ALL

Fred Hutch News Service

Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.

The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.

The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.

Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.

“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.

So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.

The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.

Neurotoxicity

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.

Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.

Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).

For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.

The 4 neurotoxicity-related deaths were due to:

• Acute cerebral edema (n=2)
• Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
• Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).

Potential biomarkers

In a univariate analysis, neurotoxicity was significantly more frequent in patients who:

• Had CRS (P<0.0001)
• Received a high CAR T-cell dose (P<0.0001)
• Had pre-existing neurologic comorbidities at baseline (P=0.0059).

In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:

• Had pre-existing neurologic comorbidities (P=0.0023)
• Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
• Received a higher CAR T-cell dose (P=0.0009)
• Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).

The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.

Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.

Algorithm

The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.

The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:

• Fever of 38.9°C or greater
• Serum levels of IL6 at 16 pg/mL or higher
• Serum levels of MCP1 at 1343.5 pg/mL or higher.

This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Funding

This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.

Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.

Fred Hutch News Service

Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.

The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.

The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.

Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.

“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.

So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.

The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.

Neurotoxicity

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.

Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.

Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).

For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.

The 4 neurotoxicity-related deaths were due to:

• Acute cerebral edema (n=2)
• Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
• Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).

Potential biomarkers

In a univariate analysis, neurotoxicity was significantly more frequent in patients who:

• Had CRS (P<0.0001)
• Received a high CAR T-cell dose (P<0.0001)
• Had pre-existing neurologic comorbidities at baseline (P=0.0059).

In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:

• Had pre-existing neurologic comorbidities (P=0.0023)
• Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
• Received a higher CAR T-cell dose (P=0.0009)
• Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).

The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.

Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.

Algorithm

The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.

The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:

• Fever of 38.9°C or greater
• Serum levels of IL6 at 16 pg/mL or higher
• Serum levels of MCP1 at 1343.5 pg/mL or higher.

This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Funding

This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.

Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.

Fred Hutch News Service

Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.

The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.

The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.

Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.

“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.

So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.

The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.

Neurotoxicity

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.

Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.

Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).

For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.

The 4 neurotoxicity-related deaths were due to:

• Acute cerebral edema (n=2)
• Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
• Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).

Potential biomarkers

In a univariate analysis, neurotoxicity was significantly more frequent in patients who:

• Had CRS (P<0.0001)
• Received a high CAR T-cell dose (P<0.0001)
• Had pre-existing neurologic comorbidities at baseline (P=0.0059).

In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:

• Had pre-existing neurologic comorbidities (P=0.0023)
• Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
• Received a higher CAR T-cell dose (P=0.0009)
• Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).

The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.

Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.

Algorithm

The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.

The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:

• Fever of 38.9°C or greater
• Serum levels of IL6 at 16 pg/mL or higher
• Serum levels of MCP1 at 1343.5 pg/mL or higher.

This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Funding

This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.

Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.

SAN FRANCISCO – A growing number of immunotherapy options for adults with acute lymphocytic leukemia (ALL) – rituximab, inotuzumab ozogamicin, blinatumomab and chimeric antigen receptor (CAR) T-cell therapy – have improved remission rates, but their collective effects on patient outcomes remain to be seen, David Maloney, MD, PhD, said at the National Comprehensive Cancer Network Annual Congress: Hematologic Malignancies.

The main challenge for the field is deciding when and how to use a variety of therapies, he said. “How are we going to put these together? What’s the order?” he asked. “Are we going to be able to decrease the need for allogeneic stem cell transplant? And, obviously, that’s the goal.”

About 30%-50% of adults with ALL exhibit CD20-positive cells, making them potentially treatable with rituximab. Data show a better event-free survival rate and a reduced relapse rate when rituximab is added to standard chemotherapy as compared with standard chemotherapy alone, Dr. Maloney of the clinical research division at the Fred Hutchinson Cancer Research Center, Seattle, noted (N Engl J Med. 2016 Sep 15;375[11]:1044-53). But the improvement was only “modest,” he said.

The anti-CD22 antibody inotuzumab ozogamicin has produced complete remission in 81% of relapsed or refractory ALL patients, compared with those getting standard therapy (N Engl J Med. 2016 Aug 25;375:740-53). Dr. Maloney said it seems well tolerated, but there is concern about an increase in veno-occlusive disease in patients who have undergone or will undergo an allogeneic stem cell transplant.

Blinatumomab produces moderate response rates and minimal residual disease–negative remissions, but delivery of the drug is “cumbersome,” requiring a 4-week continuous infusion, he said. The drug seems to be more effective in those with a lower burden of disease, he noted.

CAR T-cell therapy has produced MRD-negative complete responses in 94% of patients, based on results from a clinical trial at Fred Hutchinson. And using the chemotherapy drug fludarabine in combination with this therapy “dramatically” boosts the peak number of the CAR T cells and how long they persist, Dr. Maloney said. Still, CAR T-cell therapy is a work-intensive treatment requiring cells harvested from the patient, and the procedure often brings on cytokine-release syndrome and neurotoxicity, though both adverse events are typically reversible, he said.

It may be that using fewer CAR T cells can reduce toxicity without compromising treatment response, he said.

Questions remain over whether to transplant patients who are in remission after CAR T-cell therapy. “This is a hot debate,” he said. The decision will likely depend on their prior therapy, whether they’ve had a prior transplant, and the how robust the CAR T-cell expansion has been, he said.

Dr. Maloney reports financial relationships with Celgene, Gilead Sciences, Kite Pharma, and Roche.

SAN FRANCISCO – A growing number of immunotherapy options for adults with acute lymphocytic leukemia (ALL) – rituximab, inotuzumab ozogamicin, blinatumomab and chimeric antigen receptor (CAR) T-cell therapy – have improved remission rates, but their collective effects on patient outcomes remain to be seen, David Maloney, MD, PhD, said at the National Comprehensive Cancer Network Annual Congress: Hematologic Malignancies.

The main challenge for the field is deciding when and how to use a variety of therapies, he said. “How are we going to put these together? What’s the order?” he asked. “Are we going to be able to decrease the need for allogeneic stem cell transplant? And, obviously, that’s the goal.”

About 30%-50% of adults with ALL exhibit CD20-positive cells, making them potentially treatable with rituximab. Data show a better event-free survival rate and a reduced relapse rate when rituximab is added to standard chemotherapy as compared with standard chemotherapy alone, Dr. Maloney of the clinical research division at the Fred Hutchinson Cancer Research Center, Seattle, noted (N Engl J Med. 2016 Sep 15;375[11]:1044-53). But the improvement was only “modest,” he said.

The anti-CD22 antibody inotuzumab ozogamicin has produced complete remission in 81% of relapsed or refractory ALL patients, compared with those getting standard therapy (N Engl J Med. 2016 Aug 25;375:740-53). Dr. Maloney said it seems well tolerated, but there is concern about an increase in veno-occlusive disease in patients who have undergone or will undergo an allogeneic stem cell transplant.

Blinatumomab produces moderate response rates and minimal residual disease–negative remissions, but delivery of the drug is “cumbersome,” requiring a 4-week continuous infusion, he said. The drug seems to be more effective in those with a lower burden of disease, he noted.

