Chimeric Antigen Receptor T Cells Induce Sustained Remissions for Minority of CLL Patients

Although chronic lymphocytic leukemia (CLL) remains incurable with conventional therapies, recent studies examining the use of chimeric antigen receptor (CAR)-modified T cells targeting CD19 have induced durable complete remissions (CR) in patients with relapsed or refractory CLL, acute lymphocytic leukemia, and non-Hodgkin lymphoma. These previous attempts to use CAR-modified T cells were limited, however, by inadequate in vivo expansion and minimal persistence.

A new study by David Porter, MD, from the division of hematology/oncology at Abramson Cancer Center at the University of Pennsylvania Perelman School of Medicine in Philadelphia, Pennsylvania, demonstrated that CAR-modified T cells lead to sustained remissions in those patients with heavily pretreated CLL who achieved a CR to the treatment.

“We have found that the CD19-directed CAR (CTL019) cells expand to high levels but also persist for long periods of time,” Dr. Porter told ASH Clinical News. “The cells can persist and remain functional beyond three years following infusion. We now have patients who have gone five years with no evidence of leukemia by all measures, thus suggesting that this approach has the potential to eradicate CLL even in patients with advanced, heavily pretreated disease.”

In the study, which was published in Science Translational Medicine, Dr. Porter and colleagues presented mature results from their pilot clinical trial of CTL019 in 14 patients with CLL. Patients were infused with autologous T cells transduced with a CD19-directed CAR lentiviral vector at doses of 0.14 x 108 to 11 x 108 CTL019 cells (median = 1.6 x 108 cells). Twelve patients were male, and the median patient age was 66 years (range = 51-78 years). Patients had received a median of five prior lines of therapy (range = 1-11 therapies), and eight patients had del17p CLL. All patients had active disease at the time of CTL019 infusion.

The patients were monitored for toxicity, response, in vivo expansion, and persistence of circulating CTL019 T cells.

The median follow-up for all 14 patients was 19 months (range = 6-53 months). The overall response rate (ORR) was 57 percent (n=8; 95% CI 29-82); 29 percent of patients (n=4) reached complete remission and another 29 percent of patients (n=4) achieved partial remission (PR) within the first month following CTL019 infusion.

Among the four patients who achieved CR, none of the patients experienced a relapse, with a median duration of response of 40 months (range = 21-53 months from time of infusion).

Among those who achieved PR, the median duration of response was seven months (range = 5-13 months).

Six patients (43%) had no response to treatment and all six of these patients progressed within one to nine months (median = 4 months). Minimal residual disease was not detectable in patients who achieved CR, which suggests that disease eradication may be possible in some patient cohorts.

Median overall survival (OS) was 29 months, with an 18-month OS of 71 percent (95% CI 40.6-88.2); estimated progression-free survival (PFS) was seven months, with an 18-month PFS of 28.6 percent (95% CI 8.8-52.4).

“We have not identified any pretreatment demographic or disease-related factors to predict which patients are most likely to respond [to CTL019 treatment],” the authors wrote, adding that the study was not powered to investigate these associations. There was no distinction between responders and non-responders according to patient age, number of prior therapies, stage at enrollment, del17p subtype, IgH variable mutation status, or CTL019 dose (p>0.05 for all).

CTL019 infusions were well tolerated, with mild (<grade 2) toxicities, including low-grade fevers and chills. The most commonly reported adverse events were associated with complications of neutropenia (including fevers) and delayed cytokine release syndrome, which correlated with in vivo CTL019 expansion. One patient died in remission 21 months after CTL019 infusion, after developing overwhelming ecthyma gangrenosum from a pseudomonas wound infection at a skin biopsy site.

In addition to its small sample size, the study was limited by a small number of patients with long-term follow-up. “The long-term durability of the cells beyond four years is not yet known, and we do not know if loss of CTL019 cells would result in recurrence of CLL,” the researchers noted. In speaking with ASH Clinical News, though, Dr. Porter mentioned that some patients have survived beyond five years without disease progression or relapse.

“Previously, CLL has been considered incurable with anything but allogeneic stem cell transplantation,” Dr. Porter said. “Our data show that for some patients, CLL can potentially be eradicated with a one-time cell infusion. This is very exciting, particularly for patients with far advanced and refractory disease. If these data hold out, one can also envision applying this kind of approach earlier in the course of the disease.”


Reference

Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139.

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