HT Staff

Patient receiving chemotherapy

Photo by Rhoda Baer

A new study indicates that certain social factors may impact survival in adults with acute myelogenous leukemia (AML) who are under 65.

The research showed associations between patient survival and insurance status, marital status, and county-level income.

“We believe these 3 factors indicate lack of material and social support preventing young patients from successfully walking the long and difficult road towards a cure,” said Uma Borate, MD, of the University of Alabama at Birmingham.

To conduct this study, Dr Borate and her colleagues analyzed data on 5541 patients, ages 19 to 64, who were diagnosed with AML between 2007 and 2011.

The team reported their findings in Cancer.

Multivariable analysis showed that AML subtype, age, and sex were independently associated with patients’ survival. And the non-biological factors independently associated with survival were insurance status, marital status, and county-level median household income.

Specifically, there was a significantly increased risk of premature death among patients who were uninsured (P=0.005) or Medicaid beneficiaries (P<0.001), compared to patients with private insurance.

Single (P<0.001) or divorced (P=0.011) patients had a significantly higher risk of premature death than married patients. But there was no significant difference between married and widowed patients (P=0.206).

And patients who lived in areas with lower income—the lowest 3 of 5 income groups—had a significantly increased risk of premature death.

Compared to patients in the fifth income quintile ($58.3K-$79.9K), there was an increased risk of death in the first quintile ($16.2K-$38.8K, P=0.001), second quintile ($38.8K-$42.2K, P<0.001), and third quintile ($42.2K-$47.9K, P<0.001).

Early and late mortality

The researchers wanted to determine if the impact of non-biological factors on survival was related to early mortality (a possible surrogate for access to care or late presentation) or late mortality (a possible surrogate for access to post-remission therapy and hematopoietic stem cell transplant).

So they conducted an exploratory analysis of factors influencing the risk of death within the first 2 months of diagnosis.

Being a Medicaid beneficiary (P=0.01) or uninsured (P<0.001) was independently associated with an increased risk of death within the first 2 months.

The same was true for patients belonging to the first income quartile (P=0.001), second quartile (P=0.003), third quartile (P=0.02), and fourth quartile (P=0.028).

On the other hand, there was no significant difference in early death according to marital status.

The researchers also performed a landmark survival analysis including only patients who survived at least 2 months from diagnosis.

In this analysis, marital status (P<0.001), insurance status (P=0.001), and income (P=0.021) were all independent predictors of survival.

Implications

“As physicians, we often emphasize more of the biology of the cancer, especially with the recent focus on personalized medicine,” said study author Luciano Jose Costa, MD, PhD, also of the University of Alabama at Birmingham.

“But we need to pay the same attention to resources available to our patients, as this greatly impacts their chances to survive leukemia.”

The researchers believe this will be especially important as the US transitions to a healthcare system that ties physician and hospital payments to patient outcomes.

“Taking from the results of this study, factors that have nothing to do with quality of care need to be accounted for when comparing predicted with actual outcomes,” Dr Borate said. “Otherwise, we will create a disincentive for hospitals and doctors to care for less privileged patients.”

Patient receiving chemotherapy

Photo by Rhoda Baer

A new study indicates that certain social factors may impact survival in adults with acute myelogenous leukemia (AML) who are under 65.

The research showed associations between patient survival and insurance status, marital status, and county-level income.

“We believe these 3 factors indicate lack of material and social support preventing young patients from successfully walking the long and difficult road towards a cure,” said Uma Borate, MD, of the University of Alabama at Birmingham.

To conduct this study, Dr Borate and her colleagues analyzed data on 5541 patients, ages 19 to 64, who were diagnosed with AML between 2007 and 2011.

The team reported their findings in Cancer.

Multivariable analysis showed that AML subtype, age, and sex were independently associated with patients’ survival. And the non-biological factors independently associated with survival were insurance status, marital status, and county-level median household income.

