Compassionate Use Research Articles

Multi-Center Compassionate use Early Feasibility Evaluation of J-Valve Transcatheter Treatment for Severe Aortic Valve Regurgitation: Preliminary Results

Multi-Center Compassionate use Early Feasibility Evaluation of J-Valve Transcatheter Treatment for Severe Aortic Valve Regurgitation: Preliminary Results

When Do Firms Provide Early Access? Evidence from Expanded Access in Oncology 1990-2020

When Do Firms Provide Early Access? Evidence from Expanded Access in Oncology 1990-2020

Round-trip multi-band quantum access network

The quantum network makes use of quantum states to transmit data, which will revolutionize classical communication and allow for some breakthrough applications. Quantum key distribution (QKD) is one prominent application of quantum networks, and can protect data transmission through quantum mechanics. In this work, we propose an expandable and cost-effective quantum access network, in which the round-trip structure makes quantum states travel in a circle to carry information, and the multi-band technique is proposed to support multi-user access. Based on the round-trip multi-band quantum access network, we realize multi-user secure key sharing through the continuous-variable QKD (CV-QKD) protocol. Due to the encoding characteristics of CV-QKD, the quadrature components in different frequency bands can be used to transmit key information for different users. The feasibility of this scheme is confirmed by comprehensive noise analysis, and is verified by a proof-of-principle experiment. The results show that each user can achieve excess noise suppression and 600 bit/s level secure key generation under 30 km standard fiber transmission. Such networks have the ability of multi-user access theoretically and could be expanded by plugging in simple modules. Therefore, it paves the way for near-term large-scale quantum secure networks.

Barriers and determinants of consistent offering of HPV vaccination by healthcare facilities

ABSTRACT Expanding access to HPV vaccination is critical to increasing HPV vaccine uptake. We assessed the determinants and barriers to consistent offering of HPV vaccine among healthcare facilities. This was a cross-sectional survey of healthcare providers (HCPs) in Texas. Prevalence of the reasons healthcare practices do not consistently offer HPV vaccination was estimated. Multivariable regression analyses were conducted. Of 1169 HCPs included in the study, 47.5% (95% CI: 44.6–50.3%) reported their practices do not provide HPV vaccination or do not offer it consistently. Compared to physicians, nurses had 77% lower odds (Adjusted Odds Ratio (AOR): 0.23, 95% CI: 0.16–0.32, p-value: < .001), and physician assistants had 89% lower odds (AOR: 0.11, 95% CI: 0.07–0.16, p-value: < .001) of their healthcare practices consistently offering HPV vaccination. Compared to university/teaching hospitals, the odds of healthcare practices consistently offering HPV vaccination were 44% lower (AOR: 0.56, 95% CI: 0.35–0.91, p-value: 0.019) in solo practices but 266% higher (AOR: 3.66, 95% CI: 2.04–6.58, p-value: < .001) in FQHC/public facilities. The common reasons healthcare practices do not consistently offer HPV vaccination were; HPV vaccination is not within the scope of the practice (48.1%), referrals to other clinics (27.7%), and limited personnel (11.4%). Non-physicians were more likely to report that HPV vaccination was not in their scope and to refer patients than physicians. Moreover, solo practices were more likely to report challenges with acquisition and storage of the vaccine and referral of patients as reasons for not consistently offering HPV vaccination than university/teaching hospitals, FQHC/public facilities, or group practices. System-level interventions including training of non-physicians and expansion of practice enrollment in programs that support HPV vaccine acquisition and storage are needed.

Real-world treatment outcomes of medicines used in special situations (off-label and compassionate use) in oncology and hematology: A retrospective study from a comprehensive cancer institution.

