Diffuse Low Grade B-Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma, Primary Mediastinal Large B-cell Lymphoma (PMBCL)
Conditions
Keywords
CAR-T, Lymphoma
Brief summary
The goal of this observational study on chimeric antigen receptor T-cell therapy is to monitor the feasibility, efficacy, toxicity and biomarkers in a real life setting. Partecipants will be asked to agree to their clinical data collection and to partecipate to the optional biological study that aims to evaluate biomarkers of toxicity and response (clinical characteristics, cytokine profile, cellcomposition and type of the CAR-T cell product, lymphoma genomics). The study will evaluate even the disease response according to lugano criteria by PET and CT in routine clinical activity.
Detailed description
This observational prosopective multicenter study aims to: 1. evaluate the feasibility of CAR T-cell treatment in the real-life setting, with particular regard to eligible patients versus those subjected to leukapheresis versus those finally treated. 2. evaluate the survival outcome of PMBCL, DLBCL, MCL and FL patients treated with CAR T-cells versus those potentially eligible, but excluded from cellular therapy for other causes (either related to the patient or to the manufacturing); 3. monitor the incidence of early and late AEs up to three year after CAR-T; 4. evaluate disease response and immune recovery biomarkers at different time-points up after CAR-T (when clinically indicated or using blood sampling leftover); 5. evaluate biomarkers of toxicity and response (clinical characteristics, cytokine profile, cell composition and type of the CAR T-cell product, lymphoma genomics). 6. evaluate disease response according to Lugano criteria by PET and CT in routine clinical activity. Primary Objective: • Feasibility and efficacy of the treatment in the real life practice Secondary Objectives: * Evaluation of Outcome \[Response rate (ORR), Overall survival (OS), Progression free survival (PFS), duration of response (DoR) non-relapse mortality (NRM)\] according to Lugano criteria. * Evaluation of safety (CRS, neurotoxicity, infections, cytopenias, B cell aplasia, second malignancies) with particular attention to the safety in the new indications * Evaluation of bridging therapy (outcome and safety) * Evaluation of salvage therapy after CAR-T failure (outcome and safety) * Comparison of the different CAR T-cell products (time from patient screening to infusion, disease response and safety) * Comparison of the different histotypes (PMBCL, DLBCL, MCL FL) according to CAR-T cell products Biological Studies * Characterization of biomarkers of early response (circulating tumor cell free DNA versus PET and CT scans) * Characterization of toxicity biomarkers * Analysis of the immune reconstitution and CAR-T expression Radiomics Evaluation * Influence of PET quantitative parameters (tMTV, Distance max, Distance max bulky, metabolic changes between baseline and +30 and +90 after CAR T-cell infusion (ΔSUV max) on outcome * Influence of PET quantitative parameters (tMTV, Distance max, Distance max bulky, metabolic changes between baseline and +30 and +90 after CAR T-cell infusion (ΔSUV max) on outcome. Primary endpoint: to evaluate the percentage of patients infused versus those eligible and leukoapheresed to evaluate the overall response and survival at one year of the patients treated with CAR T cells. Secondary endpoints: Overall response rate (ORR) at 3-6-12-18 months Overall survival (OS) for all patients included in the study OS, Progression free survival (PFS), Event free survival (EFS), and duration of response (DoR), non-relapse mortality (NRM) after CAR T-cell therapy at one,two years and 5 years Incidence and grading of CRS and neurotoxicity Number of patients receiving a bridging therapy before lymphodepletion Intensive Care Unit admission rate for all treated patients Lymphoma genomics and circulating cell free DNA as early response biomarker Characterization of toxicity biomarkers Analysis of immune reconstitution and CAR-T expression Early Adverse event (grading/onset/severity/treatment) Long term Safety (AE grading/onset/severity/treatment) Incidence of second malignancies Evaluation of quantitative parameters of PET by central review, when applicable in selected sites This is an observational multicenter prospective study enrolling all consecutive patients referred to the Italian hematologic centers already qualified for CAR T-cell treatment with relapsed/refractory DLBCL, PMBCL, MCL and FL. The screening will be done according to the axi-cel, tisagen-cel, brexucabtagene autoleucel and lisocabtagene maraleucel label criteria, the eligibility of a given patient to CAR-T will be definedaccording to AIFA criteria. All patients eligible to CAR-T will be consecutively enrolled Biological samples will be stored at each institution or centralized at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milano. Fondazione Italiana Linfomi (FIL) will be in charge of the GCP management of the study. Web-based CRF are prepared by FIL.
