Phase I/II Open-label Study Evaluating The Safety And Efficacy of Concomitant Administration of Anti-CD19 CAR T-cell Therapy and Lenalidomide in Refractory/Relapsed Chronic Lymphocytic Leukemia Patients.

Patients receive ibrutinib 420 mg daily for 3 months before CAR T-cell infusion. Obinutuzumab 1000 mg is administered 14 days before leukapheresis to reduce circulating CLL cells. Lymphodepletion consists of fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² on days -5 to -3. In a 3+3 dose-escalation design, patients receive a single infusion of 25 × 10⁶ (DL1), 50 × 10⁶ (DL2), or 100 × 10⁶ (DL3) autologous CD19 CAR T cells. Lenalidomide 10 mg is administered orally on days 0 through 6. At day 28, patients with measurable residual disease (MRD)-positive disease are eligible for lenalidomide 10 mg 1-14 days per os plus obinutuzumab 1000 mg IV 1,8,15 days on cycle 1 and on day 1 on 2-6 cycles consolidation, whereas patients with MRD-negative disease receive lenalidomide 10 mg per os 1-14 days maintenance for 3 cycles.

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.
• 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