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Formaldehyde probably doesn’t cause leukemia, team says
There is little or no evidence to suggest that exposure to formaldehyde causes leukemia, according to a group of researchers.
The team reanalyzed data from a study published in 2010 that suggested a possible link between formaldehyde exposure and myeloid leukemia.
They also reviewed other recent studies investigating the health effects of formaldehyde.
“The weight of scientific evidence does not support a causal association between formaldehyde and leukemia,” said Kenneth A. Mundt, PhD, of Ramboll Environ, a consulting firm focused on environmental, health, and social issues.
Dr Mundt and his colleagues detailed the evidence in the Journal of Critical Reviews in Toxicology.
The team’s research was supported by the Foundation for Chemistry Research and Initiatives (formerly the Research Foundation for Health and Environmental Effects), an organization established by the American Chemistry Council (an industry trade association for American chemical companies).
The study that suggested a possible link between formaldehyde and myeloid leukemia, particularly acute myeloid leukemia (AML), was published in January 2010 in Cancer Epidemiology, Biomarkers & Prevention.
In this study, Luoping Zhang, PhD, of the University of California at Berkeley, and her colleagues compared 2 groups of workers in China—43 workers with occupational exposure to formaldehyde and 51 without such exposure.
The researchers looked at complete blood counts and peripheral stem/progenitor cell colony formation. They also cultured myeloid progenitor cells, aiming to determine the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in these cells.
The team found that workers exposed to formaldehyde had significantly lower peripheral blood cell counts and significantly elevated leukemia-specific chromosome changes in myeloid progenitor cells.
Dr Zhang and her colleagues said these results suggest “formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible.”
Dr Mundt and his colleagues reanalyzed raw data from this study, including previously unavailable data on individual workers’ exposure to formaldehyde. Those data were recently released by the National Cancer Institute, which co-funded Dr Zhang’s study.
The reanalysis indicated that the observed differences in blood cell counts were not dependent on formaldehyde exposure. And the researchers found no association between the individual average formaldehyde exposure estimates and chromosomal abnormalities.
Dr Mundt’s team also reviewed several other publications on the health effects of formaldehyde, and they said the data, as a whole, provide “little if any evidence of a causal association between formaldehyde exposure and AML.” 
There is little or no evidence to suggest that exposure to formaldehyde causes leukemia, according to a group of researchers.
The team reanalyzed data from a study published in 2010 that suggested a possible link between formaldehyde exposure and myeloid leukemia.
They also reviewed other recent studies investigating the health effects of formaldehyde.
“The weight of scientific evidence does not support a causal association between formaldehyde and leukemia,” said Kenneth A. Mundt, PhD, of Ramboll Environ, a consulting firm focused on environmental, health, and social issues.
Dr Mundt and his colleagues detailed the evidence in the Journal of Critical Reviews in Toxicology.
The team’s research was supported by the Foundation for Chemistry Research and Initiatives (formerly the Research Foundation for Health and Environmental Effects), an organization established by the American Chemistry Council (an industry trade association for American chemical companies).
The study that suggested a possible link between formaldehyde and myeloid leukemia, particularly acute myeloid leukemia (AML), was published in January 2010 in Cancer Epidemiology, Biomarkers & Prevention.
In this study, Luoping Zhang, PhD, of the University of California at Berkeley, and her colleagues compared 2 groups of workers in China—43 workers with occupational exposure to formaldehyde and 51 without such exposure.
The researchers looked at complete blood counts and peripheral stem/progenitor cell colony formation. They also cultured myeloid progenitor cells, aiming to determine the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in these cells.
The team found that workers exposed to formaldehyde had significantly lower peripheral blood cell counts and significantly elevated leukemia-specific chromosome changes in myeloid progenitor cells.
Dr Zhang and her colleagues said these results suggest “formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible.”
