Jhonghe, Taiwan

French Observational Study of Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in Real-World Settings

Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in the Western World. The disease is characterized by the accumulation and proliferation of mature, monoclonal, CD5+ B-cells with specific immunophenotype in the peripheral blood (above 5x109/L), bone marrow and secondary lymphoid organs. Small lymphocytic leukemia (SLL) is characterized by similar tumor cells but without increased lymphocyte count. In Europe, CLL has been identified as the second most frequent hematological malignancies after multiple myeloma (Eurocare 5 study) and its standardized incidence in the world has been estimated to be 4/100000 person-years for men and 2.1/100000 person-years for women. In France, 4674 new cases have been observed in 2018 (FRANCIM). A proportion of patients can initially be monitored only while others with symptomatic disease at diagnosis or during follow-up require therapies. The management of these patients have considerably changed over the last decade. Indeed, beyond chemo-immunotherapy, multiple targeted therapies have been approved on the basis of phase 2 and randomized phase 3 clinical trials and have subsequently been used in daily practice. The management of patients with SLL is similar to that of those with CLL. In addition to therapeutic advances, the advent of new sequencing technologies has also identified CLL genetic features that are now being incorporated in patient routine evaluation. Conventional chemo-immunotherapy (CIT) has been the long-standing option for CLL patient without TP53 disruption and different regimens have emerged depending on patient comorbidities (fludarabine-cyclophosphamide-rituximab, FCR; bendamustin-rituximab, BR; GA101-chloraminophene, G-CLB). These regimens fail to be effective in patients with TP53 disruption and alternative strategies are proposed for them. The CLL therapeutic panel is now enriched by oral kinase inhibitors targeting the B-cell receptor signaling. The Bruton's tyrosine kinase inhibitors (BTKi) have been shown to provide prolonged response, even in cases where CIT usually failed, such as patients harboring TP53 disruption. In relapsed/refractory patients, median PFS with the BTKi ibrutinib is 44 months. In the frontline setting, ibrutinib has recently been shown to result in superior PFS and less infectious complications than standard CIT regimens. The advent of the BCL2 (B-cell lymphoma 2) inhibitor venetoclax has recently added another option for the treatment of CLL patients. BCL2 is an antiapoptotic molecule governing mitochondrial apoptosis and is strongly expressed in CLL cells. Inhibiting BCL2 with venetoclax as monotherapy led to 79% response rate in the relapse/refractory setting. Combining venetoclax to rituximab demonstrated better PFS than bendamustine-rituximab in relapsed/refractory patients. However, these treatment approaches also come with new challenges that are difficult to-address in phase 3 clinical trials and that deserve larger scale studies and longer follow-up. The emergence of drug resistance, the changes of safety profiles to deal with in routine practice and the observance of these orally administered drugs are emerging as new concerns. How these compounds change the incidence of typical CLL complication such as Richter transformation, immune cytopenias and infections remains to be determined. A growing body of concerns is also raising regarding the unlimited administration of some of this the compounds (costs, resistance, tolerance). Finally, the optimal order of use of these drugs is unknown. The advent of the BCL2 (B-cell lymphoma 2) inhibitor venetoclax has recently added another option for the treatment of CLL patients 11,12. BCL2 is an antiapoptotic molecule governing mitochondrial apoptosis and is strongly expressed in CLL cells. Inhibiting BCL2 with venetoclax as monotherapy led to 79% response rate in the relapse/refractory setting. Combining venetoclax to rituximab demonstrated better PFS than bendamustine-rituximab in relapsed/refractory patients12. However, these treatment approaches also come with new challenges that are difficult to-address in phase 3 clinical trials and that deserve larger scale studies and longer follow-up. The emergence of drug resistance, the changes of safety profiles to deal with in routine practice and the observance of these orally administered drugs are emerging as new concerns. How these compounds change the incidence of typical CLL complication such as Richter transformation, immune cytopenias and infections remains to be determined. A growing body of concerns is also raising regarding the unlimited administration of some of this the compounds (costs, resistance, tolerance). Finally, the optimal order of use of these drugs is unknown. Primary objective : Setting a prospective cohort of real-world CLL/SLL patients with symptomatic disease in order to evaluate medical practices and their change and representativity over time. Secondary objectives : Overall survival and long-term toxicity, Response and PFS at each line of therapy, Impact of therapeutic trajectories on patient outcome, Representativity of the studied population

SAPHIR : Assessment of Predictive Factors for Persistence of Treatment After Initiation of Adalimumab With a Biosimilar (Adalimumab Fresenius KaBI or Substitution of Reference Adalimumab With the Fresenius Kabi Adalimumab Biosimilar in Patients With Chronic Inflammatory Diseases

