[CAR-T CELLS: How does the EBMT registry monitor European activities, identify hurdles and prepare for changes in regulations]. / CAR-T cells : comment le registre de l'EBMT monitore les activités en Europe, identifie les contraintes et prépare l'évolution des régulations.

CAR-T Cells are gene therapy medicinal products, a subcategory of Advanced Therapy Medicinal Products as defined in the EC Regulation 1394/2007. They may represent the first example of such medicinal products that are industry-manufactured and commercialized on a large scale. Their very nature, their manufacturing processes, pricing and conditions upon which they were approved by regulatory agencies, all lead the latter to require long-term follow-up after marketing approval with a view for a better definition of CAR-T Cells safety profile and efficacy profile in real world conditions. Collection and analysis of data over a 15-year period of time represents a technical and political challenge. So does the a priori definition of data to be collected for a wealth of forthcoming analyses that focus on the interests of a variety of stakeholders. EBMT has been collecting and analyzing data on hematopoietic cell transplants for decades. EBMT currently works with many interested parties to collect data on patients treated with CAR-T Cells.

[Place of coordination of complex pathways in oncology by coordinating private nurses]. / Place d'une coordination de parcours complexes en cancérologie par des infirmiers libéraux coordinateurs.

BACKGROUND: The complexity of the hospital-city care pathway is a real challenge because of the lack of coordination and communication between many stakeholders. As part of a call for projects from the General Directorate of Healthcare Provision, an experiment involving private oncology coordinating nurses was developed to address this issue. To our knowledge, there is no evaluation so far of such a protocol . METHODS: This single-center retrospective study focused on data from the ONC'IDEC program between 2015 and 2018, where 28 private nurses provided a 24/7 hotline. The objective was to qualitatively assess the coordination of this system. The nature and number of calls, patient satisfaction and medico-economic parameters were assessed. RESULTS: More than a hundred patients (n=114) were included in this device (mean age: 72 ± 12 years). The most frequent reasons for calls concerned the patient's general condition (35 %) and home treatment follow-ups (13 %) but also referrals to the primary doctor (4 %), which helped avoiding hospitalizations. The patients were satisfied with the experiment (overall score of 8.4/10). DISCUSSION: Thanks to the ONC'IDEC program, patients were able to benefit from more appropriate care through a privileged interlocutor by making their care pathway more fluid and avoiding hospitalizations. It would be interesting to confirm these results by means of a study with a higher level of evidence, by comparing this protocol to conventional hospital coordination.

Development of a disease-specific graded prognostic assessment index for the management of sarcoma patients with brain metastases (Sarcoma-GPA).

BACKGROUND: Brain metastases from sarcomatous lesions pose a management challenge owing to their rarity and the histopathological heterogeneity. Prognostic indices such as the Graded Prognostic Assessment (GPA) index have been developed for several primary tumour types presenting with brain metastases (e.g. lung, breast, melanoma), tailored to the specifics of different primary histologies and molecular profiles. Thus far, a prognostic index to direct treatment decisions is lacking for adult sarcoma patients with brain metastases. METHODS: We performed a multicentre analysis of a national group of expert sarcoma tertiary centres (French Sarcoma Group, GSF-GETO) with the participation of one Canadian and one Swiss centre. The study cohort included adult patients with a diagnosis of a bone or soft tissue sarcoma presenting parenchymal or meningeal brain metastases, managed between January 1992 and March 2012. We assessed the validity of the original GPA index in this patient population and developed a disease-specific Sarcoma-GPA index. RESULTS: The original GPA index is not prognostic for sarcoma brain metastasis patients. We have developed a dedicated Sarcoma-GPA index that identifies a sub-group of patients with particularly favourable prognosis based on histology, number of brain lesions and performance status. CONCLUSIONS: The Sarcoma-GPA index provides a novel tool for sarcoma oncologists to guide clinical decision-making and outcomes research.

