Clinical trial NCT05590702: French Observational Study of Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in Real-World Settings
Official title: French Observational Study of Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in Real-World Settings
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: CLL/SLL
Lead sponsor: French Innovative Leukemia Organisation
Sponsor class: OTHER
Collaborators: name: AbbVie
name: AstraZeneca
name: BeiGene
name: Janssen-Cilag Ltd.
First posted: 2022-10-21
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patient with CLL or SLL requiring a therapeutic strategy according to iwCLL criteria or investigator evaluation will be identified in MCM (multidisciplinary collegial meeting).

Brief summary: 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. 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.

We here propose to set a large-scale prospective and non-interventional study including patients with symptomatic CLL/SLL with the aim to evaluate the real-world clinical management of these patients and to identify the impact of treatments and therapeutic trajectories on long-term outcome.

Detailed description: 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

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18-year old
* CLL or SLL requiring a therapeutic strategy according to iwCLL criteria or investigator evaluation
* Patient requiring therapy for immune events (autoimmune Thrombocytopenia and autoimmune hemolytic anemia) are eligible
* Patients who have been informed verbally and in writing about this study, and who do not object to their data being electronically processed or subjected to data quality control
* All consecutive patients for whom a discussion in the setting of local or regional multidisciplinary collegial meeting (in french : réunion de concertation pluridisciplinaire / RCP) has retained the need for starting a therapeutic strategy (curative or palliative)
* Patients with untreated or previously treated CLL/SLL are both eligible
* Patients enrolled in a clinical trial can be included in this non-interventional cohort study
* Patients requiring therapy for CLL/SLL-associated immune events only are also eligible

Exclusion Criteria:

* Patients with no need of therapy
* Patients with asymptomatic Binet A CLL
* Patient with Richter's syndrome at inclusion
* Patient requiring immunoglobulin substitution (with no need of a more specific therapy)

Primary outcomes:
measure: Representativity of CLL therapies and sequences across
timeFrame: 7-year period of time
Secondary outcomes:
measure: Overall survival
timeFrame: 7 years
measure: Long-term toxicity
timeFrame: 7 years
Other outcomes:
Locations:
city: Amiens
country: France
facility: AMIENS - CH Amiens Picardie Site Sud
city: Angers
country: France
facility: Angers Chu
city: Annecy
country: France
facility: ANNECY - CH Annecy Genevois
city: Argenteuil
country: France
facility: ARGENTEUIL - Centre hospitalier Victor Dupouy
city: Avignon
country: France
facility: AVIGNON - Centre Hospitalier
city: Besançon
country: France
facility: BESANCON - Hôpital Jean Minjoz
city: Blois
country: France
facility: BLOIS CH
city: Bobigny
country: France
facility: APHP - Hôpital Avicenne
city: Bondy
country: France
facility: APHP - Hôpital Jean Verdier
city: Bourgoin-Jallieu
country: France
facility: BOURGOUIN-JALLIEU - CH Pierre Oudot
city: Brest
country: France
facility: BREST - Hôpital Morvan - Hématologie Clinique
city: Béziers
country: France
facility: BEZIERS - Centre Hospitalier - Hématologie
city: Caen
country: France
facility: CAEN - IHBN - Hématologie Clinique
city: Cergy-Pontoise
country: France
facility: CERGY PONTOISE - CH René Dubos
city: Chambéry
country: France
facility: CHAMBERY - CH Métropole Savoie
city: Clermont-Ferrand
country: France
facility: Clermont-Ferrand - Chu Estaing
city: Corbeil-Essonnes
country: France
facility: Corbeil-Essonnes - Chsf
city: Dijon
country: France
facility: Dijon Chu
city: Grenoble
country: France
facility: GRENOBLE GHM - Institut Daniel Hollard
city: Grenoble
country: France
facility: Grenoble - CHUGA - Hématologie Clinique
city: La Roche-sur-Yon
country: France
facility: La Roche Sur Yon - Chd Vendee
city: Le Mans
country: France
facility: Le Mans CH
city: Lens
country: France
facility: LENS - GHT Artois
city: Libourne
country: France
facility: LIBOURNE - Hôpital Robert Boulin
city: Lille
country: France
facility: LILLE GHICL - Hôpital Saint Vincent de Paul
city: Lille
country: France
facility: LILLE CHU - Hôpital Claude Huriez
city: Limoges
country: France
facility: LIMOGES - CHU Dupuytren 1
city: Lyon
country: France
facility: LYON-Centre Léon Bérard
city: Metz
country: France
facility: METZ-THIONVILLE CHR- Hôpital de Mercy
city: Montpellier
country: France
facility: MONTPELLIER - Hôpital Saint-Eloi - Hématologie Clinique
city: Morlaix
country: France
facility: MORLAIX - CH des pays de Morlaix
city: Mulhouse
country: France
facility: Mulhouse - Ghrmsa
city: Nantes
country: France
facility: NANTES - Hôpital Hôtel Dieu - Hématologie Clinique
city: Nîmes
country: France
facility: NIMES - CHU Caremeau
city: Orléans
country: France
facility: ORLEANS - CHR - Hématologie
city: Paris
country: France
facility: APHP - HOPITAL COCHIN - Hématologie
city: Paris
country: France
facility: APHP - Hôpital Pitié Salpêtrière - Hématologie
city: Perpignan
country: France
facility: PERPIGNAN - CH St Jean - Hématologie Clinique
city: Pessac
country: France
facility: Bordeaux Pessac
city: Pierre-Bénite
country: France
facility: LYON HCL - CH Lyon Sud
city: Périgueux
country: France
facility: Perigueux - Ch
city: Quimper
country: France
facility: QUIMPER - CH de Cornouaille
city: Reims
country: France
facility: Reims Chu
city: Rennes
country: France
facility: RENNES - CHU Pontchaillou - Hématologie Clinique
city: Rennes
country: France
facility: RENNES - Hôpital Pontchaillou - Hématologie
city: Rouen
country: France
facility: ROUEN - Centre Henri Becquerel - Service Hématologie Clinique
city: Saint-Brieuc
country: France
facility: SAINT-BRIEUC - Hôpila Yves Le Foll
city: Saint-pierre
country: France
facility: La Reunion - Gh Site Sud
city: Saint-Priest-en-Jarez
country: France
facility: ST ETIENNE - CHU et Institut De Cancérologie Lucien Neuwirth
city: Strasbourg
country: France
facility: Strasbourg - Icans
city: Toulouse
country: France
facility: Toulouse - IUCT Oncopole - Service d'Hématologie
city: Tours
country: France
facility: TOURS - Hôpital Bretonneau
city: Troyes
country: France
facility: Troyes Ch
city: Vandœuvre-lès-Nancy
country: France
facility: NANCY - CHU Brabois
city: Vannes
country: France
facility: Vannes - Chba
city: Versailles
country: France
facility: VERSAILLES - Hôpital André Mignot
city: Villejuif
country: France
facility: Villejuif Igr
Study officials:
affiliation: French Innovative Leukemia Organisation
name: Romain GUIEZE
role: PRINCIPAL_INVESTIGATOR
affiliation: French Innovative Leukemia Organisation
name: Xavier TROUSSARD
role: STUDY_CHAIR
References: