Team reports latest results of CTL019 in CLL

CTL019 cells

Photo from Penn Medicine

The chimeric antigen receptor (CAR) T-cell therapy CTL019 can produce durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in Science Translational Medicine.

Eight of 14 patients responded to CTL019—4 complete responses (CRs) and 4 partial responses (PRs).

Three of the patients with CRs were still alive and in remission at last follow-up. The longest remission has lasted 53 months.

Only 1 patient with a PR was still alive at last follow-up, and that patient progressed.

Nine patients developed cytokine release syndrome (CRS), some requiring intensive care. And there were 2 cases of tumor lysis syndrome.

These results are the most mature data from this trial. Results from this study were previously presented at ASH 2013 and ASH 2012, and they were published in NEJM and Science Translational Medicine in August 2011.

This study was supported by grants from Novartis, the Leukemia and Lymphoma Society, and the National Institutes of Health. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

Treatment and outcomes

The trial enrolled 23 CLL patients, but only 14 received CTL019. The 14 patients had a median age of 66 (range, 51 to 78), and most (n=14) were male.

They had received a median of 5 prior therapies (range, 1 to 11), and 8 patients had 17p deletion. All patients had active disease at the time of CTL019 infusion.

Patients received CTL019 at doses of 0.14 × 10⁸ to 11 × 10⁸ cells (median, 1.6 × 10⁸ cells). Eight patients responded to the treatment, for an overall response rate of 57%.

Four patients (29%) achieved a CR. One of these patients died while in remission at 21 months due to infectious complications that occurred after removal of a basal cell carcinoma on his leg.

The other 3 CR patients remained alive at the time of analysis, with no evidence of leukemia at 28 months, 52 months, and 53 months after receiving their infusions. They did not receive additional therapy after CTL019.

“The durability of the remissions we have observed in this study are remarkable and have given us great hope that personalized cell therapies are going to be important options for patients whose cancers are no longer treatable with standard approaches,” said study author David L. Porter, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

Four patients (29%) achieved a PR after receiving CTL019, with responses lasting a median of 7 months. Two of these patients died of disease progression 10 months and 27 months after receiving CTL019.

One PR patient died after suffering a pulmonary embolism 6 months after CTL019 infusion. The last PR patient experienced disease progression at 13 months, but the patient remained alive on other therapies 36 months after receiving CTL019.

Six patients (43%) did not respond to CTL019 and progressed within 1 month to 9 months. Tests revealed that the modified T cells did not expand as robustly in these patients as in those who experienced remissions.

Two of these patients later died from their disease or complications of other therapies, and 4 are receiving other types of treatment.

CRS and other toxicity

The investigators said infusional toxicities were infrequent and mild (less than grade 2). They were primarily low-grade fevers and chills.

The most frequent related adverse events were associated with complications of neutropenia (including fevers) and delayed CRS, which was correlated with in vivo CTL019 expansion. Nine patients (including all 8 responders) developed CRS.

Five patients with CRS required anti-cytokine-directed therapy—tocilizumab (n=4) and/or steroids (n=3). Four patients required intensive care for complications related to CRS, such as hypotension and hypoxia. They remained in the intensive care unit for a median of 6 days (range, 1-9).

Concurrent with CRS were 6 neurologic events in 5 patients—grade 1/2 hallucinations, confusion, or delirium typically associated with high fevers, intensive care, or medication use. There was 1 case of grade 4 confusion that lasted 2 days and was attributed, at least partly, to CTL019.

There were 2 cases of tumor lysis syndrome. And 1 patient died in remission 21 months after CTL019 infusion, having developed overwhelming ecthyma gangrenosum from a pseudomonas wound infection from a skin biopsy site.

CTL019 durability

“Importantly, our tests of patients who experienced complete remissions showed that the modified cells remain in patients’ bodies for years after their infusions, with no sign of cancerous or normal B cells,” said study author Carl H. June, MD, of the University of Pennsylvania Perelman School of Medicine.

“This suggests that at least some of the CTL019 cells retain their ability to hunt for cancerous cells for long periods of time.”

A lab experiment using CAR T cells isolated from one of the first patients to receive CTL019 confirmed the potential for long-term function of these cells. At nearly 3 years after infusion, the patient’s CTL019 cells demonstrated immediate and specific reactivity against cells expressing CD19.

CTL019 development

The investigators did not identify demographic or disease-related factors, such as age or types of prior therapies, that could be used to predict response to CTL019. And there was no association between T-cell dose and patient response.

An ongoing dose-optimization study is exploring this relationship in greater detail. Further future areas of study may include strategies to combine CTL019 with immune checkpoint inhibitors or other therapies to stimulate T-cell recognition of tumor cells.

In addition to CLL, CTL019 is under investigation in patients with acute lymphoblastic leukemia, non-Hodgkin lymphoma, and myeloma. The product has breakthrough designation from the US Food and Drug Administration for acute lymphoblastic leukemia.