[Requirements for academic production of CAR-T cells in accordance with Good Pharmaceutical Practice (GMP). Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Prérequis pour une production académique des cellules CART conforme aux bonnes pratiques pharmaceutiques (BPF). Recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

The extraordinary and unexpected success of cellular immunotherapy using genetically engineered T-cells to express a chimeric antigen receptor (CAR) targeting CD19, in the treatment of refractory or relapsing B-hematological malignancies, has provided a real therapeutic hope. Indeed, remission rates reach more than 80 % in patients at a stage, without any other possibilities of treatment, notably in the child's acute lymphoblastic leukemia. These results, initially resulting from academic research, led to Food and Drug accreditation for market access of two innovative autologous therapy drugs, Kimryah® and Yescarta®. Based on the impressive clinical results, mainly so far in hematological malignancies (LAL, MM, LBDGC, etc.), the development of several types of cells expressing a CAR receptor suggests a wide range of future applications, particularly in the field of solid tumors. However, while the development of CAR-T cells now appears to be in the hands of private pharmaceuticals companies, the logistical constraints, the cryopreservation and the very high cost of these personalized medicines may ultimately limit their use. The development of academic productions by CAR-T cells could bypass some of these disadvantages. The strong innovation capacity of healthcare institutions associated with research units allows them to identify the ideal tumor target and efficient performing cells. Thus, authorized production platforms could allow for shorter administration times and reasonable production costs for national health systems. The aim of this workshop is to identify the requirements for the academic production of CAR-T cells, while respecting the research standards useful to establish proof of concept, but also at the preclinical development stage, leading in fine to the manufacture, through an authorized pharmaceutical establishment, of the innovative therapy drug, and in accordance with Good Manufacturing Practice (GMP). The ultimate goal is to make these innovative and high-performance medicines available to as many patients as possible.

[Bisphosphonate and denosumab-related osteonecrosis of the jaw: Epidemiology, diagnosis and management]. / Ostéonécrose des maxillaires liée aux bisphosphonates et denosumab : épidémiologie, diagnostic et traitement.

Bisphosphonate-related osteonecrosis of the jaw have been widely described. Denosumab has recently been associated to ONJ. Guidance to clinicians is based on criteria established by the American Association of Oral and Maxillofacial Surgeons (AAOMS). Treatment should be multidisciplinary. Two options are available and have to be discussed on the basis of associated therapeutic, patient's general state of health and possibility of therapeutic window during cancer treatment: conservative (medication and conservative surgery like superficial debridement) and extensive surgery. Therefore, we report an update about management strategies of osteonecrosis of the jaw and two cases of patients with a stage 2 osteonecrosis of the jaw only treated with mouth rinses, antibiotics and debridement and complete healing.

[Impact of depressive disorders on adherence to oral anti-cancer treatment]. / Impact de la dépression sur l'adhésion aux traitements anticancéreux oraux.

The improper adherence to therapy is an emerging medical and economic issue in oncology which raised with the increasing use of oral anti-cancer treatment. Currently, the average rate of non-adherence to oral anti-cancer therapy is estimated at around 21%. In this study, we use the examples of the imatinib treatment against chronic lymphocytic leukemia and the tamoxifene treatment against breast cancer to assess the negative consequences of the non-adherence to therapy in terms of medical outcome and health care cost. One of the main causes of non-adherence to these oral cancer treatments is depression. Surprisingly, this aspect is still relatively unknown to oncologists, while depression has been taken into account for the treatment of other chronic diseases (e.g. diabetes…). We therefore propose that cancer patients should be screened for depression throughout their treatment to improve the adherence to therapy. Cancer patients should have the opportunity to explain their own perception of their disease and their treatment that are key parameters in the onset of depression. The recent use of oral therapy in cancer treatment should thus be accompanied by the establishment of a global management of cancer patient on a case-by-case basis.

Cost effectiveness of pegfilgrastim versus filgrastim after high-dose chemotherapy and autologous stem cell transplantation in patients with lymphoma and myeloma: an economic evaluation of the PALM Trial.

