Smiling baby

Photo by Petr Kratochvil

Researchers believe they have discovered how a commonly administered vaccine protects children from developing acute lymphoblastic leukemia (ALL).

The Haemophilus influenzae Type b (Hib) vaccine is part of the standard vaccination schedule recommended for children by the US Centers for Disease Control and Prevention. The vaccine is routinely given in 4 doses before children reach 15 months of age.

The Hib vaccine prevents ear infections and meningitis caused by the Hib bacterium, but it may also protect against ALL.

This protection has been suggested in previous studies, but it is not well-known among the public at large, and the mechanism underlying this effect has been poorly understood.

Now, researchers have shown that recurrent Hib infections can shift certain genes into overdrive, converting pre-leukemic cells into full-blown cancer. The team described this work in Nature Immunology.

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy,” said study author Markus Müschen, MD, PhD, of the University of California San Francisco.

“Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

For this study, Dr Müschen and his colleagues tested the idea that chronic inflammation caused by recurrent infections might cause additional genetic lesions in blood cells already carrying an oncogene, promoting their transformation to overt disease.

The team conducted experiments in mice and discovered that the enzymes AID and RAG1-RAG2 drive this process. AID and RAG1-RAG2 introduce mutations in DNA that allow immune cells to adapt to infectious challenges, and these enzymes are necessary for a normal and efficient immune response.

The researchers found that, in the presence of chronic infection, AID and RAG1-RAG2 were hyperactivated, randomly cutting and mutating genes.

Additional experiments revealed that AID and RAG1-RAG2 working together is critical to introduce the additional lesions that result in ALL.

Though the researchers focused on a bacterial infection in this study, they believe the same mechanisms may be at work in viral infections.

The team is currently conducting experiments to determine if protection against leukemia is provided by vaccines against viral infections, such as the measles-mumps-rubella vaccine.

Smiling baby

Photo by Petr Kratochvil

Researchers believe they have discovered how a commonly administered vaccine protects children from developing acute lymphoblastic leukemia (ALL).

The Haemophilus influenzae Type b (Hib) vaccine is part of the standard vaccination schedule recommended for children by the US Centers for Disease Control and Prevention. The vaccine is routinely given in 4 doses before children reach 15 months of age.

The Hib vaccine prevents ear infections and meningitis caused by the Hib bacterium, but it may also protect against ALL.

This protection has been suggested in previous studies, but it is not well-known among the public at large, and the mechanism underlying this effect has been poorly understood.

Now, researchers have shown that recurrent Hib infections can shift certain genes into overdrive, converting pre-leukemic cells into full-blown cancer. The team described this work in Nature Immunology.

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy,” said study author Markus Müschen, MD, PhD, of the University of California San Francisco.

“Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

For this study, Dr Müschen and his colleagues tested the idea that chronic inflammation caused by recurrent infections might cause additional genetic lesions in blood cells already carrying an oncogene, promoting their transformation to overt disease.

The team conducted experiments in mice and discovered that the enzymes AID and RAG1-RAG2 drive this process. AID and RAG1-RAG2 introduce mutations in DNA that allow immune cells to adapt to infectious challenges, and these enzymes are necessary for a normal and efficient immune response.

The researchers found that, in the presence of chronic infection, AID and RAG1-RAG2 were hyperactivated, randomly cutting and mutating genes.

Additional experiments revealed that AID and RAG1-RAG2 working together is critical to introduce the additional lesions that result in ALL.

Though the researchers focused on a bacterial infection in this study, they believe the same mechanisms may be at work in viral infections.

The team is currently conducting experiments to determine if protection against leukemia is provided by vaccines against viral infections, such as the measles-mumps-rubella vaccine.

Smiling baby

Photo by Petr Kratochvil

Researchers believe they have discovered how a commonly administered vaccine protects children from developing acute lymphoblastic leukemia (ALL).

The Haemophilus influenzae Type b (Hib) vaccine is part of the standard vaccination schedule recommended for children by the US Centers for Disease Control and Prevention. The vaccine is routinely given in 4 doses before children reach 15 months of age.

The Hib vaccine prevents ear infections and meningitis caused by the Hib bacterium, but it may also protect against ALL.

This protection has been suggested in previous studies, but it is not well-known among the public at large, and the mechanism underlying this effect has been poorly understood.

Now, researchers have shown that recurrent Hib infections can shift certain genes into overdrive, converting pre-leukemic cells into full-blown cancer. The team described this work in Nature Immunology.

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy,” said study author Markus Müschen, MD, PhD, of the University of California San Francisco.

“Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

For this study, Dr Müschen and his colleagues tested the idea that chronic inflammation caused by recurrent infections might cause additional genetic lesions in blood cells already carrying an oncogene, promoting their transformation to overt disease.

The team conducted experiments in mice and discovered that the enzymes AID and RAG1-RAG2 drive this process. AID and RAG1-RAG2 introduce mutations in DNA that allow immune cells to adapt to infectious challenges, and these enzymes are necessary for a normal and efficient immune response.

The researchers found that, in the presence of chronic infection, AID and RAG1-RAG2 were hyperactivated, randomly cutting and mutating genes.

Additional experiments revealed that AID and RAG1-RAG2 working together is critical to introduce the additional lesions that result in ALL.

Though the researchers focused on a bacterial infection in this study, they believe the same mechanisms may be at work in viral infections.

The team is currently conducting experiments to determine if protection against leukemia is provided by vaccines against viral infections, such as the measles-mumps-rubella vaccine.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted fast track designation to luspatercept for the treatment of patients with transfusion-dependent (TD) or non-transfusion-dependent (NTD) β-thalassemia.

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members of the transforming growth factor-β (TGF-β) superfamily involved in the late stages of erythropoiesis.

The drug regulates late-stage erythrocyte precursor differentiation and maturation. This mechanism of action is distinct from that of erythropoietin, which stimulates the proliferation of early stage erythrocyte precursor cells.

Luspatercept is currently in phase 2 trials in patients with β-thalassemia and individuals with myelodysplastic syndromes (MDS). Data from the trial in β-thalassemia were presented at the 2014 ASH Annual Meeting, and results from the MDS trial were recently presented at the 13th International Symposium on Myelodysplastic Syndromes.

Acceleron Pharma Inc. and Celgene Corporation are jointly developing luspatercept.

About fast track designation

The FDA’s fast track program is designed to facilitate the development of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

The designation provides pharmaceutical companies with the opportunity for more frequent interaction with the FDA while developing a drug. It also allows a sponsor to submit sections of a biologics license application on a rolling basis, as they are finalized.

“The FDA’s fast track designation for the luspatercept development program recognizes the serious unmet medical needs of patients with β-thalassemia and the potential for luspatercept in this area,” said Jacqualyn A. Fouse, president of hematology/oncology for Celgene.

“Celgene and Acceleron are working diligently to initiate a phase 3 clinical program in 2015 to treat patients with β-thalassemia, and we look forward to continuing to work closely with health authorities and other important stakeholders to advance this program.”

Phase 2 trial in β-thalassemia

At ASH 2014, researchers presented results of a phase 2 trial in which they investigated whether luspatercept could increase hemoglobin levels and decrease transfusion dependence.

The goal was to increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in NTD patients and decrease the transfusion burden by 20% or more over 12 weeks in TD patients.

Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 mg/kg to 1.0 mg/kg.

Three-quarters of patients who received 0.8 mg/kg to 1.0 mg/kg of luspatercept experienced an increase in their hemoglobin levels or a reduction in their transfusion burden.

Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.

TD patients had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.

Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).

There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain. And 3 patients discontinued treatment early, 1 each with occipital headache, ankle pain, and back pain.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted fast track designation to luspatercept for the treatment of patients with transfusion-dependent (TD) or non-transfusion-dependent (NTD) β-thalassemia.