Dr Mundt and his colleagues reanalyzed raw data from this study, including previously unavailable data on individual workers’ exposure to formaldehyde. Those data were recently released by the National Cancer Institute, which co-funded Dr Zhang’s study.
The reanalysis indicated that the observed differences in blood cell counts were not dependent on formaldehyde exposure. And the researchers found no association between the individual average formaldehyde exposure estimates and chromosomal abnormalities.
Dr Mundt’s team also reviewed several other publications on the health effects of formaldehyde, and they said the data, as a whole, provide “little if any evidence of a causal association between formaldehyde exposure and AML.”
There is little or no evidence to suggest that exposure to formaldehyde causes leukemia, according to a group of researchers.
The team reanalyzed data from a study published in 2010 that suggested a possible link between formaldehyde exposure and myeloid leukemia.
They also reviewed other recent studies investigating the health effects of formaldehyde.
“The weight of scientific evidence does not support a causal association between formaldehyde and leukemia,” said Kenneth A. Mundt, PhD, of Ramboll Environ, a consulting firm focused on environmental, health, and social issues.
Dr Mundt and his colleagues detailed the evidence in the Journal of Critical Reviews in Toxicology.
The team’s research was supported by the Foundation for Chemistry Research and Initiatives (formerly the Research Foundation for Health and Environmental Effects), an organization established by the American Chemistry Council (an industry trade association for American chemical companies).
The study that suggested a possible link between formaldehyde and myeloid leukemia, particularly acute myeloid leukemia (AML), was published in January 2010 in Cancer Epidemiology, Biomarkers & Prevention.
In this study, Luoping Zhang, PhD, of the University of California at Berkeley, and her colleagues compared 2 groups of workers in China—43 workers with occupational exposure to formaldehyde and 51 without such exposure.
The researchers looked at complete blood counts and peripheral stem/progenitor cell colony formation. They also cultured myeloid progenitor cells, aiming to determine the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in these cells.
The team found that workers exposed to formaldehyde had significantly lower peripheral blood cell counts and significantly elevated leukemia-specific chromosome changes in myeloid progenitor cells.
Dr Zhang and her colleagues said these results suggest “formaldehyde exposure can have an adverse effect on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible.”
Dr Mundt and his colleagues reanalyzed raw data from this study, including previously unavailable data on individual workers’ exposure to formaldehyde. Those data were recently released by the National Cancer Institute, which co-funded Dr Zhang’s study.
The reanalysis indicated that the observed differences in blood cell counts were not dependent on formaldehyde exposure. And the researchers found no association between the individual average formaldehyde exposure estimates and chromosomal abnormalities.
Dr Mundt’s team also reviewed several other publications on the health effects of formaldehyde, and they said the data, as a whole, provide “little if any evidence of a causal association between formaldehyde exposure and AML.”
Company withdraws MAA for vosaroxin in AML
Sunesis Pharmaceuticals, Inc. is withdrawing its European Marketing Authorization Application (MAA) for the anticancer quinolone derivative vosaroxin.
The MAA was for vosaroxin as a treatment for relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older.
Along with the MAA withdrawal, Sunesis has decided to scale back its investment in vosaroxin.
However, the company said it will continue developing the drug.
These decisions were made after Sunesis learned the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) was unlikely to recommend approval for vosaroxin.
“We are disappointed to not achieve approval for vosaroxin’s MAA, given its reported efficacy in a patient population with such poor outcomes,” said Daniel Swisher, president and chief executive officer of Sunesis.
“Although we did not receive a definitive CHMP opinion, we believed that a positive opinion was unlikely. Following our appearances before the committee’s Scientific Advisory Group on Oncology and CHMP, we carefully considered feedback from our rapporteurs and input from retained regulatory experts to make our decision to notify EMA to withdraw vosaroxin’s MAA, as our assessment concluded it was unlikely we could achieve a majority vote of CHMP members at this time or upon an immediate re-examination for our proposed indication based on VALOR data from a subgroup of a single pivotal trial that had missed reaching full statistical significance in its primary analysis.”