BACKGROUND: Use of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) filgrastim accelerates neutrophil recovery following myelosuppressive chemotherapy. Since filgrastim requires multiple daily administrations, forms of rhG-CSF with a longer half life, including pegfilgrastim, have been developed. Pegfilgrastim is safe and effective in supporting neutrophil recovery and reducing febrile neutropenia after conventional chemotherapy. Pegfilgrastim has also been successfully used to support patients undergoing peripheral blood stem cell (PBSC) transplantation for haematological malignancies. To our knowledge, no cost-effectiveness analysis (CEA) of pegfilgrastim in this setting has been published yet. OBJECTIVE: We undertook a CEA to compare a single injection of pegfilgrastim versus repeated administrations of filgrastim in patients who had undergone PBSC transplantation for lymphoma or myeloma. The CEA was set in France and covered a period of 100 ± 10 days from transplant. METHODS: The CEA was designed as part of an open-label, multicentre, randomized phase II trial. Costs were assessed from the hospital's point of view and are expressed in 2009 euros. Costs computation focused on inpatient, outpatient, and home care. Costs in the two arms of the study were compared using the Mann-Whitney test. When differences were statistically significant, multiple regression analyses were performed in order to identify cost drivers. Incremental cost-effectiveness ratios (ICER) were calculated for the major endpoints of the trial; i.e., duration of febrile neutropenia (absolute neutrophil count [ANC] <0.5 × 10(9)/L and temperature ≥38 °C), duration of neutropenia (ANC <1.0 × 10(9)/L and ANC <0.5 × 10(9)/L), duration of thrombopenia (platelets <50 × 10(9)/L and <20 × 10(9)/L), and days with a temperature ≥38 °C). Uncertainty around the ICER was captured by a probabilistic analysis using a non-parametric bootstrap method. RESULTS: 151 patients were enrolled at ten French centres from October 2008 to September 2009. The mean total cost in the pegfilgrastim arm of the study (n = 74) was 25,024 (SD 9,945). That in the filgrastim arm (n = 76) was 28,700 (SD 20,597). Pegfilgrastim strictly dominated filgrastim for days of febrile neutropenia avoided, days of neutropenia (ANC <1.0 × 10(9)/L) avoided, days of thrombopenia (platelets <20 × 10(9)/L) avoided, and days with temperature ≥38 °C) avoided. Pegfilgrastim was less costly and less effective than filgrastim for the number of days with ANC <0.5 × 10(9)/L avoided and the number of days with platelets <50.0 × 10(9)/L avoided. Taking uncertainty into account, the probabilities that pegfilgrastim strictly dominated filgrastim were 67 % for febrile neutropenia, 86 % for neutropenia (ANC <1.0 × 10(9)/L), 59 % for thrombopenia (platelets <20 × 10(9)/L), 86 % for temperature ≥38 °C, 32 % for neutropenia (ANC <0.5 × 10(9)/L), and 43 % for thrombopenia (platelets <50 × 10(9)/L). Conversely, the probability that filgrastim strictly dominated pegfilgrastim for neutropenia (ANC <0.5 × 10(9)/L) is 5 %. CONCLUSION: This study found no evidence that the use of pegfilgrastim is associated with greater cost in lymphoma and myeloma patients after high-dose chemotherapy and PBSC transplantation.

In vitro assessment of cytotoxic agent combinations for hormone-refractory prostate cancer treatment.

We have investigated new drug combinations of potential clinical value for treatment of hormone-refractory prostate cancer. Combinations of paclitaxel, carboplatin and mitoxantrone, and combinations of these three drugs with compounds targeting important pathways for cancer progression, 13-cis-retinoic acid and chelerythrine, were assessed. The drugs combinations were incubated for 72 h in steroid-free conditions with two androgen-independent cell lines, DU145 and PC3. Cytotoxicity assay was performed using resazurin and Hoescht 33342. Synergism and antagonism were measured by the combination index, and calculated for each combination by the median-effect method. All six compounds exhibited cytotoxic effects when tested alone. Paclitaxel exhibited the highest and 13-cis-retinoic acid the lowest effect on both cell lines. Paclitaxel demonstrated synergism or additivity with 13-cis-retinoic acid in both cell lines, whereas antagonistic effects were observed when it was tested in combination with carboplatin. Chelerythrine showed additive effects with mitoxantrone in both cell lines and with paclitaxel in PC3 cells. Our results suggest that combination of paclitaxel and 13-cis-retinoic acid, and of chelerythrine with mitoxantrone and paclitaxel, may have clinical value for the treatment of hormone-refractory prostate cancer.