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members of the transforming growth factor-β (TGF-β) superfamily involved in the late stages of erythropoiesis.

The drug regulates late-stage erythrocyte precursor differentiation and maturation. This mechanism of action is distinct from that of erythropoietin, which stimulates the proliferation of early stage erythrocyte precursor cells.

Luspatercept is currently in phase 2 trials in patients with β-thalassemia and individuals with myelodysplastic syndromes (MDS). Data from the trial in β-thalassemia were presented at the 2014 ASH Annual Meeting, and results from the MDS trial were recently presented at the 13th International Symposium on Myelodysplastic Syndromes.

Acceleron Pharma Inc. and Celgene Corporation are jointly developing luspatercept.

About fast track designation

The FDA’s fast track program is designed to facilitate the development of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

The designation provides pharmaceutical companies with the opportunity for more frequent interaction with the FDA while developing a drug. It also allows a sponsor to submit sections of a biologics license application on a rolling basis, as they are finalized.

“The FDA’s fast track designation for the luspatercept development program recognizes the serious unmet medical needs of patients with β-thalassemia and the potential for luspatercept in this area,” said Jacqualyn A. Fouse, president of hematology/oncology for Celgene.

“Celgene and Acceleron are working diligently to initiate a phase 3 clinical program in 2015 to treat patients with β-thalassemia, and we look forward to continuing to work closely with health authorities and other important stakeholders to advance this program.”

Phase 2 trial in β-thalassemia

At ASH 2014, researchers presented results of a phase 2 trial in which they investigated whether luspatercept could increase hemoglobin levels and decrease transfusion dependence.

The goal was to increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in NTD patients and decrease the transfusion burden by 20% or more over 12 weeks in TD patients.

Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 mg/kg to 1.0 mg/kg.

Three-quarters of patients who received 0.8 mg/kg to 1.0 mg/kg of luspatercept experienced an increase in their hemoglobin levels or a reduction in their transfusion burden.

Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.

TD patients had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.

Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).

There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain. And 3 patients discontinued treatment early, 1 each with occipital headache, ankle pain, and back pain.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted fast track designation to luspatercept for the treatment of patients with transfusion-dependent (TD) or non-transfusion-dependent (NTD) β-thalassemia.

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members of the transforming growth factor-β (TGF-β) superfamily involved in the late stages of erythropoiesis.

The drug regulates late-stage erythrocyte precursor differentiation and maturation. This mechanism of action is distinct from that of erythropoietin, which stimulates the proliferation of early stage erythrocyte precursor cells.

Luspatercept is currently in phase 2 trials in patients with β-thalassemia and individuals with myelodysplastic syndromes (MDS). Data from the trial in β-thalassemia were presented at the 2014 ASH Annual Meeting, and results from the MDS trial were recently presented at the 13th International Symposium on Myelodysplastic Syndromes.

Acceleron Pharma Inc. and Celgene Corporation are jointly developing luspatercept.

About fast track designation

The FDA’s fast track program is designed to facilitate the development of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

The designation provides pharmaceutical companies with the opportunity for more frequent interaction with the FDA while developing a drug. It also allows a sponsor to submit sections of a biologics license application on a rolling basis, as they are finalized.

“The FDA’s fast track designation for the luspatercept development program recognizes the serious unmet medical needs of patients with β-thalassemia and the potential for luspatercept in this area,” said Jacqualyn A. Fouse, president of hematology/oncology for Celgene.

“Celgene and Acceleron are working diligently to initiate a phase 3 clinical program in 2015 to treat patients with β-thalassemia, and we look forward to continuing to work closely with health authorities and other important stakeholders to advance this program.”

Phase 2 trial in β-thalassemia

At ASH 2014, researchers presented results of a phase 2 trial in which they investigated whether luspatercept could increase hemoglobin levels and decrease transfusion dependence.

The goal was to increase hemoglobin levels 1.5 g/dL or more for at least 2 weeks in NTD patients and decrease the transfusion burden by 20% or more over 12 weeks in TD patients.

Thirty patients, 7 TD and 23 NTD, received an injection of luspatercept every 3 weeks for 3 months at doses ranging from 0.2 mg/kg to 1.0 mg/kg.

Three-quarters of patients who received 0.8 mg/kg to 1.0 mg/kg of luspatercept experienced an increase in their hemoglobin levels or a reduction in their transfusion burden.

Of the NTD patients, 8 of 12 with iron overload at baseline experienced a reduction in liver iron concentration of 1 mg or more at 16 weeks.

TD patients had a more than 60% reduction in transfusion burden over 12 weeks. This included 2 patients with β0 β0 genotype, who experienced a 79% and 75% reduction.

Luspatercept did not cause any treatment-related serious or severe adverse events. The most common adverse events were bone pain (20%), headache (17%), myalgia (13%), and asthenia (10%).

There was 1 grade 3 dose-limiting toxicity of worsening lumbar spine bone pain. And 3 patients discontinued treatment early, 1 each with occipital headache, ankle pain, and back pain.

Enoxaparin for injection

Cancer patients with brain metastases who develop venous thromboembolism can safely receive the anticoagulant enoxaparin without further

increasing their risk of intracranial hemorrhage, according to a study published in Blood.

Cancer patients with brain metastases are known to have an increased risk of intracranial hemorrhage, but it has not been clear whether receiving anticoagulant therapy further increases that risk.

So a group of researchers set out to assess the risk of intracranial hemorrhage in cancer patients with brain metastases who received the low-molecular-weight-heparin (LMWH) enoxaparin.

Jeffrey Zwicker, MD, of Harvard Medical School in Boston, Massachusetts, and his colleagues studied the medical records of 293 cancer patients with brain metastasis, 104 of whom had received the LMWH enoxaparin and 189 who did not.

The researchers matched the patients in each group by the year of brain metastases diagnosis, tumor type, age, and gender. The team conducted a blinded review of radiographic imaging and categorized intracranial hemorrhages as “trace,” “measurable,” and “significant.”

At 1 year of follow-up, there was no significant difference between the treatment groups regarding the incidence of intracranial hemorrhage.

Nineteen percent of patients in the enoxaparin arm had measurable intracranial hemorrhages, compared to 21% of patients in the control arm (P=0.97). And 21% of patients in the enoxaparin arm had significant intracranial hemorrhages, compared to 22% of patients in the control arm (P=0.87).

The cumulative incidence of intracranial hemorrhage was 44% in the enoxaparin arm and 37% in the control arm (P=0.13).

In addition, there was no significant difference in overall survival between the treatment arms. The median overall survival was 8.4 months in the enoxaparin arm and 9.7 months in the control arm (P=0.65).

“While it is a very common clinical scenario to treat a patient with a metastatic brain tumor who also develops a blood clot, before this study, there was very little data to inform the difficult decision of whether or not to anticoagulate these patients,” Dr Zwicker said.

“Our findings, which demonstrate that current practice is safe, should reassure physicians that anticoagulants can be safely administered to patients with brain metastases and a history of blood clots.”

Enoxaparin for injection

Cancer patients with brain metastases who develop venous thromboembolism can safely receive the anticoagulant enoxaparin without further

increasing their risk of intracranial hemorrhage, according to a study published in Blood.

Cancer patients with brain metastases are known to have an increased risk of intracranial hemorrhage, but it has not been clear whether receiving anticoagulant therapy further increases that risk.

So a group of researchers set out to assess the risk of intracranial hemorrhage in cancer patients with brain metastases who received the low-molecular-weight-heparin (LMWH) enoxaparin.

Jeffrey Zwicker, MD, of Harvard Medical School in Boston, Massachusetts, and his colleagues studied the medical records of 293 cancer patients with brain metastasis, 104 of whom had received the LMWH enoxaparin and 189 who did not.

