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CTL019 induces remission in “incurable” ALL


 

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Engineered T-cell therapy using CTL019 (formerly known as CART19) rapidly induced complete remission in 27 of 30 children and adults with relapsed or refractory “incurable” acute lymphoblastic leukemia in an industry-sponsored phase I/IIA clinical trial reported online Oct. 16 in the New England Journal of Medicine.

These remissions were sustained for up to 2 years in 19 of the study participants, 15 of whom required no further therapy, said Dr. Shannon L. Maude of the University of Pennsylvania Medical Center, Philadelphia, and her associates.

Five adults aged 26-60 years and 25 children aged 5-22 years participated in the trial, which was funded largely by Novartis. A total of 26 of these patients had relapsed B-cell acute lymphoblastic leukemia (ALL), 3 had primary refractory B-cell ALL, and 1 had relapsed T-cell ALL that expressed CD19. Eighteen patients had relapsed after allogeneic stem-cell transplantation, and 3 had failed on blinatumomab therapy.

The treatment involved infusion of autologous T cells that had been engineered to express chimeric antibodies targeting tumor cells expressing CD19 (CTL019). Before now, “clinical progress has been limited by poor in vivo expansion of engineered T cells and failure of these cells to persist after infusion.” But, in this study, the infused cells showed robust proliferation and long-term persistence, the investigators said.

Within 1 month, 27 of the 30 patients (90%) attained complete morphologic remission. A test to detect minimal residual disease produced negative results in 22 of them; 3 patients who showed very low levels of residual disease subsequently tested negative at 3 months. After a median follow-up of 7 months (range, 2-24 months), 19 patients remained in remission: 15 of them required no further treatment and 4 withdrew from the trial to pursue additional therapies.

The 3 patients who had no initial response to CTL019 infusion showed very low levels of CTL019-modified T cells on blood flow cytometry, while the 27 who had an initial response showed high levels. These cells persisted in the blood for up to 11 months.

Event-free survival was 67% and overall survival was 78% at 6 months. In comparison, the most recently approved combination chemotherapy for relapsed ALL produces complete remission rates of less than 25% and has a median duration of response of 4-9 weeks, Dr. Maude and her associates said.

Seven patients died after disease progression or relapse, including one who developed myelodysplastic syndrome.

The most common and most serious adverse effect of chimeric antigen receptor T-cell therapy is the cytokine-release syndrome, a systemic inflammatory response produced by markedly high T-cell activation and proliferation. The syndrome ranges from a mild and self-limiting toxic response characterized by fever and myalgia to a severe, life-threatening response that may include vascular leakage, hypotension, respiratory and renal insufficiency, cytopenias, and coagulopathy.

All 30 patients in this study developed cytokine-release syndrome. “Some degree of cytokine-release syndrome is probably necessary for [treatment] efficacy,” the investigators said (N. Engl. J. Med 2014 Oct.16 [doi:10.1056/NEJMoa1407222]).

The syndrome was mild to moderate in 22 patients, but severe enough in the remaining 8 patients to require ICU care with varying degrees of respiratory support. The severity of cytokine-release syndrome was found to correlate with the burden of disease at baseline, with an increasing percentage of blast cells in bone marrow being significantly associated with increasing severity of the syndrome.

The use of the interleukin-6 receptor blocking antibody tocilizumab was found to rapidly resolve the syndrome, swiftly reducing fever and stabilizing blood pressure over 1-3 days. All the affected patients fully recovered, and the use of prophylactic tocilizumab for future patients is now being investigated.

Thirteen patients experienced neurotoxicity, ranging from delirium accompanying their fever to global encephalopathy characterized by aphasia, confusion, delirium, and hallucinations. These symptoms were self-limiting and resolved fully without apparent long-term sequelae in all cases.

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