Medicines in special situations (MSS) refer to off-label or to unlicensed drugs under investigation (compassionate use). Our objectives were to evaluate characteristics and to estimate overall survival (OS), event-free survival (EFS), and the duration of treatment (DT) of MSS used for cancer treatment at a multicentre comprehensive cancer institution. Retrospective cohort study on adult cancer patients for whom an MSS treatment was requested (January 2011-December 2020). A descriptive analysis was performed and median OS and EFS and 95% confidence intervals (CIs) were estimated. Survival curves were stratified by type of tumor, ECOG (Eastern Cooperative Oncology Group) performance status (PS), age, sex, treatment stage and type of drug (mechanism of action and target). Treatment was initiated in 2092 episodes (1930 patients) out of 2377 MSS episodes (2189 patients) requested, 33% for hematological treatment and 87% for advanced stage cancer. Median OS (months) was 21.1 (95% CI 19.4-22.7), median EFS was 5.6 (95% CI 5.1-6.0) months, and median DT was 4.5 [0.0; 115.3] months. OS and EFS statistically significantly favored female patients, ECOG PS ≥2 episodes showed worse OS and EFS outcomes (p < 0.0001). Statistically significant differences in survival were found within solid and hematological cancer, disease stage, drug mechanism of action, and type of cancer (p < 0.001) but not for age. Survival outcomes by tumor subtype and drug are presented both globally and separately based on disease stage. MSS uses are practiced across almost all cancer types, mostly for advanced disease. ECOG PS ≥2, along with advanced disease, was related to worse survival. Information about real-world outcomes is valuable and contributes to better decision-making regarding MSS and our experience in this field could be of interest for other colleagues.

Outcomes and clinical characteristics of the compassionate use of plitidepsin for immunocompromised adult patients with COVID-19

ObjectivesTo evaluate the compassionate use of plitidepsin as an antiviral treatment in hospitalized immunocompromised adult patients with moderate-to-severe COVID-19. DesignRetrospective observational study of data —collected from January 01, 2021 to April 30, 2022— from 35 immunocompromised adult patients with COVID-19 non-eligible for other available antiviral treatments. Main outcome measures were time to respiratory recovery (SpFi ≥ 315); COVID-19-related 30-day-cumulative mortality after first plitidepsin infusion; and time to undetectable levels of viral RNA. ResultsThirty-three patients receiving a full course of plitidepsin (2.5 mg [n = 29] or 1.5 mg [n = 4]) were included. Most (69.7%) had a malignant hematologic disease and 27.3% had solid tumors. A total of 111 infusions were administered with lack of relevant safety events. Median time from plitidepsin initiation to SpFi ≥315 was 8 days (95% confidence interval [CI], 7-19). Median time to first negative reverse transcription-polymerase chain reaction for SARS-CoV-2 (cycle threshold >36) was 17 days (95% CI 13-25). Mortality rate was 16.3% (95% CI 3-37.3). ConclusionThese data support plitidepsin as a well-tolerated treatment that might have potential clinical and antiviral efficacy in COVID-19 immunocompromised patients.

Artículo traducido] Efectividad de guselkumab en pacientes con hidradenitis supurativa en condiciones de práctica clínica: estudio retrospectivo y multicéntrico en España

BackgroundHidradenitis suppurativa (HS) is a chronic skin condition causing lesions in which high levels of interleukin (IL)-23 and T-helper17 cells are found. Adalimumab remains the only approved treatment. Guselkumab, an antibody targeting the p19 protein subunit of extracellular IL-23, is approved for the treatment of moderate-severe psoriasis, but evidence on its efficacy in treating HS is limited. ObjectivesTo assess the effectiveness and safety of guselkumab in treating moderate-severe HS under clinical practice conditions. MethodsA multicentre retrospective observational study was carried out in 13 Spanish hospitals including adult HS patients treated with guselkumab within a compassionate use programme (March 2020-March 2022). Data referred to patient demographic and clinical characteristics at treatment initiation (baseline), patient-reported outcomes (Numerical Pain Rating Scale [NPRS] and Dermatology Life Quality Index [DLQI]), physician scores (International Hidradenitis Suppurativa Severity Score System [IHS4], HS Physical Global Score [HS-PGA] and Hidradenitis Suppurativa Clinical Response [HiSCR]) were recorded at baseline and at 16, 24, and 48weeks of treatment. ResultsA total of 69 patients were included. Most (84.10%) had severe HS (HurleyIII) and had been diagnosed for over ten years (58.80%). The patients had been subjected to multiple non-biological (mean: 3.56) or biological (mean: 1.78) therapies, and almost 90% of those treated with biologics had received adalimumab. A significant decrease in IHS4, HS-PGA, NPRS, and DLQI scores was observed from baseline to 48weeks of guselkumab treatment (all P<.01). HiSCR was achieved in 58.33% and 56.52% of the patients at 16 and 24weeks, respectively. Overall, 16 patients discontinued treatment, mostly due to inefficacy (n=7) or loss of efficacy (n=3). No serious adverse events were observed. ConclusionsOur results indicate that guselkumab may be a safe and effective therapeutic alternative for patients with severe HS that fail to respond to other biologics.

Italian nivolumab Expanded Access Programme in melanoma adjuvant setting: patient outcomes and safety profile

IntroductionThe CheckMate 238 randomised study demonstrated the relevant benefit in terms of recurrence-free survival (RFS) of nivolumab versus ipilimumab in resected stage IIIB-C or IV melanoma patients with a tolerable safety profile. Materials and methodsFrom November 2018 to June 2019, 611 patients with stage III and IV resected melanoma were enroled to receive nivolumab as part of an Italian Expanded Access Programme (EAP). According to stages, 77% were stage III while 141 (23%) were stage IV with no evidence of disease (NED). Among stage III, 121 patients had IIIA (19.8%). ResultsAfter a median follow-up of 23 months, the RFS in the Intention-to-Treat (ITT) population was 76.6% at 1 year and 59.6% at 2 years; 1- and 2-year distant metastasis–free survival were 83.7% and 71.2%, respectively. The overall survival rate in the ITT population was 93.8% at 1 year and 85.5% at 2 years. No significant differences in RFS were observed according to BRAF status. Treatment-related adverse events of grades 3–4 occurred in 11.5% of patients. ConclusionThis paper reports the results of the Italian Nivolumab EAP in the adjuvant setting of stage III and IV NED melanoma patients. Our results confirm in a real-life setting the clinical activity and safety of nivolumab reported in the CheckMate238 registrative/pivotal. The enroled cohort of 611 patients highlights the relevant clinical need in this setting, also confirmed by the very short accrual time, representing one of the largest series reported as adjuvant EAP with the longest follow-up.

Temporal Trends in Hepatitis C-Related Hospitalizations, United States, 2000-2019.

Hospitalization burden related to hepatitis C virus (HCV) infection is substantial. We sought to describe temporal trends in hospitalization rates before and after release of direct-acting antiviral (DAA) agents. We analyzed 2000-2019 data from adults aged ≥18 years in the National Inpatient Sample. Hospitalizations were HCV-related if (1) hepatitis C was the primary diagnosis, or (2) hepatitis C was any secondary diagnosis with a liver-related primary diagnosis. We analyzed characteristics of HCV-related hospitalizations nationally and examined trends in age-adjusted hospitalization rates. During 2000-2019, there were an estimated 1 286 397 HCV-related hospitalizations in the United States. The annual age-adjusted hospitalization rate was lowest in 2019 (18.7/100 000 population) and highest in 2012 (29.6/100 000 population). Most hospitalizations occurred among persons aged 45-64 years (71.8%), males (67.1%), White non-Hispanic persons (60.5%), and Medicaid/Medicare recipients (64.0%). The national age-adjusted hospitalization rate increased during 2000-2003 (annual percentage change [APC], 9.4%; P < .001) and 2003-2013 (APC, 1.8%; P < .001) before decreasing during 2013-2019 (APC, -7.6%; P < .001). Comparing 2000 to 2019, the largest increases in hospitalization rates occurred among persons aged 55-64 years (132.9%), Medicaid recipients (41.6%), and Black non-Hispanic persons (22.3%). Although multiple factors likely contributed, overall HCV-related hospitalization rates declined steadily after 2013, coinciding with the release of DAAs. However, the declines were not observed equally among age, race/ethnicity, or insurance categories. Expanded access to DAA treatment is needed, particularly among Medicaid and Medicare recipients, to reduce disparities and morbidity and eliminate hepatitis C as a public health threat.