The researchers matched the patients in each group by the year of brain metastases diagnosis, tumor type, age, and gender. The team conducted a blinded review of radiographic imaging and categorized intracranial hemorrhages as “trace,” “measurable,” and “significant.”

At 1 year of follow-up, there was no significant difference between the treatment groups regarding the incidence of intracranial hemorrhage.

Nineteen percent of patients in the enoxaparin arm had measurable intracranial hemorrhages, compared to 21% of patients in the control arm (P=0.97). And 21% of patients in the enoxaparin arm had significant intracranial hemorrhages, compared to 22% of patients in the control arm (P=0.87).

The cumulative incidence of intracranial hemorrhage was 44% in the enoxaparin arm and 37% in the control arm (P=0.13).

In addition, there was no significant difference in overall survival between the treatment arms. The median overall survival was 8.4 months in the enoxaparin arm and 9.7 months in the control arm (P=0.65).

“While it is a very common clinical scenario to treat a patient with a metastatic brain tumor who also develops a blood clot, before this study, there was very little data to inform the difficult decision of whether or not to anticoagulate these patients,” Dr Zwicker said.

“Our findings, which demonstrate that current practice is safe, should reassure physicians that anticoagulants can be safely administered to patients with brain metastases and a history of blood clots.”

Enoxaparin for injection

Cancer patients with brain metastases who develop venous thromboembolism can safely receive the anticoagulant enoxaparin without further

increasing their risk of intracranial hemorrhage, according to a study published in Blood.

Cancer patients with brain metastases are known to have an increased risk of intracranial hemorrhage, but it has not been clear whether receiving anticoagulant therapy further increases that risk.

So a group of researchers set out to assess the risk of intracranial hemorrhage in cancer patients with brain metastases who received the low-molecular-weight-heparin (LMWH) enoxaparin.

Jeffrey Zwicker, MD, of Harvard Medical School in Boston, Massachusetts, and his colleagues studied the medical records of 293 cancer patients with brain metastasis, 104 of whom had received the LMWH enoxaparin and 189 who did not.

The researchers matched the patients in each group by the year of brain metastases diagnosis, tumor type, age, and gender. The team conducted a blinded review of radiographic imaging and categorized intracranial hemorrhages as “trace,” “measurable,” and “significant.”

At 1 year of follow-up, there was no significant difference between the treatment groups regarding the incidence of intracranial hemorrhage.

Nineteen percent of patients in the enoxaparin arm had measurable intracranial hemorrhages, compared to 21% of patients in the control arm (P=0.97). And 21% of patients in the enoxaparin arm had significant intracranial hemorrhages, compared to 22% of patients in the control arm (P=0.87).

The cumulative incidence of intracranial hemorrhage was 44% in the enoxaparin arm and 37% in the control arm (P=0.13).

In addition, there was no significant difference in overall survival between the treatment arms. The median overall survival was 8.4 months in the enoxaparin arm and 9.7 months in the control arm (P=0.65).

“While it is a very common clinical scenario to treat a patient with a metastatic brain tumor who also develops a blood clot, before this study, there was very little data to inform the difficult decision of whether or not to anticoagulate these patients,” Dr Zwicker said.

“Our findings, which demonstrate that current practice is safe, should reassure physicians that anticoagulants can be safely administered to patients with brain metastases and a history of blood clots.”

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted fast track designation to AG-120 for the treatment of patients with acute myelogenous leukemia (AML) who harbor an isocitrate dehydrogenase-1 (IDH1) mutation.

AG-120 is an oral, selective inhibitor of the mutated IDH1 protein that is under investigation in two phase 1 clinical trials, one in hematologic malignancies and one in advanced solid tumors.

Data from the phase 1 trial in hematologic malignancies were previously presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in November 2014.

Updated data from this trial are scheduled to be presented at the 20th Annual Congress of the European Hematology Association (EHA) next month.

About fast track designation

The FDA’s fast track drug development program is designed to expedite clinical development and submission of new drug applications for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support a drug’s approval, and also provides the opportunity to submit sections of a new drug application on a rolling basis as data become available.

“We are pleased that now both AG-120 and AG-221 have been granted fast track designation, demonstrating the FDA’s commitment to facilitate the development and expedite the review of our lead IDH programs as important new therapies for people with AML who carry these mutations,” said Chris Bowden, MD, chief medical officer of Agios Pharmaceuticals, Inc., the company developing AG-120 in cooperation with Celgene Corporation.

Phase 1 results

At the EORTC-NCI-AACR symposium, researchers presented results from the ongoing phase 1 trial of AG-120 in hematologic malignancies. The data included 17 patients with relapsed and/or refractory AML who had received a median of 2 prior treatments.

The patients were scheduled to receive AG-120 in 1 of 4 dose groups: 100 mg twice a day, 300 mg once a day, 500 mg once a day, and 800 mg once a day over continuous, 28-day cycles.

Of the 14 patients evaluable for response, 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.

Responses occurred at all the dose levels tested. The maximum-tolerated dose was not reached. All responding patients were still on AG-120 at the time of presentation, and 1 patient with stable disease remained on the drug.

Researchers said AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.

Eight patients experienced serious adverse events, but these were primarily related to disease progression.

One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested, which improved to grade 1 with dose reduction. The patient was in complete remission and remained on AG-120 at the time of presentation.

There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

“We look forward to presenting new data from the ongoing phase 1 study at the EHA Annual Congress next month,” Dr Bowden said, “and remain on track to initiate a global, registration-enabling, phase 3 study in collaboration with Celgene in AML patients who harbor an IDH1 mutation in the first half of 2016.”

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted fast track designation to AG-120 for the treatment of patients with acute myelogenous leukemia (AML) who harbor an isocitrate dehydrogenase-1 (IDH1) mutation.

AG-120 is an oral, selective inhibitor of the mutated IDH1 protein that is under investigation in two phase 1 clinical trials, one in hematologic malignancies and one in advanced solid tumors.

Data from the phase 1 trial in hematologic malignancies were previously presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in November 2014.

Updated data from this trial are scheduled to be presented at the 20th Annual Congress of the European Hematology Association (EHA) next month.

About fast track designation

The FDA’s fast track drug development program is designed to expedite clinical development and submission of new drug applications for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support a drug’s approval, and also provides the opportunity to submit sections of a new drug application on a rolling basis as data become available.

“We are pleased that now both AG-120 and AG-221 have been granted fast track designation, demonstrating the FDA’s commitment to facilitate the development and expedite the review of our lead IDH programs as important new therapies for people with AML who carry these mutations,” said Chris Bowden, MD, chief medical officer of Agios Pharmaceuticals, Inc., the company developing AG-120 in cooperation with Celgene Corporation.

Phase 1 results

At the EORTC-NCI-AACR symposium, researchers presented results from the ongoing phase 1 trial of AG-120 in hematologic malignancies. The data included 17 patients with relapsed and/or refractory AML who had received a median of 2 prior treatments.

The patients were scheduled to receive AG-120 in 1 of 4 dose groups: 100 mg twice a day, 300 mg once a day, 500 mg once a day, and 800 mg once a day over continuous, 28-day cycles.

Of the 14 patients evaluable for response, 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.

Responses occurred at all the dose levels tested. The maximum-tolerated dose was not reached. All responding patients were still on AG-120 at the time of presentation, and 1 patient with stable disease remained on the drug.

Researchers said AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.

Eight patients experienced serious adverse events, but these were primarily related to disease progression.

One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested, which improved to grade 1 with dose reduction. The patient was in complete remission and remained on AG-120 at the time of presentation.

