CAR is feasible in majority of ALL patients, team says

ALL patient

Credit: Bill Branson

SAN FRANCISCO—A chimeric antigen receptor (CAR) T-cell therapy is feasible in 90% of heavily pretreated or transplanted patients with acute lymphoblastic leukemia (ALL) and can serve as a bridge to transplant, according to investigators.

Daniel W. Lee III, MD, of the National Cancer Institute in Bethesda, Maryland, reported on a phase 1 study of this CD19 CAR T-cell therapy in children and young adults with CD19+ ALL or non-Hodgkin lymphoma at the 2014 ASH Annual Meeting (abstract 381*).

Twenty-one patients were enrolled on the trial. They had a preparative regimen of fludarabine and cyclophosphamide and were infused with CAR T cells 11 days after the peripheral blood mononuclear cells were collected.

Dose levels were 1 x 10⁶ CAR+ T cells/kg, 3 x 10⁶ CAR+ T cells/kg, or the maximum number of cells generated if below either one of these levels. Two patients received less than the dose assigned and were not evaluated for toxicity.

Patients were a median age of 13 years (range, 5 to 27). Fourteen were male, 20 had ALL, and 1 had diffuse large B-cell lymphoma.

All had detectable disease, and 2 were CNS2 at the time of T-cell infusion. Six had primary refractory disease, 8 had at least 1 prior stem cell transplant, and 4 had prior immunotherapy.

The investigators determined that the maximally tolerated dose was 1 x 10⁶ CAR+ T cells/kg. The dose-limiting toxicities were related to cytokine release syndrome (CRS), which was reversible if managed appropriately with tocilizumab, with or without steroids.

Grade 3 adverse events possibly related to therapy included fever (47%), febrile neutropenia (37%), electrolyte disturbance (29%), CRS (16%), hypotension (11%), transaminitis (16%), and 5% each for hypertension, prolonged QTc, dysphasia, LV systolic dysfunction, multiorgan failure, hypoxia, and pulmonary edema.

Grade 4 events possibly related to treatment included electrolyte disturbance (5%), CRS (16%), hypotension (11%), cardiac arrest (5%), and hypoxia (5%). There was no evidence of graft-vs-host disease.

The complete response (CR) rate was 67% in the intent-to-treat population and 70% in patients with ALL.

“Those patients who responded tended to have some degree of cytokine release syndrome, whereas those patients who did not respond or had stable disease did not have any CRS,” Dr Lee said. “But, also, it’s important to note that you don’t have to have severe grade 3 or grade 4 CRS in order to have significant response.”

Dr Lee also pointed out that in vivo CAR T-cell expansion significantly correlated with response (P=0.0028). And CRS severity correlated with IL-6 (P=0.0002), INF-γ (P=0.0002), C-reactive protein (P=0.0015), and CAR (P=0.0011).

At a median follow-up of 10 months, minimal residual disease-negative patients had a 79% leukemia-free survival. Overall survival was 52% for all patients enrolled. Two patients had CD19-negative relapses.

The investigators also found that CAR T cells can eliminate CNS leukemia, with 11 of 17 patients (65%) having CAR T cells detectable in their cerebrospinal fluid.

The team concluded that this therapy is feasible in 90% of heavily pretreated or transplanted ALL patients and can serve as a bridge to transplant.

*Information in the abstract differs from that presented at the meeting.

ALL patient

Credit: Bill Branson

SAN FRANCISCO—A chimeric antigen receptor (CAR) T-cell therapy is feasible in 90% of heavily pretreated or transplanted patients with acute lymphoblastic leukemia (ALL) and can serve as a bridge to transplant, according to investigators.

Daniel W. Lee III, MD, of the National Cancer Institute in Bethesda, Maryland, reported on a phase 1 study of this CD19 CAR T-cell therapy in children and young adults with CD19+ ALL or non-Hodgkin lymphoma at the 2014 ASH Annual Meeting (abstract 381*).

Twenty-one patients were enrolled on the trial. They had a preparative regimen of fludarabine and cyclophosphamide and were infused with CAR T cells 11 days after the peripheral blood mononuclear cells were collected.

Dose levels were 1 x 10⁶ CAR+ T cells/kg, 3 x 10⁶ CAR+ T cells/kg, or the maximum number of cells generated if below either one of these levels. Two patients received less than the dose assigned and were not evaluated for toxicity.

Patients were a median age of 13 years (range, 5 to 27). Fourteen were male, 20 had ALL, and 1 had diffuse large B-cell lymphoma.

All had detectable disease, and 2 were CNS2 at the time of T-cell infusion. Six had primary refractory disease, 8 had at least 1 prior stem cell transplant, and 4 had prior immunotherapy.

The investigators determined that the maximally tolerated dose was 1 x 10⁶ CAR+ T cells/kg. The dose-limiting toxicities were related to cytokine release syndrome (CRS), which was reversible if managed appropriately with tocilizumab, with or without steroids.

