Hypereosinophilic syndrome response to mepolizumab in the setting of a compassionate use program.

Mepolizumab, an anti-interleukin-5 antibody, has been proven a safe and effective glucocorticoid-sparing drug for many patients with non-clonal hypereosinophilic syndrome (HES) and is now approved in many countries. It remains unclear however which patients are most likely to benefit from therapy and whether the currently approved dosing regimen is appropriate for all. This observational retrospective study included all HES patients who were enrolled in the MHE104317 compassionate use program (CUP) in our center. Patient and disease characteristics, mepolizumab dosing, and both clinical and hematological responses to treatment were collected from medical files. Treatment responses and mepolizumab dosing requirements were analyzed according to disease characteristics. Eighteen HES patients were enrolled in the CUP, of which 9 are still on treatment. The median duration of exposure to mepolizumab was 45 months (maximum 18 years). A lower number of affected organs, requirement for glucocorticoid dosing ≤10 mg prednisone-equivalent, and single-organ HES were associated with a higher likelihood of complete response. Lymphocytic variant (L-) HES was less treatment-responsive, leading to withdrawal and/or requiring higher mepolizumab dosing to achieve some degree of disease control. In contrast, all patients with single-organ disease had a complete response that could often be maintained despite increasing between-dose intervals. Few potentially treatment-related adverse events were observed despite prolonged exposure. This study confirms the efficacy and safety of mepolizumab in HES, although patients with L-HES rarely experience a complete response. In contrast, patients with single-organ disease affecting the lungs are often super-responders, and decreasing mepolizumab dosing may be attempted.

The impact of expanded access programs for systemic anticancer therapy in an Irish cancer centre.

BACKGROUND: Expanded access programs (EAPs) allow cancer patients with unmet clinical need to obtain access to pre-authorisation treatments. There is no standardised process for implementing these programs nationally, and real-world data on their impact is lacking. AIMS: This study aimed to evaluate the prevalence of such EAPs and their impact in a cancer centre. METHODS: Data relating to adult cancer patients treated via EAPs from 2011 to 2021 in three Cork university hospitals was collated. Descriptive statistics were employed to get an overview of the impact these programs currently have on cancer care provision. RESULTS: We identified 193 patients who accessed EAPs during the study period, availing of 33 separate drugs for a total of 50 different cancer indications. The prevalence of EAP usage was shown to have been trending upwards in recent years with a total of 189 programs being accessed throughout the period. Drugs provided were from a number of different anti-cancer drug classes, particularly targeted therapies (n = 18) and immune checkpoint inhibitors (n = 17). Cancers from a wide range of both solid and liquid tumour types were treated with EAP drugs, and patients treated were from across a broad spectrum of ages (26-82, SD 11.99). CONCLUSIONS: EAPs have an increasing role in accessing novel cancer therapies in our community and by extension nationally. Equity of EAP access would be facilitated by a national registry of available agents which we have established. Assessment of their benefits and toxicities would be enhanced by the requirement for a real-world database as a condition of EAP approval.

Outcomes of pirtobrutinib for relapsed/refractory mantle cell lymphoma in compassionate use program in Europe.

BACKGROUND: Mantle cell lymphoma (MCL) is a type of B-cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real-world data are scarce. METHODS: In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP). RESULTS: On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow-up of 8.6 months, the mean duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented. CONCLUSIONS: In summary, pirtobrutinib represented a safe and effective treatment option in a small real-world population.

Long-Term Survival and Immune Response Dynamics in Melanoma Patients Undergoing TAPCells-Based Vaccination Therapy.

Cancer vaccines present a promising avenue for treating immune checkpoint blockers (ICBs)-refractory patients, fostering immune responses to modulate the tumor microenvironment. We revisit a phase I/II trial using Tumor Antigen-Presenting Cells (TAPCells) (NCT06152367), an autologous antigen-presenting cell vaccine loaded with heat-shocked allogeneic melanoma cell lysates. Initial findings showcased TAPCells inducing lysate-specific delayed-type hypersensitivity (DTH) reactions, correlating with prolonged survival. Here, we extend our analysis over 15 years, categorizing patients into short-term (<36 months) and long-term (≥36 months) survivors, exploring novel associations between clinical outcomes and demographic, genetic, and immunologic parameters. Notably, DTHpos patients exhibit a 53.1% three-year survival compared to 16.1% in DTHneg patients. Extended remissions are observed in long-term survivors, particularly DTHpos/M1cneg patients. Younger age, stage III disease, and moderate immune events also benefit short-term survivors. Immunomarkers like increased C-type lectin domain family 2 member D on CD4+ T cells and elevated interleukin-17A were detected in long-term survivors. In contrast, toll-like receptor-4 D229G polymorphism and reduced CD32 on B cells are associated with reduced survival. TAPCells achieved stable long remissions in 35.2% of patients, especially M1cneg/DTHpos cases. Conclusions: Our study underscores the potential of vaccine-induced immune responses in melanoma, emphasizing the identification of emerging biological markers and clinical parameters for predicting long-term remission.