Specifically, there was a significantly increased risk of premature death among patients who were uninsured (P=0.005) or Medicaid beneficiaries (P<0.001), compared to patients with private insurance.

Single (P<0.001) or divorced (P=0.011) patients had a significantly higher risk of premature death than married patients. But there was no significant difference between married and widowed patients (P=0.206).

And patients who lived in areas with lower income—the lowest 3 of 5 income groups—had a significantly increased risk of premature death.

Compared to patients in the fifth income quintile ($58.3K-$79.9K), there was an increased risk of death in the first quintile ($16.2K-$38.8K, P=0.001), second quintile ($38.8K-$42.2K, P<0.001), and third quintile ($42.2K-$47.9K, P<0.001).

Early and late mortality

The researchers wanted to determine if the impact of non-biological factors on survival was related to early mortality (a possible surrogate for access to care or late presentation) or late mortality (a possible surrogate for access to post-remission therapy and hematopoietic stem cell transplant).

So they conducted an exploratory analysis of factors influencing the risk of death within the first 2 months of diagnosis.

Being a Medicaid beneficiary (P=0.01) or uninsured (P<0.001) was independently associated with an increased risk of death within the first 2 months.

The same was true for patients belonging to the first income quartile (P=0.001), second quartile (P=0.003), third quartile (P=0.02), and fourth quartile (P=0.028).

On the other hand, there was no significant difference in early death according to marital status.

The researchers also performed a landmark survival analysis including only patients who survived at least 2 months from diagnosis.

In this analysis, marital status (P<0.001), insurance status (P=0.001), and income (P=0.021) were all independent predictors of survival.

Implications

“As physicians, we often emphasize more of the biology of the cancer, especially with the recent focus on personalized medicine,” said study author Luciano Jose Costa, MD, PhD, also of the University of Alabama at Birmingham.

“But we need to pay the same attention to resources available to our patients, as this greatly impacts their chances to survive leukemia.”

The researchers believe this will be especially important as the US transitions to a healthcare system that ties physician and hospital payments to patient outcomes.

“Taking from the results of this study, factors that have nothing to do with quality of care need to be accounted for when comparing predicted with actual outcomes,” Dr Borate said. “Otherwise, we will create a disincentive for hospitals and doctors to care for less privileged patients.”

Patient receiving chemotherapy

Photo by Rhoda Baer

A new study indicates that certain social factors may impact survival in adults with acute myelogenous leukemia (AML) who are under 65.

The research showed associations between patient survival and insurance status, marital status, and county-level income.

“We believe these 3 factors indicate lack of material and social support preventing young patients from successfully walking the long and difficult road towards a cure,” said Uma Borate, MD, of the University of Alabama at Birmingham.

To conduct this study, Dr Borate and her colleagues analyzed data on 5541 patients, ages 19 to 64, who were diagnosed with AML between 2007 and 2011.

The team reported their findings in Cancer.

Multivariable analysis showed that AML subtype, age, and sex were independently associated with patients’ survival. And the non-biological factors independently associated with survival were insurance status, marital status, and county-level median household income.

Specifically, there was a significantly increased risk of premature death among patients who were uninsured (P=0.005) or Medicaid beneficiaries (P<0.001), compared to patients with private insurance.

Single (P<0.001) or divorced (P=0.011) patients had a significantly higher risk of premature death than married patients. But there was no significant difference between married and widowed patients (P=0.206).

And patients who lived in areas with lower income—the lowest 3 of 5 income groups—had a significantly increased risk of premature death.

Compared to patients in the fifth income quintile ($58.3K-$79.9K), there was an increased risk of death in the first quintile ($16.2K-$38.8K, P=0.001), second quintile ($38.8K-$42.2K, P<0.001), and third quintile ($42.2K-$47.9K, P<0.001).