CAR T-cell therapy has produced MRD-negative complete responses in 94% of patients, based on results from a clinical trial at Fred Hutchinson. And using the chemotherapy drug fludarabine in combination with this therapy “dramatically” boosts the peak number of the CAR T cells and how long they persist, Dr. Maloney said. Still, CAR T-cell therapy is a work-intensive treatment requiring cells harvested from the patient, and the procedure often brings on cytokine-release syndrome and neurotoxicity, though both adverse events are typically reversible, he said.

It may be that using fewer CAR T cells can reduce toxicity without compromising treatment response, he said.

Questions remain over whether to transplant patients who are in remission after CAR T-cell therapy. “This is a hot debate,” he said. The decision will likely depend on their prior therapy, whether they’ve had a prior transplant, and the how robust the CAR T-cell expansion has been, he said.

Dr. Maloney reports financial relationships with Celgene, Gilead Sciences, Kite Pharma, and Roche.

SAN FRANCISCO – A growing number of immunotherapy options for adults with acute lymphocytic leukemia (ALL) – rituximab, inotuzumab ozogamicin, blinatumomab and chimeric antigen receptor (CAR) T-cell therapy – have improved remission rates, but their collective effects on patient outcomes remain to be seen, David Maloney, MD, PhD, said at the National Comprehensive Cancer Network Annual Congress: Hematologic Malignancies.

The main challenge for the field is deciding when and how to use a variety of therapies, he said. “How are we going to put these together? What’s the order?” he asked. “Are we going to be able to decrease the need for allogeneic stem cell transplant? And, obviously, that’s the goal.”

About 30%-50% of adults with ALL exhibit CD20-positive cells, making them potentially treatable with rituximab. Data show a better event-free survival rate and a reduced relapse rate when rituximab is added to standard chemotherapy as compared with standard chemotherapy alone, Dr. Maloney of the clinical research division at the Fred Hutchinson Cancer Research Center, Seattle, noted (N Engl J Med. 2016 Sep 15;375[11]:1044-53). But the improvement was only “modest,” he said.

The anti-CD22 antibody inotuzumab ozogamicin has produced complete remission in 81% of relapsed or refractory ALL patients, compared with those getting standard therapy (N Engl J Med. 2016 Aug 25;375:740-53). Dr. Maloney said it seems well tolerated, but there is concern about an increase in veno-occlusive disease in patients who have undergone or will undergo an allogeneic stem cell transplant.

Blinatumomab produces moderate response rates and minimal residual disease–negative remissions, but delivery of the drug is “cumbersome,” requiring a 4-week continuous infusion, he said. The drug seems to be more effective in those with a lower burden of disease, he noted.

CAR T-cell therapy has produced MRD-negative complete responses in 94% of patients, based on results from a clinical trial at Fred Hutchinson. And using the chemotherapy drug fludarabine in combination with this therapy “dramatically” boosts the peak number of the CAR T cells and how long they persist, Dr. Maloney said. Still, CAR T-cell therapy is a work-intensive treatment requiring cells harvested from the patient, and the procedure often brings on cytokine-release syndrome and neurotoxicity, though both adverse events are typically reversible, he said.

It may be that using fewer CAR T cells can reduce toxicity without compromising treatment response, he said.

Questions remain over whether to transplant patients who are in remission after CAR T-cell therapy. “This is a hot debate,” he said. The decision will likely depend on their prior therapy, whether they’ve had a prior transplant, and the how robust the CAR T-cell expansion has been, he said.

Dr. Maloney reports financial relationships with Celgene, Gilead Sciences, Kite Pharma, and Roche.

Photo by Bill Branson

A study of cancer drugs approved by the European Commission from 2009 to 2013 showed that few hematology drugs were known to provide a benefit in overall survival (OS) or quality of life (QOL) over existing treatments.

Of 12 drugs approved for 17 hematology indications, 3 drugs had been shown to provide a benefit in OS (for 3 indications) at the time of approval.

None of the other hematology drugs were known to provide an OS benefit even after a median follow-up of 5.4 years.

Two hematology drugs were shown to provide a benefit in QOL (for 2 indications) after approval, but none of the drugs were known to provide a QOL benefit at the time of approval.

These findings were published in The BMJ alongside a related editorial, feature article, and patient commentary.

All cancer drugs

Researchers analyzed reports on all cancer drug approvals by the European Commission from 2009 to 2013.

There were 48 drugs approved for 68 cancer indications during this period. Fifty-one of the indications were for solid tumor malignancies, and 17 were for hematologic malignancies.

For 24 indications (35%), research had demonstrated a significant improvement in OS at the time of the drugs’ approval. For 3 indications, an improvement in OS was demonstrated after approval.

There was a known improvement in QOL for 7 of the indications (10%) at the time of approval and for 5 indications after approval.

The median follow-up was 5.4 years (range, 3.3 years to 8.1 years).

Overall, there was a significant improvement in OS or QOL during the study period for 51% of the indications (35/68). For the other half (49%, n=33), it wasn’t clear if the drugs provide any benefits in OS or QOL.

All cancer trials

The 68 approvals of cancer drugs were supported by 72 clinical trials.

Sixty approvals (88%) were supported by at least 1 randomized, controlled trial. Eight approvals (12%) were based on a single-arm study. This included 6 of 10 conditional marketing authorizations and 2 of 58 regular marketing authorizations.

Eighteen of the approvals (26%) were supported by a pivotal study powered to evaluate OS as the primary endpoint. And 37 of the approvals (54%) had a supporting pivotal trial evaluating QOL, but results were not reported for 2 of these trials.

Hematology trials and drugs

Of the 12 drugs approved for 17 hematology indications, 4 were regular approvals, 5 were conditional approvals, and 8 had orphan drug designation.

The approvals were supported by data from 18 trials—13 randomized and 5 single-arm trials.

The study drug was compared to an active comparator in 9 of the trials. The drug was evaluated as an add-on treatment in 4 trials. And the drug was not compared to anything in 5 trials (the single-arm trials).

OS was the primary endpoint in 1 of the trials, and 17 trials had OS or QOL as a secondary endpoint.

There were 3 drugs that had demonstrated an OS benefit at the time of approval but no QOL benefit at any time:

• Decitabine used for first-line treatment of acute myeloid leukemia in adults 65 and older who are ineligible for chemotherapy
• Pomalidomide in combination with dexamethasone as third-line therapy for relapsed/refractory multiple myeloma (MM)
• Rituximab plus chemotherapy for first-line treatment of chronic lymphocytic leukemia (CLL).

There were 2 drugs that had demonstrated a QOL benefit, only after approval, but they were not known to provide an OS benefit at any time:

• Nilotinib as a treatment for adults with newly diagnosed, chronic phase, Ph+ chronic myeloid leukemia (CML)
• Ofatumumab for CLL that is refractory to fludarabine and alemtuzumab

For the remaining drugs, there was no evidence of an OS or QOL benefit at any time during the period studied. The drugs included:

• Bortezomib given alone or in combination with doxorubicin or dexamethasone as second-line therapy for MM patients ineligible for hematopoietic stem cell transplant (HSCT)
• Bortezomib plus dexamethasone with or without thalidomide as first-line therapy in MM patients eligible for HSCT
• Bosutinib as second- or third-line treatment of Ph+ CML (any phase)
• Brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma
• Brentuximab vedotin for relapsed or refractory, CD30+ Hodgkin lymphoma after autologous HSCT or as third-line treatment for patients ineligible for autologous HSCT
• Dasatinib for first-line treatment of chronic phase, Ph+ CML
• Pixantrone for multiply relapsed or refractory B-cell non-Hodgkin lymphoma
• Ponatinib for patients with Ph+ acute lymphoblastic leukemia who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib or characterized by T315I mutation
• Ponatinib for patients with any phase of CML who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib/nilotinib or characterized by T315I mutation
• Rituximab as maintenance after induction for patients with follicular lymphoma
• Rituximab plus chemotherapy for relapsed or refractory CLL
• Temsirolimus for relapsed or refractory mantle cell lymphoma.
  