Changes in Nursing Home Use Following Medicaid-Supported Expanded Access to Home- and Community-Based Services for Older Adults With Dementia

New York State's Medicaid managed long-term care (MLTC) program expanded access to home- and community-based services, providing an alternative to nursing home care for people with dementia. Between 2012 and 2015, the state implemented mandatory MLTC for dual Medicare and Medicaid enrollees requiring more than 120 days of community-based long-term care. To evaluate changes in nursing home use among older adults with dementia following MLTC implementation. This cohort study used longitudinal data from January 1, 2011, to December 31, 2019, from the Minimum Data Set and Medicare administrative data. The study sample included New York State Medicare beneficiaries 65 years and older with dementia. New York City residents were excluded due to insufficient pre-study period data. Data were analyzed from January 1, 2011, to December 31, 2019. Mandatory MLTC enrollment. Longitudinal models were used to evaluate changes in annual days of nursing home use following the staggered implementation of MLTC across 13 regions of the state. Two models were estimated: (1) a logistic regression model for any nursing home use in a given year and (2) a linear regression model of total nursing home days, conditional on any nursing home use. Models included annual event-time indicators specified as years until or since MLTC implementation. To capture MLTC effects for dual enrollees relative to non-dual Medicare enrollees, models included interaction terms for dual enrollment and event-time indicators. This sample included 463 947 Medicare beneficiaries with dementia who lived in New York State between 2011 and 2019 (50.2% younger than 85 years; 64.4% women). Implementation of MLTC was associated with lower odds of nursing home use among dual enrollees, ranging from 8% lower odds 2 years post implementation (adjusted odds ratio, 0.92 [95% CI, 0.86-0.98]) to 24% lower odds 6 years post implementation (adjusted odds ratio, 0.76 [95% CI, 0.69-0.84]). Compared with a scenario of no MLTC, MLTC implementation was associated with an 8% reduction in annual days of nursing home use between 2013 and 2019 (mean, -5.6 [95% CI, -6.1 to -5.1] days per year). The findings of this cohort study suggest that implementation of mandatory MLTC in New York State was associated with less nursing home use among dual enrollees with dementia and that MLTC may help prevent or delay nursing home placement among older adults with dementia.

Evolution of National Guidelines on Medicines Used to Treat COVID-19 in Pregnancy in 2020-2022: A Scoping Review.

The lack of inclusion of pregnant women in clinical trials evaluating the effectiveness of medicines to treat COVID-19 has made it difficult to establish evidence-based treatment guidelines for pregnant women. Our aim was to provide a review of the evolution and updates of the national guidelines on medicines used in pregnant women with COVID-19 published by the obstetrician and gynecologists' societies in thirteen countries in 2020-2022. Based on the results of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial, the national societies successively recommended against prescribing hydroxychloroquine, lopinavir-ritonavir and azithromycin. Guidelines for remdesivir differed completely between countries, from compassionate or conditional use to recommendation against. Nirmatrelvir-ritonavir was authorized in Australia and the UK only in research settings and was no longer recommended in the UK at the end of 2022. After initial reluctance to use corticosteroids, the results of the RECOVERY trial have enabled the recommendation of dexamethasone in case of severe COVID-19 since mid-2020. Some societies recommended prescribing tocilizumab to pregnant patients with hypoxia and systemic inflammation from June 2021. Anti-SARS-CoV-2 monoclonal antibodies were authorized at the end of 2021 with conditional use in some countries, and then no longer recommended in Belgium and the USA at the end of 2022. The gradual convergence of the recommendations, although delayed compared to the general population, highlights the importance of the inclusion of pregnant women in clinical trials and of international collaboration to improve the pharmacological treatment of pregnant women with COVID-19.