Early and late mortality

The researchers wanted to determine if the impact of non-biological factors on survival was related to early mortality (a possible surrogate for access to care or late presentation) or late mortality (a possible surrogate for access to post-remission therapy and hematopoietic stem cell transplant).

So they conducted an exploratory analysis of factors influencing the risk of death within the first 2 months of diagnosis.

Being a Medicaid beneficiary (P=0.01) or uninsured (P<0.001) was independently associated with an increased risk of death within the first 2 months.

The same was true for patients belonging to the first income quartile (P=0.001), second quartile (P=0.003), third quartile (P=0.02), and fourth quartile (P=0.028).

On the other hand, there was no significant difference in early death according to marital status.

The researchers also performed a landmark survival analysis including only patients who survived at least 2 months from diagnosis.

In this analysis, marital status (P<0.001), insurance status (P=0.001), and income (P=0.021) were all independent predictors of survival.

Implications

“As physicians, we often emphasize more of the biology of the cancer, especially with the recent focus on personalized medicine,” said study author Luciano Jose Costa, MD, PhD, also of the University of Alabama at Birmingham.

“But we need to pay the same attention to resources available to our patients, as this greatly impacts their chances to survive leukemia.”

The researchers believe this will be especially important as the US transitions to a healthcare system that ties physician and hospital payments to patient outcomes.

“Taking from the results of this study, factors that have nothing to do with quality of care need to be accounted for when comparing predicted with actual outcomes,” Dr Borate said. “Otherwise, we will create a disincentive for hospitals and doctors to care for less privileged patients.”

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Mantle cell lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has adopted a positive opinion recommending that KTE-C19 receive orphan designation to treat primary mediastinal B-cell lymphoma (PMBCL) and mantle cell lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

No other product candidate currently has orphan drug designation for the treatment of PMBCL in the European Union (EU).

KTE-C19 already has orphan drug designation to treat diffuse large B-cell lymphoma (DLBCL) in the US and the EU.

“We are conducting a phase 1/2 clinical trial of KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma, including DLBCL and PMBCL, and plan to report initial topline results from the phase 1 portion of the trial later this year [at the ASH Annual Meeting],” said Arie Belldegrun, MD, Chairman, President, and Chief Executive Officer of Kite Pharmaceuticals, the company developing KTE-C19.

Trial results

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

About orphan designation

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Mantle cell lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has adopted a positive opinion recommending that KTE-C19 receive orphan designation to treat primary mediastinal B-cell lymphoma (PMBCL) and mantle cell lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

No other product candidate currently has orphan drug designation for the treatment of PMBCL in the European Union (EU).

KTE-C19 already has orphan drug designation to treat diffuse large B-cell lymphoma (DLBCL) in the US and the EU.

“We are conducting a phase 1/2 clinical trial of KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma, including DLBCL and PMBCL, and plan to report initial topline results from the phase 1 portion of the trial later this year [at the ASH Annual Meeting],” said Arie Belldegrun, MD, Chairman, President, and Chief Executive Officer of Kite Pharmaceuticals, the company developing KTE-C19.

Trial results

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

About orphan designation

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Mantle cell lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has adopted a positive opinion recommending that KTE-C19 receive orphan designation to treat primary mediastinal B-cell lymphoma (PMBCL) and mantle cell lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

No other product candidate currently has orphan drug designation for the treatment of PMBCL in the European Union (EU).

KTE-C19 already has orphan drug designation to treat diffuse large B-cell lymphoma (DLBCL) in the US and the EU.

“We are conducting a phase 1/2 clinical trial of KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma, including DLBCL and PMBCL, and plan to report initial topline results from the phase 1 portion of the trial later this year [at the ASH Annual Meeting],” said Arie Belldegrun, MD, Chairman, President, and Chief Executive Officer of Kite Pharmaceuticals, the company developing KTE-C19.

Trial results

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

About orphan designation

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan designation for DTX101 as a treatment for hemophilia B.