“In light of this, we are significantly reducing our investment in the AML program and shifting an increasing portion of resources to our kinase inhibitor pipeline . . . . We expect to continue to advance the development of vosaroxin through a modest investment in investigator-sponsored group trials and will carefully assess business development alternatives to support the conduct of another pivotal trial to achieve future regulatory approval of vosaroxin. We expect that our current cash resources are sufficient to fund the company beyond Q1 2018.”
Sunesis Pharmaceuticals, Inc. is withdrawing its European Marketing Authorization Application (MAA) for the anticancer quinolone derivative vosaroxin.
The MAA was for vosaroxin as a treatment for relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older.
Along with the MAA withdrawal, Sunesis has decided to scale back its investment in vosaroxin.
However, the company said it will continue developing the drug.
These decisions were made after Sunesis learned the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) was unlikely to recommend approval for vosaroxin.
“We are disappointed to not achieve approval for vosaroxin’s MAA, given its reported efficacy in a patient population with such poor outcomes,” said Daniel Swisher, president and chief executive officer of Sunesis.
“Although we did not receive a definitive CHMP opinion, we believed that a positive opinion was unlikely. Following our appearances before the committee’s Scientific Advisory Group on Oncology and CHMP, we carefully considered feedback from our rapporteurs and input from retained regulatory experts to make our decision to notify EMA to withdraw vosaroxin’s MAA, as our assessment concluded it was unlikely we could achieve a majority vote of CHMP members at this time or upon an immediate re-examination for our proposed indication based on VALOR data from a subgroup of a single pivotal trial that had missed reaching full statistical significance in its primary analysis.”
“In light of this, we are significantly reducing our investment in the AML program and shifting an increasing portion of resources to our kinase inhibitor pipeline . . . . We expect to continue to advance the development of vosaroxin through a modest investment in investigator-sponsored group trials and will carefully assess business development alternatives to support the conduct of another pivotal trial to achieve future regulatory approval of vosaroxin. We expect that our current cash resources are sufficient to fund the company beyond Q1 2018.”
Sunesis Pharmaceuticals, Inc. is withdrawing its European Marketing Authorization Application (MAA) for the anticancer quinolone derivative vosaroxin.
The MAA was for vosaroxin as a treatment for relapsed/refractory acute myeloid leukemia (AML) in patients age 60 years and older.
Along with the MAA withdrawal, Sunesis has decided to scale back its investment in vosaroxin.
However, the company said it will continue developing the drug.
These decisions were made after Sunesis learned the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) was unlikely to recommend approval for vosaroxin.
“We are disappointed to not achieve approval for vosaroxin’s MAA, given its reported efficacy in a patient population with such poor outcomes,” said Daniel Swisher, president and chief executive officer of Sunesis.
“Although we did not receive a definitive CHMP opinion, we believed that a positive opinion was unlikely. Following our appearances before the committee’s Scientific Advisory Group on Oncology and CHMP, we carefully considered feedback from our rapporteurs and input from retained regulatory experts to make our decision to notify EMA to withdraw vosaroxin’s MAA, as our assessment concluded it was unlikely we could achieve a majority vote of CHMP members at this time or upon an immediate re-examination for our proposed indication based on VALOR data from a subgroup of a single pivotal trial that had missed reaching full statistical significance in its primary analysis.”
“In light of this, we are significantly reducing our investment in the AML program and shifting an increasing portion of resources to our kinase inhibitor pipeline . . . . We expect to continue to advance the development of vosaroxin through a modest investment in investigator-sponsored group trials and will carefully assess business development alternatives to support the conduct of another pivotal trial to achieve future regulatory approval of vosaroxin. We expect that our current cash resources are sufficient to fund the company beyond Q1 2018.”
Heavily promoted drugs provide less ‘health value,’ study suggests
Drugs that are promoted most heavily in the US are less likely than the top-selling drugs and the top-prescribed drugs to provide “health value,” according to researchers.
