Effectiveness and Safety of Tisagenlecleucel Therapy in Brazilian Patients With B-lymphocyte Malignancies

Eligible participants will be pediatric (\<18 years) and adult patients (aged 18 years or older) with B-cell malignancies who have received tisagenlecleucel through the commercial setting or out-of-specification (OOS) use in Brazil. We will collect data prospectively and complement missing information with retrospective data collection, when necessary. It is anticipated that approximately 200 patients will be enrolled in the cohort over 5 years divided among the study indications.

Since this is a non-interventional study, no administration of study drug or application of questionnaires will be mandated by this protocol. The study will consist of a "Pre-infusion" and a "Post infusion follow-up period" for up to 15 years post tisagenlecleucel infusion. All patients will be followed until death or last scheduled visit, whichever comes first.

For the study, "pre-infusion" and "follow-up post infusion" phases are defined as:

• "Pre-infusion" will consist of the patient's information from the time of diagnosis untiljust prior to infusion with tisagenlecleucel.
• "Follow-up Post infusion" information will comprise any information from the infusionof tisagenlecleucel onwards.

Children/young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia who received tisagenlecleucel infusion

Other: tisagenlecleucel

Adult patients with relapsed/refractory Diffuse Large B-cell Lymphoma who received tisagenlecleucel infusion

Other: tisagenlecleucel

Patients of any gender aged 18 year or older, with relapsed/refractory Follicular Lymphoma who received tisagenlecleucel infusion.

Other: tisagenlecleucel

Prospective observational study. There is no treatment allocation. Patients prescribed with tisagenlecleucel in the commercial setting or out-of-specification (OOS) are eligible to enroll into this study

Time frame: Up to 15 years

The overall response rate will be defined as the total proportion of participants exhibiting either the best overall response (BOR) of complete or partial responses and the proportion of patient with BOR of CR/PR or CR/CRi for ALL patients will be reported along with its 95% CI.

For ALL participants, the BOR will be defined as a CR or a CRi in accordance with National Comprehensive Cancer Network (NCCN) guidelines and previous guidelines (Appelbaum et al 2007)(Cheson et al 2003).

For lymphomas, the BOR will be defined as a CR or PR in accordance with the Cheson response criteria (Cheson et al 2007) and the Lugano classification (Cheson et al 2016).

Time frame: Up to 15 years

The percentage of B-cell ALL patients who achieve a Best Overall Response (BOR) of CR or CRi with a Minimal residual disease (MRD) negative bone marrow will be provided with 95% CI.

Time frame: Up to 15 years

Duration of overall response (DOR) applies only to patients whose best overall disease response was either:

• CR or PR for patients with lymphomas, or
• CR or a CRi for patients with ALL.

DOR will be defined as the time from the date of first documented disease response (Complete Response (CR) or PR for patients with lymphomas, and Complete Remission (CR) or CRi for patients with ALL), whichever occurs first, to the date of first documented progression or first documented relapse according to indication, or to the date of death due to the underlying disease.

In case a patient does not have progression/relapse or death due to underlying disease (defined as the event for this outcome) prior to data cut-off, DOR will be censored at the date of the last assessment on or prior to the earliest censoring event.

Time frame: Up to 15 years

RFS is measured by the time from date of first documented disease response as CR or CRi to relapse or death due to any cause in ALL patients.

In case a patient does not have relapse or death due to any cause prior to data cutoff, RFS will be censored at the date of the last adequate assessment on or prior to the earliest censoring event.

Time frame: Up to 15 years

EFS is the time from date of first tisagenlecleucel infusion to treatment failure, relapse or death from any cause, whichever occurred first, for B-cell ALL patients.

Time frame: Up to 15 years

PFS is defined as the time from the date of first infusion to the date of event defined as the first documented progression of lymphoma or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of the last adequate assessment.

In case a patient does not have progression or death prior to data cutoff, PFS will be censored at the date of the last adequate assessment on or prior to the earliest censoring event.

Time frame: Up to 15 years

Overall survival is the time from date of first tisagenlecleucel infusion to the date of death due to any reason, In case a patient is alive at the date of last contact on or before data cutoff, OS is censored at the date of last contact.

Time frame: Up to 15 years

Dates of hematological recovery (i.e., dates of Absolute Neutrophil Count (ANC) and platelet recovery) will be collected.

ANC recovery is defined as an ANC of ≥ 0.5 × 109/L (500/mm\^3) for 3 consecutive laboratory values obtained on different days. Date of ANC recovery is the date of the first of 3 consecutive laboratory values where the ANC is ≥ 0.5 × 109/L (CIBMTR).

The first date of the 3 consecutive laboratory values obtained on different days where the platelet count was ≥ 20 × 109/L should be recorded. It should be ensured that no platelet transfusions were administered for 7 days immediately preceding this date (CIBMTR).

Time frame: Up to 15 years

The type and frequency of SAEs and AE of special interest (including secondary malignancies) will be collected

Time frame: Up to 15 years

Incidence and severity of Cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) among Human T-cell Lymphotropic Virus (HTLV) 1 and 2 positive versus HTLV 1 and 2 negative patients.

For CRS AE the protocol will follow the American Society of Transplant and Cellular Therapy (ASTCT) CRS Consensus Grading.

For ICANS AE the protocol will follow ASTCT consensus as well. Which establishes the Immune effector Cell-associated Encephalopathy (ICE Score) for adults/ adolescents and Cornell Assessment of Pediatric Delirium (CAPD) for pediatric patients under 12 years

Time frame: Up to 15 years

Pregnancy rates will be collected

Time frame: Up to 15 years

Number of patients with confirmed secondary malignancies diagnosis will be collected

Effectiveness and Safety of Tisagenlecleucel Therapy in Brazilian Patients With B-lymphocyte Malignancies: a 15-year Prospective Registry Study on Three Cohorts.