Enrollment stalled for CAR T-cell study

Update: The hold on this trial has been lifted. Click here for additional details.

Memorial Sloan-Kettering Cancer Center has temporarily suspended enrollment in a study of chimeric antigen receptor (CAR) T-cell therapy, due to 2 patient deaths.

The study is an evaluation of CD19-targeted CAR T cells in patients with B-cell acute lymphoblastic leukemia (ALL).

Of the 22 patients enrolled on the study to date, 10 have died. But only 2 of these deaths gave researchers pause and made them question enrollment criteria.

Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 deaths that prompted the suspension of enrollment occurred within 2 weeks of the patients receiving CAR T cells.

“The first of these patients had a prior history of cardiac disease, while the second patient died due to complications associated with persistent seizure activity,” said Renier Brentjens, MD, PhD, of Memorial Sloan-Kettering in New York.

“As a matter of routine review at Sloan-Kettering for adverse events on-study, our center made the decision to pause enrollment and review these 2 patients in greater detail.”

“And as a consequence of this review, we’ve amended the enrollment criteria in regards to comorbidities, thereby excluding patients with cardiac disease, and adjusted the T-cell dose based on the extent of disease, [in the] hope that this modification will reduce the cytokine release syndrome that these patients with morphological disease have experienced.”

The researchers expect the trial to resume enrollment soon.

Some results from this study were recently published in Science Translational Medicine, and Dr Brentjens presented the latest results at the AACR Annual Meeting 2014 in San Diego (abstract CT102*).

Thus far, the researchers have enrolled 22 adult patients who had relapsed or refractory B-ALL, were minimal residual disease-positive, or were in the first complete remission (CR1) at enrollment. Patients in CR1 were monitored and only received CAR T cells if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by CAR T-cell infusion. After treatment, the options were allogeneic transplant, a different salvage therapy, or monitoring.

In all, 20 patients received a CAR T-cell dose of 3 x 10⁶ T cells/kg. Eighty-two percent of patients initially achieved a CR, and 72% had a morphologic CR. The average time to CR was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remain in remission.

Dr Brentjens noted that some patients developed cytokine release syndrome, and this was related to the amount of disease present at the time of CAR T-cell infusion.

“Those patients that had only minimal residual disease at the time of CAR T-cell infusion . . .  less than 5% blasts, generally had either no fever or very transient, low-grade fever,” he said.

“In contrast, all those patients that had morphologic residual disease at the time of CAR T-cell infusion demonstrated a high, persistent spike in fevers . . . , became hypotensive, and required transfer—for additional, closer monitoring—to our ICU.”

The researchers initially treated these patients with high-dose steroids, which reduced cytokine levels in the serum and ameliorated fevers. But it also rapidly reduced T-cell populations to undetectable levels.

Fortunately, another group of researchers subsequently discovered that the monoclonal antibody tocilizumab can treat cytokine release syndrome without inducing this side effect. So Dr Brentjens and his colleagues began using this drug and found it both safe and effective.

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

Update: The hold on this trial has been lifted. Click here for additional details.

Memorial Sloan-Kettering Cancer Center has temporarily suspended enrollment in a study of chimeric antigen receptor (CAR) T-cell therapy, due to 2 patient deaths.

The study is an evaluation of CD19-targeted CAR T cells in patients with B-cell acute lymphoblastic leukemia (ALL).

Of the 22 patients enrolled on the study to date, 10 have died. But only 2 of these deaths gave researchers pause and made them question enrollment criteria.

Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 deaths that prompted the suspension of enrollment occurred within 2 weeks of the patients receiving CAR T cells.

“The first of these patients had a prior history of cardiac disease, while the second patient died due to complications associated with persistent seizure activity,” said Renier Brentjens, MD, PhD, of Memorial Sloan-Kettering in New York.

“As a matter of routine review at Sloan-Kettering for adverse events on-study, our center made the decision to pause enrollment and review these 2 patients in greater detail.”

“And as a consequence of this review, we’ve amended the enrollment criteria in regards to comorbidities, thereby excluding patients with cardiac disease, and adjusted the T-cell dose based on the extent of disease, [in the] hope that this modification will reduce the cytokine release syndrome that these patients with morphological disease have experienced.”

The researchers expect the trial to resume enrollment soon.

Some results from this study were recently published in Science Translational Medicine, and Dr Brentjens presented the latest results at the AACR Annual Meeting 2014 in San Diego (abstract CT102*).

Thus far, the researchers have enrolled 22 adult patients who had relapsed or refractory B-ALL, were minimal residual disease-positive, or were in the first complete remission (CR1) at enrollment. Patients in CR1 were monitored and only received CAR T cells if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by CAR T-cell infusion. After treatment, the options were allogeneic transplant, a different salvage therapy, or monitoring.

In all, 20 patients received a CAR T-cell dose of 3 x 10⁶ T cells/kg. Eighty-two percent of patients initially achieved a CR, and 72% had a morphologic CR. The average time to CR was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remain in remission.

Dr Brentjens noted that some patients developed cytokine release syndrome, and this was related to the amount of disease present at the time of CAR T-cell infusion.

“Those patients that had only minimal residual disease at the time of CAR T-cell infusion . . .  less than 5% blasts, generally had either no fever or very transient, low-grade fever,” he said.

“In contrast, all those patients that had morphologic residual disease at the time of CAR T-cell infusion demonstrated a high, persistent spike in fevers . . . , became hypotensive, and required transfer—for additional, closer monitoring—to our ICU.”

The researchers initially treated these patients with high-dose steroids, which reduced cytokine levels in the serum and ameliorated fevers. But it also rapidly reduced T-cell populations to undetectable levels.

Fortunately, another group of researchers subsequently discovered that the monoclonal antibody tocilizumab can treat cytokine release syndrome without inducing this side effect. So Dr Brentjens and his colleagues began using this drug and found it both safe and effective.

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

Update: The hold on this trial has been lifted. Click here for additional details.

Memorial Sloan-Kettering Cancer Center has temporarily suspended enrollment in a study of chimeric antigen receptor (CAR) T-cell therapy, due to 2 patient deaths.

The study is an evaluation of CD19-targeted CAR T cells in patients with B-cell acute lymphoblastic leukemia (ALL).

Of the 22 patients enrolled on the study to date, 10 have died. But only 2 of these deaths gave researchers pause and made them question enrollment criteria.

Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 deaths that prompted the suspension of enrollment occurred within 2 weeks of the patients receiving CAR T cells.

“The first of these patients had a prior history of cardiac disease, while the second patient died due to complications associated with persistent seizure activity,” said Renier Brentjens, MD, PhD, of Memorial Sloan-Kettering in New York.

“As a matter of routine review at Sloan-Kettering for adverse events on-study, our center made the decision to pause enrollment and review these 2 patients in greater detail.”

“And as a consequence of this review, we’ve amended the enrollment criteria in regards to comorbidities, thereby excluding patients with cardiac disease, and adjusted the T-cell dose based on the extent of disease, [in the] hope that this modification will reduce the cytokine release syndrome that these patients with morphological disease have experienced.”

The researchers expect the trial to resume enrollment soon.

Some results from this study were recently published in Science Translational Medicine, and Dr Brentjens presented the latest results at the AACR Annual Meeting 2014 in San Diego (abstract CT102*).

Thus far, the researchers have enrolled 22 adult patients who had relapsed or refractory B-ALL, were minimal residual disease-positive, or were in the first complete remission (CR1) at enrollment. Patients in CR1 were monitored and only received CAR T cells if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by CAR T-cell infusion. After treatment, the options were allogeneic transplant, a different salvage therapy, or monitoring.

In all, 20 patients received a CAR T-cell dose of 3 x 10⁶ T cells/kg. Eighty-two percent of patients initially achieved a CR, and 72% had a morphologic CR. The average time to CR was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remain in remission.

Dr Brentjens noted that some patients developed cytokine release syndrome, and this was related to the amount of disease present at the time of CAR T-cell infusion.

“Those patients that had only minimal residual disease at the time of CAR T-cell infusion . . .  less than 5% blasts, generally had either no fever or very transient, low-grade fever,” he said.

“In contrast, all those patients that had morphologic residual disease at the time of CAR T-cell infusion demonstrated a high, persistent spike in fevers . . . , became hypotensive, and required transfer—for additional, closer monitoring—to our ICU.”

The researchers initially treated these patients with high-dose steroids, which reduced cytokine levels in the serum and ameliorated fevers. But it also rapidly reduced T-cell populations to undetectable levels.

Fortunately, another group of researchers subsequently discovered that the monoclonal antibody tocilizumab can treat cytokine release syndrome without inducing this side effect. So Dr Brentjens and his colleagues began using this drug and found it both safe and effective.

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