There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

“We look forward to presenting new data from the ongoing phase 1 study at the EHA Annual Congress next month,” Dr Bowden said, “and remain on track to initiate a global, registration-enabling, phase 3 study in collaboration with Celgene in AML patients who harbor an IDH1 mutation in the first half of 2016.”

Micrograph showing AML

The US Food and Drug Administration (FDA) has granted fast track designation to AG-120 for the treatment of patients with acute myelogenous leukemia (AML) who harbor an isocitrate dehydrogenase-1 (IDH1) mutation.

AG-120 is an oral, selective inhibitor of the mutated IDH1 protein that is under investigation in two phase 1 clinical trials, one in hematologic malignancies and one in advanced solid tumors.

Data from the phase 1 trial in hematologic malignancies were previously presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in November 2014.

Updated data from this trial are scheduled to be presented at the 20th Annual Congress of the European Hematology Association (EHA) next month.

About fast track designation

The FDA’s fast track drug development program is designed to expedite clinical development and submission of new drug applications for medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss all aspects of development to support a drug’s approval, and also provides the opportunity to submit sections of a new drug application on a rolling basis as data become available.

“We are pleased that now both AG-120 and AG-221 have been granted fast track designation, demonstrating the FDA’s commitment to facilitate the development and expedite the review of our lead IDH programs as important new therapies for people with AML who carry these mutations,” said Chris Bowden, MD, chief medical officer of Agios Pharmaceuticals, Inc., the company developing AG-120 in cooperation with Celgene Corporation.

Phase 1 results

At the EORTC-NCI-AACR symposium, researchers presented results from the ongoing phase 1 trial of AG-120 in hematologic malignancies. The data included 17 patients with relapsed and/or refractory AML who had received a median of 2 prior treatments.

The patients were scheduled to receive AG-120 in 1 of 4 dose groups: 100 mg twice a day, 300 mg once a day, 500 mg once a day, and 800 mg once a day over continuous, 28-day cycles.

Of the 14 patients evaluable for response, 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.

Responses occurred at all the dose levels tested. The maximum-tolerated dose was not reached. All responding patients were still on AG-120 at the time of presentation, and 1 patient with stable disease remained on the drug.

Researchers said AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.

Eight patients experienced serious adverse events, but these were primarily related to disease progression.

One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested, which improved to grade 1 with dose reduction. The patient was in complete remission and remained on AG-120 at the time of presentation.

There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

“We look forward to presenting new data from the ongoing phase 1 study at the EHA Annual Congress next month,” Dr Bowden said, “and remain on track to initiate a global, registration-enabling, phase 3 study in collaboration with Celgene in AML patients who harbor an IDH1 mutation in the first half of 2016.”

Menopausal hormone therapy is associated with an increased risk of major gastrointestinal bleeding, particularly in the lower gastrointestinal tract, that is associated with duration of use, a study has found.

Analysis of data from 73,863 women enrolled in the Nurses’ Health Study II in 1989 showed that current users of menopausal hormone therapy had a 46% increase in the risk of a major gastrointestinal bleed and a more than twofold increase in the risk of a lower GI bleed or ischemic colitis, compared with never users, said Dr. Prashant Singh of Massachusetts General Hospital, Boston.

Past users showed a much smaller increase risk of bleeding, while increasing duration of hormone therapy was significantly associated with increasing risk of major and low gastrointestinal bleeding.

“Although our findings show that menopausal hormone therapy may increase the risk of major GI bleeding, especially in the lower GI tract, it is important for these patients to know that this therapy is still an effective treatment; however, both clinician and patient should be more cautious in using this therapy in some cases, such as with patients who have a history of ischemic colitis,” Dr. Singh said at the annual Digestive Disease Week.

Dr. Singh does not have any relevant financial or other relationship with any manufacturer or provider of commercial products or services that he discussed during the presentation.

Menopausal hormone therapy is associated with an increased risk of major gastrointestinal bleeding, particularly in the lower gastrointestinal tract, that is associated with duration of use, a study has found.

Analysis of data from 73,863 women enrolled in the Nurses’ Health Study II in 1989 showed that current users of menopausal hormone therapy had a 46% increase in the risk of a major gastrointestinal bleed and a more than twofold increase in the risk of a lower GI bleed or ischemic colitis, compared with never users, said Dr. Prashant Singh of Massachusetts General Hospital, Boston.

Past users showed a much smaller increase risk of bleeding, while increasing duration of hormone therapy was significantly associated with increasing risk of major and low gastrointestinal bleeding.

“Although our findings show that menopausal hormone therapy may increase the risk of major GI bleeding, especially in the lower GI tract, it is important for these patients to know that this therapy is still an effective treatment; however, both clinician and patient should be more cautious in using this therapy in some cases, such as with patients who have a history of ischemic colitis,” Dr. Singh said at the annual Digestive Disease Week.

Dr. Singh does not have any relevant financial or other relationship with any manufacturer or provider of commercial products or services that he discussed during the presentation.

Menopausal hormone therapy is associated with an increased risk of major gastrointestinal bleeding, particularly in the lower gastrointestinal tract, that is associated with duration of use, a study has found.

Analysis of data from 73,863 women enrolled in the Nurses’ Health Study II in 1989 showed that current users of menopausal hormone therapy had a 46% increase in the risk of a major gastrointestinal bleed and a more than twofold increase in the risk of a lower GI bleed or ischemic colitis, compared with never users, said Dr. Prashant Singh of Massachusetts General Hospital, Boston.

Past users showed a much smaller increase risk of bleeding, while increasing duration of hormone therapy was significantly associated with increasing risk of major and low gastrointestinal bleeding.

“Although our findings show that menopausal hormone therapy may increase the risk of major GI bleeding, especially in the lower GI tract, it is important for these patients to know that this therapy is still an effective treatment; however, both clinician and patient should be more cautious in using this therapy in some cases, such as with patients who have a history of ischemic colitis,” Dr. Singh said at the annual Digestive Disease Week.

Dr. Singh does not have any relevant financial or other relationship with any manufacturer or provider of commercial products or services that he discussed during the presentation.

WASHINGTON – A simple urine test could detect gastric cancer even at an early stage, the test’s developers say.

The test, which looks for the presence of two metalloprotease enzymes labeled ADAM 12 and MMP-9/NGAL had 77.1% sensitivity and 82.9% specificity for gastric cancer when tested in 35 patients with the malignancy and an equal number of healthy controls, reported Dr. Takaya Shimura from the department of surgery at Boston Children’s Hospital and Harvard Medical School in Boston.

“This study represents the first demonstration of the presence of ADAM 12 and MMO-9/NGAL complex in the urine of gastric cancer patients,” he said at the annual Digestive Disease Week.

Dr. Stephen J. Meltzer of Johns Hopkins University, Baltimore, commented in an interview that the findings are convincing but preliminary.

A randomized clinical trial enrolling a larger number of patients and controls would be required before he would consider screening patients for the enzymes, said Dr. Meltzer, who was not involved in the study and comoderated the meeting session where the results were presented.

ADAM 12 (a disintegrin and metalloprotease 12) and MMP-9 (matrix metalloprotease 9) are both members of a family of enzymes involved in cellular adhesion, invasion, growth, and angiogenesis, Dr. Shimura explained. MMP-9, when complexed with NGAL (neutrophil gelatinase associated lipocalin) is protected from autodegradation.

The investigators, from the lab of Dr. Marsha A. Moses at Boston Children’s Hospital, and their collaborators in Japan had previously reported that MMPs in urine were independent predictors of both organ-confined and metastatic cancer.

Urinary assays are noninvasive, using easily accessed tissues that can be handled simply and inexpensively, making them ideal for cancer detection, Dr, Shimura said.

Current tests for gastric cancer, such as carcinoembryonic antigen (CEA) and cancer antigens (CA) 19-9 and 72-4, have poor sensitivity for detecting advanced disease, and are even worse at spotting early disease, he noted.

To see whether they could improve on the current lot of tests, the investigators enrolled 106 patients in a case-control study, settling eventually, after age and sex matching, on a cohort of 70 patients: 35 with primarily early-stage gastric cancer, and 35 healthy controls.

After screening the urine of participants for about 50 different antigenic proteins, they found that the patients with gastric cancer had significantly higher levels in their urine of both ADAM 12 (P < .001) and the MMP-9/NGAL complex (P = .020).

In a multivariate analysis, they showed that both enzymes were strong, independent predictors of gastric cancer, with an odds ratio for urinary MMO-9/NGAL of 6.71 (P = .002), and an OR of 15.4 for ADAM 12 (P = .002). In contrast, Helicobacter pylori infection was associated with a nonsignificant OR of 2.54.

In a receiver operating characteristic (ROC) analysis, they also found that MMP-9/NGAL was associated with an area-under-the curve (AUC) of 0.657 (P = .024), ADAM 12 was associated with an AUC of 0.757 (P < .001), and that the two combined had an AUC of 0.825 (P < .001).

As noted before, the sensitivity of the combined enzymes was 77%, and the specificity was 83%.

Finally, using immunohistochemical analysis, the investigators were able to show that gastric cancer tissues had high levels of coexpression of MMP-9 and NGAL (P <.001) and high expression levels of ADAM 12 (P < .001), compared with adjacent normal tissues.

WASHINGTON – A simple urine test could detect gastric cancer even at an early stage, the test’s developers say.

The test, which looks for the presence of two metalloprotease enzymes labeled ADAM 12 and MMP-9/NGAL had 77.1% sensitivity and 82.9% specificity for gastric cancer when tested in 35 patients with the malignancy and an equal number of healthy controls, reported Dr. Takaya Shimura from the department of surgery at Boston Children’s Hospital and Harvard Medical School in Boston.

“This study represents the first demonstration of the presence of ADAM 12 and MMO-9/NGAL complex in the urine of gastric cancer patients,” he said at the annual Digestive Disease Week.

Dr. Stephen J. Meltzer of Johns Hopkins University, Baltimore, commented in an interview that the findings are convincing but preliminary.

A randomized clinical trial enrolling a larger number of patients and controls would be required before he would consider screening patients for the enzymes, said Dr. Meltzer, who was not involved in the study and comoderated the meeting session where the results were presented.

ADAM 12 (a disintegrin and metalloprotease 12) and MMP-9 (matrix metalloprotease 9) are both members of a family of enzymes involved in cellular adhesion, invasion, growth, and angiogenesis, Dr. Shimura explained. MMP-9, when complexed with NGAL (neutrophil gelatinase associated lipocalin) is protected from autodegradation.

The investigators, from the lab of Dr. Marsha A. Moses at Boston Children’s Hospital, and their collaborators in Japan had previously reported that MMPs in urine were independent predictors of both organ-confined and metastatic cancer.

Urinary assays are noninvasive, using easily accessed tissues that can be handled simply and inexpensively, making them ideal for cancer detection, Dr, Shimura said.

Current tests for gastric cancer, such as carcinoembryonic antigen (CEA) and cancer antigens (CA) 19-9 and 72-4, have poor sensitivity for detecting advanced disease, and are even worse at spotting early disease, he noted.

To see whether they could improve on the current lot of tests, the investigators enrolled 106 patients in a case-control study, settling eventually, after age and sex matching, on a cohort of 70 patients: 35 with primarily early-stage gastric cancer, and 35 healthy controls.

After screening the urine of participants for about 50 different antigenic proteins, they found that the patients with gastric cancer had significantly higher levels in their urine of both ADAM 12 (P < .001) and the MMP-9/NGAL complex (P = .020).

In a multivariate analysis, they showed that both enzymes were strong, independent predictors of gastric cancer, with an odds ratio for urinary MMO-9/NGAL of 6.71 (P = .002), and an OR of 15.4 for ADAM 12 (P = .002). In contrast, Helicobacter pylori infection was associated with a nonsignificant OR of 2.54.

In a receiver operating characteristic (ROC) analysis, they also found that MMP-9/NGAL was associated with an area-under-the curve (AUC) of 0.657 (P = .024), ADAM 12 was associated with an AUC of 0.757 (P < .001), and that the two combined had an AUC of 0.825 (P < .001).

As noted before, the sensitivity of the combined enzymes was 77%, and the specificity was 83%.

Finally, using immunohistochemical analysis, the investigators were able to show that gastric cancer tissues had high levels of coexpression of MMP-9 and NGAL (P <.001) and high expression levels of ADAM 12 (P < .001), compared with adjacent normal tissues.

WASHINGTON – A simple urine test could detect gastric cancer even at an early stage, the test’s developers say.

The test, which looks for the presence of two metalloprotease enzymes labeled ADAM 12 and MMP-9/NGAL had 77.1% sensitivity and 82.9% specificity for gastric cancer when tested in 35 patients with the malignancy and an equal number of healthy controls, reported Dr. Takaya Shimura from the department of surgery at Boston Children’s Hospital and Harvard Medical School in Boston.

“This study represents the first demonstration of the presence of ADAM 12 and MMO-9/NGAL complex in the urine of gastric cancer patients,” he said at the annual Digestive Disease Week.

Dr. Stephen J. Meltzer of Johns Hopkins University, Baltimore, commented in an interview that the findings are convincing but preliminary.

A randomized clinical trial enrolling a larger number of patients and controls would be required before he would consider screening patients for the enzymes, said Dr. Meltzer, who was not involved in the study and comoderated the meeting session where the results were presented.

ADAM 12 (a disintegrin and metalloprotease 12) and MMP-9 (matrix metalloprotease 9) are both members of a family of enzymes involved in cellular adhesion, invasion, growth, and angiogenesis, Dr. Shimura explained. MMP-9, when complexed with NGAL (neutrophil gelatinase associated lipocalin) is protected from autodegradation.

The investigators, from the lab of Dr. Marsha A. Moses at Boston Children’s Hospital, and their collaborators in Japan had previously reported that MMPs in urine were independent predictors of both organ-confined and metastatic cancer.

Urinary assays are noninvasive, using easily accessed tissues that can be handled simply and inexpensively, making them ideal for cancer detection, Dr, Shimura said.

Current tests for gastric cancer, such as carcinoembryonic antigen (CEA) and cancer antigens (CA) 19-9 and 72-4, have poor sensitivity for detecting advanced disease, and are even worse at spotting early disease, he noted.

To see whether they could improve on the current lot of tests, the investigators enrolled 106 patients in a case-control study, settling eventually, after age and sex matching, on a cohort of 70 patients: 35 with primarily early-stage gastric cancer, and 35 healthy controls.

After screening the urine of participants for about 50 different antigenic proteins, they found that the patients with gastric cancer had significantly higher levels in their urine of both ADAM 12 (P < .001) and the MMP-9/NGAL complex (P = .020).

In a multivariate analysis, they showed that both enzymes were strong, independent predictors of gastric cancer, with an odds ratio for urinary MMO-9/NGAL of 6.71 (P = .002), and an OR of 15.4 for ADAM 12 (P = .002). In contrast, Helicobacter pylori infection was associated with a nonsignificant OR of 2.54.

In a receiver operating characteristic (ROC) analysis, they also found that MMP-9/NGAL was associated with an area-under-the curve (AUC) of 0.657 (P = .024), ADAM 12 was associated with an AUC of 0.757 (P < .001), and that the two combined had an AUC of 0.825 (P < .001).

As noted before, the sensitivity of the combined enzymes was 77%, and the specificity was 83%.

