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HL survivors should be screened for CAD after chest irradiation
VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.
The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.
These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.
The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).
“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.
“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”
Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.
The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.
CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.
Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.
Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).
Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).
The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).
Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.
Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).
“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.
“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”
“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”
Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.
He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.
“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”
“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.” 
VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.
The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.
These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.
The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).
“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.
“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”
Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.
The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.
CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.
Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.
Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).
Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).
The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).
Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.
Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).
“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.
“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”
“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”
Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.
He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.
“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”
“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.”
VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.
The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.
These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.
The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).
“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.
“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”
Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.
The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.
CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.
Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.
Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).
Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).
The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).
Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.
Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).
“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.
“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”
“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”
Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.
He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.
“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”
“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.”
Compound inhibits translation program to treat MM
A new compound has shown promise for treating multiple myeloma (MM) by inhibiting the oncogenic MYC-driven translation program supporting the disease, according to researchers.
The compound is CMLD01059, a derivative of natural products called rocaglates that are known to interfere with translation.
CMLD010509 induced apoptosis in MM cells in culture and exhibited anti-myeloma activity in 3 different mouse models.
In addition, the compound was well-tolerated by the mice and spared normal cells in culture.
Salomon Manier, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Science Translational Medicine.
The researchers found that CMLD01059 treatment significantly reduced the levels of 54 proteins in MM cell lines, including 5 known drivers of tumor progression—MYC, MDM2, CCND1, MAF, and MCL-1.
Further investigation confirmed that CMLD010509 inhibits the translation of oncoproteins that support the proliferation and survival of MM cells.
The researchers also found that CMLD010509 triggered a “strong” and “rapid” apoptotic response in MM cells (NCI-H929 and MM1S).
So the team tested the anti-myeloma activity of CMLD010509 in mouse models.
In one model (mice injected with MM1S cells), CMLD010509 “caused a marked reduction in tumor burden,” according to the researchers.
The median survival was 47 days in CMLD010509-treated mice, compared to 35 days in control mice (P<0.001).
The researchers also noted that 4 weeks of CMLD010509 treatment was well-tolerated in the mice, who maintained their weight and normal complete blood counts.
In another MM model (mice injected with KMS-11 cells), the mice received CMLD010509 or vehicle control twice a week for 4 weeks and were sacrificed at the end of treatment.
Immunohistochemistry studies conducted on bone marrow samples revealed a decrease in CD138+ plasma cells, depletion of MYC, and inhibition of proliferation in the CMLD010509-treated mice.
For the last model, the researchers injected transplantable mouse MM cells into C57BL/6 mice. The team noted that these cells are driven by plasma cell-specific MYC overexpression (Vk*Myc cells).
The mice received CMLD010509 or vehicle control twice a week starting 1 week after cell inoculation.
The researchers said CMLD010509 was well-tolerated, and they observed a “robust” decrease of M-spike in the treated mice that was associated with a significant improvement in survival.
The median survival was 39 days in the control mice, but it had not been reached by 90 days in the treated mice (P=0.0019).
The researchers said these results support targeting translation with rocaglates to treat MM.
A new compound has shown promise for treating multiple myeloma (MM) by inhibiting the oncogenic MYC-driven translation program supporting the disease, according to researchers.
The compound is CMLD01059, a derivative of natural products called rocaglates that are known to interfere with translation.
CMLD010509 induced apoptosis in MM cells in culture and exhibited anti-myeloma activity in 3 different mouse models.
In addition, the compound was well-tolerated by the mice and spared normal cells in culture.
Salomon Manier, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Science Translational Medicine.
The researchers found that CMLD01059 treatment significantly reduced the levels of 54 proteins in MM cell lines, including 5 known drivers of tumor progression—MYC, MDM2, CCND1, MAF, and MCL-1.
Further investigation confirmed that CMLD010509 inhibits the translation of oncoproteins that support the proliferation and survival of MM cells.
The researchers also found that CMLD010509 triggered a “strong” and “rapid” apoptotic response in MM cells (NCI-H929 and MM1S).
So the team tested the anti-myeloma activity of CMLD010509 in mouse models.
In one model (mice injected with MM1S cells), CMLD010509 “caused a marked reduction in tumor burden,” according to the researchers.
The median survival was 47 days in CMLD010509-treated mice, compared to 35 days in control mice (P<0.001).
The researchers also noted that 4 weeks of CMLD010509 treatment was well-tolerated in the mice, who maintained their weight and normal complete blood counts.
In another MM model (mice injected with KMS-11 cells), the mice received CMLD010509 or vehicle control twice a week for 4 weeks and were sacrificed at the end of treatment.
Immunohistochemistry studies conducted on bone marrow samples revealed a decrease in CD138+ plasma cells, depletion of MYC, and inhibition of proliferation in the CMLD010509-treated mice.