Photo by Bill Branson

A study of cancer drugs approved by the European Commission from 2009 to 2013 showed that few hematology drugs were known to provide a benefit in overall survival (OS) or quality of life (QOL) over existing treatments.

Of 12 drugs approved for 17 hematology indications, 3 drugs had been shown to provide a benefit in OS (for 3 indications) at the time of approval.

None of the other hematology drugs were known to provide an OS benefit even after a median follow-up of 5.4 years.

Two hematology drugs were shown to provide a benefit in QOL (for 2 indications) after approval, but none of the drugs were known to provide a QOL benefit at the time of approval.

These findings were published in The BMJ alongside a related editorial, feature article, and patient commentary.

All cancer drugs

Researchers analyzed reports on all cancer drug approvals by the European Commission from 2009 to 2013.

There were 48 drugs approved for 68 cancer indications during this period. Fifty-one of the indications were for solid tumor malignancies, and 17 were for hematologic malignancies.

For 24 indications (35%), research had demonstrated a significant improvement in OS at the time of the drugs’ approval. For 3 indications, an improvement in OS was demonstrated after approval.

There was a known improvement in QOL for 7 of the indications (10%) at the time of approval and for 5 indications after approval.

The median follow-up was 5.4 years (range, 3.3 years to 8.1 years).

Overall, there was a significant improvement in OS or QOL during the study period for 51% of the indications (35/68). For the other half (49%, n=33), it wasn’t clear if the drugs provide any benefits in OS or QOL.

All cancer trials

The 68 approvals of cancer drugs were supported by 72 clinical trials.

Sixty approvals (88%) were supported by at least 1 randomized, controlled trial. Eight approvals (12%) were based on a single-arm study. This included 6 of 10 conditional marketing authorizations and 2 of 58 regular marketing authorizations.

Eighteen of the approvals (26%) were supported by a pivotal study powered to evaluate OS as the primary endpoint. And 37 of the approvals (54%) had a supporting pivotal trial evaluating QOL, but results were not reported for 2 of these trials.

Hematology trials and drugs

Of the 12 drugs approved for 17 hematology indications, 4 were regular approvals, 5 were conditional approvals, and 8 had orphan drug designation.

The approvals were supported by data from 18 trials—13 randomized and 5 single-arm trials.

The study drug was compared to an active comparator in 9 of the trials. The drug was evaluated as an add-on treatment in 4 trials. And the drug was not compared to anything in 5 trials (the single-arm trials).

OS was the primary endpoint in 1 of the trials, and 17 trials had OS or QOL as a secondary endpoint.

There were 3 drugs that had demonstrated an OS benefit at the time of approval but no QOL benefit at any time:

• Decitabine used for first-line treatment of acute myeloid leukemia in adults 65 and older who are ineligible for chemotherapy
• Pomalidomide in combination with dexamethasone as third-line therapy for relapsed/refractory multiple myeloma (MM)
• Rituximab plus chemotherapy for first-line treatment of chronic lymphocytic leukemia (CLL).

There were 2 drugs that had demonstrated a QOL benefit, only after approval, but they were not known to provide an OS benefit at any time:

• Nilotinib as a treatment for adults with newly diagnosed, chronic phase, Ph+ chronic myeloid leukemia (CML)
• Ofatumumab for CLL that is refractory to fludarabine and alemtuzumab

For the remaining drugs, there was no evidence of an OS or QOL benefit at any time during the period studied. The drugs included:

• Bortezomib given alone or in combination with doxorubicin or dexamethasone as second-line therapy for MM patients ineligible for hematopoietic stem cell transplant (HSCT)
• Bortezomib plus dexamethasone with or without thalidomide as first-line therapy in MM patients eligible for HSCT
• Bosutinib as second- or third-line treatment of Ph+ CML (any phase)
• Brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma
• Brentuximab vedotin for relapsed or refractory, CD30+ Hodgkin lymphoma after autologous HSCT or as third-line treatment for patients ineligible for autologous HSCT
• Dasatinib for first-line treatment of chronic phase, Ph+ CML
• Pixantrone for multiply relapsed or refractory B-cell non-Hodgkin lymphoma
• Ponatinib for patients with Ph+ acute lymphoblastic leukemia who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib or characterized by T315I mutation
• Ponatinib for patients with any phase of CML who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib/nilotinib or characterized by T315I mutation
• Rituximab as maintenance after induction for patients with follicular lymphoma
• Rituximab plus chemotherapy for relapsed or refractory CLL
• Temsirolimus for relapsed or refractory mantle cell lymphoma.
  

Photo by Bill Branson

A study of cancer drugs approved by the European Commission from 2009 to 2013 showed that few hematology drugs were known to provide a benefit in overall survival (OS) or quality of life (QOL) over existing treatments.

Of 12 drugs approved for 17 hematology indications, 3 drugs had been shown to provide a benefit in OS (for 3 indications) at the time of approval.

None of the other hematology drugs were known to provide an OS benefit even after a median follow-up of 5.4 years.

Two hematology drugs were shown to provide a benefit in QOL (for 2 indications) after approval, but none of the drugs were known to provide a QOL benefit at the time of approval.

These findings were published in The BMJ alongside a related editorial, feature article, and patient commentary.

All cancer drugs

Researchers analyzed reports on all cancer drug approvals by the European Commission from 2009 to 2013.

There were 48 drugs approved for 68 cancer indications during this period. Fifty-one of the indications were for solid tumor malignancies, and 17 were for hematologic malignancies.

For 24 indications (35%), research had demonstrated a significant improvement in OS at the time of the drugs’ approval. For 3 indications, an improvement in OS was demonstrated after approval.

There was a known improvement in QOL for 7 of the indications (10%) at the time of approval and for 5 indications after approval.

The median follow-up was 5.4 years (range, 3.3 years to 8.1 years).

Overall, there was a significant improvement in OS or QOL during the study period for 51% of the indications (35/68). For the other half (49%, n=33), it wasn’t clear if the drugs provide any benefits in OS or QOL.

All cancer trials

The 68 approvals of cancer drugs were supported by 72 clinical trials.

Sixty approvals (88%) were supported by at least 1 randomized, controlled trial. Eight approvals (12%) were based on a single-arm study. This included 6 of 10 conditional marketing authorizations and 2 of 58 regular marketing authorizations.

Eighteen of the approvals (26%) were supported by a pivotal study powered to evaluate OS as the primary endpoint. And 37 of the approvals (54%) had a supporting pivotal trial evaluating QOL, but results were not reported for 2 of these trials.

Hematology trials and drugs

Of the 12 drugs approved for 17 hematology indications, 4 were regular approvals, 5 were conditional approvals, and 8 had orphan drug designation.

