Leukemia, Myelodysplasia, Transplantation

Photo by Chad McNeeley

A case report suggests an investigational chimeric antigen receptor (CAR) T-cell therapy can provide a bridge to transplant in relapsed/refractory acute myeloid leukemia (AML).

The therapy, known as CYAD-01, prompted a morphologic leukemia-free state in an AML patient.

This patient went on to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) and achieve a complete molecular remission, which was ongoing 6 months after transplant.

Investigators reported no adverse events related to CYAD-01.

This report was published in haematologica.

The patient is enrolled in the THINK trial (NCT03018405), which is sponsored by Celyad SA, the company developing CYAD-01.

According to Celyad, CYAD-01 consists of autologous T cells expressing a CAR based on the natural killer group 2 member D receptor (NKG2D), a transmembrane receptor expressed by natural killer cells and some T-cell subsets.

The AML patient who received CYAD-01 was 52 years old at trial enrollment. He had +8/del(7)(q22q36), FLT3/NPM1 wild-type AML.

The patient’s disease was primary refractory to 7+3 induction, so he went on to receive salvage chemotherapy with cladribine, cytarabine, G-CSF, and mitoxantrone. He achieved a complete response to this treatment and received 2 cycles of consolidation with cladribine and cytarabine.

The patient’s subsequent allo-HSCT was delayed to allow for pulmonary function test recovery. In the meantime, he relapsed.

At this point, the patient enrolled in the THINK trial. He underwent apheresis and received CYAD-01 infusions at the initial dose level of 3 x 10⁸ cells every 2 weeks for 3 administrations.

The patient achieved a morphologic leukemia-free state at 3 months, which enabled him to undergo allo-HSCT.

The patient achieved a complete molecular remission after transplant. He remained in remission at last follow-up—9 months after his first CYAD-01 infusion and 6 months after allo-HSCT.

The investigators said CYAD-01 was well tolerated in this patient. He did not develop cytokine release syndrome or experience neurotoxic effects. The patient had only non-related grade 1 adverse events.

“The THINK study case report provides the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies,” said study investigator David Sallman, MD, of Moffitt Cancer Center in Tampa, Florida.

“As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML [who] have run out of therapeutic options. It’s all the more striking that this outcome was observed without any prior lymphodepletion, highlighting the potential of using a physiologic antigen-receptor.” 

Photo by Chad McNeeley

A case report suggests an investigational chimeric antigen receptor (CAR) T-cell therapy can provide a bridge to transplant in relapsed/refractory acute myeloid leukemia (AML).

The therapy, known as CYAD-01, prompted a morphologic leukemia-free state in an AML patient.

This patient went on to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) and achieve a complete molecular remission, which was ongoing 6 months after transplant.

Investigators reported no adverse events related to CYAD-01.

This report was published in haematologica.

The patient is enrolled in the THINK trial (NCT03018405), which is sponsored by Celyad SA, the company developing CYAD-01.

According to Celyad, CYAD-01 consists of autologous T cells expressing a CAR based on the natural killer group 2 member D receptor (NKG2D), a transmembrane receptor expressed by natural killer cells and some T-cell subsets.

The AML patient who received CYAD-01 was 52 years old at trial enrollment. He had +8/del(7)(q22q36), FLT3/NPM1 wild-type AML.

The patient’s disease was primary refractory to 7+3 induction, so he went on to receive salvage chemotherapy with cladribine, cytarabine, G-CSF, and mitoxantrone. He achieved a complete response to this treatment and received 2 cycles of consolidation with cladribine and cytarabine.

The patient’s subsequent allo-HSCT was delayed to allow for pulmonary function test recovery. In the meantime, he relapsed.

At this point, the patient enrolled in the THINK trial. He underwent apheresis and received CYAD-01 infusions at the initial dose level of 3 x 10⁸ cells every 2 weeks for 3 administrations.

The patient achieved a morphologic leukemia-free state at 3 months, which enabled him to undergo allo-HSCT.

The patient achieved a complete molecular remission after transplant. He remained in remission at last follow-up—9 months after his first CYAD-01 infusion and 6 months after allo-HSCT.

The investigators said CYAD-01 was well tolerated in this patient. He did not develop cytokine release syndrome or experience neurotoxic effects. The patient had only non-related grade 1 adverse events.

“The THINK study case report provides the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies,” said study investigator David Sallman, MD, of Moffitt Cancer Center in Tampa, Florida.

“As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML [who] have run out of therapeutic options. It’s all the more striking that this outcome was observed without any prior lymphodepletion, highlighting the potential of using a physiologic antigen-receptor.” 

Photo by Chad McNeeley

A case report suggests an investigational chimeric antigen receptor (CAR) T-cell therapy can provide a bridge to transplant in relapsed/refractory acute myeloid leukemia (AML).

The therapy, known as CYAD-01, prompted a morphologic leukemia-free state in an AML patient.

This patient went on to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) and achieve a complete molecular remission, which was ongoing 6 months after transplant.

Investigators reported no adverse events related to CYAD-01.

This report was published in haematologica.

The patient is enrolled in the THINK trial (NCT03018405), which is sponsored by Celyad SA, the company developing CYAD-01.

According to Celyad, CYAD-01 consists of autologous T cells expressing a CAR based on the natural killer group 2 member D receptor (NKG2D), a transmembrane receptor expressed by natural killer cells and some T-cell subsets.

The AML patient who received CYAD-01 was 52 years old at trial enrollment. He had +8/del(7)(q22q36), FLT3/NPM1 wild-type AML.

The patient’s disease was primary refractory to 7+3 induction, so he went on to receive salvage chemotherapy with cladribine, cytarabine, G-CSF, and mitoxantrone. He achieved a complete response to this treatment and received 2 cycles of consolidation with cladribine and cytarabine.

The patient’s subsequent allo-HSCT was delayed to allow for pulmonary function test recovery. In the meantime, he relapsed.

At this point, the patient enrolled in the THINK trial. He underwent apheresis and received CYAD-01 infusions at the initial dose level of 3 x 10⁸ cells every 2 weeks for 3 administrations.

The patient achieved a morphologic leukemia-free state at 3 months, which enabled him to undergo allo-HSCT.

The patient achieved a complete molecular remission after transplant. He remained in remission at last follow-up—9 months after his first CYAD-01 infusion and 6 months after allo-HSCT.

The investigators said CYAD-01 was well tolerated in this patient. He did not develop cytokine release syndrome or experience neurotoxic effects. The patient had only non-related grade 1 adverse events.

“The THINK study case report provides the first clinical validity of CYAD-01 as a tumor-specific antigen-receptor and AML as a disease sensitive to gene-engineered cell therapies,” said study investigator David Sallman, MD, of Moffitt Cancer Center in Tampa, Florida.

“As antigen targeting offers significant challenges in AML, this outcome brings hope for the further use of gene-engineered T cells for patients with AML [who] have run out of therapeutic options. It’s all the more striking that this outcome was observed without any prior lymphodepletion, highlighting the potential of using a physiologic antigen-receptor.” 

Photo by Patrick Pelletier

The availability of generic imatinib has had limited effects on costs of the drug, according to research published in Health Affairs.

Data suggest the cost of Gleevec in the US has more than doubled since the drug was approved in 2001, and the introduction of generic imatinib has reduced costs only slightly.

Two years after generic imatinib hit the market, a month’s supply of Gleevec cost about $9000, and the cost for generic imatinib was about $8000.

“Patients and providers have all looked forward to generic entry, expecting major price reductions,” said study author Stacie Dusetzina, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“Unfortunately, we don’t see prices drop as quickly and as low as we would hope when generics are available.”