The top-promoted drugs were less likely than either or both of the other drug types to demonstrate safety and effectiveness, be affordable, represent a genuine advance in treating a disease, be included on the World Health Organization’s (WHO) list of essential medicines, or be recommended as a first-line treatment.
Among the top-promoted drugs were 4 anticoagulants—Eliquis (apixaban), Xarelto (rivaroxaban), Brilinta (ticagrelor), and Pradaxa (dabigatran).
Tyler Greenway and Joseph S. Ross, MD, both of Yale University School of Medicine in New Haven, Connecticut, conducted this research and reported their findings in The BMJ.
The researchers set out to assess the “health value” of the drugs most aggressively promoted to physicians to better understand the implications of pharmaceutical promotion for patient care.
The team identified the 25 medicinal products associated with the largest total payments to physicians and teaching hospitals from August 2013 to December 2014.
This included all direct and indirect payments, such as speaker fees for education lectures, consulting fees, and honoraria, as well as payments in kind, such as the value of food and gifts. However, research payments, royalties, and licensing fees were excluded, as these are typically not promotional.
The researchers also determined the 25 best-selling medicinal products by 2014 US sales and the 25 most-prescribed drugs in the US during 2013.
One of the 25 top-promoted products was excluded because it was used to test for adrenocortical function. And 1 of the 25 top-selling products was a pneumococcal vaccine, which was also excluded.
Four of the 24 top-promoted drugs (17%) were also among the top-selling drugs—adalimumab, glatiramer, aripiprazole, and budesonide-formoterol. But none of the top-promoted drugs were among the top-prescribed drugs.
Among the top-selling drugs were several used in the field of hematology—Rituxan (rituximab), Neulasta (pegfilgrastim), Neupogen (filgrastim), Revlimid (lenalidomide), and Gleevec (imatinib mesylate).
Results
The researchers estimated the drugs’ value to society using 5 proxy measures:
- Innovation—drugs that were first-in-class or provided a “meaningful advance” over existing treatments
- Effectiveness and safety—assessed using the ratings systems of the French drug industry watchdog Prescrire International
- Generic availability—a measure of affordability
- Clinical value—inclusion on the WHO list of essential medicines in 2015
- First-line status—being recommended as a first-line therapy.
The top-promoted drugs were significantly less likely to be considered innovative than the top-selling drugs (33% vs 72%, relative risk [RR]=0.46, P=0.01). However, the difference was not significant for the top-promoted and top-prescribed drugs (33% vs 52%, RR=0.64, P=0.25).
The top-promoted drugs were significantly less likely to be considered possibly helpful or advantageous according to Prescrire ratings than the top-prescribed drugs (19% vs 76%, RR=0.25, P<0.001). But the difference was not significant for the top-promoted and top-selling drugs (19% vs 44%, RR=0.43, P=0.11).
Generic equivalents were available for 62% of the top-promoted drugs, 32% of the top-selling drugs (RR=1.95, P=0.05), and 100% of the top-prescribed drugs (RR=0.63, P<0.001).
The top-promoted drugs were significantly less likely than either of the other drug types to be on the WHO essential medicines list. One of the top-promoted drugs was on the list, compared to 9 top-selling drugs (RR=0.12, P=0.01) and 14 top-prescribed drugs (RR=0.07, P<0.001).
The top-promoted drugs were significantly less likely to be recommended as first-line treatments than the top-prescribed drugs (33% vs 80%, RR=0.42, P=0.001). But the difference was not significant for the top-selling drugs (33% vs 60%, RR=0.56, P=0.09).
The researchers said these results raise concerns about the purpose of pharmaceutical promotion and its influence on patient care. They believe efforts are needed to better evaluate the value of drugs, ensuring this information is readily available at the point of care so it can inform clinical decision-making and promote the use of higher-value medicines.
