Forecasting the potential impact of cell and gene therapies in France: projecting product launches and patients treated.

Objective: To evaluate the potential impact of cell and gene therapies (CGTs) in France by forecasting the number of patients that will be treated with CGTs over the period 2023-2030 by therapeutic area and region. Methods: A review of CGTs in clinical development and related disease epidemiology was conducted to forecast the number of CGT launches and patient population between 2023 and 2030. The number of expected launches was identified by filtering the clinical development pipeline with estimated time to launch and probability of success values from Project ALPHA. Disease prevalence and incidence in France were combined with projected adoption rates derived from historical data to forecast the patient population to be treated. Results: Up to 44 new CGTs are forecasted to launch in France in the period 2023-2030, which translates into more than 69,400 newly treated patients in 2030. Leading indications in terms of newly treated patients per year include cardiovascular disease, hematological cancers and solid tumors with 27,300, 15,200 and 13,000 newly treated patients in 2030, respectively. Discussion: The forecast suggests that the future landscape of CGTs will undergo a shift, moving from CGTs targeting (ultra) rare diseases to more prevalent diseases. In France, this will likely pose organizational challenges hindering patient access to these transformative therapies. Further research and planning around network organization and patient distribution are needed to assess and improve the readiness of the French healthcare system for ensuring access for this growing number of patients to be treated with CGTs.

[Advanced therapy medicinal products' (ATMP) pharmaceutical circuit in France: Current situation and outlook]. / Circuit pharmaceutique du médicament de thérapie innovante (MTI) en France : état des lieux et perspectives.

OBJECTIVES: Advanced therapy medicinal products' reconstitution is an innovative pharmaceutical activity. The purpose of this work is to evaluate the current situation in France within hospital pharmacies. METHODS: An electronic questionnaire (90 questions) was sent to previously identified French pharmaceutical teams exploring advanced therapy medicinal products' reconstitution process in its various aspects. RESULTS: Thirty-eight pharmacists completed the survey. The ATMPs reconstitution is very largely carried out by pharmaceutical teams in charge of other activities, even if dedicated teams are beginning to appear. Gene therapy represents majority among advanced therapy medicinal products. The premises are very often shared, especially the controlled atmosphere areas. These vary greatly in nature, as do facilities used. The ultra-low temperature storage is most frequently used and the nitrogen equipment of hospital pharmacies is yet observed and tends to expand. Simple reconstitution processes (thawing, dilution) are mostly carried out in hospital pharmacies. The traceability still largely relies on different software and/or the use of paper formats. The reconstitution process needs devoted pharmaceutical time according to the active queues, sometimes exceeding 200 patients per year. FINDINGS: If the hospital pharmacists is going to take charge of this activity on a constant basis, the regulatory context and the increase in active queues will require a real investment plan from the public authorities in this activity to effectively implement ATMPs reconstitution to the greatest benefit of patients.

[Locally advanced or metastatic bladder cancer: Identification of barriers and levers of patients' pathway in France]. / Cancer de la vessie localement avancé ou métastatique : identification des freins et leviers du parcours des patients en France.

INTRODUCTION: Bladder cancer is currently ranked as the 8th most common cancer in France. However, the patient care pathway for this cancer is still not well known. METHODS: A telephone survey was conducted with fifteen healthcare professionals, ten patients, and five family caregivers between November 2020 and March 2021. The objectives of this survey were to identify the major steps in the care pathway according to the medical, emotional and societal dimensions, for patients with locally advanced or metastatic bladder cancer, the associated barriers, and the initiatives to be implemented to improve it. RESULTS: Several barriers were identified at different stages of the overall care pathway, including lack of knowledge of risk factors and warning signs of the disease by the general population and some healthcare professionals, difficulties linked to the announcement consultation, lack of psychological support for patients and their caregivers, and lack of information given about the disease and supportive care. DISCUSSION: These results allowed us to identify three major initiatives which could improve the overall care pathway and the quality of life of patients and their caregivers: 1/implementation of a public awareness campaign on bladder cancer; 2/creation of booklets for patients and their caregivers to provide them with a source of reliable information; and 3/the creation of communication tools between healthcare professionals and patients to facilitate exchanges during consultations.

Cancer, immune suppression and Coronavirus Disease-19 (COVID-19): Need to manage drug safety (French Society for Oncology Pharmacy [SFPO] guidelines).

