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Leukemia Drug CTL01 Achieves 90% Remission in Relapsed/Refractory ALL

New data support efficacy of chimeric antigen receptor therapy

Positive preliminary results have been reported from two pilot clinical trials evaluating the efficacy and safety of the investigational chimeric antigen receptor (CAR) therapy CTL019 (Novartis) in patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL).

The studies, conducted at the University of Pennsylvania’s Perelman School of Medicine, demonstrated that 27 of 30 pediatric and adult patients (90%) experienced complete remissions (CRs) after treatment with CTL019.

The new data — published in the New England Journal of Medicine — build on earlier research findings and are part of two pilot clinical studies that demonstrated sustained remissions of up to 2 years in pediatric and adult patients with r/r ALL. The median follow-up period was just over 6 months, with an event-free survival rate of 67% and an overall survival rate of 78%.

The probability of 6-month CTL019 persistence was 68%, and CTL019-modified T cells were detectable in the blood by flow cytometry for up to 11 months. Sustained remissions were seen in 15 patients and were associated with CAR T-cell persistence and B-cell aplasia.

In July 2014, the FDA designated CTL019 as a “breakthrough therapy,” which is intended to expedite the development and review of drugs that treat serious or life-threatening conditions if the therapy has demonstrated substantial improvement over an available therapy on at least one clinically significant endpoint.

A total 30 patients (25 pediatric subjects and five adults) were studied from April 2012 to February 2014. The patients were infused with autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector at doses of 0.7 to 20.6 x 106 CTL019 cells/kg. The study found that 27 of the 30 pediatric and adult patients with r/r ALL (90%) experienced CRs, including two blinatumomab-refractory patients and 15 with prior stem-cell transplant (SCT).

Of the 27 patients who achieved a CR, five went off-study for alternate therapy, three of whom proceeded to allogeneic SCT in remission. Fifteen patients remained in remission with a median follow-up of 7 months.

Sustained remissions were achieved for up to 2 years, with a 6-month event-free survival rate of 67% and an overall survival rate of 78%. The probability of 6-month CTL019 persistence was 68%, and rate of relapse-free B cell aplasia was 73%. CTL019-modified T cells were detectable in the blood by flow cytometry for up to 11 months, and CTL019 sequences remained detectable by quantitative PCR (Q-PCR) in patients with sustained remissions for up to 2 years.

All of the treated patients experienced cytokine-release syndrome (CRS). Of the 30 patients, 74% (n = 22) experienced mild-to-moderate CRS. Severe CRS, seen in 27% of patients (n = 8), was associated with higher disease burden and was effectively treated with the IL-6 receptor antibody tocilizumab. Several patients experienced neurologic toxicities, which resolved completely without further intervention or apparent long-term implications.

CTL019 uses CAR technology to reprogram a patient’s own T cells to “hunt” cancer cells that express CD19 proteins. After they have been reprogrammed, the T cells (now called CTL019) are re-introduced into the patient's blood; they proliferate and bind to the targeted CD19-positive cancer cells, destroying them.

Because CTL019 is an investigational therapy, its safety and efficacy profiles have not been established.

Source: Novartis; October 15, 2014.

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