For this study, Dr Dusetzina and a colleague analyzed data from the MarketScan Commercial Research Database. The database contained records of 139,233 prescription fills for imatinib, which were made by 7201 patients from May 2001 through September 2017.

The researchers noted that Gleevec was priced at nearly $4000 for a 1-month (400 mg) supply when it came on the market in 2001. That price escalated to nearly $10,000 by 2015 before a generic competitor entered the market.

However, prices for Gleevec and generic imatinib remained high 2 years later. In 2017, a month’s supply of Gleevec cost about $9000, and the cost of generic imatinib was about $8000.

The researchers said the Gleevec case demonstrates several potential barriers to effective generic price competition, including shifts in prescribing toward more expensive brand-name treatments and smaller-than-expected price reductions.

Twenty-four percent of imatinib (Gleevec) prescriptions claims were for “dispense as written,” according to the researchers. This suggests that patients or providers specifically wanted to stay on the brand-name drug instead of switching to the generic.

“The more than doubling of the drug price over time and the lack of price reductions observed with nearly 2 years of generic drug competition is concerning,” Dr Dusetzina said.

“It begs the question whether we can rely on generic entry as a primary approach to address drug pricing for high-priced specialty medications. We need robust competition to move prices in this space.”

Photo by Patrick Pelletier

The availability of generic imatinib has had limited effects on costs of the drug, according to research published in Health Affairs.

Data suggest the cost of Gleevec in the US has more than doubled since the drug was approved in 2001, and the introduction of generic imatinib has reduced costs only slightly.

Two years after generic imatinib hit the market, a month’s supply of Gleevec cost about $9000, and the cost for generic imatinib was about $8000.

“Patients and providers have all looked forward to generic entry, expecting major price reductions,” said study author Stacie Dusetzina, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“Unfortunately, we don’t see prices drop as quickly and as low as we would hope when generics are available.”

For this study, Dr Dusetzina and a colleague analyzed data from the MarketScan Commercial Research Database. The database contained records of 139,233 prescription fills for imatinib, which were made by 7201 patients from May 2001 through September 2017.

The researchers noted that Gleevec was priced at nearly $4000 for a 1-month (400 mg) supply when it came on the market in 2001. That price escalated to nearly $10,000 by 2015 before a generic competitor entered the market.

However, prices for Gleevec and generic imatinib remained high 2 years later. In 2017, a month’s supply of Gleevec cost about $9000, and the cost of generic imatinib was about $8000.

The researchers said the Gleevec case demonstrates several potential barriers to effective generic price competition, including shifts in prescribing toward more expensive brand-name treatments and smaller-than-expected price reductions.

Twenty-four percent of imatinib (Gleevec) prescriptions claims were for “dispense as written,” according to the researchers. This suggests that patients or providers specifically wanted to stay on the brand-name drug instead of switching to the generic.

“The more than doubling of the drug price over time and the lack of price reductions observed with nearly 2 years of generic drug competition is concerning,” Dr Dusetzina said.

“It begs the question whether we can rely on generic entry as a primary approach to address drug pricing for high-priced specialty medications. We need robust competition to move prices in this space.”

Photo by Patrick Pelletier

The availability of generic imatinib has had limited effects on costs of the drug, according to research published in Health Affairs.

Data suggest the cost of Gleevec in the US has more than doubled since the drug was approved in 2001, and the introduction of generic imatinib has reduced costs only slightly.

Two years after generic imatinib hit the market, a month’s supply of Gleevec cost about $9000, and the cost for generic imatinib was about $8000.

“Patients and providers have all looked forward to generic entry, expecting major price reductions,” said study author Stacie Dusetzina, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“Unfortunately, we don’t see prices drop as quickly and as low as we would hope when generics are available.”

For this study, Dr Dusetzina and a colleague analyzed data from the MarketScan Commercial Research Database. The database contained records of 139,233 prescription fills for imatinib, which were made by 7201 patients from May 2001 through September 2017.

The researchers noted that Gleevec was priced at nearly $4000 for a 1-month (400 mg) supply when it came on the market in 2001. That price escalated to nearly $10,000 by 2015 before a generic competitor entered the market.

However, prices for Gleevec and generic imatinib remained high 2 years later. In 2017, a month’s supply of Gleevec cost about $9000, and the cost of generic imatinib was about $8000.

The researchers said the Gleevec case demonstrates several potential barriers to effective generic price competition, including shifts in prescribing toward more expensive brand-name treatments and smaller-than-expected price reductions.

Twenty-four percent of imatinib (Gleevec) prescriptions claims were for “dispense as written,” according to the researchers. This suggests that patients or providers specifically wanted to stay on the brand-name drug instead of switching to the generic.

“The more than doubling of the drug price over time and the lack of price reductions observed with nearly 2 years of generic drug competition is concerning,” Dr Dusetzina said.

“It begs the question whether we can rely on generic entry as a primary approach to address drug pricing for high-priced specialty medications. We need robust competition to move prices in this space.”

Henrique Orlandi Mourao

Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.

The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).

However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.

“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.

“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”

For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.

In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.

Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.

“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.

“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”

Henrique Orlandi Mourao

Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.

The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).

However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.

“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.

“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”

For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.

In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.

Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.

“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.

“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”

Henrique Orlandi Mourao

Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.

The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).

However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.

“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.

“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”

For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.

In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.

Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.

“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.

“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”

Photo from Penn Medicine

Researchers may have discovered why some patients with advanced chronic lymphocytic leukemia (CLL) don’t respond to chimeric antigen receptor (CAR) T-cell therapy.

The team found that CLL patients with elevated levels of “early memory” T cells prior to receiving CAR T-cell therapy had a partial or complete response to treatment, while patients with lower levels of these T cells did not respond.

The early memory T cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO.

The researchers validated the association between the early memory T cells and response in a small group of patients, predicting with 100% accuracy which patients would achieve a complete response.

Joseph A. Fraietta, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in Nature Medicine. This research was supported, in part, by Novartis.

For this study, the researchers retrospectively analyzed 41 patients with advanced, heavily pretreated, high-risk CLL who received at least 1 dose of CD19-directed CAR T cells.

Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy.

Therefore, the researchers compared the gene expression profiles and phenotypes of T cells in patients who had a complete response, partial response, or no response to therapy.

The CAR T cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T cells and possess the IL-6/STAT3 signature.

Non-responders, on the other hand, expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T cells to persist, expand, and fight the CLL.

“Pre-existing T-cell qualities have previously been associated with poor clinical response to cancer therapy, as well differentiation in the T cells,” Dr Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”

Elevated levels of the IL-6/STAT3 signaling pathway in these early T cells correlated with clinical responses to CAR T-cell therapy.

To validate these findings, the researchers screened for the early memory T cells in a group of 8 CLL patients, before and after CAR T-cell therapy. The team identified the complete responders with 100% specificity and sensitivity.

“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T-cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Dr Fraietta said.

“The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”

These findings also suggest the possibility of improving CAR T-cell therapy by selecting for cell manufacturing the subpopulation of T cells responsible for driving responses. However, this approach would come with challenges.

“What we’ve seen in these non-responders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations,” said study author J. Joseph Melenhorst, PhD, also of the University of Pennsylvania.

“But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”

The researchers also noted that it’s unclear why some patients’ T cells are suboptimal prior to treatment. However, the team believes this could have to do with prior therapies.

 

Future studies with a larger group of CLL patients should be conducted to help answer these questions and validate the findings from this study, the researchers said.

Photo from Penn Medicine

Researchers may have discovered why some patients with advanced chronic lymphocytic leukemia (CLL) don’t respond to chimeric antigen receptor (CAR) T-cell therapy.

The team found that CLL patients with elevated levels of “early memory” T cells prior to receiving CAR T-cell therapy had a partial or complete response to treatment, while patients with lower levels of these T cells did not respond.