Compassionate use of a novel β-lactam enhancer-based investigational antibiotic cefepime/zidebactam (WCK 5222) for the treatment of extensively-drug-resistant NDM-expressing Pseudomonas aeruginosa infection in an intra-abdominal infection-induced sepsis patient: a case report

Infections in critically-ill patients caused by extensively-drug-resistant (XDR)-Pseudomonas aeruginosa are challenging to manage due to paucity of effective treatment options. Cefepime/zidebactam, which is currently in global Phase 3 clinical development (Clinical Trials Identifier: NCT04979806, registered on July 28, 2021) is a novel mechanism of action based β-lactam/ β-lactam-enhancer combination with a promising activity against a broad-range of Gram-negative pathogens including XDR P. aeruginosa. We present a case report of an intra-abdominal infection-induced sepsis patient infected with XDR P. aeruginosa and successfully treated with cefepime/zidebactam under compassionate use. The 50 year old female patient with past-history of bariatric surgery and recent elective abdominoplasty and liposuction developed secondary pneumonia and failed a prolonged course of polymyxins. The organism repeatedly isolated from the patient was a New-Delhi metallo β-lactamase-producing XDR P. aeruginosa resistant to ceftazidime/avibactam, imipenem/relebactam and ceftolozane/tazobactam, susceptible only to cefepime/zidebactam. As polymyxins failed to rescue the patient, cefepime/zidebactam was administered under compassionate grounds leading to discharge of patient in stable condition. The present case highlights the prevailing precarious scenario of antimicrobial resistance and the need for novel antibiotics to tackle infections caused by XDR phenotype pathogens.

Measuring Safety and Outcomes for the Use of Compassionate and Off-Label Therapies for Children, Adolescents, and Young Adults With Cancer in the SACHA-France Study

Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use programs. However, no clinical data of these prescriptions is systematically collected. To measure the feasibility of the collection of clinical safety and efficacy data of compassionate and off-label innovative anticancer therapies, with adequate pharmacovigilance declaration to inform further use and development of these medicines. This cohort study included patients treated at French pediatric oncology centers from March 2020 to June 2022. Eligible patients were aged 25 years or younger with pediatric malignant neoplasms (solid tumors, brain tumors, or hematological malignant neoplasms) or related conditions who received compassionate use or off-label innovative anticancer therapies. Follow up was conducted through August 10, 2022. All patients treated in a French Society of Pediatric Oncology (SFCE) center. Collection of adverse drug reactions and anticancer activity attributable to the treatment. A total of 366 patients were included, with a median age of 11.1 years (range, 0.2-24.6 years); 203 of 351 patients (58%) in the final analysis were male. Fifty-five different drugs were prescribed, half of patients (179 of 351 [51%]) were prescribed these drugs within a compassionate use program, mainly as single agents (74%) and based on a molecular alteration (65%). Main therapies were MEK/BRAF inhibitors followed by multi-targeted tyrosine kinase inhibitors. In 34% of patients at least a grade 2 clinical and/or grade 3 laboratory adverse drug reaction was reported, leading to delayed therapy and permanent discontinuation of the innovative therapy in 13% and 5% of patients, respectively. Objective responses were reported in 57 of 230 patients (25%) with solid tumors, brain tumors, and lymphomas. Early identification of exceptional responses supported the development of specific clinical trials for this population. This cohort study of the SACHA-France (Secured Access to Innovative Medicines for Children with Cancer) suggested the feasibility of prospective multicenter clinical safety and activity data collection for compassionate and off-label new anticancer medicines. This study allowed adequate pharmacovigilance reporting and early identification of exceptional responses allowing further pediatric drug development within clinical trials; based on this experience, this study will be enlarged to the international level.

Will the End of the X-Waiver Expand Access to Buprenorphine Treatment? Achieving the Full Potential of the 2023 Consolidated Appropriations Act.