Finally, using immunohistochemical analysis, the investigators were able to show that gastric cancer tissues had high levels of coexpression of MMP-9 and NGAL (P <.001) and high expression levels of ADAM 12 (P < .001), compared with adjacent normal tissues.

WASHINGTON – A novel, edible colon preparation could make obsolete the fasting and large volume of salty liquid cleansing that keep many a patient from completing their colonoscopies.

A pilot study showed that all 10 patients who ate a series of nutritionally balanced meals, drinks, and snacks such as pretzels and pudding had a successful colon cleansing according to the endoscopist at the time of the procedure, Dr. L. Campbell Levy of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., reported at the annual Digestive Disease Week.

The preparation, which is blended with polyethylene glycol 3350, sorbitol, and ascorbic acid, did not produce any significant changes in electrolytes or creatinine.

There were no adverse events and, equally important, all 10 patients said that they would follow the edible bowel regimen again for a subsequent procedure.

In a video interview, he discussed the small study’s results and the plans for larger, randomized studies.

Dr. Levy reported no relevant conflicts. The inventor of the diet and the founder of Colonary Concepts were involved in the study.

[email protected]

On Twitter @pwendl

WASHINGTON – A novel, edible colon preparation could make obsolete the fasting and large volume of salty liquid cleansing that keep many a patient from completing their colonoscopies.

A pilot study showed that all 10 patients who ate a series of nutritionally balanced meals, drinks, and snacks such as pretzels and pudding had a successful colon cleansing according to the endoscopist at the time of the procedure, Dr. L. Campbell Levy of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., reported at the annual Digestive Disease Week.

The preparation, which is blended with polyethylene glycol 3350, sorbitol, and ascorbic acid, did not produce any significant changes in electrolytes or creatinine.

There were no adverse events and, equally important, all 10 patients said that they would follow the edible bowel regimen again for a subsequent procedure.

In a video interview, he discussed the small study’s results and the plans for larger, randomized studies.

Dr. Levy reported no relevant conflicts. The inventor of the diet and the founder of Colonary Concepts were involved in the study.

[email protected]

On Twitter @pwendl

WASHINGTON – A novel, edible colon preparation could make obsolete the fasting and large volume of salty liquid cleansing that keep many a patient from completing their colonoscopies.

A pilot study showed that all 10 patients who ate a series of nutritionally balanced meals, drinks, and snacks such as pretzels and pudding had a successful colon cleansing according to the endoscopist at the time of the procedure, Dr. L. Campbell Levy of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., reported at the annual Digestive Disease Week.

The preparation, which is blended with polyethylene glycol 3350, sorbitol, and ascorbic acid, did not produce any significant changes in electrolytes or creatinine.

There were no adverse events and, equally important, all 10 patients said that they would follow the edible bowel regimen again for a subsequent procedure.

In a video interview, he discussed the small study’s results and the plans for larger, randomized studies.

Dr. Levy reported no relevant conflicts. The inventor of the diet and the founder of Colonary Concepts were involved in the study.

[email protected]

On Twitter @pwendl

While effective in outpatient settings, the Wells score was not effective at detecting deep vein thrombosis in an inpatient setting, according to Dr. Patricia Silveira and her associates from Harvard Medical School, Boston.

Of 1,135 patients included in the study, 137 had proximal DVT. DVT incidence in the low, medium, and high pretest probability groups were 5.9%, 9.5%, and 16.4%, respectively. Although statistically significantly different, this is a very narrow range, in contrast to findings in previous studies, where incidence among the three groups was 3.0%, 16.6%, and 74.6% respectively.

The AUC for the accuracy of the Wells score was 0.6, only slightly better than chance. The failure rate in the low pretest group was 5.9%, and the efficiency was 11.9%.

“In inpatients,Wells DVT scores are inflated by comorbidities and nonspecific physical findings common among hospitalized patients, leaving very few patients in the low-probability Wells score category, and many patients without DVT in the moderate- and high-probability categories,” Dr. Erika Leemann Price and Dr. Tracy Minichiello wrote in a related editorial.

Find the full study and editorial in JAMA Internal Medicine (doi:10.1001/jamainternmed.2015.1687; doi:10.1001/jamainternmed.2015.1699).

While effective in outpatient settings, the Wells score was not effective at detecting deep vein thrombosis in an inpatient setting, according to Dr. Patricia Silveira and her associates from Harvard Medical School, Boston.

Of 1,135 patients included in the study, 137 had proximal DVT. DVT incidence in the low, medium, and high pretest probability groups were 5.9%, 9.5%, and 16.4%, respectively. Although statistically significantly different, this is a very narrow range, in contrast to findings in previous studies, where incidence among the three groups was 3.0%, 16.6%, and 74.6% respectively.

The AUC for the accuracy of the Wells score was 0.6, only slightly better than chance. The failure rate in the low pretest group was 5.9%, and the efficiency was 11.9%.

“In inpatients,Wells DVT scores are inflated by comorbidities and nonspecific physical findings common among hospitalized patients, leaving very few patients in the low-probability Wells score category, and many patients without DVT in the moderate- and high-probability categories,” Dr. Erika Leemann Price and Dr. Tracy Minichiello wrote in a related editorial.

Find the full study and editorial in JAMA Internal Medicine (doi:10.1001/jamainternmed.2015.1687; doi:10.1001/jamainternmed.2015.1699).

While effective in outpatient settings, the Wells score was not effective at detecting deep vein thrombosis in an inpatient setting, according to Dr. Patricia Silveira and her associates from Harvard Medical School, Boston.

Of 1,135 patients included in the study, 137 had proximal DVT. DVT incidence in the low, medium, and high pretest probability groups were 5.9%, 9.5%, and 16.4%, respectively. Although statistically significantly different, this is a very narrow range, in contrast to findings in previous studies, where incidence among the three groups was 3.0%, 16.6%, and 74.6% respectively.

The AUC for the accuracy of the Wells score was 0.6, only slightly better than chance. The failure rate in the low pretest group was 5.9%, and the efficiency was 11.9%.

“In inpatients,Wells DVT scores are inflated by comorbidities and nonspecific physical findings common among hospitalized patients, leaving very few patients in the low-probability Wells score category, and many patients without DVT in the moderate- and high-probability categories,” Dr. Erika Leemann Price and Dr. Tracy Minichiello wrote in a related editorial.

Find the full study and editorial in JAMA Internal Medicine (doi:10.1001/jamainternmed.2015.1687; doi:10.1001/jamainternmed.2015.1699).

T-cell ALL

© Hind Medyouf, German

Cancer Research Center

A new study suggests that minimal residual disease (MRD) alone is not predictive of outcomes in children with T-cell acute lymphoblastic leukemia (T-ALL).

Study investigators analyzed a small group of T-ALL patients who received similar treatment regimens, comparing those with and without MRD after induction.

None of the MRD-positive patients relapsed within the follow-up period, despite not receiving intensified treatment to fully eradicate their disease.

These results, published in Pediatric Blood & Cancer, suggest T-ALL patients with MRD may not need intensified treatment and can therefore avoid additional toxicities.

“Until now, the dogma has been that, for patients with leukemia who have minimal residual disease at the end of induction, we need to intensify their treatment, which also increases side effects,” said study author Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles in California.

“We have found, for T-ALL, patients have excellent outcomes without therapy intensification and its associated toxicities.”

Dr Abdel-Azim and his colleagues studied 33 children (ages 1 to 21) with newly diagnosed T-ALL. Their treatment included induction, augmented consolidation, interim maintenance (high-dose [5 g/m²] or escalating-dose intravenous methotrexate), 1 delayed intensification, and maintenance. Twenty-one patients underwent cranial irradiation, and 1 received a transplant.