The early memory T cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO.

The researchers validated the association between the early memory T cells and response in a small group of patients, predicting with 100% accuracy which patients would achieve a complete response.

Joseph A. Fraietta, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in Nature Medicine. This research was supported, in part, by Novartis.

For this study, the researchers retrospectively analyzed 41 patients with advanced, heavily pretreated, high-risk CLL who received at least 1 dose of CD19-directed CAR T cells.

Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy.

Therefore, the researchers compared the gene expression profiles and phenotypes of T cells in patients who had a complete response, partial response, or no response to therapy.

The CAR T cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T cells and possess the IL-6/STAT3 signature.

Non-responders, on the other hand, expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T cells to persist, expand, and fight the CLL.

“Pre-existing T-cell qualities have previously been associated with poor clinical response to cancer therapy, as well differentiation in the T cells,” Dr Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”

Elevated levels of the IL-6/STAT3 signaling pathway in these early T cells correlated with clinical responses to CAR T-cell therapy.

To validate these findings, the researchers screened for the early memory T cells in a group of 8 CLL patients, before and after CAR T-cell therapy. The team identified the complete responders with 100% specificity and sensitivity.

“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T-cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Dr Fraietta said.

“The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”

These findings also suggest the possibility of improving CAR T-cell therapy by selecting for cell manufacturing the subpopulation of T cells responsible for driving responses. However, this approach would come with challenges.

“What we’ve seen in these non-responders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations,” said study author J. Joseph Melenhorst, PhD, also of the University of Pennsylvania.

“But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”

The researchers also noted that it’s unclear why some patients’ T cells are suboptimal prior to treatment. However, the team believes this could have to do with prior therapies.

 

Future studies with a larger group of CLL patients should be conducted to help answer these questions and validate the findings from this study, the researchers said.

Photo from Penn Medicine

Researchers may have discovered why some patients with advanced chronic lymphocytic leukemia (CLL) don’t respond to chimeric antigen receptor (CAR) T-cell therapy.

The team found that CLL patients with elevated levels of “early memory” T cells prior to receiving CAR T-cell therapy had a partial or complete response to treatment, while patients with lower levels of these T cells did not respond.

The early memory T cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO.

The researchers validated the association between the early memory T cells and response in a small group of patients, predicting with 100% accuracy which patients would achieve a complete response.

Joseph A. Fraietta, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in Nature Medicine. This research was supported, in part, by Novartis.

For this study, the researchers retrospectively analyzed 41 patients with advanced, heavily pretreated, high-risk CLL who received at least 1 dose of CD19-directed CAR T cells.

Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy.

Therefore, the researchers compared the gene expression profiles and phenotypes of T cells in patients who had a complete response, partial response, or no response to therapy.

The CAR T cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T cells and possess the IL-6/STAT3 signature.

Non-responders, on the other hand, expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T cells to persist, expand, and fight the CLL.

“Pre-existing T-cell qualities have previously been associated with poor clinical response to cancer therapy, as well differentiation in the T cells,” Dr Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”

Elevated levels of the IL-6/STAT3 signaling pathway in these early T cells correlated with clinical responses to CAR T-cell therapy.

To validate these findings, the researchers screened for the early memory T cells in a group of 8 CLL patients, before and after CAR T-cell therapy. The team identified the complete responders with 100% specificity and sensitivity.

“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T-cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Dr Fraietta said.

“The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”

These findings also suggest the possibility of improving CAR T-cell therapy by selecting for cell manufacturing the subpopulation of T cells responsible for driving responses. However, this approach would come with challenges.

“What we’ve seen in these non-responders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations,” said study author J. Joseph Melenhorst, PhD, also of the University of Pennsylvania.

“But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”

The researchers also noted that it’s unclear why some patients’ T cells are suboptimal prior to treatment. However, the team believes this could have to do with prior therapies.

 

Future studies with a larger group of CLL patients should be conducted to help answer these questions and validate the findings from this study, the researchers said.

Image by Difu Wu

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended changes to the marketing authorization for dasatinib (Sprycel).

The CHMP is recommending approval for dasatinib as a treatment for pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or Ph+ CML-CP that is resistant or intolerant to prior therapy, including imatinib.

The CHMP has also recommended approval of a new formulation of dasatinib—a powder for oral suspension (PFOS)—for use in pediatric patients.

Dasatinib is already approved in the European Union to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The CHMP’s opinion on dasatinib for pediatric patients will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The CHMP’s opinion on dasatinib for pediatric patients is supported by 2 studies. Results from the phase 1 study (NCT00306202) were published in the Journal of Clinical Oncology in 2013. Phase 2 (NCT00777036) results were published in the same journal this year.

Phase 1

The phase 1 trial included 17 patients with CML-CP, all of whom had received prior imatinib.

Eleven patients received dasatinib at a starting dose of 60 mg/m² once daily, and 6 received the drug at a starting dose of 80 mg/m² once daily. Dose escalation was allowed based on tolerance and response. The median duration of treatment was 24.1 months (range, 2.3 to 50.6 months).

The 60 mg/m² starting dose appeared more tolerable than 80 mg/m² dose.

Drug-related adverse events (AEs) occurring in at least 20% of patients included neutropenia (82.4%), anemia (70.6%), thrombocytopenia (64.7%), nausea (29.4%), headache (35.3%), diarrhea (23.5%), and pain in extremity (23.5%). Grade 3-4 AEs included neutropenia (23.5%), thrombocytopenia (11.8%), and headache (5.9%). There were no drug-related deaths.

Ninety-four percent of patients achieved a complete hematologic response (CHR), 88% had a major cytogenetic response (MCyR), 82% had a complete cytogenetic response (CCyR), 47% had a major molecular response (MMR), and 24% had a complete molecular response (CMR).

Patients who received the lower starting dose of dasatinib had lower rates of cumulative CCyR (72.7% vs 100%) and CHR (90.9% vs 100%) but higher rates of cumulative MMR (54.5% vs 33.3%) and CMR (27.3% vs 16.7).

The median progression-free survival (PFS) and overall survival (OS) had not been reached at last follow-up. At 24 months, the estimated PFS was 61%, and the estimated OS was 88%.

Phase 2

The phase 2 trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33). Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

 

Rates of confirmed CHR (at any time) were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had an MMR rate of 41% and a CMR rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of MCyR at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of CCyR at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median PFS and OS had not been reached at last follow-up. The estimated 48-month PFS was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month OS was 96% and 100%, respectively.

Dasatinib-related AEs occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Image by Difu Wu

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended changes to the marketing authorization for dasatinib (Sprycel).

The CHMP is recommending approval for dasatinib as a treatment for pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or Ph+ CML-CP that is resistant or intolerant to prior therapy, including imatinib.

The CHMP has also recommended approval of a new formulation of dasatinib—a powder for oral suspension (PFOS)—for use in pediatric patients.

Dasatinib is already approved in the European Union to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The CHMP’s opinion on dasatinib for pediatric patients will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The CHMP’s opinion on dasatinib for pediatric patients is supported by 2 studies. Results from the phase 1 study (NCT00306202) were published in the Journal of Clinical Oncology in 2013. Phase 2 (NCT00777036) results were published in the same journal this year.

Phase 1

The phase 1 trial included 17 patients with CML-CP, all of whom had received prior imatinib.

Eleven patients received dasatinib at a starting dose of 60 mg/m² once daily, and 6 received the drug at a starting dose of 80 mg/m² once daily. Dose escalation was allowed based on tolerance and response. The median duration of treatment was 24.1 months (range, 2.3 to 50.6 months).

The 60 mg/m² starting dose appeared more tolerable than 80 mg/m² dose.