CTL019 cells

Photo from Penn Medicine

The chimeric antigen receptor (CAR) T-cell therapy CTL019 can produce durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in Science Translational Medicine.

Eight of 14 patients responded to CTL019—4 complete responses (CRs) and 4 partial responses (PRs).

Three of the patients with CRs were still alive and in remission at last follow-up. The longest remission has lasted 53 months.

Only 1 patient with a PR was still alive at last follow-up, and that patient progressed.

Nine patients developed cytokine release syndrome (CRS), some requiring intensive care. And there were 2 cases of tumor lysis syndrome.

These results are the most mature data from this trial. Results from this study were previously presented at ASH 2013 and ASH 2012, and they were published in NEJM and Science Translational Medicine in August 2011.

This study was supported by grants from Novartis, the Leukemia and Lymphoma Society, and the National Institutes of Health. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

Treatment and outcomes

The trial enrolled 23 CLL patients, but only 14 received CTL019. The 14 patients had a median age of 66 (range, 51 to 78), and most (n=14) were male.

They had received a median of 5 prior therapies (range, 1 to 11), and 8 patients had 17p deletion. All patients had active disease at the time of CTL019 infusion.

Patients received CTL019 at doses of 0.14 × 10⁸ to 11 × 10⁸ cells (median, 1.6 × 10⁸ cells). Eight patients responded to the treatment, for an overall response rate of 57%.

Four patients (29%) achieved a CR. One of these patients died while in remission at 21 months due to infectious complications that occurred after removal of a basal cell carcinoma on his leg.

The other 3 CR patients remained alive at the time of analysis, with no evidence of leukemia at 28 months, 52 months, and 53 months after receiving their infusions. They did not receive additional therapy after CTL019.

“The durability of the remissions we have observed in this study are remarkable and have given us great hope that personalized cell therapies are going to be important options for patients whose cancers are no longer treatable with standard approaches,” said study author David L. Porter, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

Four patients (29%) achieved a PR after receiving CTL019, with responses lasting a median of 7 months. Two of these patients died of disease progression 10 months and 27 months after receiving CTL019.

One PR patient died after suffering a pulmonary embolism 6 months after CTL019 infusion. The last PR patient experienced disease progression at 13 months, but the patient remained alive on other therapies 36 months after receiving CTL019.

Six patients (43%) did not respond to CTL019 and progressed within 1 month to 9 months. Tests revealed that the modified T cells did not expand as robustly in these patients as in those who experienced remissions.

Two of these patients later died from their disease or complications of other therapies, and 4 are receiving other types of treatment.

CRS and other toxicity

The investigators said infusional toxicities were infrequent and mild (less than grade 2). They were primarily low-grade fevers and chills.

The most frequent related adverse events were associated with complications of neutropenia (including fevers) and delayed CRS, which was correlated with in vivo CTL019 expansion. Nine patients (including all 8 responders) developed CRS.

Five patients with CRS required anti-cytokine-directed therapy—tocilizumab (n=4) and/or steroids (n=3). Four patients required intensive care for complications related to CRS, such as hypotension and hypoxia. They remained in the intensive care unit for a median of 6 days (range, 1-9).

Concurrent with CRS were 6 neurologic events in 5 patients—grade 1/2 hallucinations, confusion, or delirium typically associated with high fevers, intensive care, or medication use. There was 1 case of grade 4 confusion that lasted 2 days and was attributed, at least partly, to CTL019.

There were 2 cases of tumor lysis syndrome. And 1 patient died in remission 21 months after CTL019 infusion, having developed overwhelming ecthyma gangrenosum from a pseudomonas wound infection from a skin biopsy site.

CTL019 durability

“Importantly, our tests of patients who experienced complete remissions showed that the modified cells remain in patients’ bodies for years after their infusions, with no sign of cancerous or normal B cells,” said study author Carl H. June, MD, of the University of Pennsylvania Perelman School of Medicine.

“This suggests that at least some of the CTL019 cells retain their ability to hunt for cancerous cells for long periods of time.”

A lab experiment using CAR T cells isolated from one of the first patients to receive CTL019 confirmed the potential for long-term function of these cells. At nearly 3 years after infusion, the patient’s CTL019 cells demonstrated immediate and specific reactivity against cells expressing CD19.

CTL019 development

The investigators did not identify demographic or disease-related factors, such as age or types of prior therapies, that could be used to predict response to CTL019. And there was no association between T-cell dose and patient response.

An ongoing dose-optimization study is exploring this relationship in greater detail. Further future areas of study may include strategies to combine CTL019 with immune checkpoint inhibitors or other therapies to stimulate T-cell recognition of tumor cells.

In addition to CLL, CTL019 is under investigation in patients with acute lymphoblastic leukemia, non-Hodgkin lymphoma, and myeloma. The product has breakthrough designation from the US Food and Drug Administration for acute lymphoblastic leukemia.