The 2023 Consolidated Appropriations Act repealed the special waiver for prescribing buprenorphine to patients with opioid use disorder, a bipartisan goal long sought by advocates. The change has symbolic importance in recognizing that buprenorphine is a mainstream medical treatment. We argue that the maximum potential of the law can be achieved by addressing three bottlenecks. First, it is important that new training requirements for all controlled substances prescribers be grounded in scientific principles of addiction treatment and are robustly evaluated to ensure they meet quality standards. Second, even with the elimination of the waiver, there are potential constraints from state law such as state-specific requirements that practitioners require counseling or obtain a separate credential, and many states also have limiting scope of practice regulations. We recommend that these requirements are eased wherever possible to improve treatment access. Third, it is critical to build onramps to treatment in settings such as primary care, hospitals, and correctional facilities. While we anticipate that buprenorphine prescribing will primarily occur in high-volume practices, there is the potential to activate a broader workforce to serve as entry points to care. We conclude that the stage is set for significant increases in lifesaving treatment but the difficult task ahead is ensuring that the resources and training are available to build strong capacity.

Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report

A genetically engineered pig cardiac xenotransplantation was done on Jan 7, 2022, in a non-ambulatory male patient, aged 57 years, with end-stage heart failure, and on veno-arterial extracorporeal membrane oxygenation support, who was ineligible for an allograft. This report details our current understanding of factors important to the xenotransplantation outcome. Physiological and biochemical parameters critical for the care of all heart transplant recipients were collected in extensive clinical monitoring in an intensive care unit. To ascertain the cause of xenograft dysfunction, we did extensive immunological and histopathological studies, including electron microscopy and quantification of porcine cytomegalovirus or porcine roseolovirus (PCMV/PRV) in the xenograft, recipient cells, and tissue by DNA PCR and RNA transcription. We performed intravenous immunoglobulin (IVIG) binding to donor cells and single-cell RNA sequencing of peripheral blood mononuclear cells. After successful xenotransplantation, the graft functioned well on echocardiography and sustained cardiovascular and other organ systems functions until postoperative day 47 when diastolic heart failure occurred. At postoperative day 50, the endomyocardial biopsy revealed damaged capillaries with interstitial oedema, red cell extravasation, rare thrombotic microangiopathy, and complement deposition. Increased anti-pig xenoantibodies, mainly IgG, were detected after IVIG administration for hypogammaglobulinaemia and during the first plasma exchange. Endomyocardial biopsy on postoperative day 56 showed fibrotic changes consistent with progressive myocardial stiffness. Microbial cell-free DNA testing indicated increasing titres of PCMV/PRV cell-free DNA. Post-mortem single-cell RNA sequencing showed overlapping causes. Hyperacute rejection was avoided. We identified potential mediators of the observed endothelial injury. First, widespread endothelial injury indicates antibody-mediated rejection. Second, IVIG bound strongly to donor endothelium, possibly causing immune activation. Finally, reactivation and replication of latent PCMV/PRV in the xenograft possibly initiated a damaging inflammatory response. The findings point to specific measures to improve xenotransplant outcomes in the future. The University of Maryland School of Medicine, and the University of Maryland Medical Center.

Results of the compassionate program of inotuzumab ozogamicin for adult patients with relapsed or refractory acute lymphoblastic leukemia in Spain.