The approvals were supported by data from 18 trials—13 randomized and 5 single-arm trials.

The study drug was compared to an active comparator in 9 of the trials. The drug was evaluated as an add-on treatment in 4 trials. And the drug was not compared to anything in 5 trials (the single-arm trials).

OS was the primary endpoint in 1 of the trials, and 17 trials had OS or QOL as a secondary endpoint.

There were 3 drugs that had demonstrated an OS benefit at the time of approval but no QOL benefit at any time:

• Decitabine used for first-line treatment of acute myeloid leukemia in adults 65 and older who are ineligible for chemotherapy
• Pomalidomide in combination with dexamethasone as third-line therapy for relapsed/refractory multiple myeloma (MM)
• Rituximab plus chemotherapy for first-line treatment of chronic lymphocytic leukemia (CLL).

There were 2 drugs that had demonstrated a QOL benefit, only after approval, but they were not known to provide an OS benefit at any time:

• Nilotinib as a treatment for adults with newly diagnosed, chronic phase, Ph+ chronic myeloid leukemia (CML)
• Ofatumumab for CLL that is refractory to fludarabine and alemtuzumab

For the remaining drugs, there was no evidence of an OS or QOL benefit at any time during the period studied. The drugs included:

• Bortezomib given alone or in combination with doxorubicin or dexamethasone as second-line therapy for MM patients ineligible for hematopoietic stem cell transplant (HSCT)
• Bortezomib plus dexamethasone with or without thalidomide as first-line therapy in MM patients eligible for HSCT
• Bosutinib as second- or third-line treatment of Ph+ CML (any phase)
• Brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma
• Brentuximab vedotin for relapsed or refractory, CD30+ Hodgkin lymphoma after autologous HSCT or as third-line treatment for patients ineligible for autologous HSCT
• Dasatinib for first-line treatment of chronic phase, Ph+ CML
• Pixantrone for multiply relapsed or refractory B-cell non-Hodgkin lymphoma
• Ponatinib for patients with Ph+ acute lymphoblastic leukemia who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib or characterized by T315I mutation
• Ponatinib for patients with any phase of CML who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib/nilotinib or characterized by T315I mutation
• Rituximab as maintenance after induction for patients with follicular lymphoma
• Rituximab plus chemotherapy for relapsed or refractory CLL
• Temsirolimus for relapsed or refractory mantle cell lymphoma.
  

Image by Tom Ellenberger

Preclinical research suggests the TOX protein is an oncogenic driver of T-cell acute lymphoblastic leukemia (T-ALL).

Results indicate that TOX may be expressed in as many as 95% of human T-ALL cases, and the protein is required for the cancer’s growth and persistence.

“A major role for TOX in T-ALL is to elicit defects in DNA repair, leading to genetic changes that drive normal cells into cancer,” said study author David Langenau, PhD, of Massachusetts General Hospital in Boston.

“TOX then continues to be expressed within leukemic cells and is required for continued tumor growth. That means that, if we can successfully target TOX with small molecules in the future, the 95% of T-ALL patients whose tumors express TOX would have new treatment options for this aggressive leukemia.”

Dr Langenau and his colleagues described this new role for TOX in Cancer Discovery.

The team noted that T-ALL has several molecular subtypes, many of which are driven by common oncogenes such as MYC and NOTCH. However, evidence has suggested the cancer’s initiation is likely driven by aberrations in DNA repair.

To identify genes that might help drive T-ALL, the researchers performed a transgenic screen in zebrafish.

The team found that TOX collaborates with known oncogene pathways to transform T-cell precursors into leukemia cells by altering DNA repair and then expanding the population of transformed cells.

In human T-ALL cells, TOX was shown to suppress non-homologous end joining (NHEJ) repair, a pathway required for repairing double-strand DNA breaks that, when disrupted, is known to cause errant DNA repair and genomic instability.

Nearly all of the human T-ALL samples the researchers tested were found to express TOX. And TOX proved essential for the proliferation and survival of T-ALL.

Dr Langenau explained that TOX is known to have important roles in the development and maturation of several types of immune cells, yet its roles in leukemia initiation and genomic instability were not described until this work.

TOX belongs to a group of proteins known to regulate the configuration or expression of genes by binding to DNA molecules, yet its mechanism in T-ALL—blocking NHEJ repair by binding to DNA repair proteins rather than directly to DNA—was totally unexpected.

The researchers believe that, in addition to better understanding how TOX regulates the continued growth of T-ALL, it will be important to determine whether related proteins have similar molecular functions in other cancers.

Image by Tom Ellenberger

Preclinical research suggests the TOX protein is an oncogenic driver of T-cell acute lymphoblastic leukemia (T-ALL).

Results indicate that TOX may be expressed in as many as 95% of human T-ALL cases, and the protein is required for the cancer’s growth and persistence.

“A major role for TOX in T-ALL is to elicit defects in DNA repair, leading to genetic changes that drive normal cells into cancer,” said study author David Langenau, PhD, of Massachusetts General Hospital in Boston.

“TOX then continues to be expressed within leukemic cells and is required for continued tumor growth. That means that, if we can successfully target TOX with small molecules in the future, the 95% of T-ALL patients whose tumors express TOX would have new treatment options for this aggressive leukemia.”

Dr Langenau and his colleagues described this new role for TOX in Cancer Discovery.

The team noted that T-ALL has several molecular subtypes, many of which are driven by common oncogenes such as MYC and NOTCH. However, evidence has suggested the cancer’s initiation is likely driven by aberrations in DNA repair.

To identify genes that might help drive T-ALL, the researchers performed a transgenic screen in zebrafish.

The team found that TOX collaborates with known oncogene pathways to transform T-cell precursors into leukemia cells by altering DNA repair and then expanding the population of transformed cells.

In human T-ALL cells, TOX was shown to suppress non-homologous end joining (NHEJ) repair, a pathway required for repairing double-strand DNA breaks that, when disrupted, is known to cause errant DNA repair and genomic instability.

Nearly all of the human T-ALL samples the researchers tested were found to express TOX. And TOX proved essential for the proliferation and survival of T-ALL.

Dr Langenau explained that TOX is known to have important roles in the development and maturation of several types of immune cells, yet its roles in leukemia initiation and genomic instability were not described until this work.

TOX belongs to a group of proteins known to regulate the configuration or expression of genes by binding to DNA molecules, yet its mechanism in T-ALL—blocking NHEJ repair by binding to DNA repair proteins rather than directly to DNA—was totally unexpected.

The researchers believe that, in addition to better understanding how TOX regulates the continued growth of T-ALL, it will be important to determine whether related proteins have similar molecular functions in other cancers.

Image by Tom Ellenberger

Preclinical research suggests the TOX protein is an oncogenic driver of T-cell acute lymphoblastic leukemia (T-ALL).

Results indicate that TOX may be expressed in as many as 95% of human T-ALL cases, and the protein is required for the cancer’s growth and persistence.

“A major role for TOX in T-ALL is to elicit defects in DNA repair, leading to genetic changes that drive normal cells into cancer,” said study author David Langenau, PhD, of Massachusetts General Hospital in Boston.