After induction, 19 of the 32 patients analyzed had MRD, which was defined as ≥ 0.01% residual leukemia cells. At the end of consolidation, 6 of the 11 patients tested were MRD-positive. And at the end of interim maintenance, 2 of the 4 patients tested were MRD-positive.

The 19 patients who were MRD-positive after induction were in continuous complete remission at a median follow-up of 4 years (range, 1.3-7.1 years). The same was true for 13 of the 14 MRD-negative patients. One of the MRD-negative patients relapsed 18 months after diagnosis but was still alive with refractory disease at last follow-up.

Dr Abdel-Azim and his colleagues noted that there were no significant differences in treatment variables between MRD-positive patients and MRD-negative patients. However, 1 patient did receive a transplant for rising MRD at 5.4 months after diagnosis.

The investigators also said they did not find any associations between MRD positivity after induction and patients’ age, sex, ethnicity, weight, white blood cell count at diagnosis, cytogenetics, immunophenotype, or the type of steroid they received during induction therapy.

The team said these results may be explained by the fact that clearance of leukemia cells from the blood is slower in patients with T-ALL than in those with B-cell ALL. However, the leukemia cells ultimately clear in T-ALL without changes in therapy.

T-cell ALL

© Hind Medyouf, German

Cancer Research Center

A new study suggests that minimal residual disease (MRD) alone is not predictive of outcomes in children with T-cell acute lymphoblastic leukemia (T-ALL).

Study investigators analyzed a small group of T-ALL patients who received similar treatment regimens, comparing those with and without MRD after induction.

None of the MRD-positive patients relapsed within the follow-up period, despite not receiving intensified treatment to fully eradicate their disease.

These results, published in Pediatric Blood & Cancer, suggest T-ALL patients with MRD may not need intensified treatment and can therefore avoid additional toxicities.

“Until now, the dogma has been that, for patients with leukemia who have minimal residual disease at the end of induction, we need to intensify their treatment, which also increases side effects,” said study author Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles in California.

“We have found, for T-ALL, patients have excellent outcomes without therapy intensification and its associated toxicities.”

Dr Abdel-Azim and his colleagues studied 33 children (ages 1 to 21) with newly diagnosed T-ALL. Their treatment included induction, augmented consolidation, interim maintenance (high-dose [5 g/m²] or escalating-dose intravenous methotrexate), 1 delayed intensification, and maintenance. Twenty-one patients underwent cranial irradiation, and 1 received a transplant.

After induction, 19 of the 32 patients analyzed had MRD, which was defined as ≥ 0.01% residual leukemia cells. At the end of consolidation, 6 of the 11 patients tested were MRD-positive. And at the end of interim maintenance, 2 of the 4 patients tested were MRD-positive.

The 19 patients who were MRD-positive after induction were in continuous complete remission at a median follow-up of 4 years (range, 1.3-7.1 years). The same was true for 13 of the 14 MRD-negative patients. One of the MRD-negative patients relapsed 18 months after diagnosis but was still alive with refractory disease at last follow-up.

Dr Abdel-Azim and his colleagues noted that there were no significant differences in treatment variables between MRD-positive patients and MRD-negative patients. However, 1 patient did receive a transplant for rising MRD at 5.4 months after diagnosis.

The investigators also said they did not find any associations between MRD positivity after induction and patients’ age, sex, ethnicity, weight, white blood cell count at diagnosis, cytogenetics, immunophenotype, or the type of steroid they received during induction therapy.

The team said these results may be explained by the fact that clearance of leukemia cells from the blood is slower in patients with T-ALL than in those with B-cell ALL. However, the leukemia cells ultimately clear in T-ALL without changes in therapy.

T-cell ALL

© Hind Medyouf, German

Cancer Research Center

A new study suggests that minimal residual disease (MRD) alone is not predictive of outcomes in children with T-cell acute lymphoblastic leukemia (T-ALL).

Study investigators analyzed a small group of T-ALL patients who received similar treatment regimens, comparing those with and without MRD after induction.

None of the MRD-positive patients relapsed within the follow-up period, despite not receiving intensified treatment to fully eradicate their disease.

These results, published in Pediatric Blood & Cancer, suggest T-ALL patients with MRD may not need intensified treatment and can therefore avoid additional toxicities.

“Until now, the dogma has been that, for patients with leukemia who have minimal residual disease at the end of induction, we need to intensify their treatment, which also increases side effects,” said study author Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles in California.

“We have found, for T-ALL, patients have excellent outcomes without therapy intensification and its associated toxicities.”

Dr Abdel-Azim and his colleagues studied 33 children (ages 1 to 21) with newly diagnosed T-ALL. Their treatment included induction, augmented consolidation, interim maintenance (high-dose [5 g/m²] or escalating-dose intravenous methotrexate), 1 delayed intensification, and maintenance. Twenty-one patients underwent cranial irradiation, and 1 received a transplant.

After induction, 19 of the 32 patients analyzed had MRD, which was defined as ≥ 0.01% residual leukemia cells. At the end of consolidation, 6 of the 11 patients tested were MRD-positive. And at the end of interim maintenance, 2 of the 4 patients tested were MRD-positive.

The 19 patients who were MRD-positive after induction were in continuous complete remission at a median follow-up of 4 years (range, 1.3-7.1 years). The same was true for 13 of the 14 MRD-negative patients. One of the MRD-negative patients relapsed 18 months after diagnosis but was still alive with refractory disease at last follow-up.

Dr Abdel-Azim and his colleagues noted that there were no significant differences in treatment variables between MRD-positive patients and MRD-negative patients. However, 1 patient did receive a transplant for rising MRD at 5.4 months after diagnosis.

The investigators also said they did not find any associations between MRD positivity after induction and patients’ age, sex, ethnicity, weight, white blood cell count at diagnosis, cytogenetics, immunophenotype, or the type of steroid they received during induction therapy.

The team said these results may be explained by the fact that clearance of leukemia cells from the blood is slower in patients with T-ALL than in those with B-cell ALL. However, the leukemia cells ultimately clear in T-ALL without changes in therapy.

Plasmodium parasite infecting

a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

New research indicates that manipulating the permeability of parasitophorous vacuoles could defeat malaria parasites.

The researchers unearthed this finding while studying the way in which the Toxoplasma gondii parasite, which causes toxoplasmosis, and Plasmodium parasites,

which cause malaria, access vital nutrients from their host cells.

The team described this work in Cell Host & Microbe.

Roughly a third of the world’s deadly infectious diseases are caused by pathogens that spend a large portion of their life inside parasitophorous vacuoles. This type of vacuole separates the host cytoplasm and the parasite by a membrane, protecting the parasite from the host cell’s defenses and providing an environment tailored to the parasite’s needs.

However, the membrane of the vacuole also acts as a barrier between the parasite and the host cell. This makes it more difficult for the parasite to release proteins involved in the transformation of the host cell beyond the membrane to spread the disease and for the pathogen to gain access to vital nutrients.

“Ultimately, what defines a parasite is that they require certain key nutrients from their host,” said study author Dan Gold, PhD, of the Massachusetts Institute of Technology in Cambridge.

“So they have had to evolve ways to get around their own barriers to gain access to these nutrients.”

Previous research suggested the vacuoles are selectively permeable to small molecules, allowing certain nutrients to pass through pores in the membrane. But until now, no one has been able to determine the molecular makeup of these pores or how they are formed.

When studying Toxoplasma, Dr Gold and his colleagues discovered 2 proteins secreted by the parasite, known as GRA17 and GRA23, which are responsible for forming these pores in the vacuole. The researchers discovered the proteins’ roles by accident while investigating how the parasites are able to release their own proteins out into the host cell beyond the vacuole membrane.

Similar research into how the related Plasmodium pathogens perform this trick revealed a protein export complex that transports encoded proteins from a parasite into its host red blood cell, which transforms the cell in a way that is vital to the spread of malaria.