CTL019 cells

Photo from Penn Medicine

The chimeric antigen receptor (CAR) T-cell therapy CTL019 can produce durable responses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in Science Translational Medicine.

Eight of 14 patients responded to CTL019—4 complete responses (CRs) and 4 partial responses (PRs).

Three of the patients with CRs were still alive and in remission at last follow-up. The longest remission has lasted 53 months.

Only 1 patient with a PR was still alive at last follow-up, and that patient progressed.

Nine patients developed cytokine release syndrome (CRS), some requiring intensive care. And there were 2 cases of tumor lysis syndrome.

These results are the most mature data from this trial. Results from this study were previously presented at ASH 2013 and ASH 2012, and they were published in NEJM and Science Translational Medicine in August 2011.

This study was supported by grants from Novartis, the Leukemia and Lymphoma Society, and the National Institutes of Health. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

Treatment and outcomes

The trial enrolled 23 CLL patients, but only 14 received CTL019. The 14 patients had a median age of 66 (range, 51 to 78), and most (n=14) were male.

They had received a median of 5 prior therapies (range, 1 to 11), and 8 patients had 17p deletion. All patients had active disease at the time of CTL019 infusion.

Patients received CTL019 at doses of 0.14 × 10⁸ to 11 × 10⁸ cells (median, 1.6 × 10⁸ cells). Eight patients responded to the treatment, for an overall response rate of 57%.

Four patients (29%) achieved a CR. One of these patients died while in remission at 21 months due to infectious complications that occurred after removal of a basal cell carcinoma on his leg.

The other 3 CR patients remained alive at the time of analysis, with no evidence of leukemia at 28 months, 52 months, and 53 months after receiving their infusions. They did not receive additional therapy after CTL019.

“The durability of the remissions we have observed in this study are remarkable and have given us great hope that personalized cell therapies are going to be important options for patients whose cancers are no longer treatable with standard approaches,” said study author David L. Porter, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

Four patients (29%) achieved a PR after receiving CTL019, with responses lasting a median of 7 months. Two of these patients died of disease progression 10 months and 27 months after receiving CTL019.

One PR patient died after suffering a pulmonary embolism 6 months after CTL019 infusion. The last PR patient experienced disease progression at 13 months, but the patient remained alive on other therapies 36 months after receiving CTL019.

Six patients (43%) did not respond to CTL019 and progressed within 1 month to 9 months. Tests revealed that the modified T cells did not expand as robustly in these patients as in those who experienced remissions.

Two of these patients later died from their disease or complications of other therapies, and 4 are receiving other types of treatment.

CRS and other toxicity

The investigators said infusional toxicities were infrequent and mild (less than grade 2). They were primarily low-grade fevers and chills.

The most frequent related adverse events were associated with complications of neutropenia (including fevers) and delayed CRS, which was correlated with in vivo CTL019 expansion. Nine patients (including all 8 responders) developed CRS.

Five patients with CRS required anti-cytokine-directed therapy—tocilizumab (n=4) and/or steroids (n=3). Four patients required intensive care for complications related to CRS, such as hypotension and hypoxia. They remained in the intensive care unit for a median of 6 days (range, 1-9).

Concurrent with CRS were 6 neurologic events in 5 patients—grade 1/2 hallucinations, confusion, or delirium typically associated with high fevers, intensive care, or medication use. There was 1 case of grade 4 confusion that lasted 2 days and was attributed, at least partly, to CTL019.

There were 2 cases of tumor lysis syndrome. And 1 patient died in remission 21 months after CTL019 infusion, having developed overwhelming ecthyma gangrenosum from a pseudomonas wound infection from a skin biopsy site.

CTL019 durability

“Importantly, our tests of patients who experienced complete remissions showed that the modified cells remain in patients’ bodies for years after their infusions, with no sign of cancerous or normal B cells,” said study author Carl H. June, MD, of the University of Pennsylvania Perelman School of Medicine.

“This suggests that at least some of the CTL019 cells retain their ability to hunt for cancerous cells for long periods of time.”

A lab experiment using CAR T cells isolated from one of the first patients to receive CTL019 confirmed the potential for long-term function of these cells. At nearly 3 years after infusion, the patient’s CTL019 cells demonstrated immediate and specific reactivity against cells expressing CD19.

CTL019 development

The investigators did not identify demographic or disease-related factors, such as age or types of prior therapies, that could be used to predict response to CTL019. And there was no association between T-cell dose and patient response.

An ongoing dose-optimization study is exploring this relationship in greater detail. Further future areas of study may include strategies to combine CTL019 with immune checkpoint inhibitors or other therapies to stimulate T-cell recognition of tumor cells.

In addition to CLL, CTL019 is under investigation in patients with acute lymphoblastic leukemia, non-Hodgkin lymphoma, and myeloma. The product has breakthrough designation from the US Food and Drug Administration for acute lymphoblastic leukemia.