For the last model, the researchers injected transplantable mouse MM cells into C57BL/6 mice. The team noted that these cells are driven by plasma cell-specific MYC overexpression (Vk*Myc cells).
The mice received CMLD010509 or vehicle control twice a week starting 1 week after cell inoculation.
The researchers said CMLD010509 was well-tolerated, and they observed a “robust” decrease of M-spike in the treated mice that was associated with a significant improvement in survival.
The median survival was 39 days in the control mice, but it had not been reached by 90 days in the treated mice (P=0.0019).
The researchers said these results support targeting translation with rocaglates to treat MM.
A new compound has shown promise for treating multiple myeloma (MM) by inhibiting the oncogenic MYC-driven translation program supporting the disease, according to researchers.
The compound is CMLD01059, a derivative of natural products called rocaglates that are known to interfere with translation.
CMLD010509 induced apoptosis in MM cells in culture and exhibited anti-myeloma activity in 3 different mouse models.
In addition, the compound was well-tolerated by the mice and spared normal cells in culture.
Salomon Manier, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Science Translational Medicine.
The researchers found that CMLD01059 treatment significantly reduced the levels of 54 proteins in MM cell lines, including 5 known drivers of tumor progression—MYC, MDM2, CCND1, MAF, and MCL-1.
Further investigation confirmed that CMLD010509 inhibits the translation of oncoproteins that support the proliferation and survival of MM cells.
The researchers also found that CMLD010509 triggered a “strong” and “rapid” apoptotic response in MM cells (NCI-H929 and MM1S).
So the team tested the anti-myeloma activity of CMLD010509 in mouse models.
In one model (mice injected with MM1S cells), CMLD010509 “caused a marked reduction in tumor burden,” according to the researchers.
The median survival was 47 days in CMLD010509-treated mice, compared to 35 days in control mice (P<0.001).
The researchers also noted that 4 weeks of CMLD010509 treatment was well-tolerated in the mice, who maintained their weight and normal complete blood counts.
In another MM model (mice injected with KMS-11 cells), the mice received CMLD010509 or vehicle control twice a week for 4 weeks and were sacrificed at the end of treatment.
Immunohistochemistry studies conducted on bone marrow samples revealed a decrease in CD138+ plasma cells, depletion of MYC, and inhibition of proliferation in the CMLD010509-treated mice.
For the last model, the researchers injected transplantable mouse MM cells into C57BL/6 mice. The team noted that these cells are driven by plasma cell-specific MYC overexpression (Vk*Myc cells).
The mice received CMLD010509 or vehicle control twice a week starting 1 week after cell inoculation.
The researchers said CMLD010509 was well-tolerated, and they observed a “robust” decrease of M-spike in the treated mice that was associated with a significant improvement in survival.
The median survival was 39 days in the control mice, but it had not been reached by 90 days in the treated mice (P=0.0019).
The researchers said these results support targeting translation with rocaglates to treat MM.
EMA recommends drug receive orphan designation for PNH
The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).
APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).
This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.
APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).
Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.
In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.
In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.
The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).
APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).
This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.
APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).
Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.
In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.
In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.
The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).
APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).
This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.
APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).
Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.
In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.
In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.
About orphan designation
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.
The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.
Engineered bone marrow could make transplants safer
Engineers say they have developed biomimetic bone tissues that could one day provide new bone marrow for patients requiring transplants.
The team created bone tissues with functional bone marrow that can be filled with donor cells and implanted under the skin of mice.
The implant gives donor cells their own space to live and grow without competition, eliminating the need for a conditioning regimen to wipe out the host’s pre-existing cells prior to transplant.
“We’ve made an accessory bone that can separately accommodate donor cells,” explained Shyni Varghese, PhD, of the University of California, San Diego.
“This way, we can keep the host cells and bypass irradiation.”
In mice that received the engineered bone tissue, donor hematopoietic cells survived for at least 6 months and supplied the mice with new blood cells.
“In the future, our work could contribute to improved therapies for bone marrow disease,” said Yu-Ru Vernon Shih, PhD, a researcher in Dr Varghese’s lab.
The researchers noted that these implants would be limited to patients with non-malignant bone marrow diseases, such as aplastic anemia, where there aren’t any cancerous cells that need to be eliminated prior to transplant.
The team described their bone tissue implants in PNAS.
The implants mimic the structure of long bones in the body, consisting of an outer bone compartment and an inner marrow compartment.
The implants are made of a porous hydrogel matrix. The outer matrix contains calcium phosphate minerals. Stem cells grown in this mineralized matrix differentiate into bone-building cells. The inner matrix houses donor stem cells that produce blood cells.
When implanted beneath the skin of mice, the structures matured into bone tissues that have a working blood vessel network and a bone marrow that supplies new blood cells.