The prognosis of relapsed B cell precursor acute lymphoblastic leukemia (B-ALL) is poor and few patients can be successfully rescued with conventional therapies. Inotuzumab ozogamicin (IO), an antibody against the CD22 antigen linked to calicheamicin, has been approved as a rescue treatment in relapsed/refractory (R/R) B-ALL. This was an observational, retrospective, multicenter study of adult patients included in the Spanish program of compassionate use of IO in centers from the PETHEMA group (Programa Español de Tratamientos en Hematología). Thirty-four patients with a median age of 43 years (range, 19-73) were included. Twenty patients (59%) were refractory to the last treatment, IO treatment was given as ≥3rd salvage treatment in 25 patients (73%) and 20 patients (59%) received allogeneic hematopoietic stem cell transplantation before IO treatment. After a median of 2 cycles of IO, 64% of patients achieved complete response (CR)/complete response with incomplete recovery. The median response duration, progression-free survival and overall survival (OS) were 4.7 (95%CI, 2.4-7.0 months), 3.5 (95%CI, 1.0-5.0 months) and 4 months (95%CI, 1.9-6.1 months) respectively, with better OS for patients with relapsed B-ALL versus refractory disease (10.4 vs. 2.5 months, respectively) (p = .01). There was a trend for better OS for patients with first CR duration >12 months (7.2 months [95%CI, 3.2-11.2] vs. 3 months [95% CI, 1.8-4.2] respectively) (p = .054). There was no sinusoidal obstruction syndrome (SOS) event during IO treatment, but three patients (9%) developed grade 3-4 SOS during alloHSCT after IO treatment. Our study showed slightly inferior outcomes of the pivotal trial probably due to poorer risk factors and late onset of IO therapy of recruited patients. Our results support early use of IO in relapsed/refractory ALL patients.

A pooled subgroup analysis of glucarpidase treatment in 86 pediatric, adolescent, and young adult patients receiving high-dose methotrexate therapy in open-label trials.

Delayed methotrexate elimination can occur in patients undergoing high-dose methotrexate cancer treatment. Effectiveness of glucarpidase for rapidly reducing methotrexate concentrations was shown in compassionate-use trials in patients aged 0-84years. We performed post hoc analyses of infants (≥28days to <2years), children (≥2 to <12years), adolescents (≥12 to <15years), and young adults (≥15 to <25years) from four multicenter, open-label, single-arm, glucarpidase compassionate-use trials. Patients had toxic methotrexate levels due to delayed methotrexate elimination and/or renal dysfunction, and received glucarpidase (50U/kg). The primary endpoint was clinically important reduction (CIR) in plasma methotrexate (methotrexate ≤1μmol/L at all post-glucarpidase measurements) based on high-performance liquid chromatography. Among 86 patients included in efficacy analyses, CIR was achieved by zero of one infant (0.0%), five of 16 children (31.3%), seven of 24 adolescents (29.2%), and 26/45 young adults (57.8%). Median methotrexate reduction was 98.7% or higher in each group 15minutes post-glucarpidase. Patients with pre-glucarpidase methotrexate less than 50μmol/L (35/42, 83.3%) were more likely to achieve CIR than those with methotrexate 50μmol/L or higher (1/37, 2.7%). The most common treatment-related adverse event was paresthesia, occurring in three adolescents (4.5%) and six young adults (5.2%). No other treatment-related adverse event occurred in 5% or higher of any age group. After accounting for pre-glucarpidase methotrexate levels, glucarpidase efficacy at inducing CIR in pediatric/young adult patients was consistent, with efficacy observed in the overall study population (i.e., patients aged 0-84), and no unexpected safety findings were observed. These findings demonstrate glucarpidase (50U/kg) is an effective and well-tolerated dose for pediatric, adolescent, and young adult patients.

Effect and Tolerance of N5 and N6 Chemotherapy Cycles in Combination with Dinutuximab Beta in Relapsed High-Risk Neuroblastoma Patients Who Failed at Least One Second-Line Therapy.

