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

Prior treatment

• Prior treatment with anti-CD19 therapy, T cell therapy, or any prior gene therapy product
• Treatment with any systemic lymphoma-directed second line anticancer therapy prior to randomization. Only steroids and local irradiation are permitted for disease control
• Patients with active central nervous system (CNS) involvement by disease under study are excluded, except if the CNS involvement has been effectively treated and local treatment was \>4 weeks before randomization
• Prior allogeneic HSCT

Other illness

• Clinically significant active infection
• Patients with active neurological autoimmune or inflammatory disorders (e.g., Guillain-Barré Syndrome (GBS), Amyotrophic Lateral Sclerosis (ALS)) and clinically significant active cerebrovascular disorders (e.g. cerebral edema, posterior reversible encephalopathy syndrome (PRES))

Lab values

• Any of the following cardiovascular conditions:
  • Unstable angina, myocardial infarction, coronary artery bypass graft (CABG), or stroke 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 unless adequately controlled by pacemaker implantation.
  • Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or inability to determine the QTcF interval
  • Risk factors for Torsades de Pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia, or any of the following:
  • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome
  • Concomitant medication(s) with a "Known Risk of Torsades de Pointes" per crediblemeds.org that cannot be discontinued or replaced by safe alternative medication.

• Histologically confirmed, aggressive B-cell NHL at relapse/progression or PR after front line therapy. Aggressive B-cell NHL is heretofore defined by the following list 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 and classical 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 and anthracycline containing first line immunochemotherapy or refractory (have not achieved a CR).
• Patient is considered eligible for autologous HSCT as per local investigator assessment. 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 short axis, and/or
  • Extranodal lesions (outside lymph node or nodal mass, but including liver and spleen) \>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 glomerular filtration 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 who may 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-mobilized cells available for manufacturing.