“TOX then continues to be expressed within leukemic cells and is required for continued tumor growth. That means that, if we can successfully target TOX with small molecules in the future, the 95% of T-ALL patients whose tumors express TOX would have new treatment options for this aggressive leukemia.”

Dr Langenau and his colleagues described this new role for TOX in Cancer Discovery.

The team noted that T-ALL has several molecular subtypes, many of which are driven by common oncogenes such as MYC and NOTCH. However, evidence has suggested the cancer’s initiation is likely driven by aberrations in DNA repair.

To identify genes that might help drive T-ALL, the researchers performed a transgenic screen in zebrafish.

The team found that TOX collaborates with known oncogene pathways to transform T-cell precursors into leukemia cells by altering DNA repair and then expanding the population of transformed cells.

In human T-ALL cells, TOX was shown to suppress non-homologous end joining (NHEJ) repair, a pathway required for repairing double-strand DNA breaks that, when disrupted, is known to cause errant DNA repair and genomic instability.

Nearly all of the human T-ALL samples the researchers tested were found to express TOX. And TOX proved essential for the proliferation and survival of T-ALL.

Dr Langenau explained that TOX is known to have important roles in the development and maturation of several types of immune cells, yet its roles in leukemia initiation and genomic instability were not described until this work.

TOX belongs to a group of proteins known to regulate the configuration or expression of genes by binding to DNA molecules, yet its mechanism in T-ALL—blocking NHEJ repair by binding to DNA repair proteins rather than directly to DNA—was totally unexpected.

The researchers believe that, in addition to better understanding how TOX regulates the continued growth of T-ALL, it will be important to determine whether related proteins have similar molecular functions in other cancers.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Anderson Cancer Center

Researchers say they have created guidelines for managing the unique toxicities associated with chimeric antigen receptor (CAR) T-cell therapy.

The guidelines focus on cytokine release syndrome (CRS); neurological toxicity, which the researchers have dubbed “CAR-T-cell-related encephalopathy syndrome (CRES);” and adverse effects related to these syndromes.

“The toxicities are unique, and every member of the care team needs to be trained to recognize them and act accordingly,” said Sattva Neelapu, MD, of University of Texas MD Anderson Cancer Center in Houston.

Dr Neelapu and his colleagues described the toxicities and related recommendations in Nature Reviews Clinical Oncology.

The team’s guidelines include supportive-care considerations for patients receiving CAR T‑cell therapy. For example, they recommend:

• Baseline brain MRI to rule out central nervous system disease
• Cardiac monitoring starting on the day of CAR T‑cell infusion
• Assessing a patient’s vital signs every 4 hours after CAR T-cell infusion
• Assessing and grading CRS at least twice daily and whenever the patient’s status changes
• Assessing and grading CRES at least every 8 hours.

CRS

One section of the guidelines is dedicated to CRS, with subsections on pathophysiology, precautions and supportive care, the use of corticosteroids and IL‑6/IL‑6R antagonists, and grading CRS.

The researchers noted that CRS typically manifests with constitutional symptoms, such as fever, malaise, anorexia, and myalgias. However, CRS can affect any organ system in the body.

The team recommends managing CRS according to grade. For example, patients with grade 1 CRS should typically receive supportive care. However, physicians should consider giving tocilizumab or siltuximab to grade 1 patients who have a refractory fever lasting more than 3 days.

The researchers also noted that CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH), also known as macrophage-activation syndrome (MAS).

The team said HLH/MAS encompasses a group of severe immunological disorders characterized by hyperactivation of macrophages and lymphocytes, proinflammatory cytokine production, lymphohistiocytic tissue infiltration, and immune-mediated multi-organ failure.

The guidelines include diagnostic criteria for CAR T‑cell-related HLH/MAS and recommendations for managing the condition.

CRES

One section of the guidelines is dedicated to the grading and treatment of CRES, which typically mani­fests as a toxic encephalopathy.

The researchers said the earliest signs of CRES are diminished attention, language disturbance, and impaired handwriting. Other symptoms include confusion, disorientation, agitation, apha­sia, somnolence, and tremors.

Patients with severe CRES (grade >2) may experience seizures, motor weakness, incontinence, mental obtundation, increased intracra­nial pressure, papilledema, and cerebral edema.

Therefore, the guidelines include recommendations for the management of status epilepticus and raised intracranial pressure after CAR T‑cell therapy.

The researchers also devised an algorithm, known as CARTOX-10, for identifying neurotoxicity. (An existing general method didn’t effectively quantify the neurological effects caused by CAR T-cell therapies.)

CARTOX-10 is a 10-point test in which patients are asked to do the following:

• Name the current month (1 point) and year (1 point)
• Name the city (1 point) and hospital they are in (1 point)
• Name the president/prime minister of their home country (1 point)
• Name 3 nearby objects (3 points)
• Write a standard sentence (1 point)
• Count backward from 100 by tens (1 point).

A perfect score indicates normal cognitive function. A patient has mild to severe impairment depending on the number of questions or activities missed.

Dr Neelapu and his colleagues believe their recommendations will be applicable to other types of cell-based immunotherapy as well, including CAR natural killer cells, T-cell receptor engineered T cells, and combination drugs that use an antibody to connect T cells to targets on cancer cells.

Researchers involved in this work have received funding from companies developing/marketing CAR T-cell therapies.

Anderson Cancer Center

Researchers say they have created guidelines for managing the unique toxicities associated with chimeric antigen receptor (CAR) T-cell therapy.

The guidelines focus on cytokine release syndrome (CRS); neurological toxicity, which the researchers have dubbed “CAR-T-cell-related encephalopathy syndrome (CRES);” and adverse effects related to these syndromes.

“The toxicities are unique, and every member of the care team needs to be trained to recognize them and act accordingly,” said Sattva Neelapu, MD, of University of Texas MD Anderson Cancer Center in Houston.

Dr Neelapu and his colleagues described the toxicities and related recommendations in Nature Reviews Clinical Oncology.

The team’s guidelines include supportive-care considerations for patients receiving CAR T‑cell therapy. For example, they recommend:

• Baseline brain MRI to rule out central nervous system disease
• Cardiac monitoring starting on the day of CAR T‑cell infusion
• Assessing a patient’s vital signs every 4 hours after CAR T-cell infusion
• Assessing and grading CRS at least twice daily and whenever the patient’s status changes
• Assessing and grading CRES at least every 8 hours.

CRS

One section of the guidelines is dedicated to CRS, with subsections on pathophysiology, precautions and supportive care, the use of corticosteroids and IL‑6/IL‑6R antagonists, and grading CRS.

The researchers noted that CRS typically manifests with constitutional symptoms, such as fever, malaise, anorexia, and myalgias. However, CRS can affect any organ system in the body.

The team recommends managing CRS according to grade. For example, patients with grade 1 CRS should typically receive supportive care. However, physicians should consider giving tocilizumab or siltuximab to grade 1 patients who have a refractory fever lasting more than 3 days.

The researchers also noted that CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH), also known as macrophage-activation syndrome (MAS).

The team said HLH/MAS encompasses a group of severe immunological disorders characterized by hyperactivation of macrophages and lymphocytes, proinflammatory cytokine production, lymphohistiocytic tissue infiltration, and immune-mediated multi-organ failure.

The guidelines include diagnostic criteria for CAR T‑cell-related HLH/MAS and recommendations for managing the condition.

CRES

One section of the guidelines is dedicated to the grading and treatment of CRES, which typically mani­fests as a toxic encephalopathy.

The researchers said the earliest signs of CRES are diminished attention, language disturbance, and impaired handwriting. Other symptoms include confusion, disorientation, agitation, apha­sia, somnolence, and tremors.

Patients with severe CRES (grade >2) may experience seizures, motor weakness, incontinence, mental obtundation, increased intracra­nial pressure, papilledema, and cerebral edema.

Therefore, the guidelines include recommendations for the management of status epilepticus and raised intracranial pressure after CAR T‑cell therapy.

The researchers also devised an algorithm, known as CARTOX-10, for identifying neurotoxicity. (An existing general method didn’t effectively quantify the neurological effects caused by CAR T-cell therapies.)

CARTOX-10 is a 10-point test in which patients are asked to do the following:

• Name the current month (1 point) and year (1 point)
• Name the city (1 point) and hospital they are in (1 point)
• Name the president/prime minister of their home country (1 point)
• Name 3 nearby objects (3 points)
• Write a standard sentence (1 point)
• Count backward from 100 by tens (1 point).

A perfect score indicates normal cognitive function. A patient has mild to severe impairment depending on the number of questions or activities missed.

Dr Neelapu and his colleagues believe their recommendations will be applicable to other types of cell-based immunotherapy as well, including CAR natural killer cells, T-cell receptor engineered T cells, and combination drugs that use an antibody to connect T cells to targets on cancer cells.

Researchers involved in this work have received funding from companies developing/marketing CAR T-cell therapies.

Anderson Cancer Center

Researchers say they have created guidelines for managing the unique toxicities associated with chimeric antigen receptor (CAR) T-cell therapy.

The guidelines focus on cytokine release syndrome (CRS); neurological toxicity, which the researchers have dubbed “CAR-T-cell-related encephalopathy syndrome (CRES);” and adverse effects related to these syndromes.

“The toxicities are unique, and every member of the care team needs to be trained to recognize them and act accordingly,” said Sattva Neelapu, MD, of University of Texas MD Anderson Cancer Center in Houston.

Dr Neelapu and his colleagues described the toxicities and related recommendations in Nature Reviews Clinical Oncology.

The team’s guidelines include supportive-care considerations for patients receiving CAR T‑cell therapy. For example, they recommend:

• Baseline brain MRI to rule out central nervous system disease
• Cardiac monitoring starting on the day of CAR T‑cell infusion
• Assessing a patient’s vital signs every 4 hours after CAR T-cell infusion
• Assessing and grading CRS at least twice daily and whenever the patient’s status changes
• Assessing and grading CRES at least every 8 hours.

CRS

One section of the guidelines is dedicated to CRS, with subsections on pathophysiology, precautions and supportive care, the use of corticosteroids and IL‑6/IL‑6R antagonists, and grading CRS.

The researchers noted that CRS typically manifests with constitutional symptoms, such as fever, malaise, anorexia, and myalgias. However, CRS can affect any organ system in the body.

The team recommends managing CRS according to grade. For example, patients with grade 1 CRS should typically receive supportive care. However, physicians should consider giving tocilizumab or siltuximab to grade 1 patients who have a refractory fever lasting more than 3 days.

The researchers also noted that CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH), also known as macrophage-activation syndrome (MAS).

The team said HLH/MAS encompasses a group of severe immunological disorders characterized by hyperactivation of macrophages and lymphocytes, proinflammatory cytokine production, lymphohistiocytic tissue infiltration, and immune-mediated multi-organ failure.

The guidelines include diagnostic criteria for CAR T‑cell-related HLH/MAS and recommendations for managing the condition.

CRES

One section of the guidelines is dedicated to the grading and treatment of CRES, which typically mani­fests as a toxic encephalopathy.

The researchers said the earliest signs of CRES are diminished attention, language disturbance, and impaired handwriting. Other symptoms include confusion, disorientation, agitation, apha­sia, somnolence, and tremors.

Patients with severe CRES (grade >2) may experience seizures, motor weakness, incontinence, mental obtundation, increased intracra­nial pressure, papilledema, and cerebral edema.

Therefore, the guidelines include recommendations for the management of status epilepticus and raised intracranial pressure after CAR T‑cell therapy.

The researchers also devised an algorithm, known as CARTOX-10, for identifying neurotoxicity. (An existing general method didn’t effectively quantify the neurological effects caused by CAR T-cell therapies.)

CARTOX-10 is a 10-point test in which patients are asked to do the following:

• Name the current month (1 point) and year (1 point)
• Name the city (1 point) and hospital they are in (1 point)
• Name the president/prime minister of their home country (1 point)
• Name 3 nearby objects (3 points)
• Write a standard sentence (1 point)
• Count backward from 100 by tens (1 point).

A perfect score indicates normal cognitive function. A patient has mild to severe impairment depending on the number of questions or activities missed.

Dr Neelapu and his colleagues believe their recommendations will be applicable to other types of cell-based immunotherapy as well, including CAR natural killer cells, T-cell receptor engineered T cells, and combination drugs that use an antibody to connect T cells to targets on cancer cells.

Researchers involved in this work have received funding from companies developing/marketing CAR T-cell therapies.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Welcome to our new online feature, "How would you treat?"
This new item seeks to stimulate a lively conversation around cases that address the "art of medicine," in which there are no right or wrong ways to treat a specific patient. Instead, we posit to you "if this was your patient, how would you treat her?" The goal is to offer each other our thoughts on how we view treatment options from the perspectives of potential for cure and quality of life for a specific patient given his or her unique treatment history.  

Our first case for your consideration will examine perspectives on the treatment of recurrent acute lymphoblastic leukemia, a condition with increasing therapeutic options.

A 24-year-old female was diagnosed with pre-B Acute Lymphoblastic Leukemia. She achieved complete remission on a standard chemotherapy protocol that included L-asparaginase and completed maintenance therapy 1 year ago, but no tests for MRD were performed. Routine surveillance blood counts worsened and a bone marrow biopsy confirms relapse. She feels well. There is no detectable BCR/ABL, but the leukemic blasts express CD19, CD20, and CD22. She has an HLA-matched sibling donor. Her exam is normal with WBC 23,000 (76% Blasts), Hgb 10.3, Plt 32K.

Welcome to our new online feature, "How would you treat?"
This new item seeks to stimulate a lively conversation around cases that address the "art of medicine," in which there are no right or wrong ways to treat a specific patient. Instead, we posit to you "if this was your patient, how would you treat her?" The goal is to offer each other our thoughts on how we view treatment options from the perspectives of potential for cure and quality of life for a specific patient given his or her unique treatment history.  

Our first case for your consideration will examine perspectives on the treatment of recurrent acute lymphoblastic leukemia, a condition with increasing therapeutic options.

A 24-year-old female was diagnosed with pre-B Acute Lymphoblastic Leukemia. She achieved complete remission on a standard chemotherapy protocol that included L-asparaginase and completed maintenance therapy 1 year ago, but no tests for MRD were performed. Routine surveillance blood counts worsened and a bone marrow biopsy confirms relapse. She feels well. There is no detectable BCR/ABL, but the leukemic blasts express CD19, CD20, and CD22. She has an HLA-matched sibling donor. Her exam is normal with WBC 23,000 (76% Blasts), Hgb 10.3, Plt 32K.