Long-term treatment of hereditary transthyretin amyloidosis with patisiran: multicentre, real-world experience in Italy.

BACKGROUND: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP. METHODS: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed. RESULTS: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m2; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged. CONCLUSIONS: Patisiran largely stabilised disease in patients with ATTRv amyloidosis.

Effects of Religious Versus Non-religious Self-compassion Interventions on Anxiety and Quality of Life of Iranian Infertile Women: A Randomized Controlled Trial.

Anxiety is one of the common psychological problems among infertile women, which affects their quality of life. The purpose of this study was to compare the effects of self-compassion intervention based on a religious and non-religious perspective regarding the anxiety and quality of life of infertile women. A randomized clinical trial design with experimental and control groups was used. A total of 78 infertile women who lived in Yazd province, Iran, were referred to Yazd reproductive sciences institute, were selected by available sampling and randomly assigned to two experimental and one control groups. The participants of the first experimental group received eight sessions of self-compassion-focused intervention based on religious instructions. The second experimental group received eight sessions of non-religious self-compassion intervention, while the control group was put on the waiting list. Data were collected using Quality of Life in Infertile Couples Questionnaire (QOLICQ) and Beck anxiety inventory (BDI) in the pretest, posttest and 2-month follow-up phases and then analyzed using repeated measures as well as one-way analysis of variance. The results showed as compared to control group at the posttest and follow-up phases, the quality of life (p < 0.001) and anxiety (p < 0.001) of infertile women increased and decreased, respectively, across both experimental groups. Comparison of experimental groups showed that although the difference between the two groups in the subscales of social relationships and sexual satisfaction was not significant, the gain scores of quality of life and anxiety were significantly greater in the first experimental group. These findings indicate that given the religious background of infertile women, religious self-compassion intervention can be relatively more effective in improving the quality of life and anxiety of infertile women than non-religious intervention.

Global Risdiplam Compassionate Use Program for Patients with Type 1 or 2 Spinal Muscular Atrophy.

PURPOSE: Spinal muscular atrophy (SMA) is a genetic neuromuscular disease causing progressive muscle weakness and reducing life expectancy. Risdiplam (Evrysdi; Genentech/F. Hoffmann-La Roche Ltd, Basel, Switzerland) is a drug approved for use in the treatment of patients with SMA. The ongoing global risdiplam Compassionate Use Program (CUP), initiated in November 2019, is the largest CUP in SMA, currently providing access to risdiplam for >2000 patients with type 1 or 2 SMA in 59 countries. Here, the challenges and learnings from the risdiplam CUP are presented. METHODS: Enrolled patients (aged ≥2 months) had type 1 or 2 SMA and no alternative treatment options (ie, they were not medically eligible for approved SMA treatments, were unable to continue their SMA treatment due to medical reasons, were at risk for lack/loss of SMA treatment efficacy, or did not qualify for/had no access to SMA treatment within a clinical trial). Requests were made by the treating physicians via an end-to-end system. FINDINGS: The risdiplam CUP highlighted the importance of collaborating with patient advocacy groups early to learn about patients' perspectives on unmet medical needs, understanding the sometimes-unique nature of local regulations and requirements, and adapting physician- and patient-eligibility criteria. Key learnings were obtained from enrolling patients from low- to middle-income countries and from countries without dedicated Compassionate Use regulations, and from operating the CUP during the coronavirus disease 2019 pandemic. IMPLICATIONS: The risdiplam CUP experience was successful in many ways and may help to design and implement future CUPs in rare diseases, as well as patients living in countries or in circumstances in which access to innovative treatments is a challenge.