Interventions
None listed
Sponsors
Annalisa Chiappella
Cristiana Carniti
Anna Dodero
Paolo Corradini
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with diagnosis of DLCBL, PMBCL, MCL and FL eligible for CAR-T treatment with commercialy available products in Italy.
Exclusion criteria
* Not applicable
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of the CAR-T cells treatment in lymphomas in the italian real life practice | 10 years enrollment, minimum 1 year follow-up | Evaluate the feasibility of CAR T-cell treatment in the real-life setting, with particular regard to eligible patients versus those subjected to leukapheresis versus those finally treated. The percentage of patients infused will be estimated as the number of patients infused divided by the total number of those declared eligible; the corresponding exact confidence intervals at 95% will also be estimated. |
| Efficacy of the CAR-T cells treatment in lymphomas in the italian real life practice | 10 years enrollment, minimum 1 year follow-up | Evaluate the survival outcome of PMBCL, DLBCL, MCL and FL patients treated with CAR T-cells versus those potentially eligible, but excluded from cellular therapy for other causes (either related to the patient or to the manufacturing) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Outcome: duration of response (DoR) | 10 years, minimum f-up 1 year | Duration of Response (DoR): for patients who will respond to treatment, the duration of response will be measured as the interval between the response achievement and the date of progression or death, whichever occurs first, with censoring at the date of the latest follow-up in alive patients without progression. DoR curves will be estimated with the Kaplan Meier method. |
| Evaluation of Outcome: non-relapse mortality (NRM) | 10 years, minimum f-up 1 year | Non-relapse mortality (NRM) after CAR-T cell therapy: time will be measured as the interval between the date of treatment start and the date of non-relapse death, with censoring at the date of the latest follow-up in alive patients without relapse. NRM cumulative incidence curves will be estimated regarding disease recurrence as competing event, and between groups comparisons will be performed using the Gray test. |
| Evaluation of safety (CRS, neurotoxicity, infections, cytopenias, B cell aplasia, second malignancies) with particular attention to the safety in the new indications | 10 years, minimum f-up 1 year | CRS and ICANS will be measured according to ASCTC. Other toxicities will be measured according to CTCAE. |
| Evaluation of bridging therapy: safety | 10 years, minimum f-up 1 year | Bridging therapy will be analysed in terms of safety as per adverse event occurrence (according to CTCAE). |
| Evaluation of bridging therapy: efficay | 10 years, minimum f-up 1 year | Bridging therapy will be analysed in terms of efficacy in terms of response achievement compared to response assessment prior to bridging therapy. |
| Evaluation of salvage therapy after CAR-T failure | 10 years, minimum f-up 1 year | In case of relapse after CAR-T, data regarding salvage therapy will be collected in terms of reponse (PFS) |
| Comparison of the different CAR T-cell products (time from patient screening to infusion, disease response and safety) | 10 years, minimum f-up 1 year | Time form screening to infusion will be compared between CAR-T products, disease response will be evaluated in terms of CR, PR and SD. |
| Comparison of the different histotypes (PMBCL, DLBCL, MCL FL) according to CAR-T cell products | 10 years, minimum f-up 1 year | Study popoulation will be analysed in terms of reponse and type CAR-T product. |
| Evaluation of Outcome: Overall Response rate (ORR), according to Lugano criteria. | 10 years, minimum f-up 1 year | Overall response rate (ORR): the percentage of responding patients will be estimated as the number of patients with complete response (CR) + partial response (PR) divided by the total number of patients assessable at each specific timepoint (3-6-12-18 months). Patients not assessable for response for any reason will be considered as non-responding in the calculation of the response rate. The exact 95% confidence intervals of the response percentage will also be estimated. |