The Coronavirus disease (COVID-19) pandemic is disrupting our health environment. As expected, studies highlighted the great susceptibility of cancer patients to COVID-19 and more severe complications, leading oncologists to deeply rethink patient cancer care. This review is dedicated to the optimization of care pathways and therapeutics in cancer patients during the pandemic and aims to discuss successive issues. First we focused on the international guidelines proposing adjustments and alternative options to cancer care in order to limit hospital admission and cytopenic treatment in cancer patients, most of whom are immunocompromised. In addition cancer patients are prone to polypharmacy, enhancing the risk of drug-related problems as adverse events and drug-drug interactions. Due to increased risk in case of COVID-19, we reported a comprehensive review of all the drug-related problems between COVID-19 and antineoplastics. Moreover, in the absence of approved drug against COVID-19, infected patients may be included in clinical trials evaluating new drugs with a lack of knowledge, particularly in cancer patients. Focusing on the several experimental drugs currently being evaluated, we set up an original data board helping oncologists and pharmacists to identify promptly drug-related problems between antineoplastics and experimental drugs. Finally additional and concrete recommendations are provided, supporting oncologists and pharmacists in their efforts to manage cancer patients and to optimize their treatments in this new era related to COVID-19.

Providing Oncology Pharmacy Services During the Coronavirus Pandemic: French Society for Oncology Pharmacy (Société Francaise de Pharmacie Oncologique [SFPO]) Guidelines.

PURPOSE: Patients with cancer are at higher risk for contracting the COVID-19 infection and are more likely to have higher morbidity and mortality. This is a big challenge for oncology teams that have to treat patients to avoid contamination by SARS-CoV-2. The aim of the current work is to present oncology pharmacy practice guidelines during the COVID-19 pandemic to secure the pharmaceutical care of patients with cancer. METHODS: The bureau of the French Society for Oncology Pharmacy proposed these recommendations according to the French High Authority of Health following the Guidelines of Good Practice, slightly modified according to the pandemic crisis situation. These guidelines were developed by a working group of 7 experts in oncology pharmacy practice. Furthermore, the guidelines were assessed by 31 independent reviewers. RESULTS: One hundred percent of reviewers approved the guidelines and 90% of them suggested some improvements. The final version incorporates the best comments and consists of 26 recommendations organized in 8 different sections. CONCLUSION: These guidelines allow secure pharmaceutical management of patients with cancer during the COVID-19 pandemic.

Efficacy and safety of autologous stem cell transplantation after induction therapy with lenalidomide, bortezomib, and dexamethasone.

OBJECTIVES: Recently, phase III trials assessed a new combination of lenalidomide, bortezomib, and dexamethasone (RVD) in induction therapy in transplantation-eligible multiple myeloma (MM) patients, before consolidation with RVD and lenalidomide maintenance. We present a retrospective study evaluating this approach with patients from the real life. METHODS: We conducted a retrospective single-arm study to assess efficacy and safety of RVD combination in induction therapy before high-dose chemotherapy with melphalan followed by autologous stem cell transplantation, and RVD consolidation followed by lenalidomide maintenance, from February 2011 to May 2016. RESULTS: Forty patients were enrolled. The mean age at diagnosis was 56 years. Median progression-free survival was 45 months, and median overall survival was 76 months. The only factor found associated with better PFS was a negative minimal residual disease (P < .01). Twenty-six (65%) patients experimented adverse events: 8 patients (20%) underwent 12 serious AE (≥grade 3). Treatment discontinuation occurred in 2 patients (5%) because of severe AE. CONCLUSION: To our knowledge, this work provides the first evidence of the efficacy and the safety of RVD combination in patients treated in common practice.

Thrombotic microangiopathy associated with gemcitabine use: Presentation and outcome in a national French retrospective cohort.

AIMS: Gemcitabine has been associated with thrombotic microangiopathy (TMA). We conducted a national retrospective study of gemcitabine-associated TMA (G-TMA). METHODS: From 1998 to 2015, all cases of G-TMA reported to the French Pharmacovigilance Network and the French TMA Reference Center, and cases explored for complement alternative pathway abnormalities, were analysed. RESULTS: G-TMA was diagnosed in 120 patients (median age 61.5 years), after a median of 210 days of treatment, and a cumulative dose of 12 941 mg m-2 . Gemcitabine indications were: pancreatic (52.9%), pulmonary (12.6%) and breast (7.6%) cancers, metastatic in 34.2% of cases. Main symptoms were oedema (56.7%) and new-onset or exacerbated hypertension (62.2%). Most patients presented with haemolytic anaemia (95.6%) and thrombocytopenia (74.6%). Acute kidney injury was reported in 97.4% and dialysis was required in 27.8% of patients. Treatment consisted of: plasma exchange (PE; 39.8%), fresh frozen plasma (21.4%), corticosteroids (15.3%) and eculizumab (5.1%). A complete remission of TMA was obtained in 42.1% of patients and haematological remission in 23.1%, while 34.7% did not improve. The survival status was known for 52 patients, with 29 deaths (54.7%). Patients treated with PE, despite a more severe acute kidney injury, requiring dialysis more frequently, displayed comparable rates of remission, but with more adverse events. No abnormality in complement alternative pathway was documented in patients explored. CONCLUSION: This large cohort confirms the severity of G-TMA, associated with severe renal failure and death. Oedema and hypertension could be monitored in patients treated with gemcitabine to detect early TMA. The benefit of PE or eculizumab deserves further investigation.

