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An historical cohort of patients will be identified and selected both on a clinical base and according to the availability of Formaline-fixed paraffin-embedded (FFPE) material, frozen material or viable cryopreserved cells at Mantle Cell Lymphoma (MCL) diagnosis. Samples will be analyzed in 4 subgroups, each with different clinical specificity:

1. refractory to Induction Chemoimmunotherapy (CIT);
2. refractory to Bruton Tyrosine kinase (BTK) inhibitors (BTKi);
3. sensitive to Induction Chemoimmunotherapy (CIT);
4. sensitive to Bruton Tyrosine kinase (BTK) inhibitors (BTKi).

Marina Cesaretti

Elena Borgo

Elsa Pennese, MD

Alberto Fabbri, MD

Guido Gini

Guido Gini, MD

Pietro Bulian, MD

Attilio Guarini, MD

Alessandro Re, MD

Luca Nassi

Luca Nassi, MD

Nicola Di Renzo, MD

Andres Ferreri, Dott.

Francesca G Rossi, Dott.ssa

Francesca G Rossi, MD

Riccardo Moia, Dott.

Riccardo Moia, MD

Luca Arcaini, Prof.

Annalisa Arcari, MD

Angelo Fama, MD

Alice Di Rocco, MD

Stefan Hohaus, Prof.

Carola Boccomini, MD

Simone Ferrero, MD

Chandrakala Toldo, Dott.ssa

Chandrakala Toldo, MD

Piero Maria Stefani, MD

Michele Merli, MD

Francesca Maria Quaglia, Dott.ssa

Francesca Maria Quaglia, MD

Maria Chiara Tisi, Dott.ssa

Maria Chiara Tisi, MD

Francesca Maria Quaglia

Retrospective observational study with a prospective biological evaluation of an historical cohort of first relapsed-refractory patients with mantle cell lymphoma who were relapsed or refractory to rituximab and chemotherapy containing induction regimens with curative intent.

Biological samples from 80 Mantle Cell Lymphoma (MCL) patients will be collected and analyzed in 30 Italian sites in 36 months.

Patients will be identified and selected both on a clinical base and according to the availability of Formaline-fixed paraffin-embedded (FFPE) material, frozen material or viable cryopreserved cells at Mantle Cell Lymphoma (MCL) diagnosis. They will be analyzed in 4 subgroups, each with different clinical specificity: 1) refractory to Induction Chemoimmunotherapy (CIT); 2) refractory to Bruton Tyrosine kinase (BTK) inhibitors (BTKi); 3) sensitive to induction Induction Chemoimmunotherapy (CIT); 4) sensitive to BTK inhibitors (BTKi).

Each group will undergo central pathology revision with other immunohistochemical studies (Verona, Dr. Parisi; Milano, Prof. Ponzoni; Vicenza, Dr. D'Amore; Brescia, Prof. Facchetti). Formaline-fixed paraffin-embedded (FFPE) diagnostic specimens of Mantle Cell Lymphoma (MCL) will be screened by immunohistochemistry for the expression of immunoglobulin (Ig) heavy chains to identify Mantle Cell Lymphoma (MCL) cases lacking Immunoglobulin (Ig) expression.

Cytofluorimetric and molecular studies will be performed in the laboratories of the Verona University and at IFOM (Istituto FIRC di Oncologia Molecolare (FIRC = Fondazione Italiana per la Ricerca sul Cancro)). Specific methods will be used: Flow cytometry for the status of surface Ig expression and multiplexed phospho-specific flow cytometry, NGS (Next Generation Sequencing), Immunoglobulin (IgH/IgL V(D)J) profiling by BIOMED2 protocol-based, NGS (Next Generation Sequencing) technology in the relapsed-refractory mantle cell lymphoma (R/R MCL) cases, Chromatin accessibility studies by Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) (on viable cell suspensions or frozen pellets) and Gene Expression Profiling (GEP) by RNA-sequencing and RNA studies of the MALT1-MYC ((Mucosa-associated lymphoid tissue lymphoma translocation protein 1 - MYC) pathway.