After 4 weeks, the implanted marrow contained a mix of host and donor blood cells. This mix was still circulating in the bloodstream after 24 weeks.
The researchers said these findings suggest the implanted marrow is functional, donor cells can grow and survive for long time periods in the presence of host cells, and host and donor cells can travel between the implanted marrow and the host’s circulating blood via the blood vessel network formed in the implanted bone tissue.
In another set of experiments, the researchers took hematopoietic stem cells from the implanted marrow and transplanted them into a second group of mice that had their stem cells destroyed by radiation and drugs. The team found the transplanted cells had diffused into the bloodstream of these mice.
“We did these experiments to show that the bone marrow cells from the engineered bone tissues function similar to native bone,” Dr Shih said.
“We’re working on making this a platform to generate more bone marrow stem cells,” Dr Varghese added. “That would have useful applications for cell transplantations in the clinic.”
Engineers say they have developed biomimetic bone tissues that could one day provide new bone marrow for patients requiring transplants.
The team created bone tissues with functional bone marrow that can be filled with donor cells and implanted under the skin of mice.
The implant gives donor cells their own space to live and grow without competition, eliminating the need for a conditioning regimen to wipe out the host’s pre-existing cells prior to transplant.
“We’ve made an accessory bone that can separately accommodate donor cells,” explained Shyni Varghese, PhD, of the University of California, San Diego.
“This way, we can keep the host cells and bypass irradiation.”
In mice that received the engineered bone tissue, donor hematopoietic cells survived for at least 6 months and supplied the mice with new blood cells.
“In the future, our work could contribute to improved therapies for bone marrow disease,” said Yu-Ru Vernon Shih, PhD, a researcher in Dr Varghese’s lab.
The researchers noted that these implants would be limited to patients with non-malignant bone marrow diseases, such as aplastic anemia, where there aren’t any cancerous cells that need to be eliminated prior to transplant.
The team described their bone tissue implants in PNAS.
The implants mimic the structure of long bones in the body, consisting of an outer bone compartment and an inner marrow compartment.
The implants are made of a porous hydrogel matrix. The outer matrix contains calcium phosphate minerals. Stem cells grown in this mineralized matrix differentiate into bone-building cells. The inner matrix houses donor stem cells that produce blood cells.
When implanted beneath the skin of mice, the structures matured into bone tissues that have a working blood vessel network and a bone marrow that supplies new blood cells.
After 4 weeks, the implanted marrow contained a mix of host and donor blood cells. This mix was still circulating in the bloodstream after 24 weeks.
The researchers said these findings suggest the implanted marrow is functional, donor cells can grow and survive for long time periods in the presence of host cells, and host and donor cells can travel between the implanted marrow and the host’s circulating blood via the blood vessel network formed in the implanted bone tissue.
In another set of experiments, the researchers took hematopoietic stem cells from the implanted marrow and transplanted them into a second group of mice that had their stem cells destroyed by radiation and drugs. The team found the transplanted cells had diffused into the bloodstream of these mice.
“We did these experiments to show that the bone marrow cells from the engineered bone tissues function similar to native bone,” Dr Shih said.
“We’re working on making this a platform to generate more bone marrow stem cells,” Dr Varghese added. “That would have useful applications for cell transplantations in the clinic.”
Engineers say they have developed biomimetic bone tissues that could one day provide new bone marrow for patients requiring transplants.
The team created bone tissues with functional bone marrow that can be filled with donor cells and implanted under the skin of mice.
The implant gives donor cells their own space to live and grow without competition, eliminating the need for a conditioning regimen to wipe out the host’s pre-existing cells prior to transplant.
“We’ve made an accessory bone that can separately accommodate donor cells,” explained Shyni Varghese, PhD, of the University of California, San Diego.
“This way, we can keep the host cells and bypass irradiation.”
In mice that received the engineered bone tissue, donor hematopoietic cells survived for at least 6 months and supplied the mice with new blood cells.
“In the future, our work could contribute to improved therapies for bone marrow disease,” said Yu-Ru Vernon Shih, PhD, a researcher in Dr Varghese’s lab.
The researchers noted that these implants would be limited to patients with non-malignant bone marrow diseases, such as aplastic anemia, where there aren’t any cancerous cells that need to be eliminated prior to transplant.
The team described their bone tissue implants in PNAS.
The implants mimic the structure of long bones in the body, consisting of an outer bone compartment and an inner marrow compartment.
The implants are made of a porous hydrogel matrix. The outer matrix contains calcium phosphate minerals. Stem cells grown in this mineralized matrix differentiate into bone-building cells. The inner matrix houses donor stem cells that produce blood cells.
When implanted beneath the skin of mice, the structures matured into bone tissues that have a working blood vessel network and a bone marrow that supplies new blood cells.
After 4 weeks, the implanted marrow contained a mix of host and donor blood cells. This mix was still circulating in the bloodstream after 24 weeks.
The researchers said these findings suggest the implanted marrow is functional, donor cells can grow and survive for long time periods in the presence of host cells, and host and donor cells can travel between the implanted marrow and the host’s circulating blood via the blood vessel network formed in the implanted bone tissue.
In another set of experiments, the researchers took hematopoietic stem cells from the implanted marrow and transplanted them into a second group of mice that had their stem cells destroyed by radiation and drugs. The team found the transplanted cells had diffused into the bloodstream of these mice.
“We did these experiments to show that the bone marrow cells from the engineered bone tissues function similar to native bone,” Dr Shih said.
“We’re working on making this a platform to generate more bone marrow stem cells,” Dr Varghese added. “That would have useful applications for cell transplantations in the clinic.”
Drug elicits responses in MDS patients
VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).
Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).
However, patients without prior ESA exposure were more likely to achieve transfusion independence.
Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.
Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.
The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.
Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.
He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.
The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.
There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.
The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).
IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.
RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.
Response data
In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.
Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.
In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.
| Baseline
EPO (IU/L) |
RS status | IWG HI-E, n=82
n (%) |
RBC-TI, n=56
n (%) |
| ≤ 500 | RS+ | 30/46 (65%) | 16/29 (55%) |
| RS- | 6/14 (43%) | 4/7 (57%) | |
| > 500 | RS+ | 5/9 (56%) | 2/9 (22%) |
| RS- | 1/11 (9%) | 0/9 (0%) | |
| Unknown | 0/2 (0%) | 0/2 (0%) |
*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.
Safety data
All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).
Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.
Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia.
VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).
Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).
However, patients without prior ESA exposure were more likely to achieve transfusion independence.
Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.
Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.
The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.
Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.
He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.
The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.
There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.
The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).
IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.
RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.
Response data
In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.
Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.
In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.
| Baseline
EPO (IU/L) |
RS status | IWG HI-E, n=82
n (%) |
RBC-TI, n=56
n (%) |
| ≤ 500 | RS+ | 30/46 (65%) | 16/29 (55%) |
| RS- | 6/14 (43%) | 4/7 (57%) | |
| > 500 | RS+ | 5/9 (56%) | 2/9 (22%) |
| RS- | 1/11 (9%) | 0/9 (0%) | |
| Unknown | 0/2 (0%) | 0/2 (0%) |
*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.
Safety data
All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).
Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.
Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia.
VALENCIA, SPAIN—Phase 2 results suggest luspatercept can produce erythroid responses and enable transfusion independence in patients with myelodysplastic syndromes (MDS).
Erythroid response rates were similar whether or not patients had received prior treatment with erythropoiesis-stimulating agents (ESAs).
However, patients without prior ESA exposure were more likely to achieve transfusion independence.
Most adverse events (AEs) considered possibly or probably related to luspatercept were grade 1 or 2.
Uwe Platzbecker, MD, of Universitätsklinikum Carl Gustav Carus in Dresden, Germany, presented these results at the 14th International Symposium on MDS.
The research was sponsored by Acceleron Pharma Inc., the company developing luspatercept in collaboration with Celgene Corporation.
Dr Platzbecker explained that luspatercept, formerly ACE-536, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for GDF11 and other TGF-βfamily ligands to suppress Smad2/3 signaling.
He presented data from a phase 2 base study and an extension study of luspatercept. The base study included 89 patients who received luspatercept for 3 months. The long-term extension study included 52 patients who may receive luspatercept for an additional 5 years.
The patients received luspatercept at doses ranging from 0.125 mg/kg to 1.75 mg/kg in the base study and 1.0 mg/kg to 1.75 mg/kg in the extension study. They received the drug subcutaneously every 3 weeks.
There were 82 patients evaluable for efficacy. They were a median of 2.3 years from diagnosis (range, 0-14). Their median age was 72 (range, 29-90), 63% were male, and 52% had prior treatment with ESAs.
The outcome measures used in these studies were clinically meaningful erythroid hematologic improvement per the International Working Group’s criteria (IWG HI-E) and red blood cell transfusion independence (RBC-TI).
IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with a transfusion burden at baseline of less than 4 RBC units every 8 weeks and baseline hemoglobin levels below 10 g/dL. For patients with a greater transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 RBC units sustained for ≥ 8 weeks.
RBC-TI was defined as no RBC transfusions for ≥ 8 weeks in patients with a baseline transfusion burden of at least 2 RBC units every 8 weeks.
Response data
In ESA-naïve patients, 48% (11/23) achieved RBC-TI with luspatercept, and 51% (20/39) achieved an IWG HI-E response.
Among patients with prior ESA treatment, 33% (11/33) achieved RBC-TI with luspatercept, and 51% (22/43) achieved an IWG HI-E response.