Welcome to our new online feature, "How would you treat?"
This new item seeks to stimulate a lively conversation around cases that address the "art of medicine," in which there are no right or wrong ways to treat a specific patient. Instead, we posit to you "if this was your patient, how would you treat her?" The goal is to offer each other our thoughts on how we view treatment options from the perspectives of potential for cure and quality of life for a specific patient given his or her unique treatment history.  

Our first case for your consideration will examine perspectives on the treatment of recurrent acute lymphoblastic leukemia, a condition with increasing therapeutic options.

A 24-year-old female was diagnosed with pre-B Acute Lymphoblastic Leukemia. She achieved complete remission on a standard chemotherapy protocol that included L-asparaginase and completed maintenance therapy 1 year ago, but no tests for MRD were performed. Routine surveillance blood counts worsened and a bone marrow biopsy confirms relapse. She feels well. There is no detectable BCR/ABL, but the leukemic blasts express CD19, CD20, and CD22. She has an HLA-matched sibling donor. Her exam is normal with WBC 23,000 (76% Blasts), Hgb 10.3, Plt 32K.

Micrograph showing DLBCL

MAINZ/FRANKFURT, GERMANY—Outcomes of treatment with a third-generation chimeric antigen receptor (CAR) T-cell therapy are associated with a patient’s immune status, according to a phase 1/2a trial.

The CD19-specific CAR T-cell therapy produced a complete response (CR) in 6 of 15 patients with relapsed/refractory CD19-positive leukemia or lymphoma.

Though all responders eventually relapsed, 4 patients—including 2 with stable disease (SD) after treatment—responded to subsequent therapy and are still alive, 1 of them beyond 36 months.

An analysis of blood samples taken throughout the study revealed that a patient’s immune status was associated with treatment failure and overall survival.

Tanja Lövgren, PhD, of Uppsala University in Sweden, and her colleagues presented these findings at the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (abstract B156).

“CD19-specific CAR T-cell therapy has yielded remarkable response rates for patients who have B-cell acute lymphoblastic leukemia,” Dr Lövgren said. “However, many patients relapse.”

“In addition, response rates are more variable for patients who have other CD19-positive B-cell malignancies, and many patients experience serious adverse events. We set out to investigate the safety and effectiveness of a third-generation CD19-specific CAR T-cell therapy and to identify potential biomarkers of treatment outcome.”

Dr Lövgren and her colleagues studied 15 patients (ages 24-72) who had relapsed or refractory CD19-positive B-cell malignancies:

• Six patients with diffuse large B-cell lymphoma (DLBCL), including 3 cases that were transformed from follicular lymphoma (FL)
• Four patients with pre-B acute lymphoblastic leukemia (ALL)
• Two patients with mantle cell lymphoma (MCL)
• Two patients with chronic lymphocytic leukemia (CLL)
• One patient with FL transformed from Burkitt lymphoma.

Eleven patients received preconditioning with cyclophosphamide (500 mg/m²) and fludarabine (3 doses at 25 mg/m²).

All patients received CAR T cells at 1 x 10⁸, 2 x 10⁷, or 2 x 10⁸ cells/m². These were autologous, CD19-targeting CAR T cells with 3 intracellular signaling domains derived from CD3 zeta, CD28, and 4-1BB.

The researchers assessed tumor responses via bone marrow/blood analysis and/or radiology, depending on the type of malignancy. The team also collected blood samples before CAR T-cell infusion and at multiple times after infusion.

Efficacy and safety

Six patients achieved a CR to treatment—3 with DLBCL (1 transformed), 2 with ALL, and 1 with CLL. Two patients had SD—1 with MCL and 1 with CLL. The remaining patients progressed.

All patients with a CR eventually relapsed. The median duration of CR was 5 months (range, 3-24 months).

Four patients—2 complete responders and 2 with SD—responded well to subsequent therapy and are still alive with 27 to 36 months of follow-up. This includes 1 patient with DLBCL, 1 with MCL, and 2 with CLL.

Four patients had serious adverse events. Three had cytokine-release syndrome, and 2 had neurological toxicity.

All cases of cytokine-release syndrome resolved after treatment with corticosteroids/anti-IL6R therapy. The neurological toxicity resolved spontaneously.

Immune status

An analysis of the blood samples taken throughout the study showed that high levels of monocytic myeloid-derived suppressor cells (MDSCs) prior to treatment was associated with decreased overall survival. In addition, increased levels of MDSCs after treatment preceded treatment failure.

Furthermore, high plasma levels of immunosuppressive factors—such as PD-L1 and PD-L2—after treatment were associated with decreased overall survival.

High plasma levels of biomarkers of an immunostimulatory environment—including IL-12, DC-LAMP, TRAIL, and FasL—before the administration of CAR T-cell therapy was associated with increased overall survival.

“[A]n immunostimulatory environment was associated with improved overall survival, while immunosuppressive cells and factors were associated with treatment failure and decreased overall survival,” Dr Lövgren said.

“We are hoping to follow up this study with another clinical trial that will combine CAR T-cell therapy with chemotherapy known to decrease the number of monocytic myeloid-derived suppressive cells. We are also looking to further optimize the CAR T-cell therapy.”

Dr Lövgren said the main limitations of this study are that it only included 15 patients, the patients had several different malignancies, and some patients may have been too sick to respond to any treatment.

This study was supported by funds from AFA Insurance AB, the Swedish Cancer Society, the Swedish Research Council, the Lions Fund at Uppsala University Hospital, and the Swedish State Support for Clinical Research. Dr Lövgren declared no conflicts of interest.

Micrograph showing DLBCL

MAINZ/FRANKFURT, GERMANY—Outcomes of treatment with a third-generation chimeric antigen receptor (CAR) T-cell therapy are associated with a patient’s immune status, according to a phase 1/2a trial.

The CD19-specific CAR T-cell therapy produced a complete response (CR) in 6 of 15 patients with relapsed/refractory CD19-positive leukemia or lymphoma.

Though all responders eventually relapsed, 4 patients—including 2 with stable disease (SD) after treatment—responded to subsequent therapy and are still alive, 1 of them beyond 36 months.

An analysis of blood samples taken throughout the study revealed that a patient’s immune status was associated with treatment failure and overall survival.

Tanja Lövgren, PhD, of Uppsala University in Sweden, and her colleagues presented these findings at the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (abstract B156).

“CD19-specific CAR T-cell therapy has yielded remarkable response rates for patients who have B-cell acute lymphoblastic leukemia,” Dr Lövgren said. “However, many patients relapse.”

“In addition, response rates are more variable for patients who have other CD19-positive B-cell malignancies, and many patients experience serious adverse events. We set out to investigate the safety and effectiveness of a third-generation CD19-specific CAR T-cell therapy and to identify potential biomarkers of treatment outcome.”

Dr Lövgren and her colleagues studied 15 patients (ages 24-72) who had relapsed or refractory CD19-positive B-cell malignancies:

• Six patients with diffuse large B-cell lymphoma (DLBCL), including 3 cases that were transformed from follicular lymphoma (FL)
• Four patients with pre-B acute lymphoblastic leukemia (ALL)
• Two patients with mantle cell lymphoma (MCL)
• Two patients with chronic lymphocytic leukemia (CLL)
• One patient with FL transformed from Burkitt lymphoma.