The researchers also suggested that clinicians consider taking steps to limit their exposure to industry promotion and consider engaging with non-commercial educational outreach programs that provide evidence-based recommendations about medication choices.
Drugs that are promoted most heavily in the US are less likely than the top-selling drugs and the top-prescribed drugs to provide “health value,” according to researchers.
The top-promoted drugs were less likely than either or both of the other drug types to demonstrate safety and effectiveness, be affordable, represent a genuine advance in treating a disease, be included on the World Health Organization’s (WHO) list of essential medicines, or be recommended as a first-line treatment.
Among the top-promoted drugs were 4 anticoagulants—Eliquis (apixaban), Xarelto (rivaroxaban), Brilinta (ticagrelor), and Pradaxa (dabigatran).
Tyler Greenway and Joseph S. Ross, MD, both of Yale University School of Medicine in New Haven, Connecticut, conducted this research and reported their findings in The BMJ.
The researchers set out to assess the “health value” of the drugs most aggressively promoted to physicians to better understand the implications of pharmaceutical promotion for patient care.
The team identified the 25 medicinal products associated with the largest total payments to physicians and teaching hospitals from August 2013 to December 2014.
This included all direct and indirect payments, such as speaker fees for education lectures, consulting fees, and honoraria, as well as payments in kind, such as the value of food and gifts. However, research payments, royalties, and licensing fees were excluded, as these are typically not promotional.
The researchers also determined the 25 best-selling medicinal products by 2014 US sales and the 25 most-prescribed drugs in the US during 2013.
One of the 25 top-promoted products was excluded because it was used to test for adrenocortical function. And 1 of the 25 top-selling products was a pneumococcal vaccine, which was also excluded.
Four of the 24 top-promoted drugs (17%) were also among the top-selling drugs—adalimumab, glatiramer, aripiprazole, and budesonide-formoterol. But none of the top-promoted drugs were among the top-prescribed drugs.
Among the top-selling drugs were several used in the field of hematology—Rituxan (rituximab), Neulasta (pegfilgrastim), Neupogen (filgrastim), Revlimid (lenalidomide), and Gleevec (imatinib mesylate).
Results
The researchers estimated the drugs’ value to society using 5 proxy measures:
- Innovation—drugs that were first-in-class or provided a “meaningful advance” over existing treatments
- Effectiveness and safety—assessed using the ratings systems of the French drug industry watchdog Prescrire International
- Generic availability—a measure of affordability
- Clinical value—inclusion on the WHO list of essential medicines in 2015
- First-line status—being recommended as a first-line therapy.
The top-promoted drugs were significantly less likely to be considered innovative than the top-selling drugs (33% vs 72%, relative risk [RR]=0.46, P=0.01). However, the difference was not significant for the top-promoted and top-prescribed drugs (33% vs 52%, RR=0.64, P=0.25).
The top-promoted drugs were significantly less likely to be considered possibly helpful or advantageous according to Prescrire ratings than the top-prescribed drugs (19% vs 76%, RR=0.25, P<0.001). But the difference was not significant for the top-promoted and top-selling drugs (19% vs 44%, RR=0.43, P=0.11).
Generic equivalents were available for 62% of the top-promoted drugs, 32% of the top-selling drugs (RR=1.95, P=0.05), and 100% of the top-prescribed drugs (RR=0.63, P<0.001).
The top-promoted drugs were significantly less likely than either of the other drug types to be on the WHO essential medicines list. One of the top-promoted drugs was on the list, compared to 9 top-selling drugs (RR=0.12, P=0.01) and 14 top-prescribed drugs (RR=0.07, P<0.001).
The top-promoted drugs were significantly less likely to be recommended as first-line treatments than the top-prescribed drugs (33% vs 80%, RR=0.42, P=0.001). But the difference was not significant for the top-selling drugs (33% vs 60%, RR=0.56, P=0.09).