In patients with baseline erythropoietin (EPO) levels ≤ 500 international units per liter (IU/L), RBC-TI and IWG HI-E response rates were positive in both ring sideroblast-positive (RS+) and RS-negative (RS-) patients, according to the researchers.
| Baseline
EPO (IU/L) |
RS status | IWG HI-E, n=82
n (%) |
RBC-TI, n=56
n (%) |
| ≤ 500 | RS+ | 30/46 (65%) | 16/29 (55%) |
| RS- | 6/14 (43%) | 4/7 (57%) | |
| > 500 | RS+ | 5/9 (56%) | 2/9 (22%) |
| RS- | 1/11 (9%) | 0/9 (0%) | |
| Unknown | 0/2 (0%) | 0/2 (0%) |
*Table includes ESA-refractory and ESA-naïve patients. Patients treated at dose levels ≥ 0.75 mg/kg.
Safety data
All 89 patients were evaluable for safety. Common AEs (occurring in at least 3 patients) that were considered possibly or probably related to study drug were fatigue (6.7%), headache (6.7%), hypertension (5.6%), diarrhea (4.5%), arthralgia (3.4%), bone pain (3.4%), injection site erythema (3.4%), myalgia (3.4%), and peripheral edema (3.4%).
Grade 3 AEs possibly or probably related to study drug were ascites, blast cell count increase, blood bilirubin increase, hypertension, platelet count increase, and pleural effusion.
Grade 3 serious AEs possibly or probably related to study drug were general physical health deterioration and myalgia.
Postmarket safety events common in FDA-approved drugs
New research suggests postmarket safety events are common for therapeutics approved by the US Food and Drug Administration (FDA).
Researchers evaluated more than 200 pharmaceuticals and biologics approved by the FDA from 2001 through 2010 and found that nearly a third of these products were affected by a postmarket safety event.
Most of the events were boxed warnings or safety communications, but there were a few products withdrawn from the market due to safety issues.
Joseph S. Ross, MD, of the Yale University School of Medicine in New Haven, Connecticut, and his colleagues reported these findings in JAMA.
The researchers noted that most pivotal trials that form the basis for FDA approval enroll fewer than 1000 patients and have follow-up of 6 months or less.
Therefore, uncommon or long-term serious safety risks may only become evident after approval, when new therapeutics are used in larger patient populations and for longer periods of time.
With this in mind, Dr Ross and his colleagues examined postmarket safety events for all novel therapeutics approved by the FDA between January 2001 and December 2010 (followed-up through February 2017).
Safety events included withdrawals due to safety concerns, FDA issuance of incremental boxed warnings added in the postmarket period, and FDA issuance of safety communications.
From 2001 through 2010, the FDA approved 222 novel therapeutics—183 pharmaceuticals and 39 biologics.
During a median follow-up of 11.7 years, there were 123 postmarket safety events—3 withdrawals, 61 boxed warnings, and 59 safety communications.
“The fact that the FDA is issuing safety communications means it is doing a good job of following newly approved drugs and evaluating their safety up in the postmarket period,” Dr Ross said.
The 123 safety events identified affected 71 (32%) of the 222 therapeutics.
The median time from FDA approval to the first postmarket safety event was 4.2 years. And 31% of the therapeutics were still affected by a postmarket safety event at 10 years.
The researchers found that postmarket safety events were significantly more frequent in biologics (P=0.03), drugs used to treat psychiatric disease (P<0.001), products approved near their regulatory deadline (P=0.008), and therapeutics granted accelerated approval (P=0.02).
“[The accelerated approval finding] shows that there is the potential for compromising patient safety when drug evaluation is persistently sped up,” Dr Ross said.
On the other hand, the researchers also found that postmarket safety events were significantly less frequent in therapeutics the FDA reviewed in less than 200 days (P=0.02).
The researchers said these findings should be interpreted cautiously, but they can be used to inform ongoing surveillance efforts.
New research suggests postmarket safety events are common for therapeutics approved by the US Food and Drug Administration (FDA).
Researchers evaluated more than 200 pharmaceuticals and biologics approved by the FDA from 2001 through 2010 and found that nearly a third of these products were affected by a postmarket safety event.
Most of the events were boxed warnings or safety communications, but there were a few products withdrawn from the market due to safety issues.
Joseph S. Ross, MD, of the Yale University School of Medicine in New Haven, Connecticut, and his colleagues reported these findings in JAMA.
The researchers noted that most pivotal trials that form the basis for FDA approval enroll fewer than 1000 patients and have follow-up of 6 months or less.
Therefore, uncommon or long-term serious safety risks may only become evident after approval, when new therapeutics are used in larger patient populations and for longer periods of time.
With this in mind, Dr Ross and his colleagues examined postmarket safety events for all novel therapeutics approved by the FDA between January 2001 and December 2010 (followed-up through February 2017).
