This is a Phase I/II interventional, open-label treatment study designed to evaluate the safety and efficacy of concomitant therapy with anti-CD19 CAR T-cells and Lenalidomide in adult patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have been pretreated with Ibrutinib for 3 months prior to leukapheresis.

This is a single-center, open-label study. After meeting the eligibility criteria and enrolling in the trial, patients will take Ibrutinib for 3 months up to Day -1. Leukapheresis for the collection of autologous lymphocytes will take place 2-3 weeks before Day 0. Once the cells have been manufactured, patients will proceed to lymphodepleting chemotherapy with cyclophosphamide and fludarabine from Days -5 to -3, followed by the infusion of anti-CD19-4-1BB-CD3z CAR T-cells at two fixed dose levels: DL1 (50 x 10^6 cells) and DL2 (150 x 10^6 cells), concomitantly with Lenalidomide intake. Lenalidomide maintenance at the dose of 25 mg will be administered from Day +30 for 3 months.

The main purposes of the Phase I part are:

• To preliminarily explore the safety (incidence of CRS, ICANS, HLH, infections, late ICAHT, and cytopenias) and tolerability.
• To explore the pharmacokinetics of CAR-T cells.

The main purposes of the Phase II part are:

• Overall response rate, including complete response (CR) and partial response (PR) rates.
• Duration of response (DOR).
• Progression-free survival rates.
• Overall survival rates.
• MRD negativity rates measured by flow cytometry.

Inclusion Criteria:

• Documented CD19+ CLL or SLL
• Patients must have failed at least 1 prior regimen
• Patients must be currently receiving ibrutinib for at least 3 months prior to enrollment in the study and:
• Not experiencing any ≥ grade 2 non-hematologic ibrutinib-related toxicity
• ECOG Performance status 0 or 1
• 18 years of age and older
• Adequate organ system function including:

Creatinine < 1.6 mg/dl ALT/AST < 3x upper limit of normal Total Bilirubin <2.0 mg/dl with the exception of patients with Gilbert syndrome; patients with Gilbert syndrome may be included if their total bilirubin is ≥ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN.

• Have no active GVHD and require no immunosuppression
• Are more than 6 months from transplant
• No contraindications for leukapheresis
• Left Ventricular Ejection fraction >50%
• Gives informed consent

Exclusion Criteria:

• CLL patients with known or suspected transformed disease (i.e. Richter's transformation).
• Pregnant or lactating women.
• Uncontrolled active infection.
• Active hepatitis B or hepatitis C infection.
• Concurrent use of systemic steroids or chronic use of immunosuppressant medications.
• Any uncontrolled active medical disorder
• HIV infection.
• Patients with active CNS involvement with malignancy.
• Class III/IV cardiovascular disability according to the New York Heart Association Classification.
• Subjects with clinically apparent arrhythmia or arrhythmias who are not stable