DTX101 is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat rare diseases or conditions that affect fewer than 200,000 people in the US.

Orphan designation provides the company developing a drug with certain benefits, such as tax credits for qualified clinical trials, exemption from FDA user fees, and 7 years of market exclusivity if the drug is approved.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan designation for DTX101 as a treatment for hemophilia B.

DTX101 is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat rare diseases or conditions that affect fewer than 200,000 people in the US.

Orphan designation provides the company developing a drug with certain benefits, such as tax credits for qualified clinical trials, exemption from FDA user fees, and 7 years of market exclusivity if the drug is approved.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan designation for DTX101 as a treatment for hemophilia B.

DTX101 is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat rare diseases or conditions that affect fewer than 200,000 people in the US.

Orphan designation provides the company developing a drug with certain benefits, such as tax credits for qualified clinical trials, exemption from FDA user fees, and 7 years of market exclusivity if the drug is approved.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

T cells

Image courtesy of NIAID

New research has revealed a population of T cells associated with relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT).

Patients experienced an increase in this cell population before their relapse was diagnosed clinically.

The cells also appear to be markers of T-cell exhaustion, which suggests therapies targeting T-cell exhaustion might be able to treat or prevent AML relapse after

allo-SCT.

Hong Zheng, MD, PhD, of Penn State University College of Medicine in Hershey, Pennsylvania, and her colleagues conducted this research and reported the results in Blood Cancer Journal.

The investigators noted that T cells are major players in the graft-vs-leukemia effect, but persistent antigen stimulation can lead to T-cell exhaustion.

To determine whether T-cell exhaustion is involved in relapse after allo-SCT, the team performed phenotypic and functional studies on T cells from the peripheral blood of AML transplant recipients.

Dr Zheng and her colleagues discovered that patients who relapsed after allo-SCT had significantly elevated levels of PD-1^hiTIM-3⁺ T cells.

These T cells produced fewer cytokines—interleukin 2, tumor necrosis factor-α, and interferon-γ—than normal T cells, which is a sign of T-cell exhaustion.

In addition, while other T cells mostly consisted of all 4 T-cell subsets, PD-1^hiTIM-3⁺ T cells had no naive T cells (CCR7⁺CD45RA⁺) and significantly decreased levels of terminally differentiated effector T cells (CCR7^-CD45RA⁺).

The investigators said this suggests PD-1^hiTIM-3⁺ cells are phenotypically antigen-experienced T cells that have lost functional subsets, which is consistent with a state of T-cell exhaustion.

The team believes their findings could pave the way for new treatments for AML patients undergoing allo-SCT.

The PD-1 inhibitor nivolumab has been shown to block T-cell exhaustion in patients with solid tumors. So Dr Zheng is planning a clinical trial to see if such treatment could work for AML patients as well.

She also believes that PD-1^hiTIM-3⁺ T cells could be used to diagnose relapses earlier than is currently possible.

“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Dr Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”

Dr Zheng is currently investigating the trigger for T-cell exhaustion in transplant recipients with AML.

“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”

T cells

Image courtesy of NIAID

New research has revealed a population of T cells associated with relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT).

Patients experienced an increase in this cell population before their relapse was diagnosed clinically.

The cells also appear to be markers of T-cell exhaustion, which suggests therapies targeting T-cell exhaustion might be able to treat or prevent AML relapse after

allo-SCT.

Hong Zheng, MD, PhD, of Penn State University College of Medicine in Hershey, Pennsylvania, and her colleagues conducted this research and reported the results in Blood Cancer Journal.

The investigators noted that T cells are major players in the graft-vs-leukemia effect, but persistent antigen stimulation can lead to T-cell exhaustion.

To determine whether T-cell exhaustion is involved in relapse after allo-SCT, the team performed phenotypic and functional studies on T cells from the peripheral blood of AML transplant recipients.