Safety events included withdrawals due to safety concerns, FDA issuance of incremental boxed warnings added in the postmarket period, and FDA issuance of safety communications.
From 2001 through 2010, the FDA approved 222 novel therapeutics—183 pharmaceuticals and 39 biologics.
During a median follow-up of 11.7 years, there were 123 postmarket safety events—3 withdrawals, 61 boxed warnings, and 59 safety communications.
“The fact that the FDA is issuing safety communications means it is doing a good job of following newly approved drugs and evaluating their safety up in the postmarket period,” Dr Ross said.
The 123 safety events identified affected 71 (32%) of the 222 therapeutics.
The median time from FDA approval to the first postmarket safety event was 4.2 years. And 31% of the therapeutics were still affected by a postmarket safety event at 10 years.
The researchers found that postmarket safety events were significantly more frequent in biologics (P=0.03), drugs used to treat psychiatric disease (P<0.001), products approved near their regulatory deadline (P=0.008), and therapeutics granted accelerated approval (P=0.02).
“[The accelerated approval finding] shows that there is the potential for compromising patient safety when drug evaluation is persistently sped up,” Dr Ross said.
On the other hand, the researchers also found that postmarket safety events were significantly less frequent in therapeutics the FDA reviewed in less than 200 days (P=0.02).
The researchers said these findings should be interpreted cautiously, but they can be used to inform ongoing surveillance efforts.
New research suggests postmarket safety events are common for therapeutics approved by the US Food and Drug Administration (FDA).
Researchers evaluated more than 200 pharmaceuticals and biologics approved by the FDA from 2001 through 2010 and found that nearly a third of these products were affected by a postmarket safety event.
Most of the events were boxed warnings or safety communications, but there were a few products withdrawn from the market due to safety issues.
Joseph S. Ross, MD, of the Yale University School of Medicine in New Haven, Connecticut, and his colleagues reported these findings in JAMA.
The researchers noted that most pivotal trials that form the basis for FDA approval enroll fewer than 1000 patients and have follow-up of 6 months or less.
Therefore, uncommon or long-term serious safety risks may only become evident after approval, when new therapeutics are used in larger patient populations and for longer periods of time.
With this in mind, Dr Ross and his colleagues examined postmarket safety events for all novel therapeutics approved by the FDA between January 2001 and December 2010 (followed-up through February 2017).
Safety events included withdrawals due to safety concerns, FDA issuance of incremental boxed warnings added in the postmarket period, and FDA issuance of safety communications.
From 2001 through 2010, the FDA approved 222 novel therapeutics—183 pharmaceuticals and 39 biologics.
During a median follow-up of 11.7 years, there were 123 postmarket safety events—3 withdrawals, 61 boxed warnings, and 59 safety communications.
“The fact that the FDA is issuing safety communications means it is doing a good job of following newly approved drugs and evaluating their safety up in the postmarket period,” Dr Ross said.
The 123 safety events identified affected 71 (32%) of the 222 therapeutics.
The median time from FDA approval to the first postmarket safety event was 4.2 years. And 31% of the therapeutics were still affected by a postmarket safety event at 10 years.
The researchers found that postmarket safety events were significantly more frequent in biologics (P=0.03), drugs used to treat psychiatric disease (P<0.001), products approved near their regulatory deadline (P=0.008), and therapeutics granted accelerated approval (P=0.02).
“[The accelerated approval finding] shows that there is the potential for compromising patient safety when drug evaluation is persistently sped up,” Dr Ross said.
On the other hand, the researchers also found that postmarket safety events were significantly less frequent in therapeutics the FDA reviewed in less than 200 days (P=0.02).
The researchers said these findings should be interpreted cautiously, but they can be used to inform ongoing surveillance efforts.
Novel inhibitor proves ‘potent’ in hematologic malignancies
BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.
In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.
In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).
Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).
Both studies involved researchers from Aptose Biosciences, the company developing CG’806.
Poster 25
Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”
The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.
Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.
With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).
The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).
The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.
Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.
This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.
Poster 44
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”
The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).
The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.
Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).
The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said.
BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.
In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.
In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).
Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).
Both studies involved researchers from Aptose Biosciences, the company developing CG’806.
Poster 25
Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”
The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.
Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.
With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).
The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).
The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.
Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.
This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.
Poster 44
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”
The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).
The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.
Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).
The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said.
BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.
In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.
In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).
Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).
Both studies involved researchers from Aptose Biosciences, the company developing CG’806.
Poster 25
Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”
The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.
Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.
With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).
The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).
The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.
Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.
This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.
Poster 44
Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”
The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).
The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.
Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).
The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.
“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said.
IV and SC rituximab produce similar results in FL
In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).
Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.
Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.
Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.
Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.
The study was funded by Roche, which markets rituximab as Rituxan and MabThera.
The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.
Patients were randomized to receive IV rituximab at 375 mg/m2 (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.
Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.
Patients then received rituximab maintenance every 8 weeks.
The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.
Efficacy
In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between the treatment arms at cycle 7.
The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean Ctrough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).
In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.
At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.
At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.
At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).
Safety
The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.
Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).
Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.
Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.
The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL.
In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).
Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.
Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.
Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.
Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.
The study was funded by Roche, which markets rituximab as Rituxan and MabThera.
The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.
Patients were randomized to receive IV rituximab at 375 mg/m2 (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.
Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.
Patients then received rituximab maintenance every 8 weeks.
The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.
Efficacy
In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between the treatment arms at cycle 7.
The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean Ctrough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).
In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.
At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.
At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.
At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).
Safety
The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.
Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).
Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.
Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.
The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL.
In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).
Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.
Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.
Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.
Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.
The study was funded by Roche, which markets rituximab as Rituxan and MabThera.
The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.
Patients were randomized to receive IV rituximab at 375 mg/m2 (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.
Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.
Patients then received rituximab maintenance every 8 weeks.
The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.
Efficacy
In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between the treatment arms at cycle 7.
The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean Ctrough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).
In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.
At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.
At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.
At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).
Safety
The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.
Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).
Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.
Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.
The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL.
Study provides new insight into HSC dormancy
Preclinical research has revealed new insights regarding hematopoietic stem cells’ (HSCs) transition from a dormant state to an active one.
Investigators said they found the transition to be “a continuous developmental path” that is different for each individual cell, rather than a stepwise progression, as researchers previously believed.
The team also found the transition was characterized by low levels of Myc and high expression of retinoic acid.
In fact, the group’s experiments suggested that a diet lacking vitamin A can have a detrimental effect on HSCs.
Nina Cabezas-Wallscheid, PhD, of the German Cancer Research Center (DKFZ) in Heidelberg, Germany, and her colleagues conducted this research and reported their findings in Cell.
The investigators used single-cell RNA sequencing to show that HSCs’ transition from dormant to active cells is “a continuous stream-like progression of steadily increasing metabolic activity and preparation for cell-cycle entry without the apparent presence of accumulating cellular intermediates.”
The team said they observed robust downregulation of biosynthetic processes in dormant HSCs (compared to active HSCs) that was associated with the downregulation of Myc target genes.
The investigators also found that retinoic acid-induced signaling was “highly enriched” in dormant HSCs, and all-trans retinoic acid (ATRA) treatment maintained dormant HSCs in vitro.
In mice, ATRA protected dormant HSCs from activation.
The investigators exposed mice to a few different HSC activation conditions, including bacterial liposaccharide, the double-stranded RNA analog polyI:polyC, and the chemotherapeutic agent 5-fluorouracil. But pre-treatment with ATRA allowed HSCs to maintain a quiescent state in all 3 cases.
Finally, the investigators evaluated the effects of a vitamin A-free diet on HSCs. Adult mice fed a vitamin A-free diet for 14 to 17 weeks lost HSCs, particularly dormant HSCs. And without vitamin A, active HSCs were unable to return to a dormant state.
“Thus, we can prove, for the first time, that vitamin A has a direct impact on blood stem cells,” Dr Cabezas-Wallscheid said. “This shows how vitally important it is to have a sufficient intake of vitamin A from a balanced diet.”
The investigators also believe these findings could be applied in cancer research, as there is evidence to suggest that cancer cells rest in a state of dormancy, which makes them resistant to chemotherapy.
“Once we understand in detail how vitamin A or retinoic acid, respectively, sends normal and malignant stem cells into dormancy, we can try to turn the tables,” said study author Andreas Trumpp, PhD, also of DKFZ.
“If we could make cancer cells temporarily enter an active state, we could thus make them vulnerable to modern therapies.”
Preclinical research has revealed new insights regarding hematopoietic stem cells’ (HSCs) transition from a dormant state to an active one.
Investigators said they found the transition to be “a continuous developmental path” that is different for each individual cell, rather than a stepwise progression, as researchers previously believed.
The team also found the transition was characterized by low levels of Myc and high expression of retinoic acid.
In fact, the group’s experiments suggested that a diet lacking vitamin A can have a detrimental effect on HSCs.
Nina Cabezas-Wallscheid, PhD, of the German Cancer Research Center (DKFZ) in Heidelberg, Germany, and her colleagues conducted this research and reported their findings in Cell.
The investigators used single-cell RNA sequencing to show that HSCs’ transition from dormant to active cells is “a continuous stream-like progression of steadily increasing metabolic activity and preparation for cell-cycle entry without the apparent presence of accumulating cellular intermediates.”
The team said they observed robust downregulation of biosynthetic processes in dormant HSCs (compared to active HSCs) that was associated with the downregulation of Myc target genes.