The researchers said these results raise concerns about the purpose of pharmaceutical promotion and its influence on patient care. They believe efforts are needed to better evaluate the value of drugs, ensuring this information is readily available at the point of care so it can inform clinical decision-making and promote the use of higher-value medicines.
The researchers also suggested that clinicians consider taking steps to limit their exposure to industry promotion and consider engaging with non-commercial educational outreach programs that provide evidence-based recommendations about medication choices.
Drugs that are promoted most heavily in the US are less likely than the top-selling drugs and the top-prescribed drugs to provide “health value,” according to researchers.
The top-promoted drugs were less likely than either or both of the other drug types to demonstrate safety and effectiveness, be affordable, represent a genuine advance in treating a disease, be included on the World Health Organization’s (WHO) list of essential medicines, or be recommended as a first-line treatment.
Among the top-promoted drugs were 4 anticoagulants—Eliquis (apixaban), Xarelto (rivaroxaban), Brilinta (ticagrelor), and Pradaxa (dabigatran).
Tyler Greenway and Joseph S. Ross, MD, both of Yale University School of Medicine in New Haven, Connecticut, conducted this research and reported their findings in The BMJ.
The researchers set out to assess the “health value” of the drugs most aggressively promoted to physicians to better understand the implications of pharmaceutical promotion for patient care.
The team identified the 25 medicinal products associated with the largest total payments to physicians and teaching hospitals from August 2013 to December 2014.
This included all direct and indirect payments, such as speaker fees for education lectures, consulting fees, and honoraria, as well as payments in kind, such as the value of food and gifts. However, research payments, royalties, and licensing fees were excluded, as these are typically not promotional.
The researchers also determined the 25 best-selling medicinal products by 2014 US sales and the 25 most-prescribed drugs in the US during 2013.
One of the 25 top-promoted products was excluded because it was used to test for adrenocortical function. And 1 of the 25 top-selling products was a pneumococcal vaccine, which was also excluded.
Four of the 24 top-promoted drugs (17%) were also among the top-selling drugs—adalimumab, glatiramer, aripiprazole, and budesonide-formoterol. But none of the top-promoted drugs were among the top-prescribed drugs.
Among the top-selling drugs were several used in the field of hematology—Rituxan (rituximab), Neulasta (pegfilgrastim), Neupogen (filgrastim), Revlimid (lenalidomide), and Gleevec (imatinib mesylate).
Results
The researchers estimated the drugs’ value to society using 5 proxy measures:
- Innovation—drugs that were first-in-class or provided a “meaningful advance” over existing treatments
- Effectiveness and safety—assessed using the ratings systems of the French drug industry watchdog Prescrire International
- Generic availability—a measure of affordability
- Clinical value—inclusion on the WHO list of essential medicines in 2015
- First-line status—being recommended as a first-line therapy.
The top-promoted drugs were significantly less likely to be considered innovative than the top-selling drugs (33% vs 72%, relative risk [RR]=0.46, P=0.01). However, the difference was not significant for the top-promoted and top-prescribed drugs (33% vs 52%, RR=0.64, P=0.25).
The top-promoted drugs were significantly less likely to be considered possibly helpful or advantageous according to Prescrire ratings than the top-prescribed drugs (19% vs 76%, RR=0.25, P<0.001). But the difference was not significant for the top-promoted and top-selling drugs (19% vs 44%, RR=0.43, P=0.11).
Generic equivalents were available for 62% of the top-promoted drugs, 32% of the top-selling drugs (RR=1.95, P=0.05), and 100% of the top-prescribed drugs (RR=0.63, P<0.001).
The top-promoted drugs were significantly less likely than either of the other drug types to be on the WHO essential medicines list. One of the top-promoted drugs was on the list, compared to 9 top-selling drugs (RR=0.12, P=0.01) and 14 top-prescribed drugs (RR=0.07, P<0.001).
The top-promoted drugs were significantly less likely to be recommended as first-line treatments than the top-prescribed drugs (33% vs 80%, RR=0.42, P=0.001). But the difference was not significant for the top-selling drugs (33% vs 60%, RR=0.56, P=0.09).
