In a study reported in The New England Journal of Medicine, Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia, and Noelle Frey, MD, of the Perelman School of Medicine, University of Pennsylvania, and colleagues reported achieving sustained remissions in children and adults with relapsed/refractory acute lymphoblastic leukemia (ALL) using autologous CD19-targeted chimeric antigen receptor (CAR)–modified T cells.1
Study Details
In the study, 25 patients aged 5 to 22 years at Children’s Hospital of Philadelphia and 5 patients aged 26 to 60 years at Hospital of the University of Pennsylvania with relapsed or refractory ALL received infusions of autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector at doses of 0.76×106 to 20.6×106 CTL019 cells/kg. Of the 30 patients, 26 had B-cell ALL in first to fourth relapse, 3 had primary refractory B-cell ALL, and 1 had relapsed T-cell ALL expressing CD19; 18 had relapsed disease after allogeneic stem cell transplantation and 3 had disease previously shown to be refractory to blinatumomab, a bispecific antibody that binds to both CD3 on T cells and CD19.
Remissions
Complete remission was achieved in 27 patients (90%), including 2 of the 3 patients with blinatumomab-refractory disease and 15 of 18 patients who had undergone stem cell transplantation.
With a follow-up period of 2 to 24 months, sustained remissions were observed in 19 patients, with 15 receiving no further treatment; these remissions were associated with persistence of CTL019 and B-cell aplasia, which continued for up to 2 years. Six-month event-free survival was 67% (95% confidence interval [CI] = 51%–88%), and overall survival was 78% (95% CI = 65%–95%).
Relapses
Seven patients with complete remission had relapse between 6 weeks and 8.5 months after infusion, with 3 developing relapses after early loss of CTL019-modified T cells at 2 weeks to 3 months and the relapsed ALL remaining CD19-positive in each case. After recovery of normal B cells at 2 to 3 months, one relapse occurred rapidly at 3 months, and two were delayed, occurring at 6 and 8.5 months. One patient, who had minimal residual disease (0.22%) at 1 month, had relapse with CD19-positive ALL at 6 weeks, which progressed rapidly and resulted in death; this patient had highly refractory disease in fourth relapse at baseline and was not eligible for stem cell transplantation. Loss of expression of CD19 in leukemia cells resulted in relapse in three patients, including one who had received blinatumomab therapy; CTL019 cells were not lost at the time of relapse in these patients.
Expansion and Persistence of CTL019
Detection of CTL019 cells by flow cytometry showed in vivo proliferation. The median peak proportion in blood was 39.8% of CTL019-positive cells in CD3-positive cells (range 4.4%–69.3%) in responders compared with 0.2%, 0.6%, and 8.2% of CD3-positive cells at peak levels in the three nonresponders. CTL019 cells were detectable in blood for up to 11 months, with a probability of persistence at 6 months of 68% (95% CI = 50%–92%).
Further, CTL019 sequences remained detectable by quantitative polymerase chain reaction (PCR) assay until 2 years in patients with sustained remissions. PCR showed high levels of proliferation, with all patients having peak levels > 5,000 copies/µg of genomic DNA and 26 having peak levels > 15,000 copies/µg.
Persistence of CTL019 was observed in one patient after reinfusion at 3 months and 6 months due to early loss of CTL019 cells with B-cell recovery. The patient with the longest remission (2 years) exhibited B-cell aplasia (absence of CD19-positive cells) for 1 year after CTL019 cells were no longer detectable on flow cytometry; this finding suggests functional persistence of CTL019 cells below flow cytometry limits of detection but at levels detectable by means of quantitative PCR. Overall, the probability of relapse-free B-cell aplasia at 6 months was 73% (95% CI = 57%–94%).
Cytokine-Release Syndrome
No deaths appeared to be related to the study treatment. Seven patients died after disease progression or relapse, including one who died of myelodysplastic syndrome that developed during ALL remission and withdrew from the study to receive other treatment.
All patients exhibited cytokine-release syndrome. Severe cytokine-release syndrome, requiring intensive care with varying degrees of respiratory support, developed in eight patients (27%), with all requiring vasopressor support for hypotension. These patients also exhibited coagulopathy, with clinical bleeding observed in three (10%).
Severe cytokine-release syndrome started a median of 1 day after infusion, compared with a median of 4 days in patients with nonsevere syndrome (P = .005). Inflammatory markers, including C-reactive protein and ferritin, were elevated in all patients; patients with severe reactions had higher peak levels of interleukin-6 (P < .001), C-reactive protein (P = .02), ferritin (P = .005), interferon-γ (P < .001), and soluble interleukin-2 receptor (P < .001). Higher disease burden at baseline (percentage of blast cells in marrow before infusion) was significantly associated with an increased risk of severe cytokine-release syndrome (P = .002), and severity was also associated with higher levels of CTL019-positive CD8 cells (P = .012) and CTL019-positive CD3 cells (P = .026).
Nine patients with severe reactions received the anti–interleukin-6 receptor antibody tocilizumab, which produced rapid reduction of fever and stabilization of blood pressure over 1 to 3 days. Six patients also received short glucocorticoid course and four received a second dose of tocilizumab (Actemra) for recurrence of the cytokine-release syndrome after transient improvement with the first dose. All patients recovered fully, with complete reversal of symptoms and normalization of lab results. Relapses were observed in two of the nine patients who received immunosuppressive therapy for cytokine-release syndrome.
The investigators concluded: “Chimeric antigen receptor–modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem cell transplantation had failed, and durable remissions up to 24 months were observed.” ■
Disclosure: The study was funded by Novartis and others. For full disclosures of the study authors, visit www.nejm.org.
Reference
1. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014.
See commentary by Andrew Evens, DO, MSc, here.