Drug-related adverse events (AEs) occurring in at least 20% of patients included neutropenia (82.4%), anemia (70.6%), thrombocytopenia (64.7%), nausea (29.4%), headache (35.3%), diarrhea (23.5%), and pain in extremity (23.5%). Grade 3-4 AEs included neutropenia (23.5%), thrombocytopenia (11.8%), and headache (5.9%). There were no drug-related deaths.

Ninety-four percent of patients achieved a complete hematologic response (CHR), 88% had a major cytogenetic response (MCyR), 82% had a complete cytogenetic response (CCyR), 47% had a major molecular response (MMR), and 24% had a complete molecular response (CMR).

Patients who received the lower starting dose of dasatinib had lower rates of cumulative CCyR (72.7% vs 100%) and CHR (90.9% vs 100%) but higher rates of cumulative MMR (54.5% vs 33.3%) and CMR (27.3% vs 16.7).

The median progression-free survival (PFS) and overall survival (OS) had not been reached at last follow-up. At 24 months, the estimated PFS was 61%, and the estimated OS was 88%.

Phase 2

The phase 2 trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33). Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

 

Rates of confirmed CHR (at any time) were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had an MMR rate of 41% and a CMR rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of MCyR at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of CCyR at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median PFS and OS had not been reached at last follow-up. The estimated 48-month PFS was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month OS was 96% and 100%, respectively.

Dasatinib-related AEs occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Image by Difu Wu

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended changes to the marketing authorization for dasatinib (Sprycel).

The CHMP is recommending approval for dasatinib as a treatment for pediatric patients with newly diagnosed, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) or Ph+ CML-CP that is resistant or intolerant to prior therapy, including imatinib.

The CHMP has also recommended approval of a new formulation of dasatinib—a powder for oral suspension (PFOS)—for use in pediatric patients.

Dasatinib is already approved in the European Union to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The CHMP’s opinion on dasatinib for pediatric patients will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

The CHMP’s opinion on dasatinib for pediatric patients is supported by 2 studies. Results from the phase 1 study (NCT00306202) were published in the Journal of Clinical Oncology in 2013. Phase 2 (NCT00777036) results were published in the same journal this year.

Phase 1

The phase 1 trial included 17 patients with CML-CP, all of whom had received prior imatinib.

Eleven patients received dasatinib at a starting dose of 60 mg/m² once daily, and 6 received the drug at a starting dose of 80 mg/m² once daily. Dose escalation was allowed based on tolerance and response. The median duration of treatment was 24.1 months (range, 2.3 to 50.6 months).

The 60 mg/m² starting dose appeared more tolerable than 80 mg/m² dose.

Drug-related adverse events (AEs) occurring in at least 20% of patients included neutropenia (82.4%), anemia (70.6%), thrombocytopenia (64.7%), nausea (29.4%), headache (35.3%), diarrhea (23.5%), and pain in extremity (23.5%). Grade 3-4 AEs included neutropenia (23.5%), thrombocytopenia (11.8%), and headache (5.9%). There were no drug-related deaths.

Ninety-four percent of patients achieved a complete hematologic response (CHR), 88% had a major cytogenetic response (MCyR), 82% had a complete cytogenetic response (CCyR), 47% had a major molecular response (MMR), and 24% had a complete molecular response (CMR).

Patients who received the lower starting dose of dasatinib had lower rates of cumulative CCyR (72.7% vs 100%) and CHR (90.9% vs 100%) but higher rates of cumulative MMR (54.5% vs 33.3%) and CMR (27.3% vs 16.7).

The median progression-free survival (PFS) and overall survival (OS) had not been reached at last follow-up. At 24 months, the estimated PFS was 61%, and the estimated OS was 88%.

Phase 2

The phase 2 trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33). Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

 

Rates of confirmed CHR (at any time) were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had an MMR rate of 41% and a CMR rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of MCyR at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of CCyR at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median PFS and OS had not been reached at last follow-up. The estimated 48-month PFS was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month OS was 96% and 100%, respectively.

Dasatinib-related AEs occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

 

The prognosis of AML in the elderly is very poor, with 5-year survival rates less than 10% in patients aged 65 years and older. However, in recent years, novel therapeutic approaches have been developed to focus on the older AML population. Have we begun to witness an improvement in the survival of these patients?

A key question to ask at the outset of any discussion pertaining to improving survival in older patients with AML is how poorly do patients fare with no disease-specific therapy at all? This is important because it speaks to the issue of treatment itself (of any type) being important in the achievement of a survival benefit.

Several clinical trials and observational registration studies have made it very clear that, without treatment, the survival in AML is very short – ranging from 11-16 weeks (for patients enrolled in therapeutic trials who received best supportive care only) to only 6-8 weeks in the “real-world” setting, based upon observational studies.^1,2,3,4

These data are very meaningful because older AML patients often do not receive active therapy. As recently as 2009, SEER data indicate that 50% of patients aged 65 years or older receive no treatment for AML. This trend appears to be changing, based upon data from the AMLSG in 2012-2014, in which only a minority of patients in this age range received best supportive care only for their AML.

Knowing the very poor outcomes of patients who are not treated for AML, along with a high number of patients who are not treated, we must next ask whether any treatment at all is superior to no treatment. The data appear relatively clear on this question, with two representative publications highlighting the superiority of treatment vs. no treatment. First, in the SEER registry analysis by Medeiros et al., treated patients had a median survival of 5 months, compared with 2.5 months in untreated patients, and there was an unequivocal survival advantage attributed to treatment after adjustment for covariates and propensity score matching. Treatment included both traditional induction regimens and hypomethylating agent (HMA) therapy. Similarly, a phase 3 clinical trial testing low-dose cytarabine (LDAC) vs. best supportive care demonstrated survival improvement with LDAC (odds ratio, 0.60).

Recognizing that treatment improves survival in older adults with AML and that there is an upward trend in the percent of patients who receive active therapy, we can reasonably ask next whether survival has begun to trend upward over the past several years. This, of course, is a challenging question, but one that can be at least partially addressed through analyses of registration cohorts.

SEER data regarding AML patients aged 65 and older from the 1970s to 2013 suggest modestly improved 2-year survival, from less than 10% in the 1970s to 10%-15% since the early 2000s. The Moffitt Cancer Center database of patients aged 70 years and older also indicates a strong trend toward modestly improved survival after 2005, compared with prior to 2005 (unpublished data). Although the precise reason for trending improvements in overall survival of these patients over time is not clear, it is reasonable to suggest that a greater proportion of patients who receive actual therapy for AML could explain the modest improvements being observed. Improvements in supportive care through the years could also contribute to survival improvement trends over time, though this hypothesis has not been formally tested.

 

Next, we should ask about the most effective currently available therapy for older adults with AML. Standard treatment options for these patients, as mentioned previously, include high-intensity (traditional induction chemotherapy) and lower-intensity (LDAC, HMAs) regimens. Unfortunately, a prospective, randomized comparison between such regimens has not been undertaken, so it is impossible to declare with any certainty as to the superiority of one approach versus another. Larger database analyses, utilizing multivariate cox regression analyses, have been performed, suggesting that HMAs and intensive therapies perform similarly, such that offering an older adult with AML frontline therapy with a lower-intensity regimen is very reasonable.⁵

It is quite important to address the possibility that newer therapies in AML are changing the natural history of the disease. First of all, strategies utilizing HMA therapy with 5-azacitidine or decitabine have been widely studied. Unfortunately, a clear and convincing signal of survival benefit of frontline HMA therapy, compared with conventional care regimens (most commonly LDAC) has not been demonstrated, although trends toward a very modest survival advantage favoring HMAs were observed.^6,7

Interestingly, in the AZA-AML-001 study, only the subgroup of patients who were preselected to receive best supportive care achieved survival benefit from 5-azacitidine, again suggesting that treatment vs. no treatment is among the most important factors leading to survival improvement in elderly AML.