| Evaluation of Outcome: Overall survival (OS), according to Lugano criteria. | 10 years, minimum f-up 1 year | Overall survival (OS): time will be measured as the interval between the date of CAR-T infusion and the date of death for all causes, with censoring at the date of the latest follow-up in alive patients. OS curves will be estimated with the Kaplan Meier method. |
| Evaluation of Outcome: Progression free survival (PFS) | 10 years, minimum f-up 1 year | Progression-free survival (PFS): time will be measured as the interval between the CAR-T infusion and the date of progression disease (PD), or death, whichever occurs first. |
| Evaluation of Outcome: Overall survival (OS) | 10 years, minimum f-up 1 year | Overall survival (OS): time will be measured as the interval between the date of CAR-T infusion and the date of death for all causes, with censoring at the date of the latest follow-up in alive patients. OS curves will be estimated with the Kaplan Meier method. |
| Evaluation of Outcome: Overall Response rate (ORR) | 10 years, minimum f-up 1 year | Overall response rate (ORR): the percentage of responding patients will be estimated as the number of patients with complete response (CR) + partial response (PR) divided by the total number of patients assessable at each specific timepoint (3-6-12-18 months). Patients not assessable for response for any reason will be considered as non-responding in the calculation of the response rate. The exact 95% confidence intervals of the response percentage will also be estimated. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Analysis of the CAR-T expression | 10 years, minimum f-up 1 year | Evaluate the persistence of CAR-T after administration |
| Influence of PET quantitative parameters: tMTV changes between baseline and +30 and +90 after CAR T-cell infusion (ΔSUV max) related to outcome | 10 years, minimum f-up 1 year | In our study, the PET scans will be collected and anonymized. A central review with analyses of quantitative parameters will be performed. Evaluation of baseline tMTV calculated by MTV4 method which automatically segments area with SUV ≥4.0. |
| Influence of PET quantitative parameters: Distance max | 10 years, minimum f-up 1 year | In our study, the PET scans will be collected and anonymized. A central review with analyses of quantitative parameters will be performed. Dmax between baseline and +30 and +90 after CAR-T cells infusion |
| Influence of PET quantitative parameters: Distance max bulky | 10 years, minimum f-up 1 year | In our study, the PET scans will be collected and anonymized. A central review with analyses of quantitative parameters will be performed. Dmax bulk is the maximum distance to the bulk and we wil analyse its change between baseline and day +30 and +90. |
| Characterization of toxicity biomarkers | 10 years, minimum f-up 1 year | Biomarkers will be analysed in relation to toxicities occurrence on order to identify predictors of toxicity onset and severity |
| Characterization of biomarkers of early response (circulating tumor cell free DNA versus PET and CT scans) | 10 years, minimum f-up 1 year | To study the circulating cell free DNA modulation during time, besides descriptive statistical analyses, we will use non parametric factorial models for longitudinal data \[Brunner E, Domhof S, Langer F. Nonparametric analysis of longitudinal data in factorial experiments. John Wiley & Sons 2002, New York\]. Such models were chosen because they allow take into account measurement incompleteness and positive asymmetry of biomarker distribution, and because they are robust to outliers. The models also allow to test the difference in the longitudinal profiles according to specific covariates. |
| Analysis of the immune reconstitution | 10 years, minimum f-up 1 year | Evaluate disease response and immune recovery biomarkers at different time-points up after CAR-T (when clinically indicated or using blood sampling leftover) |
Countries
Italy
Contacts
Primary ContactPaolo Corradini, Professor
Backup ContactAnisa Bermema, PhD
Outcome results
None listed