The anti-disialoganglioside (GD2) monoclonal antibody dinutuximab beta is approved for the maintenance treatment of high-risk neuroblastoma. Dinutuximab beta combined with different chemotherapy regimens is being investigated in various clinical settings. We conducted a retrospective clinical chart review of 25 patients with relapsed/refractory neuroblastoma who had failed ≥1 second-line therapy and received compassionate use treatment with dinutuximab beta long-term infusion combined with the induction chemotherapy regimens N5 (cisplatin, etoposide, vindesine) and N6 (vincristine, dacarbazine, ifosfamide, doxorubicin) recommended by the German Pediatric Oncology and Hematology Group [GPOH] guidelines. The treatment did not result in any unexpected severe toxicities or in any major treatment delays. Grade 3/4 pain was reported by 4/25 patients in cycle 1, decreasing to 0/9 patients in cycles 3 and 4. The median follow-up was 0.6 years. The best response in this group was 48% (12/25 patients), which included three patients with minor responses. At 1 year, the estimated event-free survival was 27% (95% confidence interval [CI] 8-47) and overall survival was 44% (95% CI 24-65). Combining long-term infusion of dinutuximab beta with N5 and N6 chemotherapy demonstrated an acceptable safety profile and encouraging objective response rates in heavily pretreated patients with high-risk neuroblastoma, warranting further evaluation in clinical trials.

A regulatory framework review of Schedule I psychedelics in the United States

AbstractPsychoactive substances such as psilocybin and 3,4‐methylenedioxy‐methamphetamine (MDMA) are currently being investigated for a variety of psychiatric indications including major depressive disorder and post‐traumatic stress disorder. It is critical that clinicians working in the mental health field understand the regulatory framework that balances access and control for such substances. While both psilocybin and MDMA are designated as “Breakthrough Therapy” by the Food and Drug Administration (FDA), they remain classified as Schedule I substances under the Controlled Substances Act (CSA) of 1970. There are programs such as Expanded Access (EA) and federal Right‐to‐Try (RTT) legislation that can accommodate patient access to investigational drugs under certain circumstances, but these programs are not without their limits—particularly for Schedule I substances that do not currently have an accepted medical use per the CSA. It is in the clinical community's best interest to understand the administrative procedures, key court cases, and federal legislative initiatives related to these substances in order to make well‐informed decisions for themselves and their patients. Furthermore, understanding the administrative proceedings related to controlled substances will also allow subject matter experts to participate in and shape the policies governing such substances.

Cefiderocol Treatment for Patients with Multidrug- and Carbapenem-Resistant Pseudomonas aeruginosa Infections in the Compassionate Use Program.

Cefiderocol is an option for infections caused by multidrug-resistant Pseudomonas aeruginosa, but its in vitro activity against these isolates and its clinical effectiveness for isolates with MICs of >1 μg/mL is unclear. We investigated the in vitro activity of cefiderocol against P. aeruginosa isolates collected from patients treated with cefiderocol through the compassionate use program and assessed physician-reported clinical response and 28-day all-cause mortality by cefiderocol MIC values. P. aeruginosa isolates underwent susceptibility testing to cefiderocol and comparator agents by using reference broth microdilution. U.S. Food and Drug Administration (FDA; susceptible, ≤1 μg/mL) and Clinical and Laboratory Standards Institute (CLSI; susceptible, ≤4 μg/mL) cefiderocol breakpoints were applied. Additionally, molecular characterization of β-lactamase genes was performed. Clinical response and vital status were reported by treating physicians. Forty-six patients with P. aeruginosa infections were evaluated. Twenty-nine (63%) and 42 (91%) isolates were susceptible to cefiderocol using FDA and CLSI breakpoints, respectively. Thirty-seven (80%) and 32 (70%) isolates were not susceptible to ceftolozane-tazobactam and ceftazidime-avibactam, respectively. The clinical response rate was 69% (20/29) with a cefiderocol MIC of ≤1 μg/mL, 69% (9/13) with a cefiderocol MIC of 2 to 4 μg/mL, and 100% (4/4) with an MIC of ≥8 μg/mL, while day 28 all-cause mortality rates were 23% (6/26; MIC ≤ 1 μg/mL), 33% (4/12; MIC, 2 to 4 μg/mL), and 0% (0/4; MIC ≥8 μg/mL), respectively. Cefiderocol was active in vitro against most P. aeruginosa isolated from patients with limited or no alternative therapies. Patients with cefiderocol MICs of 2 to 4 μg/mL did not have significantly worse outcomes than those with MICs of ≤1 μg/mL.