Other novel agents are coming to the forefront, with the potential to change the natural history of AML in elderly patients. CPX-351 is a liposomal product that encapsulates cytarabine and daunorubicin in a fixed and synergistic molar ratio, thereby allowing delivery of both agents to the leukemic cell in the optimal fashion for cell kill. A recently completed phase 3 trial in older adults with secondary AML demonstrated statistically significant survival improvement with CPX-351 as compared with traditional daunorubicin plus cytarabine induction. A substantial minority of patients on this trial went to allogeneic hematopoietic cell transplant during first remission, and a landmark analysis performed at the time of transplant indicated better survival among patients who had received initial therapy with CPX-351.⁸

 

These data suggest that, in selected older adults with secondary AML who are fit enough to receive induction chemotherapy, CPX-351 offers a survival advantage, even among traditionally higher-risk subgroups, including patients with adverse karyotype of above age 70 years. As such, CPX-351 (Vyxeos) received FDA approval as frontline therapy for secondary AML in 2017.

Newer targeted therapies for older adults with AML also appear to hold promise. Glasdegib, an inhibitor of SMO (part of the hedgehog signaling pathway) was recently studied in combination with LDAC versus LDAC alone in a randomized phase 2 trial in older patients considered unfit for intensive induction chemotherapy. In this trial, patients assigned to glasdegib plus LDAC had longer median and overall survival than patients treated with LDAC alone, suggesting a promising novel agent on the horizon.⁹

Another example of a promising and novel targeted agent for AML is venetoclax, an inhibitor of BCL-2. Encouragingly high response rates and overall survival in phase 2 trials that combined venetoclax with LDAC or HMAs have driven randomized trials to definitively ascertain a survival advantage in older patients considered unfit for intensive therapy.^10,11

The question also arises as to whether therapeutic outcomes can be optimized by better selection of currently available therapies for any given. This concept requires development of a decision analysis model that can be used to accurately predict outcomes among older patients with newly diagnosed AML. At Moffitt Cancer Center, such a model is being developed using a systematic review of the literature, followed by validation in a large institutional database. To date, there is the strong initial suggestion that initial therapy selection can be optimized for best outcome, taking into account variables including ECOG performance status, Charlson Comorbidity Index, and cytogenetic risk.¹²

 

The goal of improving survival in older adults with AML remains elusive. The decision to treat (regardless of high vs. low intensity) appears critical toward achieving this goal. New therapies such as CPX-351, glasdegib, and venetoclax also hold promise in further improving survival in subgroups of older patients. Finally, development of accurate predictive models to optimize initial therapy will be of critical importance for improving survival in this very heterogeneous disease that afflicts a very heterogeneous group of patients.

Dr. Lancet is chair of the department of malignant hematology at H. Lee Moffitt Cancer Center in Tampa. He has received consulting fees from Astellas, BioSight, Celgene, Janssen R&D, and Jazz Pharmaceuticals.

References

1. Burnett AK et al. Cancer. 2007 Mar 15;109(6):1114-24.

2. Harousseau JL et al. Blood. 2009 Aug 6;114(6):1166-73.

3. Medeiros BC et al. Ann Hematol. 2015 Mar 20; 94(7):1127-38.

4. Oran B et al. Haematologica. 2012 Dec;97(12):1916-24.

5. Lancet JE et al. J Clin Oncol. 2017. doi: 10.1200/JCO.2017.35.15_suppl.7031.

6. Dombret H et al. Blood. 2015 Jul 16;126(3):291-9.

7. Kantarjian HM et al. J Clin Oncol. 2012 Jul 20;30(21):2670-7.

8. Lancet JE et al. Blood 2016 128:906.

9. Cortes JE et al. Blood 2016 128:99.

10. DiNardo CD et al. Blood 2017 130:2628.

11. Wei A et al. Blood 2017 130:890.

12. Extermann M et al. SIOG 2017.

 

The prognosis of AML in the elderly is very poor, with 5-year survival rates less than 10% in patients aged 65 years and older. However, in recent years, novel therapeutic approaches have been developed to focus on the older AML population. Have we begun to witness an improvement in the survival of these patients?

A key question to ask at the outset of any discussion pertaining to improving survival in older patients with AML is how poorly do patients fare with no disease-specific therapy at all? This is important because it speaks to the issue of treatment itself (of any type) being important in the achievement of a survival benefit.

Several clinical trials and observational registration studies have made it very clear that, without treatment, the survival in AML is very short – ranging from 11-16 weeks (for patients enrolled in therapeutic trials who received best supportive care only) to only 6-8 weeks in the “real-world” setting, based upon observational studies.^1,2,3,4

These data are very meaningful because older AML patients often do not receive active therapy. As recently as 2009, SEER data indicate that 50% of patients aged 65 years or older receive no treatment for AML. This trend appears to be changing, based upon data from the AMLSG in 2012-2014, in which only a minority of patients in this age range received best supportive care only for their AML.

Knowing the very poor outcomes of patients who are not treated for AML, along with a high number of patients who are not treated, we must next ask whether any treatment at all is superior to no treatment. The data appear relatively clear on this question, with two representative publications highlighting the superiority of treatment vs. no treatment. First, in the SEER registry analysis by Medeiros et al., treated patients had a median survival of 5 months, compared with 2.5 months in untreated patients, and there was an unequivocal survival advantage attributed to treatment after adjustment for covariates and propensity score matching. Treatment included both traditional induction regimens and hypomethylating agent (HMA) therapy. Similarly, a phase 3 clinical trial testing low-dose cytarabine (LDAC) vs. best supportive care demonstrated survival improvement with LDAC (odds ratio, 0.60).

Recognizing that treatment improves survival in older adults with AML and that there is an upward trend in the percent of patients who receive active therapy, we can reasonably ask next whether survival has begun to trend upward over the past several years. This, of course, is a challenging question, but one that can be at least partially addressed through analyses of registration cohorts.

SEER data regarding AML patients aged 65 and older from the 1970s to 2013 suggest modestly improved 2-year survival, from less than 10% in the 1970s to 10%-15% since the early 2000s. The Moffitt Cancer Center database of patients aged 70 years and older also indicates a strong trend toward modestly improved survival after 2005, compared with prior to 2005 (unpublished data). Although the precise reason for trending improvements in overall survival of these patients over time is not clear, it is reasonable to suggest that a greater proportion of patients who receive actual therapy for AML could explain the modest improvements being observed. Improvements in supportive care through the years could also contribute to survival improvement trends over time, though this hypothesis has not been formally tested.

 

Next, we should ask about the most effective currently available therapy for older adults with AML. Standard treatment options for these patients, as mentioned previously, include high-intensity (traditional induction chemotherapy) and lower-intensity (LDAC, HMAs) regimens. Unfortunately, a prospective, randomized comparison between such regimens has not been undertaken, so it is impossible to declare with any certainty as to the superiority of one approach versus another. Larger database analyses, utilizing multivariate cox regression analyses, have been performed, suggesting that HMAs and intensive therapies perform similarly, such that offering an older adult with AML frontline therapy with a lower-intensity regimen is very reasonable.⁵

It is quite important to address the possibility that newer therapies in AML are changing the natural history of the disease. First of all, strategies utilizing HMA therapy with 5-azacitidine or decitabine have been widely studied. Unfortunately, a clear and convincing signal of survival benefit of frontline HMA therapy, compared with conventional care regimens (most commonly LDAC) has not been demonstrated, although trends toward a very modest survival advantage favoring HMAs were observed.^6,7

Interestingly, in the AZA-AML-001 study, only the subgroup of patients who were preselected to receive best supportive care achieved survival benefit from 5-azacitidine, again suggesting that treatment vs. no treatment is among the most important factors leading to survival improvement in elderly AML.

Other novel agents are coming to the forefront, with the potential to change the natural history of AML in elderly patients. CPX-351 is a liposomal product that encapsulates cytarabine and daunorubicin in a fixed and synergistic molar ratio, thereby allowing delivery of both agents to the leukemic cell in the optimal fashion for cell kill. A recently completed phase 3 trial in older adults with secondary AML demonstrated statistically significant survival improvement with CPX-351 as compared with traditional daunorubicin plus cytarabine induction. A substantial minority of patients on this trial went to allogeneic hematopoietic cell transplant during first remission, and a landmark analysis performed at the time of transplant indicated better survival among patients who had received initial therapy with CPX-351.⁸

 

These data suggest that, in selected older adults with secondary AML who are fit enough to receive induction chemotherapy, CPX-351 offers a survival advantage, even among traditionally higher-risk subgroups, including patients with adverse karyotype of above age 70 years. As such, CPX-351 (Vyxeos) received FDA approval as frontline therapy for secondary AML in 2017.

Newer targeted therapies for older adults with AML also appear to hold promise. Glasdegib, an inhibitor of SMO (part of the hedgehog signaling pathway) was recently studied in combination with LDAC versus LDAC alone in a randomized phase 2 trial in older patients considered unfit for intensive induction chemotherapy. In this trial, patients assigned to glasdegib plus LDAC had longer median and overall survival than patients treated with LDAC alone, suggesting a promising novel agent on the horizon.⁹

Another example of a promising and novel targeted agent for AML is venetoclax, an inhibitor of BCL-2. Encouragingly high response rates and overall survival in phase 2 trials that combined venetoclax with LDAC or HMAs have driven randomized trials to definitively ascertain a survival advantage in older patients considered unfit for intensive therapy.^10,11

The question also arises as to whether therapeutic outcomes can be optimized by better selection of currently available therapies for any given. This concept requires development of a decision analysis model that can be used to accurately predict outcomes among older patients with newly diagnosed AML. At Moffitt Cancer Center, such a model is being developed using a systematic review of the literature, followed by validation in a large institutional database. To date, there is the strong initial suggestion that initial therapy selection can be optimized for best outcome, taking into account variables including ECOG performance status, Charlson Comorbidity Index, and cytogenetic risk.¹²

 

The goal of improving survival in older adults with AML remains elusive. The decision to treat (regardless of high vs. low intensity) appears critical toward achieving this goal. New therapies such as CPX-351, glasdegib, and venetoclax also hold promise in further improving survival in subgroups of older patients. Finally, development of accurate predictive models to optimize initial therapy will be of critical importance for improving survival in this very heterogeneous disease that afflicts a very heterogeneous group of patients.

Dr. Lancet is chair of the department of malignant hematology at H. Lee Moffitt Cancer Center in Tampa. He has received consulting fees from Astellas, BioSight, Celgene, Janssen R&D, and Jazz Pharmaceuticals.

References

1. Burnett AK et al. Cancer. 2007 Mar 15;109(6):1114-24.

2. Harousseau JL et al. Blood. 2009 Aug 6;114(6):1166-73.

3. Medeiros BC et al. Ann Hematol. 2015 Mar 20; 94(7):1127-38.

4. Oran B et al. Haematologica. 2012 Dec;97(12):1916-24.

5. Lancet JE et al. J Clin Oncol. 2017. doi: 10.1200/JCO.2017.35.15_suppl.7031.

6. Dombret H et al. Blood. 2015 Jul 16;126(3):291-9.

7. Kantarjian HM et al. J Clin Oncol. 2012 Jul 20;30(21):2670-7.

8. Lancet JE et al. Blood 2016 128:906.

9. Cortes JE et al. Blood 2016 128:99.

10. DiNardo CD et al. Blood 2017 130:2628.

11. Wei A et al. Blood 2017 130:890.

12. Extermann M et al. SIOG 2017.

 

The prognosis of AML in the elderly is very poor, with 5-year survival rates less than 10% in patients aged 65 years and older. However, in recent years, novel therapeutic approaches have been developed to focus on the older AML population. Have we begun to witness an improvement in the survival of these patients?

A key question to ask at the outset of any discussion pertaining to improving survival in older patients with AML is how poorly do patients fare with no disease-specific therapy at all? This is important because it speaks to the issue of treatment itself (of any type) being important in the achievement of a survival benefit.

Several clinical trials and observational registration studies have made it very clear that, without treatment, the survival in AML is very short – ranging from 11-16 weeks (for patients enrolled in therapeutic trials who received best supportive care only) to only 6-8 weeks in the “real-world” setting, based upon observational studies.^1,2,3,4

These data are very meaningful because older AML patients often do not receive active therapy. As recently as 2009, SEER data indicate that 50% of patients aged 65 years or older receive no treatment for AML. This trend appears to be changing, based upon data from the AMLSG in 2012-2014, in which only a minority of patients in this age range received best supportive care only for their AML.

Knowing the very poor outcomes of patients who are not treated for AML, along with a high number of patients who are not treated, we must next ask whether any treatment at all is superior to no treatment. The data appear relatively clear on this question, with two representative publications highlighting the superiority of treatment vs. no treatment. First, in the SEER registry analysis by Medeiros et al., treated patients had a median survival of 5 months, compared with 2.5 months in untreated patients, and there was an unequivocal survival advantage attributed to treatment after adjustment for covariates and propensity score matching. Treatment included both traditional induction regimens and hypomethylating agent (HMA) therapy. Similarly, a phase 3 clinical trial testing low-dose cytarabine (LDAC) vs. best supportive care demonstrated survival improvement with LDAC (odds ratio, 0.60).

Recognizing that treatment improves survival in older adults with AML and that there is an upward trend in the percent of patients who receive active therapy, we can reasonably ask next whether survival has begun to trend upward over the past several years. This, of course, is a challenging question, but one that can be at least partially addressed through analyses of registration cohorts.

SEER data regarding AML patients aged 65 and older from the 1970s to 2013 suggest modestly improved 2-year survival, from less than 10% in the 1970s to 10%-15% since the early 2000s. The Moffitt Cancer Center database of patients aged 70 years and older also indicates a strong trend toward modestly improved survival after 2005, compared with prior to 2005 (unpublished data). Although the precise reason for trending improvements in overall survival of these patients over time is not clear, it is reasonable to suggest that a greater proportion of patients who receive actual therapy for AML could explain the modest improvements being observed. Improvements in supportive care through the years could also contribute to survival improvement trends over time, though this hypothesis has not been formally tested.

 

Next, we should ask about the most effective currently available therapy for older adults with AML. Standard treatment options for these patients, as mentioned previously, include high-intensity (traditional induction chemotherapy) and lower-intensity (LDAC, HMAs) regimens. Unfortunately, a prospective, randomized comparison between such regimens has not been undertaken, so it is impossible to declare with any certainty as to the superiority of one approach versus another. Larger database analyses, utilizing multivariate cox regression analyses, have been performed, suggesting that HMAs and intensive therapies perform similarly, such that offering an older adult with AML frontline therapy with a lower-intensity regimen is very reasonable.⁵

It is quite important to address the possibility that newer therapies in AML are changing the natural history of the disease. First of all, strategies utilizing HMA therapy with 5-azacitidine or decitabine have been widely studied. Unfortunately, a clear and convincing signal of survival benefit of frontline HMA therapy, compared with conventional care regimens (most commonly LDAC) has not been demonstrated, although trends toward a very modest survival advantage favoring HMAs were observed.^6,7

Interestingly, in the AZA-AML-001 study, only the subgroup of patients who were preselected to receive best supportive care achieved survival benefit from 5-azacitidine, again suggesting that treatment vs. no treatment is among the most important factors leading to survival improvement in elderly AML.

Other novel agents are coming to the forefront, with the potential to change the natural history of AML in elderly patients. CPX-351 is a liposomal product that encapsulates cytarabine and daunorubicin in a fixed and synergistic molar ratio, thereby allowing delivery of both agents to the leukemic cell in the optimal fashion for cell kill. A recently completed phase 3 trial in older adults with secondary AML demonstrated statistically significant survival improvement with CPX-351 as compared with traditional daunorubicin plus cytarabine induction. A substantial minority of patients on this trial went to allogeneic hematopoietic cell transplant during first remission, and a landmark analysis performed at the time of transplant indicated better survival among patients who had received initial therapy with CPX-351.⁸

 

These data suggest that, in selected older adults with secondary AML who are fit enough to receive induction chemotherapy, CPX-351 offers a survival advantage, even among traditionally higher-risk subgroups, including patients with adverse karyotype of above age 70 years. As such, CPX-351 (Vyxeos) received FDA approval as frontline therapy for secondary AML in 2017.

Newer targeted therapies for older adults with AML also appear to hold promise. Glasdegib, an inhibitor of SMO (part of the hedgehog signaling pathway) was recently studied in combination with LDAC versus LDAC alone in a randomized phase 2 trial in older patients considered unfit for intensive induction chemotherapy. In this trial, patients assigned to glasdegib plus LDAC had longer median and overall survival than patients treated with LDAC alone, suggesting a promising novel agent on the horizon.⁹

Another example of a promising and novel targeted agent for AML is venetoclax, an inhibitor of BCL-2. Encouragingly high response rates and overall survival in phase 2 trials that combined venetoclax with LDAC or HMAs have driven randomized trials to definitively ascertain a survival advantage in older patients considered unfit for intensive therapy.^10,11

The question also arises as to whether therapeutic outcomes can be optimized by better selection of currently available therapies for any given. This concept requires development of a decision analysis model that can be used to accurately predict outcomes among older patients with newly diagnosed AML. At Moffitt Cancer Center, such a model is being developed using a systematic review of the literature, followed by validation in a large institutional database. To date, there is the strong initial suggestion that initial therapy selection can be optimized for best outcome, taking into account variables including ECOG performance status, Charlson Comorbidity Index, and cytogenetic risk.¹²

 

The goal of improving survival in older adults with AML remains elusive. The decision to treat (regardless of high vs. low intensity) appears critical toward achieving this goal. New therapies such as CPX-351, glasdegib, and venetoclax also hold promise in further improving survival in subgroups of older patients. Finally, development of accurate predictive models to optimize initial therapy will be of critical importance for improving survival in this very heterogeneous disease that afflicts a very heterogeneous group of patients.

Dr. Lancet is chair of the department of malignant hematology at H. Lee Moffitt Cancer Center in Tampa. He has received consulting fees from Astellas, BioSight, Celgene, Janssen R&D, and Jazz Pharmaceuticals.

References

1. Burnett AK et al. Cancer. 2007 Mar 15;109(6):1114-24.

2. Harousseau JL et al. Blood. 2009 Aug 6;114(6):1166-73.

3. Medeiros BC et al. Ann Hematol. 2015 Mar 20; 94(7):1127-38.

4. Oran B et al. Haematologica. 2012 Dec;97(12):1916-24.

5. Lancet JE et al. J Clin Oncol. 2017. doi: 10.1200/JCO.2017.35.15_suppl.7031.

6. Dombret H et al. Blood. 2015 Jul 16;126(3):291-9.

7. Kantarjian HM et al. J Clin Oncol. 2012 Jul 20;30(21):2670-7.

8. Lancet JE et al. Blood 2016 128:906.

9. Cortes JE et al. Blood 2016 128:99.

10. DiNardo CD et al. Blood 2017 130:2628.

11. Wei A et al. Blood 2017 130:890.

12. Extermann M et al. SIOG 2017.

 

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, and will “completely transform oncology,” according to Carl June, MD.

That approval is anticipated sometime in 2019.

“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.

The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.

Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.

Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.

“Now he considers himself cured,” Dr. June said.

 

More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.

The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.

Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

 

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.

Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.

Sharon Worcester/MDedge News

The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.

LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.

 

The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.

Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.

“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.

With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.

 

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.

Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.

That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.

“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

 

CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.

“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”

Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

 

[email protected]

 

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, and will “completely transform oncology,” according to Carl June, MD.

That approval is anticipated sometime in 2019.

“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.

The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.

Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.

Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.

“Now he considers himself cured,” Dr. June said.

 

More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.

The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.

Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

 

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.

Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.

Sharon Worcester/MDedge News

The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.

LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.

 

The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.

Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.

“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.

With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.

 

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.

Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.

That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.

“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

 

CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.

“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”

Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

 

[email protected]

 

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, and will “completely transform oncology,” according to Carl June, MD.

That approval is anticipated sometime in 2019.

“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.

The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.

Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.

Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.

“Now he considers himself cured,” Dr. June said.

 

More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.

The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.

Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

 

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.

Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.

Sharon Worcester/MDedge News

The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.

LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.

 

The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.

Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.

“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.

With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.

 

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.

Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.

That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.

“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

 

CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.

“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”

Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

 

[email protected]

Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.

In particular, they may be at risk of developing multiple myeloma at an earlier age.

The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.

The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).

“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.

However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.

“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.

 

A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.

The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.

In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.

Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.

 

“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.

Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.

The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.

“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.

 

The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.

The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.

SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.

Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.

In particular, they may be at risk of developing multiple myeloma at an earlier age.

The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.

The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).

“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.

However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.

“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.

 

A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.

The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.

In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.

Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.

 

“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.

Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.

The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.

“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.

 

The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.

The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.

SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.

Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.

In particular, they may be at risk of developing multiple myeloma at an earlier age.

The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.

The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).

“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.

However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.

“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.

 

A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.

The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.

In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.

Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.

 

“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.

Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.

The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.

“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.

 

The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.

The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.

SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.

Micrograph showing CLL

CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).

Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.

The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.

William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).

This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.

The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.

Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.

Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.

The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.

The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.

Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.

The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.

The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.

“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.

“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”

Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.

Micrograph showing CLL

CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).

Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.

The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.

William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).

This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.

The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.

Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.

Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.

The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.

The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.

Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.

The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.

The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.

“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.

“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”

Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.

Micrograph showing CLL

CHICAGO—Researchers have reported “strong synergy” between the CDK2/9 inhibitor CYC065 and the Bcl-2 inhibitor venetoclax in chronic lymphocytic leukemia (CLL).

Experiments indicated that CYC065 and venetoclax target parallel mechanisms that promote survival in CLL cells, working together to induce apoptosis.

The drugs demonstrated synergy even in CLL samples that are inherently resistant to each drug alone.

William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center in Houston, Texas, and his colleagues reported these findings at the AACR Annual Meeting 2018 (abstract 3905).

This research was supported by Cyclacel Pharmaceuticals, Inc., the company developing CYC065.

The researchers explained that CYC065 depletes Mcl-1 to induce apoptosis in CLL cells, while venetoclax induces apoptosis via inhibition of Bcl-2. However, upregulation of Mcl-1 is associated with resistance to venetoclax.

Therefore, the researchers theorized that combining CYC065 and venetoclax would serve to target 2 mechanisms that promote survival in CLL cells.

Experiments showed that CYC065 and venetoclax combined synergistically in CLL samples with or without 17p deletion. However, the researchers observed heterogeneity in response across samples.

The team said both drugs appeared to be less potent in some del(17p) samples. However, they also observed “great synergy” in del(17p) samples that were resistant to CYC065 or venetoclax alone.

The researchers noted differences in the kinetics of cell death in response to each drug and said this is consistent with the drugs’ different mechanisms of action.

Maximal cell death was reached at 6 to 8 hours with venetoclax but took at least 24 hours with CYC065.

The researchers also assessed the reversibility of CYC065 and venetoclax. They incubated CLL cells with each drug alone and in combination, then washed and incubated cells in drug-free media.

The team observed no additional cell death after the removal of CYC065, venetoclax, or the combination. They said this suggests an “adequate exposure time” is needed to maximize the induction of apoptosis with these drugs.

“[T]he combination of CYC065 and venetoclax is strongly synergistic in primary CLL cells from patients, including those with 17p deletions,” said Spiro Rombotis, president and chief executive officer of Cyclacel.

“In addition, the combination was active in 2 CLL samples which were resistant to either agent alone. These findings support the hypothesis that dual targeting of the Mcl-1- and Bcl-2-dependent mechanisms could induce synergistic cell death by apoptosis.”

Based on these results, Cyclacel is planning a trial of CYC065 and venetoclax in patients with relapsed/refractory CLL.

Image by Lance Liotta

New research suggests SHARP1 may be a therapeutic target in MLL-AF6 acute myeloid leukemia (AML).

Researchers found that SHARP1, a circadian clock transcription factor, is overexpressed in MLL-AF6 AML.

In mouse models, suppression of SHARP1 induced apoptosis in leukemic cells, while deletion of SHARP1 delayed AML development and weakened leukemia-initiating potential.

“We found that MLL-AF6 binds with SHARP1, leading to an increase in the level of SHARP1,” explained study author Dan Tenen, MD, of the Cancer Science Institute of Singapore.

“The increase of SHARP1 levels has the 2-fold effect of initiating leukemia development, as well as maintaining the growth of leukemic cells. [O]ur study also revealed that SHARP1 could act upon other target genes of MLL-AF6 to aggravate the progression of AML, but, by removing or reducing the level of SHARP1, the growth of leukemic cells could be stopped.”

Dr Tenen and his colleagues reported these findings in Nature Communications.

The researchers found that SHARP1 was overexpressed in MLL-AF6 AML, but its expression was decreased in most other subtypes of AML analyzed as well as in normal bone marrow CD34+ cells.

Experiments in AML cell lines revealed that SHARP1 expression is regulated by MLL-AF6/DOT1L. The researchers said MLL-AF6 and MEN1/LEDGF directly bind to the SHARP1 gene locus to positively regulate SHARP1 expression through DOT1L activity.

Dr Tenen and his colleagues performed knockdown experiments in mice and found that SHARP1 plays a “critical” role in maintaining clonogenic growth and preventing apoptosis in MLL-AF6 AML cells.

The team also assessed the effects of SHARP1 deletion in mouse models of MLL-AF6 AML.

SHARP1 knockout mice had superior survival compared to wild-type mice. In addition, the knockout mice exhibited signs of less aggressive disease—fewer AML cells, lower white blood cell counts, and higher red blood cell counts.

The researchers also found that SHARP1 deletion reduced MLL-AF6 leukemia-initiating ability but did not affect normal hematopoiesis.

Finally, the team discovered that SHARP1 cooperates with MLL-AF6 to regulate target genes in MLL-AF6 AML cells.

Image by Lance Liotta

New research suggests SHARP1 may be a therapeutic target in MLL-AF6 acute myeloid leukemia (AML).

Researchers found that SHARP1, a circadian clock transcription factor, is overexpressed in MLL-AF6 AML.

In mouse models, suppression of SHARP1 induced apoptosis in leukemic cells, while deletion of SHARP1 delayed AML development and weakened leukemia-initiating potential.

“We found that MLL-AF6 binds with SHARP1, leading to an increase in the level of SHARP1,” explained study author Dan Tenen, MD, of the Cancer Science Institute of Singapore.

“The increase of SHARP1 levels has the 2-fold effect of initiating leukemia development, as well as maintaining the growth of leukemic cells. [O]ur study also revealed that SHARP1 could act upon other target genes of MLL-AF6 to aggravate the progression of AML, but, by removing or reducing the level of SHARP1, the growth of leukemic cells could be stopped.”

Dr Tenen and his colleagues reported these findings in Nature Communications.

The researchers found that SHARP1 was overexpressed in MLL-AF6 AML, but its expression was decreased in most other subtypes of AML analyzed as well as in normal bone marrow CD34+ cells.

Experiments in AML cell lines revealed that SHARP1 expression is regulated by MLL-AF6/DOT1L. The researchers said MLL-AF6 and MEN1/LEDGF directly bind to the SHARP1 gene locus to positively regulate SHARP1 expression through DOT1L activity.

Dr Tenen and his colleagues performed knockdown experiments in mice and found that SHARP1 plays a “critical” role in maintaining clonogenic growth and preventing apoptosis in MLL-AF6 AML cells.

The team also assessed the effects of SHARP1 deletion in mouse models of MLL-AF6 AML.

SHARP1 knockout mice had superior survival compared to wild-type mice. In addition, the knockout mice exhibited signs of less aggressive disease—fewer AML cells, lower white blood cell counts, and higher red blood cell counts.

The researchers also found that SHARP1 deletion reduced MLL-AF6 leukemia-initiating ability but did not affect normal hematopoiesis.

Finally, the team discovered that SHARP1 cooperates with MLL-AF6 to regulate target genes in MLL-AF6 AML cells.

Image by Lance Liotta

New research suggests SHARP1 may be a therapeutic target in MLL-AF6 acute myeloid leukemia (AML).

Researchers found that SHARP1, a circadian clock transcription factor, is overexpressed in MLL-AF6 AML.

In mouse models, suppression of SHARP1 induced apoptosis in leukemic cells, while deletion of SHARP1 delayed AML development and weakened leukemia-initiating potential.

“We found that MLL-AF6 binds with SHARP1, leading to an increase in the level of SHARP1,” explained study author Dan Tenen, MD, of the Cancer Science Institute of Singapore.

“The increase of SHARP1 levels has the 2-fold effect of initiating leukemia development, as well as maintaining the growth of leukemic cells. [O]ur study also revealed that SHARP1 could act upon other target genes of MLL-AF6 to aggravate the progression of AML, but, by removing or reducing the level of SHARP1, the growth of leukemic cells could be stopped.”

Dr Tenen and his colleagues reported these findings in Nature Communications.

The researchers found that SHARP1 was overexpressed in MLL-AF6 AML, but its expression was decreased in most other subtypes of AML analyzed as well as in normal bone marrow CD34+ cells.

Experiments in AML cell lines revealed that SHARP1 expression is regulated by MLL-AF6/DOT1L. The researchers said MLL-AF6 and MEN1/LEDGF directly bind to the SHARP1 gene locus to positively regulate SHARP1 expression through DOT1L activity.

Dr Tenen and his colleagues performed knockdown experiments in mice and found that SHARP1 plays a “critical” role in maintaining clonogenic growth and preventing apoptosis in MLL-AF6 AML cells.

The team also assessed the effects of SHARP1 deletion in mouse models of MLL-AF6 AML.

SHARP1 knockout mice had superior survival compared to wild-type mice. In addition, the knockout mice exhibited signs of less aggressive disease—fewer AML cells, lower white blood cell counts, and higher red blood cell counts.

The researchers also found that SHARP1 deletion reduced MLL-AF6 leukemia-initiating ability but did not affect normal hematopoiesis.

Finally, the team discovered that SHARP1 cooperates with MLL-AF6 to regulate target genes in MLL-AF6 AML cells.