The researchers said these results raise concerns about the purpose of pharmaceutical promotion and its influence on patient care. They believe efforts are needed to better evaluate the value of drugs, ensuring this information is readily available at the point of care so it can inform clinical decision-making and promote the use of higher-value medicines.
The researchers also suggested that clinicians consider taking steps to limit their exposure to industry promotion and consider engaging with non-commercial educational outreach programs that provide evidence-based recommendations about medication choices.
FDA approves first ready-to-use oral solution of methotrexate
The US Food and Drug Administration (FDA) has approved a ready-to-use oral solution of methotrexate (Xatmep) for use in certain pediatric patients.
The drug is approved as part of a multi-phase, combination chemotherapy maintenance regimen to treat pediatric patients with acute lymphoblastic leukemia.
Xatmep is also approved for use in pediatric patients with active polyarticular juvenile idiopathic arthritis who have had an insufficient response to, or cannot tolerate, an adequate trial of first-line therapy, including full-dose non-steroidal anti-inflammatory agents.
Xatmep is the first ready-to-use oral solution of methotrexate to be approved by the FDA.
There was previously no such formulation of the drug approved for use in pediatric patients requiring body surface area dosing (mg/m2), patients who have difficulty swallowing or cannot consume tablets, or those with needle-phobia.
Xatmep (methotrexate) Oral Solution, 2.5 mg/mL, requires no preparation. It eliminates the need for needles, crushing or splitting tablets, or for compounding tablets into a liquid formulation.
Xatmep requires refrigeration but may be stored at room temperature for 60 days after dispensing.
For more on Xatmep, see the prescribing information, which includes a boxed warning detailing the risk of severe toxic reactions, including embryo-fetal toxicity.
Xatmep is available through pharmacies and a qualified mail-order service. For information on how to obtain the drug, call 1-855-379-0382.
Xatmep is a product of Silvergate Pharmaceuticals, Inc.
The US Food and Drug Administration (FDA) has approved a ready-to-use oral solution of methotrexate (Xatmep) for use in certain pediatric patients.
The drug is approved as part of a multi-phase, combination chemotherapy maintenance regimen to treat pediatric patients with acute lymphoblastic leukemia.
Xatmep is also approved for use in pediatric patients with active polyarticular juvenile idiopathic arthritis who have had an insufficient response to, or cannot tolerate, an adequate trial of first-line therapy, including full-dose non-steroidal anti-inflammatory agents.
Xatmep is the first ready-to-use oral solution of methotrexate to be approved by the FDA.
There was previously no such formulation of the drug approved for use in pediatric patients requiring body surface area dosing (mg/m2), patients who have difficulty swallowing or cannot consume tablets, or those with needle-phobia.
Xatmep (methotrexate) Oral Solution, 2.5 mg/mL, requires no preparation. It eliminates the need for needles, crushing or splitting tablets, or for compounding tablets into a liquid formulation.
Xatmep requires refrigeration but may be stored at room temperature for 60 days after dispensing.
For more on Xatmep, see the prescribing information, which includes a boxed warning detailing the risk of severe toxic reactions, including embryo-fetal toxicity.
Xatmep is available through pharmacies and a qualified mail-order service. For information on how to obtain the drug, call 1-855-379-0382.
Xatmep is a product of Silvergate Pharmaceuticals, Inc.
The US Food and Drug Administration (FDA) has approved a ready-to-use oral solution of methotrexate (Xatmep) for use in certain pediatric patients.
The drug is approved as part of a multi-phase, combination chemotherapy maintenance regimen to treat pediatric patients with acute lymphoblastic leukemia.
Xatmep is also approved for use in pediatric patients with active polyarticular juvenile idiopathic arthritis who have had an insufficient response to, or cannot tolerate, an adequate trial of first-line therapy, including full-dose non-steroidal anti-inflammatory agents.