“The clinical symptoms of malaria are dependent on this process and this remodeling of the red blood cell that occurs,” Dr Gold said.

The researchers identified proteins secreted by Toxoplasma that appeared to be homologues of this protein export complex in Plasmodium. But when they stopped these proteins from functioning, the team found it made no difference to the export of proteins from the parasite beyond the vacuole.

“We were left wondering what GRA17 and GRA23 actually do if they are not involved in protein export, and so we went back to look at this longstanding phenomenon of nutrient transport,” Dr Gold said.

When they added dyes to the host cell and knocked out the 2 proteins, the researchers found that it prevented the dyes flowing into the vacuole.

“That was our first indication that these proteins actually have a role in small-molecule transfer,” Dr Gold said.

When the researchers expressed a Plasmodium export complex gene in the modified Toxoplasma, they found the dyes were able to flow into the vacuole once again, suggesting this small-molecule transport function had been restored.

Since these proteins are only found in the parasite phylum Apicomplexa, to which both Toxoplasma and Plasmodium belong, they could be used as a drug target against the diseases they cause, the researchers said.

“This very strongly suggests that you could find small-molecule drugs to target these pores, which would be very damaging to these parasites but likely wouldn’t have any interaction with any human molecules,” Dr Gold said. “So I think this is a really strong potential drug target for restricting the access of these parasites to a set of nutrients.”

Plasmodium parasite infecting

a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

New research indicates that manipulating the permeability of parasitophorous vacuoles could defeat malaria parasites.

The researchers unearthed this finding while studying the way in which the Toxoplasma gondii parasite, which causes toxoplasmosis, and Plasmodium parasites,

which cause malaria, access vital nutrients from their host cells.

The team described this work in Cell Host & Microbe.

Roughly a third of the world’s deadly infectious diseases are caused by pathogens that spend a large portion of their life inside parasitophorous vacuoles. This type of vacuole separates the host cytoplasm and the parasite by a membrane, protecting the parasite from the host cell’s defenses and providing an environment tailored to the parasite’s needs.

However, the membrane of the vacuole also acts as a barrier between the parasite and the host cell. This makes it more difficult for the parasite to release proteins involved in the transformation of the host cell beyond the membrane to spread the disease and for the pathogen to gain access to vital nutrients.

“Ultimately, what defines a parasite is that they require certain key nutrients from their host,” said study author Dan Gold, PhD, of the Massachusetts Institute of Technology in Cambridge.

“So they have had to evolve ways to get around their own barriers to gain access to these nutrients.”

Previous research suggested the vacuoles are selectively permeable to small molecules, allowing certain nutrients to pass through pores in the membrane. But until now, no one has been able to determine the molecular makeup of these pores or how they are formed.

When studying Toxoplasma, Dr Gold and his colleagues discovered 2 proteins secreted by the parasite, known as GRA17 and GRA23, which are responsible for forming these pores in the vacuole. The researchers discovered the proteins’ roles by accident while investigating how the parasites are able to release their own proteins out into the host cell beyond the vacuole membrane.

Similar research into how the related Plasmodium pathogens perform this trick revealed a protein export complex that transports encoded proteins from a parasite into its host red blood cell, which transforms the cell in a way that is vital to the spread of malaria.

“The clinical symptoms of malaria are dependent on this process and this remodeling of the red blood cell that occurs,” Dr Gold said.

The researchers identified proteins secreted by Toxoplasma that appeared to be homologues of this protein export complex in Plasmodium. But when they stopped these proteins from functioning, the team found it made no difference to the export of proteins from the parasite beyond the vacuole.

“We were left wondering what GRA17 and GRA23 actually do if they are not involved in protein export, and so we went back to look at this longstanding phenomenon of nutrient transport,” Dr Gold said.

When they added dyes to the host cell and knocked out the 2 proteins, the researchers found that it prevented the dyes flowing into the vacuole.

“That was our first indication that these proteins actually have a role in small-molecule transfer,” Dr Gold said.

When the researchers expressed a Plasmodium export complex gene in the modified Toxoplasma, they found the dyes were able to flow into the vacuole once again, suggesting this small-molecule transport function had been restored.

Since these proteins are only found in the parasite phylum Apicomplexa, to which both Toxoplasma and Plasmodium belong, they could be used as a drug target against the diseases they cause, the researchers said.

“This very strongly suggests that you could find small-molecule drugs to target these pores, which would be very damaging to these parasites but likely wouldn’t have any interaction with any human molecules,” Dr Gold said. “So I think this is a really strong potential drug target for restricting the access of these parasites to a set of nutrients.”

Plasmodium parasite infecting

a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

New research indicates that manipulating the permeability of parasitophorous vacuoles could defeat malaria parasites.

The researchers unearthed this finding while studying the way in which the Toxoplasma gondii parasite, which causes toxoplasmosis, and Plasmodium parasites,

which cause malaria, access vital nutrients from their host cells.

The team described this work in Cell Host & Microbe.

Roughly a third of the world’s deadly infectious diseases are caused by pathogens that spend a large portion of their life inside parasitophorous vacuoles. This type of vacuole separates the host cytoplasm and the parasite by a membrane, protecting the parasite from the host cell’s defenses and providing an environment tailored to the parasite’s needs.

However, the membrane of the vacuole also acts as a barrier between the parasite and the host cell. This makes it more difficult for the parasite to release proteins involved in the transformation of the host cell beyond the membrane to spread the disease and for the pathogen to gain access to vital nutrients.

“Ultimately, what defines a parasite is that they require certain key nutrients from their host,” said study author Dan Gold, PhD, of the Massachusetts Institute of Technology in Cambridge.

“So they have had to evolve ways to get around their own barriers to gain access to these nutrients.”

Previous research suggested the vacuoles are selectively permeable to small molecules, allowing certain nutrients to pass through pores in the membrane. But until now, no one has been able to determine the molecular makeup of these pores or how they are formed.

When studying Toxoplasma, Dr Gold and his colleagues discovered 2 proteins secreted by the parasite, known as GRA17 and GRA23, which are responsible for forming these pores in the vacuole. The researchers discovered the proteins’ roles by accident while investigating how the parasites are able to release their own proteins out into the host cell beyond the vacuole membrane.

Similar research into how the related Plasmodium pathogens perform this trick revealed a protein export complex that transports encoded proteins from a parasite into its host red blood cell, which transforms the cell in a way that is vital to the spread of malaria.

“The clinical symptoms of malaria are dependent on this process and this remodeling of the red blood cell that occurs,” Dr Gold said.

The researchers identified proteins secreted by Toxoplasma that appeared to be homologues of this protein export complex in Plasmodium. But when they stopped these proteins from functioning, the team found it made no difference to the export of proteins from the parasite beyond the vacuole.

“We were left wondering what GRA17 and GRA23 actually do if they are not involved in protein export, and so we went back to look at this longstanding phenomenon of nutrient transport,” Dr Gold said.

When they added dyes to the host cell and knocked out the 2 proteins, the researchers found that it prevented the dyes flowing into the vacuole.

“That was our first indication that these proteins actually have a role in small-molecule transfer,” Dr Gold said.

When the researchers expressed a Plasmodium export complex gene in the modified Toxoplasma, they found the dyes were able to flow into the vacuole once again, suggesting this small-molecule transport function had been restored.

Since these proteins are only found in the parasite phylum Apicomplexa, to which both Toxoplasma and Plasmodium belong, they could be used as a drug target against the diseases they cause, the researchers said.

“This very strongly suggests that you could find small-molecule drugs to target these pores, which would be very damaging to these parasites but likely wouldn’t have any interaction with any human molecules,” Dr Gold said. “So I think this is a really strong potential drug target for restricting the access of these parasites to a set of nutrients.”