Evaluation of a pharmacist-led workflow for the FDA Expanded Access Program.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: This project aimed to characterize the resources necessary for pharmacists to support the required steps for obtaining and handling investigational drugs outside of a study protocol in the individual patient and intermediate-size population Expanded Access Program (EAP) processes. The second aim was to characterize the types of EAP requests received. SUMMARY: This retrospective, single-center, observational study was performed by reviewing EAP requests initiated at Duke University Hospital (DUH) between August 1, 2017, and February 11, 2023. The annualized cost of unreimbursed EAP study services was projected to be approximately $196,500 at DUH for 2023. Of the 168 EAP requests submitted after the institutional policy requiring pharmacy and therapeutics (P&T) committee approval was established, 162 (96.4%) were approved by the P&T committee. CONCLUSION: Given the lack of published information on a pharmacist-led workflow related to EAP services, this study sought to share DUH's process for managing EAP requests. As there is no mechanism for reimbursement of EAP services, they can be difficult to manage given the labor resources required. Further work is needed to recoup unreimbursed investigational drug service labor costs to ensure compassionate use programs can be implemented in a manner that is financially sustainable for a health system.

US state laws on medical freedom and investigational stem cell procedures: a call to focus on state-based legislation.

The premature marketing of investigational stem cell interventions (SCIs) is a growing market in the US. Several US states have passed legislation to permit and promote unproven and experimental SCIs for individuals with terminal or chronic diseases. These SCI medical freedom laws, which are largely based on right-to-try legislation, increase access to experimental SCIs with little to no oversight. They undermine federal regulatory authority and can compromise patient safety and informed decision-making. SCI medical freedom laws have gone largely unnoticed by scientific societies interested in the responsible translation of stem cell medicine. In this article, we analyze state SCI medical freedom laws and describe their detrimental impact on patients and society. We contend that scientific and medical societies are uniquely poised to advocate against state-based policy promoting unproven SCIs but recognize resource and other constraints to advocate for or against legislation in 50 states. We recommend societies establish coalitions and share resources to address state-based SCI medical freedom laws and other legislation surrounding unproven SCIs.

Compassionate use of contezolid in a toddler with severe community-acquired pneumonia induced by staphylococcus aureus: a case report and follow-up.

Background: Initial choices of antimicrobial therapy for most cases of community-acquired pneumonia (CAP) in children under 5 years of age are typically based on local epidemiology, risk factors assessment, and subsequent clinical parameters and positive cultures, which can lead to the underdiagnosis and underestimation of lung infections caused by uncommon pathogens. Contezolid, an orally administered oxazolidinone antibiotic, gained approval from the National Medical Products Administration (NMPA) of China in June 2021 for managing complicated skin and soft tissue infections (cSSTI) caused by staphylococcus aureus (SA), streptococcus pyogenes, or streptococcus agalactis. Owing to its enhanced safety profile and ongoing clinical progress, the scope of contezolid's clinical application continues to expand, benefiting a growing number of patients with Gram-positive bacterial infections. Case summary: In this report, we present the first use of contezolid in a toddler with severe CAP caused by SA, aiming to avoid potential adverse drug reactions (ADRs) associated with vancomycin and linezolid. Conclusion: Although contezolid has not been officially indicated for CAP, it has been shown to be effective and safe in the management of SA-induced severe CAP in this toddler, suggesting its potential as an alternative option in the dilemma, especially for patients who are susceptible or intolerant to ADRs associated with first-line anti-methicillin-resistant staphylococcus aureus (MRSA) antimicrobial agents.

Treating Treatment-resistant Depression with Esketamine Nasal Spray When All Therapeutic Options Have Been Exhausted: Clinical Experience from a Spanish Cohort of Expanded Use.

Objective: : Treatment Resistant Depression (TRD) is commonly defined as the lack of response to two or more anti-depressants with different mechanisms of action. Up to 30% of patients diagnosed with major depressive disorder might be considered to present TRD. The objective of this study was to assess the effectiveness and tolerability of esketamine in patients diagnosed with TRD, who were referred to our program after exhausting all available treatments. A secondary objective consisted in researching the relationship between response and previous use of electroconvulsive therapy. Methods: : A prospective, observational study was carried out in patients enrolled in the expanded use of esketamine in our center. They received esketamine prior to its marketing authorisation, for therapeutic purposes. Sixteen subjects were analyzed. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS). Patients were followed up to 4 months after the administration. Results: : Esketamine showed a rapid, robust effect in improving depressive symptoms, with no specific correlation between outcome and any demographic or clinical traits evaluated. No differences were found between patients that previously received Electroconvulsive Therapy, and those that didn't. 10 out of 16 patients responded (＞ 50% change in baseline MADRS scores), but only five achieved remission (＜ 12 points in the global MADRS score). We provide some recommendations, based on clinical experience, to improve tolerability and adherence, and to manage adverse effects. Conclusion: : Results suggest that esketamine is a safe, effective and rapid-acting option for TRD. More studies are needed to properly assess predictors of response outcome.