Eleven patients received preconditioning with cyclophosphamide (500 mg/m²) and fludarabine (3 doses at 25 mg/m²).

All patients received CAR T cells at 1 x 10⁸, 2 x 10⁷, or 2 x 10⁸ cells/m². These were autologous, CD19-targeting CAR T cells with 3 intracellular signaling domains derived from CD3 zeta, CD28, and 4-1BB.

The researchers assessed tumor responses via bone marrow/blood analysis and/or radiology, depending on the type of malignancy. The team also collected blood samples before CAR T-cell infusion and at multiple times after infusion.

Efficacy and safety

Six patients achieved a CR to treatment—3 with DLBCL (1 transformed), 2 with ALL, and 1 with CLL. Two patients had SD—1 with MCL and 1 with CLL. The remaining patients progressed.

All patients with a CR eventually relapsed. The median duration of CR was 5 months (range, 3-24 months).

Four patients—2 complete responders and 2 with SD—responded well to subsequent therapy and are still alive with 27 to 36 months of follow-up. This includes 1 patient with DLBCL, 1 with MCL, and 2 with CLL.

Four patients had serious adverse events. Three had cytokine-release syndrome, and 2 had neurological toxicity.

All cases of cytokine-release syndrome resolved after treatment with corticosteroids/anti-IL6R therapy. The neurological toxicity resolved spontaneously.

Immune status

An analysis of the blood samples taken throughout the study showed that high levels of monocytic myeloid-derived suppressor cells (MDSCs) prior to treatment was associated with decreased overall survival. In addition, increased levels of MDSCs after treatment preceded treatment failure.

Furthermore, high plasma levels of immunosuppressive factors—such as PD-L1 and PD-L2—after treatment were associated with decreased overall survival.

High plasma levels of biomarkers of an immunostimulatory environment—including IL-12, DC-LAMP, TRAIL, and FasL—before the administration of CAR T-cell therapy was associated with increased overall survival.

“[A]n immunostimulatory environment was associated with improved overall survival, while immunosuppressive cells and factors were associated with treatment failure and decreased overall survival,” Dr Lövgren said.

“We are hoping to follow up this study with another clinical trial that will combine CAR T-cell therapy with chemotherapy known to decrease the number of monocytic myeloid-derived suppressive cells. We are also looking to further optimize the CAR T-cell therapy.”

Dr Lövgren said the main limitations of this study are that it only included 15 patients, the patients had several different malignancies, and some patients may have been too sick to respond to any treatment.

This study was supported by funds from AFA Insurance AB, the Swedish Cancer Society, the Swedish Research Council, the Lions Fund at Uppsala University Hospital, and the Swedish State Support for Clinical Research. Dr Lövgren declared no conflicts of interest.

Micrograph showing DLBCL

MAINZ/FRANKFURT, GERMANY—Outcomes of treatment with a third-generation chimeric antigen receptor (CAR) T-cell therapy are associated with a patient’s immune status, according to a phase 1/2a trial.

The CD19-specific CAR T-cell therapy produced a complete response (CR) in 6 of 15 patients with relapsed/refractory CD19-positive leukemia or lymphoma.

Though all responders eventually relapsed, 4 patients—including 2 with stable disease (SD) after treatment—responded to subsequent therapy and are still alive, 1 of them beyond 36 months.

An analysis of blood samples taken throughout the study revealed that a patient’s immune status was associated with treatment failure and overall survival.

Tanja Lövgren, PhD, of Uppsala University in Sweden, and her colleagues presented these findings at the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (abstract B156).

“CD19-specific CAR T-cell therapy has yielded remarkable response rates for patients who have B-cell acute lymphoblastic leukemia,” Dr Lövgren said. “However, many patients relapse.”

“In addition, response rates are more variable for patients who have other CD19-positive B-cell malignancies, and many patients experience serious adverse events. We set out to investigate the safety and effectiveness of a third-generation CD19-specific CAR T-cell therapy and to identify potential biomarkers of treatment outcome.”

Dr Lövgren and her colleagues studied 15 patients (ages 24-72) who had relapsed or refractory CD19-positive B-cell malignancies:

• Six patients with diffuse large B-cell lymphoma (DLBCL), including 3 cases that were transformed from follicular lymphoma (FL)
• Four patients with pre-B acute lymphoblastic leukemia (ALL)
• Two patients with mantle cell lymphoma (MCL)
• Two patients with chronic lymphocytic leukemia (CLL)
• One patient with FL transformed from Burkitt lymphoma.

Eleven patients received preconditioning with cyclophosphamide (500 mg/m²) and fludarabine (3 doses at 25 mg/m²).

All patients received CAR T cells at 1 x 10⁸, 2 x 10⁷, or 2 x 10⁸ cells/m². These were autologous, CD19-targeting CAR T cells with 3 intracellular signaling domains derived from CD3 zeta, CD28, and 4-1BB.

The researchers assessed tumor responses via bone marrow/blood analysis and/or radiology, depending on the type of malignancy. The team also collected blood samples before CAR T-cell infusion and at multiple times after infusion.

Efficacy and safety

Six patients achieved a CR to treatment—3 with DLBCL (1 transformed), 2 with ALL, and 1 with CLL. Two patients had SD—1 with MCL and 1 with CLL. The remaining patients progressed.

All patients with a CR eventually relapsed. The median duration of CR was 5 months (range, 3-24 months).

Four patients—2 complete responders and 2 with SD—responded well to subsequent therapy and are still alive with 27 to 36 months of follow-up. This includes 1 patient with DLBCL, 1 with MCL, and 2 with CLL.

Four patients had serious adverse events. Three had cytokine-release syndrome, and 2 had neurological toxicity.

All cases of cytokine-release syndrome resolved after treatment with corticosteroids/anti-IL6R therapy. The neurological toxicity resolved spontaneously.

Immune status

An analysis of the blood samples taken throughout the study showed that high levels of monocytic myeloid-derived suppressor cells (MDSCs) prior to treatment was associated with decreased overall survival. In addition, increased levels of MDSCs after treatment preceded treatment failure.

Furthermore, high plasma levels of immunosuppressive factors—such as PD-L1 and PD-L2—after treatment were associated with decreased overall survival.

High plasma levels of biomarkers of an immunostimulatory environment—including IL-12, DC-LAMP, TRAIL, and FasL—before the administration of CAR T-cell therapy was associated with increased overall survival.

“[A]n immunostimulatory environment was associated with improved overall survival, while immunosuppressive cells and factors were associated with treatment failure and decreased overall survival,” Dr Lövgren said.

“We are hoping to follow up this study with another clinical trial that will combine CAR T-cell therapy with chemotherapy known to decrease the number of monocytic myeloid-derived suppressive cells. We are also looking to further optimize the CAR T-cell therapy.”

Dr Lövgren said the main limitations of this study are that it only included 15 patients, the patients had several different malignancies, and some patients may have been too sick to respond to any treatment.

This study was supported by funds from AFA Insurance AB, the Swedish Cancer Society, the Swedish Research Council, the Lions Fund at Uppsala University Hospital, and the Swedish State Support for Clinical Research. Dr Lövgren declared no conflicts of interest.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.