Grade 3 adverse events possibly related to therapy included fever (47%), febrile neutropenia (37%), electrolyte disturbance (29%), CRS (16%), hypotension (11%), transaminitis (16%), and 5% each for hypertension, prolonged QTc, dysphasia, LV systolic dysfunction, multiorgan failure, hypoxia, and pulmonary edema.

Grade 4 events possibly related to treatment included electrolyte disturbance (5%), CRS (16%), hypotension (11%), cardiac arrest (5%), and hypoxia (5%). There was no evidence of graft-vs-host disease.

The complete response (CR) rate was 67% in the intent-to-treat population and 70% in patients with ALL.

“Those patients who responded tended to have some degree of cytokine release syndrome, whereas those patients who did not respond or had stable disease did not have any CRS,” Dr Lee said. “But, also, it’s important to note that you don’t have to have severe grade 3 or grade 4 CRS in order to have significant response.”

Dr Lee also pointed out that in vivo CAR T-cell expansion significantly correlated with response (P=0.0028). And CRS severity correlated with IL-6 (P=0.0002), INF-γ (P=0.0002), C-reactive protein (P=0.0015), and CAR (P=0.0011).

At a median follow-up of 10 months, minimal residual disease-negative patients had a 79% leukemia-free survival. Overall survival was 52% for all patients enrolled. Two patients had CD19-negative relapses.

The investigators also found that CAR T cells can eliminate CNS leukemia, with 11 of 17 patients (65%) having CAR T cells detectable in their cerebrospinal fluid.

The team concluded that this therapy is feasible in 90% of heavily pretreated or transplanted ALL patients and can serve as a bridge to transplant.

*Information in the abstract differs from that presented at the meeting.

ALL patient

Credit: Bill Branson

SAN FRANCISCO—A chimeric antigen receptor (CAR) T-cell therapy is feasible in 90% of heavily pretreated or transplanted patients with acute lymphoblastic leukemia (ALL) and can serve as a bridge to transplant, according to investigators.

Daniel W. Lee III, MD, of the National Cancer Institute in Bethesda, Maryland, reported on a phase 1 study of this CD19 CAR T-cell therapy in children and young adults with CD19+ ALL or non-Hodgkin lymphoma at the 2014 ASH Annual Meeting (abstract 381*).

Twenty-one patients were enrolled on the trial. They had a preparative regimen of fludarabine and cyclophosphamide and were infused with CAR T cells 11 days after the peripheral blood mononuclear cells were collected.

Dose levels were 1 x 10⁶ CAR+ T cells/kg, 3 x 10⁶ CAR+ T cells/kg, or the maximum number of cells generated if below either one of these levels. Two patients received less than the dose assigned and were not evaluated for toxicity.

Patients were a median age of 13 years (range, 5 to 27). Fourteen were male, 20 had ALL, and 1 had diffuse large B-cell lymphoma.

All had detectable disease, and 2 were CNS2 at the time of T-cell infusion. Six had primary refractory disease, 8 had at least 1 prior stem cell transplant, and 4 had prior immunotherapy.

The investigators determined that the maximally tolerated dose was 1 x 10⁶ CAR+ T cells/kg. The dose-limiting toxicities were related to cytokine release syndrome (CRS), which was reversible if managed appropriately with tocilizumab, with or without steroids.

Grade 3 adverse events possibly related to therapy included fever (47%), febrile neutropenia (37%), electrolyte disturbance (29%), CRS (16%), hypotension (11%), transaminitis (16%), and 5% each for hypertension, prolonged QTc, dysphasia, LV systolic dysfunction, multiorgan failure, hypoxia, and pulmonary edema.

Grade 4 events possibly related to treatment included electrolyte disturbance (5%), CRS (16%), hypotension (11%), cardiac arrest (5%), and hypoxia (5%). There was no evidence of graft-vs-host disease.

The complete response (CR) rate was 67% in the intent-to-treat population and 70% in patients with ALL.

“Those patients who responded tended to have some degree of cytokine release syndrome, whereas those patients who did not respond or had stable disease did not have any CRS,” Dr Lee said. “But, also, it’s important to note that you don’t have to have severe grade 3 or grade 4 CRS in order to have significant response.”

Dr Lee also pointed out that in vivo CAR T-cell expansion significantly correlated with response (P=0.0028). And CRS severity correlated with IL-6 (P=0.0002), INF-γ (P=0.0002), C-reactive protein (P=0.0015), and CAR (P=0.0011).

At a median follow-up of 10 months, minimal residual disease-negative patients had a 79% leukemia-free survival. Overall survival was 52% for all patients enrolled. Two patients had CD19-negative relapses.

The investigators also found that CAR T cells can eliminate CNS leukemia, with 11 of 17 patients (65%) having CAR T cells detectable in their cerebrospinal fluid.

The team concluded that this therapy is feasible in 90% of heavily pretreated or transplanted ALL patients and can serve as a bridge to transplant.

*Information in the abstract differs from that presented at the meeting.