Addressing the needs of people with extensively drug-resistant TB through pre-approval access to drugs and research.

Multiple therapeutic options exist for people with drug-resistant TB (DR-TB), but there is an urgent need to improve access to novel compounds and regimens for people with difficult to treat forms of TB. In additional to formal research studies and clinical trials, other mechanisms of accessing promising new TB compounds need to be introduced as soon as these drugs have shown efficacy and safety in phase II trials. Pre-approval access programs for newer TB drugs such as bedaquiline, delamanid, and pretomanid all suffered from shortcomings. These can be addressed for the next generation of new TB drugs through a series of concerted actions by stakeholders at multiple levels. In this viewpoint, we advocate for transparent, accessible pre-approval access as a core element of person-centered care for DR-TB.

Il existe de nombreuses options thérapeutiques pour les personnes atteintes de TB résistante aux médicaments (DR-TB), mais il est urgent d'améliorer l'accès aux nouvelles molécules et aux nouveaux schémas thérapeutiques pour les personnes atteintes de formes de TB difficiles à traiter. Outre les études de recherche formelles et les essais cliniques, d'autres mécanismes d'accès aux nouvelles molécules prometteuses contre la TB doivent être mis en place dès que ces médicaments ont démontré leur efficacité et leur innocuité lors des essais de phase II. Les programmes d'accès avant approbation pour les nouveaux médicaments contre la TB tels que la bédaquiline, le delamanid et le pretomanid ont tous souffert de lacunes. Ces problèmes peuvent être résolus pour la prochaine génération de nouveaux médicaments contre la TB grâce à une série d'actions concertées entre les parties prenantes à différents niveaux. Dans cette optique, nous préconisons un accès transparent et accessible avant approbation, en tant qu'élément central des soins centrés sur la personne pour la DR-TB.

Efficacy and safety of compassionate use for rare diseases: a scoping review from 1991 to 2022.

BACKGROUND: Compassionate use is a system that provides patients with expedited access to drugs which has not yet been approved, but currently in clinical trials. The investigational drugs have been authorized for compassionate use in cases involving patients suffered from life-threatening diseases and with no alternative treatments. For instance, patients afflicted with highly heterogeneous rare diseases are eligible for treatment assistance through the compassionate use program. This study aims to investigate the characteristics of compassionate use in the context of rare diseases, evaluate the efficacy and safety of compassionate use for rare diseases, and analyze the marketing approval of investigational drugs. METHODS: The case reports/case series of compassionate use were collected by conducting searches on Embase, PubMed, Web of Science, CNKI and SinoMed, spanning from January 1991 to December 2022. Subsequently, two independent reviewers evaluated these reports. Case reports/case series that met the inclusion criteria and exclusion criteria were enrolled. Information extracted from these reports and series included patients' basic information, the investigational drug's name, its indication, adverse events, treatment outcomes, and other relevant data. RESULTS: A total of forty-six studies were included, encompassing 2079 patients with an average age of 38.1 years. Thirty-nine different drugs were involved in 46 studies. Furthermore, neoplasms emerged as the most common therapeutic area for compassionate use in rare disease management (23/46, 50.0%). Regarding the treatment efficacy, four studies reported successful disease resolution, while 35 studies observed symptom improvement among patients. Conversely, four studies documented no significant effects on patients' diseases. Moreover, one study reported worsened results following compassionate use, while the efficacy was not described in 2 studies. Adverse events were reported in 31 studies (67.4%) because of the compassionate use, while no adverse events occurred in 13 studies (28.3%). In other 2 studies, there was no description about whether treatment-emergent adverse events (TEAEs) were happened. 136 patients (6.5%) had Grade 5 adverse events (death), of which 19 deaths (0.9%) were considered to be related to compassionate use. Furthermore, the investigational drugs in 33 studies (33/46, 71.7%) received new drug approval at the end of January 31, 2023.The time lag from the start of the compassionate use to the formal approval of the investigational drug was 790.5 (IQR 359-2199.3) days. We found that in 11 studies, encompassing 9 different drugs, some compassionate use indications had not received regulatory authorities at the end of January 31, 2023. CONCLUSION: The current status of compassionate use for rare diseases was clarified systematically in this study. Compassionate use of investigational drug is a significant treatment option for rare disease. In general, compassionate use appears to demonstrate favorable efficacy in the context of rare diseases, with a significant proportion of compassionate use drugs subsequently receiving marketing approval. However, the safety of drugs for compassionate use cannot be fully evaluated due to the safety data were not covered in some enrolled studies. Therefore, the establishment of an adverse event reporting system specific to compassionate use is warranted.

