Background: Autologous T cells genetically modified to express CD19-targeted 19-28z chimeric antigen receptors (CARs) induce durable responses in a subset of patients (pts) with relapsed/refractory CLL; greater disease burden may limit efficacy. We conducted a phase I dose escalation study to assess safety and efficacy of consolidative outpatient CAR T cell therapy in pts with residual CLL following first-line pentostatin, cyclophosphamide (Cy) and rituximab (PCR). Methods: Pts with CLL achieving partial response (PR) following first-line PCR x6 cycles were enrolled. Autologous T cells were transduced with a retroviral vector encoding anti-CD19 scFv linked to CD28 costimulatory and CD3ζ signaling domains (19-28z). Pts received Cy 600 mg/m²followed 2 days later by escalating doses of 19-28z T cells, administered outpatient. Response was assessed by NCI-WG criteria at 3 months (m) and 6 m. Results: 8 CLL pts (unmutated IgHV, n = 7; del11q, n = 1), median age 58.5 (45-68), achieved PR following PCR and received 3x10⁶ (n = 3), 1x10⁷ (n = 3) or 3x10⁷ (n = 2) 19-28z⁺ T cells/kg. 5 pts had clearly enlarged lymph nodes (LNs) prior to T cell infusion. 4/5 pts receiving ≥ 1x10⁷19-28z T cells/kg were admitted with fevers with mild cytokine release syndrome; peak IL-6 ranged from 39 to > 10,000 pg/mL in these pts. No DLT was observed. Maximal detected CAR T cell persistence was 8 wks. Median follow up is 32.4 m (14-41). Best response after 19-28z T cells was clinical complete response (CR, n = 2), PR (n = 2), stable disease (n = 1), progression of disease (PD, n = 3). Of 3 pts with PD, 1 pt had rising ALC by time of infusion; 2 pts had marrow response (nPR, n = 1; MRD+ CR, n = 1) with PD in LNs. Median time to PD was 13.6 m. 5/7 evaluable pts have received further CLL-directed therapy. Conclusions: Outpatient 19-28z CAR T cell therapy is well tolerated in pts with residual CLL following initial PCR. 4/8 pts achieved clinical CR or PR. Limited observed efficacy in LNs was noted. Low-dose Cy monotherapy may be insufficient for lymphodepletion. CAR T cell expansion and antitumor efficacy may be limited by a hostile CLL microenvironment. Strategies to enhance CAR T cell expansion and efficacy in pts with CLL are in preparation. Clinical trial information: NCT01416974