Tisagenlecleucel in Adult Patients With Aggressive B-cell Non-Hodgkin Lymphoma

Inclusion Criteria:

• Histologically confirmed, aggressive B-cell NHL at relapse/progression or PR afterfront line therapy. Aggressive B-cell NHL is heretofore defined by the followinglist of subtypes (Swerdlow et al 2016):

• DLBCL, NOS,

• FL grade 3B,

• Primary mediastinal large B cell lymphoma (PMBCL),

• T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL),

• DLBCL associated with chronic inflammation,

• Intravascular large B-cell lymphoma,

• ALK+ large B-cell lymphoma,

• B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL andclassical Hodgkin's Lymphoma (HL)),

• High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements,

• High-grade B-cell lymphoma, NOS

• HHV8+ DLBCL, NOS

• DLBCL transforming from follicular lymphoma

• DLBCL transforming from marginal zone lymphoma

• DLBCL, leg type

• Relapse or progression within 365 days from last dose of anti CD20 antibody andanthracycline containing first line immunochemotherapy or refractory (have notachieved a CR).

• Patient is considered eligible for autologous HSCT as per local investigatorassessment. Note: Intention to transplant and type of high dose chemotherapy (HDCT)regimen will be documented at the time of study entry

• Disease that is both active on PET scan (defined as 5-Deauville scorepoint-scale of 4 or 5) and measurable on CT scan, defined as::

• Nodal lesions >15 mm in the long axis, regardless of the length of the shortaxis, and/or

• Extranodal lesions (outside lymph node or nodal mass, but including liver andspleen) >10 mm in long AND short axis

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Adequate organ function:

Renal function defined as:

• Serum creatinine of ≤1.5 x upper limit of normal (ULN), OR estimated glomerularfiltration rate (eGFR) ≥ 60 mL/min/1.73 m2

Hepatic function defined as:

• Alanine Transaminase (ALT) and Aspartate Transiminase (AST) ≤ 5 × ULN

• Total bilirubin ≤ 1.5 x ULN with the exception of patients with Gilbert syndrome whomay be included if their total bilirubin is ≤3.0 × ULN and direct bilirubin ≤1.5 ×ULN

Hematologic Function (regardless of transfusions) defined as:

• Absolute neutrophil count (ANC) >1000/mm3

• Absolute lymphocyte count (ALC) >300/mm3 OR Absolute number of CD3+ T cells >150/mm3 (only for patients with non-historical apheresis)

• Platelets ≥50000/mm3

• Hemoglobin >8.0 g/dl

Adequate pulmonary function defined as:

• No or mild dyspnea (≤ Grade 1)

• Oxygen saturation measured by pulse oximetry > 90% on room air

• Forced expiratory volume in 1 s (FEV1) ≥ 50% and/or carbon monoxide diffusion test (DLCO) ≥50% of predicted level - Must have a leukapheresis material of non-mobilizedcells available for manufacturing.

Exclusion Criteria:

• Prior treatment with anti-CD19 therapy, T cell therapy, or any prior gene therapyproduct

• Treatment with any systemic lymphoma-directed second line anticancer therapy priorto randomization. Only steroids and local irradiation are permitted for diseasecontrol

• Patients with active central nervous system (CNS) involvement by disease under studyare excluded, except if the CNS involvement has been effectively treated and localtreatment was >4 weeks before randomization

• Prior allogeneic HSCT

• Clinically significant active infection

• Any of the following cardiovascular conditions:

• Unstable angina, myocardial infarction, coronary artery bypass graft (CABG), orstroke within 6 months prior to screening,

• Left ventricle ejection fraction (LVEF) <45% as determined by echocardiogram (ECHO) or magnetic resonance angiography (MRA) or multigated acquisition (MUGA)at the screening assessment.

• New York Heart Association (NYHA) functional class III or IV (Chavey et al 2001), within the past 12 months.

• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II) and third degree AV block unlessadequately controlled by pacemaker implantation.

• Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or inabilityto determine the QTcF interval

• Risk factors for Torsades de Pointes (TdP), including uncorrected hypokalemiaor hypomagnesemia, history of cardiac failure, or history of clinicallysignificant/ symptomatic bradycardia, or any of the following:

• Long QT syndrome, family history of idiopathic sudden death or congenital longQT syndrome

• Concomitant medication(s) with a "Known Risk of Torsades de Pointes" percrediblemeds.org that cannot be discontinued or replaced by safe alternativemedication.

• Patients with active neurological autoimmune or inflammatory disorders (e.g.,Guillain-Barré Syndrome (GBS), Amyotrophic Lateral Sclerosis (ALS)) and clinicallysignificant active cerebrovascular disorders (e.g. cerebral edema, posteriorreversible encephalopathy syndrome (PRES))