From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer.

PURPOSE: Nanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo. MATERIALS AND METHODS: Immunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging. RESULTS: In vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado-trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB-453 and MDA-MB-231 bearing mice. When compared to free docetaxel + free trastuzumab, tumor growth was reduced by 89% (MDA-MB-453) and 25% (MDA-MB-231) and reduced by 66% (MDA-MB-453) and 29% (MDA-MB-231) when compared to T-DM1, an observation in line with data collected from 3D spheroids experiments. CONCLUSION: We demonstrated the predictivity of 3D in vitro models when developing and testing nanoparticles in experimental oncology. In vitro and in vivo data showed efficient drug delivery with higher efficacy and prolonged survival with immunoliposomes when compared to current anti-Her2 breast cancer strategies.

Recurrent extraneural sonic hedgehog medulloblastoma exhibiting sustained response to vismodegib and temozolomide monotherapies and inter-metastatic molecular heterogeneity at progression.

BACKGROUND: Response to targeting and non-targeting agents is variable and molecular information remains poorly described in patients with recurrent sonic-hedgehog-driven medulloblastoma (SHH-MB). MATERIALS AND METHODS: Clinical and PET/CT findings during treatment with successive hedgehog antagonists and temozolomide monotherapies are described in a heavily pre-treated patient with recurrent extraneural metastases from PTCH1 mutated/ wild type smoothened (SMO) CNS SHH-MB. Molecular tests were prospectively performed in tissue from two extraneural sites at progression. RESULTS: Sustained clinical/metabolic response was obtained to vismodegib. At progression, itraconazole was ineffective, but salvage temozolomide treatment results in a response similar to vismodegib. At further progression, acquired SMO and PIK3CA mutations were identified in bone (G477L and H1047A, respectively) and epidural (L412P and H1065L, respectively) metastases. No response was observed with subsequent sonidegib treatment. CONCLUSIONS: This is the first clinical report of recurrent extraneural PTCH1 mutated SHH-MB exhibiting: 1) a sustained response to vismodegib and temozolomide, and 2) inter-metastatic molecular heterogeneity and acquired SMO-G477L, SMO-L412P, and PIK3CA-H1065L mutations at progression, highlighting the need for a multitarget treatment approach.

Acute myositis: an unusual and severe side effect of docetaxel: a case report and literature review.

Docetaxel is an antimicrotubules cytotoxic agent prescribed widely by medical oncologists in multiple tumor types (breast, lung, prostate, stomach, head, and neck). However, the side effects of docetaxel are numerous (cytopenia, peripheral edema, myalgia, arthralgia, alopecia, and sensitive neuropathy) and recent concerns have been raised about neutropenic enterocolitis in France. Here, we report the case of a 57-year-old patient with metastatic prostatic cancer, who developed a severe myositis and fasciitis grade IV 1 week after his second docetaxel infusion. We reviewed the five cases of docetaxel-related myositis described in the literature, and found that most of them occurred in patients with diabetes (n=5/5) or hypertension (n=4/5). A vascular toxicity may explain this severe complication, and patients with diabetes or hypertension should be monitored closely in the context of a docetaxel chemotherapy.

A simple and rapid LC-MS/MS method for therapeutic drug monitoring of cetuximab: a GPCO-UNICANCER proof of concept study in head-and-neck cancer patients.

Administration of first-in-class anti-EGFR monoclonal antibody cetuximab is contingent upon extensive pharmacogenomic testing. However in addition to tumor genomics, drug exposure levels could play a critical, yet largely underestimated role, because several reports have demonstrated that cetuximab pharmacokinetic parameters, in particular clearance values, were associated with survival in patients. Here, we have developed an original bioanalytical method based upon the use of LC-MS/MS technology and a simplified sample preparation procedure to assay cetuximab in plasma samples from patients, thus meeting the requirements of standard Therapeutic Drug Monitoring in routine clinical practice. When tested prospectively in a pilot study in 25 head-and-neck cancer patients, this method showed that patients with clinical benefit had cetixumab residual concentrations higher than non-responding patients (i.e., 49 ± 16.3 µg/ml VS. 25.8 ± 17 µg/ml, p < 0.01 t test). Further ROC analysis showed that 33.8 µg/ml was the Cmin threshold predictive of response with an acceptable sensitivity (87%) and specificity (78%). Mass spectrometry-based therapeutic drug monitoring of cetuximab in head-and-neck cancer patients could therefore help to rapidly predict cetuximab efficacy and to adapt dosing if required.

Safe Cytotoxic Drug Preparation Using Closed-system Transfer Device: Technical and Practical Evaluation of a New Device (Vialshield/Texium) Comparatively to a Reference One (Phaseal).

Closed-system transfer devices enhance the drug handlers' protection against hazardous drugs exposure by prohibiting the escape of liquid or vapor from the system. PhaSeal (Becton Dickinson), a reference closed-system transfer device, includes a vial protector with an expansion chamber, and an injector with an enclosed needle. VialShield (CareFusion) is another more recent closed-system transfer device including an expansion-chamber and a non-return valve, designed to be used in association with Texium (CareFusion), a closed, needle-free male luer with its preassembled syringe. Evaluation of VialShield/Texium was done comparatively to a classic spike device (Spike Swan, Codan) and PhaSeal. Evaluation methods consisted in practical evaluation by pharmacy technicians (evaluation of ease to use by nine operators in practical conditions during a complete week of production), microbiological safety performance (by Media Fill Test), and leakage assessment (fluorescein, titanium tetrachloride smoke, and radioactive tracer). Results showed that 100% of those operators evaluated would be ready to use VialShield/Texium for daily use, whereas only 75% of them would be ready to use PhaSeal. The use of PhaSeal and VialShield/Texium increased the duration of preparations compared to Spike Swan. No microbiological growth was observed with any of the three devices. A leakage of smoke was observed only with Spike Swan. Fluorescein leakage assessment confirmed that PhaSeal is a performing closed system with a dry connection. Spike Swan showed fluorescein leaks. Fluorescein drops were visible on the connection sites of the VialShield/Texium. Nevertheless, no fluorescein was found on compress after connections swapping. Transfer performance, assessed using technetium-99m, was 98.1 ± 1.4%, 97.9 ± 1.1% and 97.0 ± 1.3% and dead volume of the devices, were 1.0 ± 0.8%, 1.7 ± 0.6%, and 3.0 ± 1.1% for Spike Swan, PhaSeal, and VialShield/Texium, respectively. VialShield/Texium appeared as a very interesting device with performances close to PhaSeal (except dry connection), with a higher satisfaction assessment from the operators.

Stability of a highly concentrated solution of epirubicin for conventional transcatheter arterial chemoembolization.

INTRODUCTION: Epirubicin is widely used for conventional transcatheter arterial chemoembolization (cTACE) in patients with hepatocellular-carcinoma. However, there is no data about its stability in solution at concentration higher than 2 mg/L, yet needed when mixing it with a standard volume of Lipiodol(®) to produce an efficient water-in-oil emulsion. The aim of this study was therefore to evaluate the stability of a highly concentrated solution of epirubicin for cTACE and verify whether epirubicin solution could be prepared in advance. MATERIALS AND METHODS: Fifty milligrams of epirubicin were dissolved in 6 mL of 0.9% sodium chloride and conditioned in brown polypropylene syringe. Physical and chemical stability assays including particles and HPLC-DAD analysis were performed in triplicate, using series of 5 syringes stored over 72 h at 4±2 °C followed by 4h at 22±4°C. RESULTS: Neither weight loss nor pH or spectrum change occurred. No haze or turbidity was observed and the number of subvisible particles was below the recommended limits. Epirubicin concentration remained above 95% of the initial value over the 72 h of storage at +4 °C followed by 4h at 22±4 °C and no degradation was observed. CONCLUSION: Epirubicin at 50mg/6 mL in 0.9% NaCl conditioned in brown propylene syringe is stable for at least 72 h at 4±2 °C with additional 4h at 22±4 °C allowing its preparation in advance for programmed cTACE and the standardization of its use in clinical practice.

[Pertinence of Off-label Prescriptions of Innovating and Expensive Drugs in a University Hospital]. / Pertinence des prescriptions « hors AMM/RTU ¼ des molécules onéreuses dans un hôpital universitaire.

OBJECTIVES: Pertinence of off-label prescriptions of innovative and expensive drugs needs a strict scientific appraisal to prevent adverse reaction risks and financial drift. METHODS: Pertinence of such prescriptions has been analyzed in a University Hospital by bibliometric methods. Scientific publications issued from this clinical activity have been also evaluated. RESULTS: Oncology differed from other clinical specialties by a better pertinence in justifying off-label prescriptions (good evidence level in 46% vs. 21%, scientific publications issued from A/B ranked journals: 51% versus 41%). Quality of scientific production from oncologists was also better (publication impact factor [IF] mean: 4.571 versus 2.245). CONCLUSIONS: The better pertinence of off-label prescriptions by oncologists in comparison to others clinicians' ones was mainly due to a shorter field of indications but also to a more efficient organisation such as systematic prescription by seniors, dedicated computerized provider order entry, multidisciplinary team meetings and collaborative culture.