In a population of adult patients who are targeted to initiate adalimumab or previously treated with Humira® to get switched to a biosimilar (FK adalimumab) and followed up for a period of 12 months under routine medical practice conditions. - Primary objective: to define predictive factors for the persistence of treatment - Secondary objectives: - To assess the therapeutic benefit and the tolerability of the treatment - To describe the reasons for treatment discontinuations occurring during follow-up

Mean Arterial Pressure After Out-of-hospital Cardiac Arrest

Evaluation of the Ambulatory Medical Assistance Nurse Program in Chronic Lymphocytic Leukemia

This research is a prospective randomized multicenter comparative study in 2 parallel groups (1: 1) : patients benefiting from the ambulatory medical assistance nurse program in addition to conventional care versus patients benefiting from conventional care. For each patient, data will be collected during 2 years.

A Clinical-biological Prospective Cohort of Patients With BRAFV600E-mutated Metastatic Colorectal Cancer

Despite substantial progress made in the first- and second line mCRC settings, there are still unmet clinical needs for patients harboring BRAFV600E mutations, especially those with microsatellite stability (MSS) / proficient mismatch repair (pMMR) tumor. The overall survival and access to different treatment in the real-life setting are unknown. Moreover, patient prognosis remains poor and therapeutic resistance to combinations with BRAF inhibitors, is at present, nearly universal. Therefore, it seems essential to prospectively collect clinical and biological data about this rare mCRC subtype. These data will allow us to improve knowledge and to identify clinical and biological factors that could drive therapeutic decisions, predict resistance to treatments, and that are prognostic for survival. In this context, we designed this large, prospective, cohort study to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with BRAFV600E mCRC. This collection of clinical and biological data (tumor tissue and blood samples) will allow us to identify predictive and prognostic biomarkers with several research work packages planned: i. To evaluate the circulating tumor DNA (ctDNA) during the metastatic first-, second-, and third-line treatment to: - Evaluate its positive and negative predictive value. - Identify molecular alterations preceding and explaining clinical resistance during BRAF/EGFR inhibition therapy and immunotherapy. ii. To evaluate BRAFV600E mCRC immune environment both at the tumor and blood level (immunomonitoring). iii. To study specific the dMMR/MSI BRAFV600E subgroup. Furthermore, the data collected will describe the therapeutic management of BRAFV600E mCRC patients in the routine-practice setting which will bring very useful data. The results of the COBRAF study could lay the groundwork to better understand BRAFV600E mCRC and to identify prognostic and predictive biomarkers helping the development of new therapeutic approaches in this population.

Neoadjuvant and Adjuvant Ribociclib and ET for Clinically High-risk ER+ and HER2- Breast Cancer

All patients will receive letrozole plus ribociclib as neoadjuvant therapy. Treatment will consist of six 28-days cycles of daily letrozole (2.5mg; continuous) and ribociclib (600 mg/day; 3 weeks ON and 1 week OFF). In pre-menopausal and men patients, monthly LHRH agonists will be added to letrozole and ribociclib, beginning at least two weeks before starting letrozole and ribociclib. After finalization of neoadjuvant treatment, patients will undergo surgery. Surgery samples of the residual tumor tissue (or tumor bed if pathological complete response [pCR] is achieved) will be collected regardless of whether they completed full neoadjuvant treatment. This is not a randomized study; therefore, adjuvant treatment will be decided according to centrally assessed ROR and pathological stage after surgery. Patients are considered responders if they achieve a pCR or have ypN0 and ROR ≤ 30 or ypN1mi (cancer the lymph node is > 0.2 mm but < 2 mm) and ROR ≤ 20 or ypN1 and ROR ≤ 10. All patients with ypN0 and ROR > 30, ypN1mi and ROR > 20, ypN1 and ROR > 10 or ypN2-3 are considered non-responders. Patients who progress during neoadjuvant treatment with ribociclib will be considered non-responders. If indicated, adjuvant radiotherapy will be performed after surgery in the responder group and after adjuvant chemotherapy in the non-responders group. Patients considered as responders will continue on treatment after optimal recovery of surgery and radiotherapy if indicated. Treatment with ribociclib (400 mg/day; 3 weeks ON and 1 week OFF) in the adjuvant setting will be maintained for 30 months approximately corresponding to 33 cycles. Letrozole treatment duration must be of at least 5 years. Visits during ribociclib treatment will be scheduled every three cycles. At the end of ribociclib treatment, visits will be every 6 months until 5 years from last patient's surgery. Patients considered as non-responders will be treated with standard chemotherapy regimens. Patients will continue treatment with ribociclib and letrozole after optimal recovery of adjuvant chemotherapy and radiotherapy if indicated. Treatment with ribociclib (400 mg/day; 3 weeks ON and 1 week OFF) in the adjuvant setting will be maintained for 30 months approximately corresponding to 33 cycles after adjuvant chemotherapy. Endocrine therapy treatment duration must be of at least 5 years. Visits during ribociclib treatment will be scheduled every three cycles. At the end of ribociclib treatment, visits will be every 6 months until 5 years from last patient's surgery. During adjuvant treatment (both responders and non-responders), letrozole can be switched to another aromatase inhibirtor (AI). Tamoxifen is only permitted after the 30-day post ribociclib visit, according to investigator criteria. Maintaining suppression of ovarian function by luteinizing hormone releasing hormone (LHRH) agonists during adjuvant treatment is mandatory (if AI are taken)/ recommended (if tamoxifen is taken) in premenopausal and men patients unless there is unmanageable toxicity. Adjuvant hormonal treatment of patients who progress during neoadjuvant Ribociclib will be at the investigator's discretion. Blood samples for ctDNA will be collected at screening, C2D1, pre-surgery, post-surgery, and every 6 months during the adjuvant period. Blood samples will be also collected in case of recurrence. The global end of the study is defined as the date when the last patient accomplishes 5 years of follow up after surgery. The total duration of the study is expected to be 32 months for enrollment, 3 years of adjuvant treatment (including 2.5 years of ribociclib treatment), and additional 2.5 years of follow-up.