Dr Zheng and her colleagues discovered that patients who relapsed after allo-SCT had significantly elevated levels of PD-1^hiTIM-3⁺ T cells.

These T cells produced fewer cytokines—interleukin 2, tumor necrosis factor-α, and interferon-γ—than normal T cells, which is a sign of T-cell exhaustion.

In addition, while other T cells mostly consisted of all 4 T-cell subsets, PD-1^hiTIM-3⁺ T cells had no naive T cells (CCR7⁺CD45RA⁺) and significantly decreased levels of terminally differentiated effector T cells (CCR7^-CD45RA⁺).

The investigators said this suggests PD-1^hiTIM-3⁺ cells are phenotypically antigen-experienced T cells that have lost functional subsets, which is consistent with a state of T-cell exhaustion.

The team believes their findings could pave the way for new treatments for AML patients undergoing allo-SCT.

The PD-1 inhibitor nivolumab has been shown to block T-cell exhaustion in patients with solid tumors. So Dr Zheng is planning a clinical trial to see if such treatment could work for AML patients as well.

She also believes that PD-1^hiTIM-3⁺ T cells could be used to diagnose relapses earlier than is currently possible.

“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Dr Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”

Dr Zheng is currently investigating the trigger for T-cell exhaustion in transplant recipients with AML.

“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”

T cells

Image courtesy of NIAID

New research has revealed a population of T cells associated with relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT).

Patients experienced an increase in this cell population before their relapse was diagnosed clinically.

The cells also appear to be markers of T-cell exhaustion, which suggests therapies targeting T-cell exhaustion might be able to treat or prevent AML relapse after

allo-SCT.

Hong Zheng, MD, PhD, of Penn State University College of Medicine in Hershey, Pennsylvania, and her colleagues conducted this research and reported the results in Blood Cancer Journal.

The investigators noted that T cells are major players in the graft-vs-leukemia effect, but persistent antigen stimulation can lead to T-cell exhaustion.

To determine whether T-cell exhaustion is involved in relapse after allo-SCT, the team performed phenotypic and functional studies on T cells from the peripheral blood of AML transplant recipients.

Dr Zheng and her colleagues discovered that patients who relapsed after allo-SCT had significantly elevated levels of PD-1^hiTIM-3⁺ T cells.

These T cells produced fewer cytokines—interleukin 2, tumor necrosis factor-α, and interferon-γ—than normal T cells, which is a sign of T-cell exhaustion.

In addition, while other T cells mostly consisted of all 4 T-cell subsets, PD-1^hiTIM-3⁺ T cells had no naive T cells (CCR7⁺CD45RA⁺) and significantly decreased levels of terminally differentiated effector T cells (CCR7^-CD45RA⁺).

The investigators said this suggests PD-1^hiTIM-3⁺ cells are phenotypically antigen-experienced T cells that have lost functional subsets, which is consistent with a state of T-cell exhaustion.

The team believes their findings could pave the way for new treatments for AML patients undergoing allo-SCT.

The PD-1 inhibitor nivolumab has been shown to block T-cell exhaustion in patients with solid tumors. So Dr Zheng is planning a clinical trial to see if such treatment could work for AML patients as well.

She also believes that PD-1^hiTIM-3⁺ T cells could be used to diagnose relapses earlier than is currently possible.

“Two months before we were able to clinically diagnose relapse in these patients, we found these markers elevated in them,” Dr Zheng said. “If we can have an early diagnostic marker, we will potentially be able to improve clinical outcome significantly.”

Dr Zheng is currently investigating the trigger for T-cell exhaustion in transplant recipients with AML.

“The hypothesis is that when you have chronic antigen stimulation, the T cell can get exhausted,” she said. “We think that residual leukemia in our patients is the chronic stimulator that causes this.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have designed an online tool that can predict the role of proteins and genes involved in immunological diseases and processes.

The tool uses information compiled from 38,088 public experiments to predict new immune pathway interactions, mechanisms, and disease-associated genes.

Details on this publicly available tool, known as ImmuNet, were recently published in Immunity.

“This new tool unlocks the insight contained in big data, the world’s biomedical research output, to help understand immunological mechanisms and diseases,” said Stuart Sealfon, MD, of Mount Sinai Health System in New York, New York.

“The goal of ImmuNet is to accelerate the understanding of immune pathways and genes, ultimately leading to the development of improved treatment for diseases with an immunological component.”

ImmuNet enables immunology researchers without special computational training to use the statistical techniques of Bayesian data integration and machine learning algorithms to “interrogate” this compendium of public data.

“We expect the applicability of ImmuNet to wide-ranging areas of immunology will grow with the incorporation of continually increasing public big data,” said Olga Troyanskaya, PhD, of Princeton University in New Jersey.

“By enabling immune researchers from diverse backgrounds to leverage these valuable and heterogeneous data collections, ImmuNet has the potential to accelerate discovery in immunology.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have designed an online tool that can predict the role of proteins and genes involved in immunological diseases and processes.

The tool uses information compiled from 38,088 public experiments to predict new immune pathway interactions, mechanisms, and disease-associated genes.

Details on this publicly available tool, known as ImmuNet, were recently published in Immunity.

“This new tool unlocks the insight contained in big data, the world’s biomedical research output, to help understand immunological mechanisms and diseases,” said Stuart Sealfon, MD, of Mount Sinai Health System in New York, New York.

“The goal of ImmuNet is to accelerate the understanding of immune pathways and genes, ultimately leading to the development of improved treatment for diseases with an immunological component.”

ImmuNet enables immunology researchers without special computational training to use the statistical techniques of Bayesian data integration and machine learning algorithms to “interrogate” this compendium of public data.

“We expect the applicability of ImmuNet to wide-ranging areas of immunology will grow with the incorporation of continually increasing public big data,” said Olga Troyanskaya, PhD, of Princeton University in New Jersey.

“By enabling immune researchers from diverse backgrounds to leverage these valuable and heterogeneous data collections, ImmuNet has the potential to accelerate discovery in immunology.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have designed an online tool that can predict the role of proteins and genes involved in immunological diseases and processes.

The tool uses information compiled from 38,088 public experiments to predict new immune pathway interactions, mechanisms, and disease-associated genes.

Details on this publicly available tool, known as ImmuNet, were recently published in Immunity.

“This new tool unlocks the insight contained in big data, the world’s biomedical research output, to help understand immunological mechanisms and diseases,” said Stuart Sealfon, MD, of Mount Sinai Health System in New York, New York.

“The goal of ImmuNet is to accelerate the understanding of immune pathways and genes, ultimately leading to the development of improved treatment for diseases with an immunological component.”

ImmuNet enables immunology researchers without special computational training to use the statistical techniques of Bayesian data integration and machine learning algorithms to “interrogate” this compendium of public data.

“We expect the applicability of ImmuNet to wide-ranging areas of immunology will grow with the incorporation of continually increasing public big data,” said Olga Troyanskaya, PhD, of Princeton University in New Jersey.

“By enabling immune researchers from diverse backgrounds to leverage these valuable and heterogeneous data collections, ImmuNet has the potential to accelerate discovery in immunology.”

AML cells

Image by Lance Liotta

The investigational therapy SL-401 has received orphan designation to treat acute myeloid leukemia (AML) in the European Union (EU).

SL-401 targets the interleukin-3 receptor (IL-3R). It is comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 is under development to treat a range of hematologic malignancies, as IL-3R is overexpressed on cancer stem cells in multiple hematologic malignancies.

SL-401 has orphan designation from the US Food and Drug Administration (FDA) for the treatment of AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR.  Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

1. BPDCN and relapsed/refractory AML
2. AML patients in first complete remission with minimal residual disease
3. Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the EU benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

AML cells

Image by Lance Liotta

The investigational therapy SL-401 has received orphan designation to treat acute myeloid leukemia (AML) in the European Union (EU).