For the primary objective of the study: Formaline-fixed paraffin-embedded (FFPE) material.

For the secondary objectives of the study: viable cell suspensions, DNA extracted from Formaline-fixed paraffin-embedded (FFPE) tissue sections or frozen pellets, frozen cell suspensions.

Biological Insights of First Relapsed-refractory Patients With Mantle Cell Lymphoma: the MANTLE-FIRST BIO Study.

Histopathological characterization of patients with mantle cell lymphoma (MCL) who were relapsed or refractory to rituximab and chemotherapy containing induction regimens with curative intent. 80 Mantel Cell Lymphoma (MCL) patients stratified according to Chemo-immunotherapy (CIT) or Bruton Tyrosine kinase inhibitors (BTKi) resistance (20 for each of the groups previously identified) will undergo central pathology revision with assessment of Immunoglobulin (Ig) expression and other histopathological studies.

Performed on formalin-fixed paraffin-embedded (FFPE) tissue sections as well as, when available, on frozen material or viable cryopreserved cells at Mantle Cell Lymphoma (MCL) diagnosis. The aim is to perform a mutational analysis for Mantle Cell Lymphoma (MCL) driver genes: Next Generation Sequencing (NGS) on approximately 80 cases of Mantle Cell Lymphoma (MCL), including 20 cases Relapsed/Refractory (R/R) to Bruton Tyrosine kinase inhibitors (BTKi)

Performed on formalin-fixed paraffin-embedded (FFPE) tissue sections as well as, when available, on frozen material or viable cryopreserved cells at Mantle Cell Lymphoma (MCL) diagnosis. The aim is to perform a functional study of the B-Cell Receptor (BCR) activity: multiplexed phospho-specific flow cytometry on 10-20 Relapsed/Refractory (R/R) Mantle Cell Lymphoma cases.

Performed on formalin-fixed paraffin-embedded (FFPE) tissue sections as well as, when available, on frozen material or viable cryopreserved cells at Mantle Cell Lymphoma (MCL) diagnosis. The aim is to understand the mechanisms of evasion from B-Cell Receptor (BCR) requirement as follow:

* Immunoglobulin (IgH/IgL V(D)J) profiling by Next Generation Sequencing (NGS) on 80 mantle cell lymphoma (MCL) cases;
* Chromatin accessibility studies (Assay for Transposase-Accessible Chromatin sequencing, ATAC-seq) on approximately 20 cases among the Immunoglobulin (Ig)-negative identified cases or Bruton Tyrosine kinase inhibitors (BTKi) refractory cases, irrespective of their B-Cell Receptor (BCR) status, and on other 20 cases, from the group of patients sensitive to Bruton Tyrosine kinase inhibitors (BTKi);
* Gene Expression Profiling (GEP) by RNA-seq, on about 20 cases selected on the basis of results of the Assay for Transposase-Accessible Chromatin sequencing (ATAC-Seq) analysis;

Performed on formalin-fixed paraffin-embedded (FFPE) tissue sections as well as, when available, on frozen material or viable cryopreserved cells at Mantle Cell Lymphoma (MCL) diagnosis. The aim is to perform RNA studies on 20 cases

About 80 cases of Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) with available tissue samples will be considered for correlation between biological studies with clinical characteristics of patients, response to treatment and conventional outcomes (Progression Free Survival, Progression Free Survival at 2 years, Overall Survival, Overall Survival at 2 years)

Fondazione Italiana Linfomi - ETS

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Biological Insights of First Relapsed-refractory Patients With Mantle Cell Lymphoma: the MANTLE-FIRST BIO Study.	NCT04882475	Mantle Cell Lym...		18 Years - 80 Years	Fondazione Italiana Linfomi - ETS
Biological Insights of First Relapsed-refractory Patients With Mantle Cell Lymphoma: the MANTLE-FIRST BIO Study.	NCT04882475	Mantle Cell Lym...		18 Years - 80 Years	Fondazione Italiana Linfomi - ETS

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