Taking AIM at serious illness: implementing an access to investigational medicines expanded access program.

When seriously ill patients have exhausted all treatment options available as part of usual care, the use of investigational agents may be warranted. Food and Drug Administration's (FDA) Expanded Access (EA) pathway provides a mechanism for these patient's physicians to pursue use of an investigational agent outside of a clinical trial when trial enrollment is not a feasible option. Though FDA has recently implemented processes to significantly streamline the regulatory portion of the process, the overall pathway has several time-consuming components including communication with the pharmaceutical company and the associated institutional requirements for EA use (contracting, Institutional Review Board [IRB], pharmacy, billing). Here, we present our experience building infrastructure at the Vanderbilt University Medical Center (VUMC) to support physicians and patients in pursuing EA, called the Access to Investigational Medicines (AIM) Platform, aligning the needs and responsibilities of institutional stakeholders and streamlining to ensure efficiency and regulatory compliance. Since its launch, the AIM team has experienced steady growth, supporting 40 EA cases for drugs/biologics, including both single patient cases and intermediate-size EA protocols in the emergent and non-emergent setting. As the EA pathway is a complex process that requires expert facilitation, we propose prioritizing EA support infrastructure at major academic medical centers as an essential regulatory knowledge function.

Expanded access to investigational drugs in psychiatry: A systematic review.

Some psychiatric patients have exhausted all approved treatment options. Numerous investigational drugs are currently being developed and tested in clinical trials. However, not all patients can participate in clinical trials. Expanded access programs may provide an opportunity for patients who cannot participate in clinical trials to use investigational drugs as a therapeutic option outside of clinical trials. It is unknown to what extent expanded access occurs in psychiatry. We conducted a systematic literature search on PubMed, Embase, and PscyInfo, with additional information from ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and FDA/EMA approvals, in order to find all expanded access programs ever conducted, globally, in the field of psychiatry. This resulted in a total of fourteen expanded access programs ever conducted in psychiatry. Given the prevalence of psychiatric disorders, the activity in clinical research in psychiatry, the regulatory framework enabling expanded access, and the impact of psychiatric disorders on patients, their families, and society, we had expected a higher utilization of expanded access. We propose that the psychiatric community, with pharmaceutical industry, should consider establishing and optimizing expanded access programs.

Applying real-world data from expanded-access ("compassionate use") patients to drug development.

Our drug development process has produced many life-saving medications, but patients experiencing rare diseases and similar conditions often are left with limited options for treatment. For an approved treatment to be developed, research on a new candidate or existing drug must validate safety and efficacy based on contemporary research expectations. Randomized clinical trials are conducted for this purpose, but they are also costly, laborious, and time-consuming. For this reason, The 21st Century Cures Act mandates that the US Food and Drug Administration look for alternative methods for approving drugs, in particular exploring the uses of real-world data and evidence. Expanded access ("compassionate use") is a pathway for the clinical treatment of patients using drugs that are not yet approved for prescribing in the United States. Using real-world evidence generated from expanded-access patients presents an opportunity to provide critical data on patient outcomes that can serve regulatory approval in conjunction with other observational datasets or clinical trials, and in limited circumstances may be the best data available for regulatory review. In doing so, we may also support and encourage patient-centered care and a personalized medicine approach to drug development.

CAR-T State of the Art and Future Challenges, A Regulatory Perspective.

This review is an outlook on CAR-T development up to the beginning of 2023, with a special focus on the European landscape and its regulatory field, highlighting the main features and limitations affecting this innovative therapy in cancer treatment. We analysed the current state of the art in the EU and set out a showcase of the field's potential advancements in the coming years. For this analysis, the data used came from the available scientific literature as well as from the European Medicines Agency and from clinical trial databases. The latter were investigated to query the studies on CAR-Ts that are active and/or relevant to the review process. As of this writing, CAR-Ts have started to move past the "ceiling" of third-line treatment with positive results in comparison trials with the Standard of Care (SoC). One such example is the trial Zuma-7 (NCT03391466), which resulted in approval of CAR-T products (Yescarta™) for second-line treatment, a crucial achievement for the field which can increase the use of this type of therapy. Despite exciting results in clinical trials, limitations are still many: they regard access, production, duration of response, resistance, safety, overall efficacy, and cost mitigation strategies. Nonetheless, CAR-T constructs are becoming more diverse, and the technology is starting to produce some remarkable results in treating diseases other than cancer.

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.

PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

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 ß-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.