SL-401 targets the interleukin-3 receptor (IL-3R). It is comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 is under development to treat a range of hematologic malignancies, as IL-3R is overexpressed on cancer stem cells in multiple hematologic malignancies.

SL-401 has orphan designation from the US Food and Drug Administration (FDA) for the treatment of AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR.  Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

1. BPDCN and relapsed/refractory AML
2. AML patients in first complete remission with minimal residual disease
3. Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the EU benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

AML cells

Image by Lance Liotta

The investigational therapy SL-401 has received orphan designation to treat acute myeloid leukemia (AML) in the European Union (EU).

SL-401 targets the interleukin-3 receptor (IL-3R). It is comprised of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.

SL-401 is under development to treat a range of hematologic malignancies, as IL-3R is overexpressed on cancer stem cells in multiple hematologic malignancies.

SL-401 has orphan designation from the US Food and Drug Administration (FDA) for the treatment of AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN).

SL-401 research

At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).

At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.

Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.

With regimen A, 45 patients received doses ranging from 4 to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 to 22.1 μg/kg daily for up to 5 doses.

Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.

Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR.  Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.

And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.

The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.

Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).

Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.

Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).

The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.

Three multicenter clinical trials of SL-401 are currently open in the following indications:

1. BPDCN and relapsed/refractory AML
2. AML patients in first complete remission with minimal residual disease
3. Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.

Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.

About orphan designation

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug in the EU benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

Lab mouse

Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.

STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.

But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.

Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.

The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.

The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh₂, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.

“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”

MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.

Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.

When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).

Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.

“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”

Lab mouse

Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.

STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.

But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.

Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.

The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.

The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh₂, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.

“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”

MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.

Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.

When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).

Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.

“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”

Lab mouse

Compounds that target a novel binding site on STAT3 may one day be used to prevent relapse in acute myeloid leukemia (AML), according to researchers.

STAT3 is known to interfere with chemotherapy and is thought to play a role in many cases of AML relapse.

But preclinical research suggests a compound known as MM-206 can disrupt STAT3’s disease-promoting effects by targeting a previously unknown ligand-binding site on the protein.

Zachary Ball, PhD, of Rice University in Houston, Texas, and his colleagues described this research in Angewandte Chemie.

The team first discovered that the coiled–coil domain (CCD) is a novel ligand-binding site on STAT3. Then, they identified a naphthalene sulfonamide compound, known as C188, that can target CCD and inhibit STAT3.

The researchers tested C188 and compounds synthesized from it—C188-9, C188-9-Rh₂, and MM-206—in vitro and in vivo. Only MM-206 proved effective in vivo.

“Our main advance, from a medicinal perspective, is that this compound also works in a mouse model,” Dr Ball said. “All the other compounds worked in cells, but, in mice, they weren’t potent enough or stable enough.”

MM-206 inhibited STAT3 phosphorylation and induced apoptosis in 3 different AML cell lines. The compound also prompted apoptosis in primary tumor cells from pediatric AML patients.

Among mice engrafted with luciferase-expressing MV4-11 AML cells, those that received MM-206 exhibited slower disease progression than untreated mice.

When the mice received 4 weeks of treatment with MM-206, they had significantly fewer tumor cells in their bone marrow and lived significantly longer than control mice (P=0.019 at 10 weeks).

Follow-up studies should lead to improved versions of MM-206, according to Dr Ball.

“The discovery raises new questions about STAT3 biology and points the way to future anticancer approaches,” he said, “including combination therapies of coiled-coil STAT3 inhibitors in tandem with other agents.”

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m²), reinfusion of autologous stem cells (≥2.1×10⁶ cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m²), reinfusion of autologous stem cells (≥2.1×10⁶ cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m²), reinfusion of autologous stem cells (≥2.1×10⁶ cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.