The investigators also found that retinoic acid-induced signaling was “highly enriched” in dormant HSCs, and all-trans retinoic acid (ATRA) treatment maintained dormant HSCs in vitro.
In mice, ATRA protected dormant HSCs from activation.
The investigators exposed mice to a few different HSC activation conditions, including bacterial liposaccharide, the double-stranded RNA analog polyI:polyC, and the chemotherapeutic agent 5-fluorouracil. But pre-treatment with ATRA allowed HSCs to maintain a quiescent state in all 3 cases.
Finally, the investigators evaluated the effects of a vitamin A-free diet on HSCs. Adult mice fed a vitamin A-free diet for 14 to 17 weeks lost HSCs, particularly dormant HSCs. And without vitamin A, active HSCs were unable to return to a dormant state.
“Thus, we can prove, for the first time, that vitamin A has a direct impact on blood stem cells,” Dr Cabezas-Wallscheid said. “This shows how vitally important it is to have a sufficient intake of vitamin A from a balanced diet.”
The investigators also believe these findings could be applied in cancer research, as there is evidence to suggest that cancer cells rest in a state of dormancy, which makes them resistant to chemotherapy.
“Once we understand in detail how vitamin A or retinoic acid, respectively, sends normal and malignant stem cells into dormancy, we can try to turn the tables,” said study author Andreas Trumpp, PhD, also of DKFZ.
“If we could make cancer cells temporarily enter an active state, we could thus make them vulnerable to modern therapies.”
Preclinical research has revealed new insights regarding hematopoietic stem cells’ (HSCs) transition from a dormant state to an active one.
Investigators said they found the transition to be “a continuous developmental path” that is different for each individual cell, rather than a stepwise progression, as researchers previously believed.
The team also found the transition was characterized by low levels of Myc and high expression of retinoic acid.
In fact, the group’s experiments suggested that a diet lacking vitamin A can have a detrimental effect on HSCs.
Nina Cabezas-Wallscheid, PhD, of the German Cancer Research Center (DKFZ) in Heidelberg, Germany, and her colleagues conducted this research and reported their findings in Cell.
The investigators used single-cell RNA sequencing to show that HSCs’ transition from dormant to active cells is “a continuous stream-like progression of steadily increasing metabolic activity and preparation for cell-cycle entry without the apparent presence of accumulating cellular intermediates.”
The team said they observed robust downregulation of biosynthetic processes in dormant HSCs (compared to active HSCs) that was associated with the downregulation of Myc target genes.
The investigators also found that retinoic acid-induced signaling was “highly enriched” in dormant HSCs, and all-trans retinoic acid (ATRA) treatment maintained dormant HSCs in vitro.
In mice, ATRA protected dormant HSCs from activation.
The investigators exposed mice to a few different HSC activation conditions, including bacterial liposaccharide, the double-stranded RNA analog polyI:polyC, and the chemotherapeutic agent 5-fluorouracil. But pre-treatment with ATRA allowed HSCs to maintain a quiescent state in all 3 cases.
Finally, the investigators evaluated the effects of a vitamin A-free diet on HSCs. Adult mice fed a vitamin A-free diet for 14 to 17 weeks lost HSCs, particularly dormant HSCs. And without vitamin A, active HSCs were unable to return to a dormant state.
“Thus, we can prove, for the first time, that vitamin A has a direct impact on blood stem cells,” Dr Cabezas-Wallscheid said. “This shows how vitally important it is to have a sufficient intake of vitamin A from a balanced diet.”
The investigators also believe these findings could be applied in cancer research, as there is evidence to suggest that cancer cells rest in a state of dormancy, which makes them resistant to chemotherapy.
“Once we understand in detail how vitamin A or retinoic acid, respectively, sends normal and malignant stem cells into dormancy, we can try to turn the tables,” said study author Andreas Trumpp, PhD, also of DKFZ.
“If we could make cancer cells temporarily enter an active state, we could thus make them vulnerable to modern therapies.”
EC approves pembrolizumab for cHL patients
The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).
The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.
The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).
This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.
The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.
Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.
KEYNOTE-087
In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:
- Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
- Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
- Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.
Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.
In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.
In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.
For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.
The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).
The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).
There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.
KEYNOTE-013
KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.
Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.
The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.
The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.
The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.
The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).
The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).
AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths.
The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).
The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.
The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).
This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.
The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.
Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.
KEYNOTE-087
In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:
- Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
- Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
- Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.
Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.
In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.
In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.
For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.
The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).
The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).
There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.
KEYNOTE-013
KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.
Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.
The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.
The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.
The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.
The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).
The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).
AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths.
The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).
The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.
The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).
This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.
The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.
Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.
KEYNOTE-087
In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:
- Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
- Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
- Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.
Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.
In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.
In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.
For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.
The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).
The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).
There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.
KEYNOTE-013
KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.
Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.
The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.
The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.
The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.
The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).
The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).
AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths.