipstick. Time-to-event analyses were conducted for hypertension and proteinuria. The relationship of cumulative dose of bevacizumab to mean arterial pressure (MAP) was examined using mixed model analysis, while the relationship to urine protein was examined using generalized estimating equations. RESULTS: Thirty-three patients (median age 28 years) were included in the study, with a median treatment time of 34.1 months. 15/26 (58 %) patients became hypertensive and 18/29 (62 %) developed proteinuria during treatment. Median time to develop hypertension was 12.8 months. Median time to develop 1+ and 2+ proteinuria was 23.7 and 31.9 months, respectively. Eight patients required treatment holidays for proteinuria (median length 3.2 months). A significant positive relationship existed between cumulative bevacizumab dose and MAP (p < 0.0001) but not between cumulative dose and proteinuria (p > 0.30). CONCLUSION: In our cohort of NF2 patients, extended use of bevacizumab was associated with manageable toxicity. However, bevacizumab treatment still requires careful monitoring of blood pressure and proteinuria, and future studies should investigate optimal dosing schedules to minimize long-term toxicity.

Off-label use of anti-cancer drugs between clinical practice and research: the Italian experience.

BACKGROUND: Off-label use is the practice of prescribing a drug outside the terms of its official labeling. Worldwide, about 20% of the commonly prescribed medications are off-label, and the percentage increases in specific patient populations, such as children, pregnant women, and cancer patients. Off-label use is particularly widespread in oncology for many reasons, including the wide variety of cancer subtypes, the difficulties involved in performing clinical trials, the rapid diffusion of preliminary results, and delays in the approval of new drugs by regulatory organizations/agencies. OBJECTIVE: The aim of this article is to describe the use of off-label drugs in oncology, with an emphasis on the role of the world's leading regulatory agencies and an assessment of current Italian legislation. CONCLUSION: Off-label drug utilization is essential in oncology when based on evidence. However, off-label drugs must be prescribed in accordance with existing national laws and only when the potential benefit outweighs the potential toxic effects.