Diagnostic Performance of Spot Urine Sample for the Monoclonal Components Detection in Patients With Multiple Myeloma

To evaluate the detection sensitivity of the urinary monoclonal component on a spot urine sample, compared to the reference measurement on 24-hour urine, in Multiple Myeloma patients. 300 evaluable patients are required. For each of them, both spot urine sample and 24h urine sample will be collected at Cycle1 Day1, Cycle 2 Day 1 and Cycle 4 Day 1. The detection of urine monoclonal component will be performed by urine protein electrophoresis (quantitative) and urine immunofixation (qualitative).

AVAJAK: Apixaban/Rivaroxaban Versus Aspirin for Primary Prevention of Thrombo-embolic Complications in JAK2V617F-positive Myeloproliferative Neoplasms

Analysis of Biological Characteristics of Advanced ALK-rearranged NSCLC

BioEXALK is a prospective study evaluating the biological characteristics of advanced ALK-rearranged NSCLC treated with new generation TKIs in first line, included in the national EXPLORE ALK cohort (GFPC 03-2019). Explore ALK GFPC 03-2019 is a non-interventional, national, multi-center cohort of ALK-rearranged NSCLC patients, whose RCB reference is 2020-A00771-38 and which obtained an approval from the IDF II Ethic Committee on 25/05/2020. Biological analysis will be performed on tissue at diagnosis and at the time of disease progression when available and on circulating tumor DNA (ctDNA) on three timepoints (diagnosis, at first tumor evaluation and at the time of disease progression). - Tissue : RNAseq will be performed on tumor biopsy (10 slides of 5 microns) to identify the ALK fusion partner and its variant and associated co-mutations.. - ctDNA : NGS panel on DNA including a large panel of fusions and mutations will be performed on blood samples (30mL on EDTA or STRECKs tubes) at diagnosis, at the time of the first evaluation and at the time of progression). For plasma testing, after obtained patient consent, blood samples (35mL on EDTA or STRECKs tubes) at diagnosis, at the first evaluation and at disease progression will be taken. The ALKis include alectinib and brigatinib as first-line therapy or other drugs with marketing authorizations (lorlatinib, entrectinib) or in early access programs (EAPs). Liquid biopsies will be analyzed with a NGS panel allowing the identification of ALK fusion partners and resistance mechanisms (mutations, fusions, copy number variations). Samples will be sent for centralized analysis to the Léon Bérard Center (Lyon). For biological analysis on tissue obtained at diagnosis, the ALK fusion partner and its variant will be identified by RNAseq. Whenever a tissue re-biopsy is performed at the time of disease progression as part of the standard of care management of the patient, the remaining tissue sample will be collected as part of the BioExALK study, so that RNAseq analysis will be performed to look for resistance mechanisms. Tissue samples (10 slides of 5 microns) will be sent for centralized analysis to the Rouen University Hospital.

Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis Collection