Xatmep is the first ready-to-use oral solution of methotrexate to be approved by the FDA.
There was previously no such formulation of the drug approved for use in pediatric patients requiring body surface area dosing (mg/m2), patients who have difficulty swallowing or cannot consume tablets, or those with needle-phobia.
Xatmep (methotrexate) Oral Solution, 2.5 mg/mL, requires no preparation. It eliminates the need for needles, crushing or splitting tablets, or for compounding tablets into a liquid formulation.
Xatmep requires refrigeration but may be stored at room temperature for 60 days after dispensing.
For more on Xatmep, see the prescribing information, which includes a boxed warning detailing the risk of severe toxic reactions, including embryo-fetal toxicity.
Xatmep is available through pharmacies and a qualified mail-order service. For information on how to obtain the drug, call 1-855-379-0382.
Xatmep is a product of Silvergate Pharmaceuticals, Inc.
Blood groups associated with risk of heart attack
PARIS—Having a blood type other than O is associated with a higher risk of heart attack, according to a meta-analysis.
“It has been suggested that people with non-O blood groups (A, B, AB) are at higher risk for heart attacks and overall cardiovascular mortality, but this suggestion comes from case-control studies, which have a low level of evidence,” said Tessa Kole, a student at the University Medical Centre Groningen in the Netherlands.
Therefore, Kole and her fellow investigators conducted a meta-analysis of prospective studies reporting on blood groups and incident cardiovascular events.
The team presented their findings at Heart Failure 2017 and the 4th World Congress on Acute Heart Failure (abstract 697).
The study included 1,362,569 subjects from 11 prospective cohorts, described in 9 articles. There were a total of 23,154 cardiovascular events.
The investigators analyzed the association between blood group and all coronary events, combined cardiovascular events, and fatal coronary events.
The analysis of all coronary events included 771,113 subjects with a non-O blood group and 519,743 with an O blood group, of whom 11,437 (1.5%) and 7220 (1.4%), respectively, suffered a coronary event.
The odds ratio (OR) for all coronary events was significantly higher in subjects with a non-O blood group, at 1.09 (95% confidence interval [CI], 1.06-1.13, P<0.00001).
The analysis of combined cardiovascular events included 708,276 subjects with a non-O blood group and 476,868 with an O blood group, of whom 17,449 (2.5%) and 10,916 (2.3%), respectively, had an event.
The OR for combined cardiovascular events was significantly higher in subjects with non-O blood groups, at 1.09 (95% CI, 1.06-1.11, P=0.006).
The analysis of fatal coronary events did not show a significant difference between people with O and non-O blood groups. The OR was 1.00 (95% CI, 0.85-1.18, P=0.98).
“We demonstrate that having a non-O blood group is associated with a 9% increased risk of coronary events and a 9% increased risk of cardiovascular events, especially myocardial infarction,” Kole said.
“More research is needed to identify the cause of the apparent increased cardiovascular risk in people with a non-O blood group. Obtaining more information about risk in each non-O blood group (A, B, and AB) might provide further explanations of the causes.”
“In future, blood group should be considered in risk assessment for cardiovascular prevention, together with cholesterol, age, sex, and systolic blood pressure. It could be that people with an A blood group should have a lower treatment threshold for dyslipidemia or hypertension, for example. We need further studies to validate if the excess cardiovascular risk in non-O blood group carriers may be amenable to treatment.”
PARIS—Having a blood type other than O is associated with a higher risk of heart attack, according to a meta-analysis.
“It has been suggested that people with non-O blood groups (A, B, AB) are at higher risk for heart attacks and overall cardiovascular mortality, but this suggestion comes from case-control studies, which have a low level of evidence,” said Tessa Kole, a student at the University Medical Centre Groningen in the Netherlands.
Therefore, Kole and her fellow investigators conducted a meta-analysis of prospective studies reporting on blood groups and incident cardiovascular events.
The team presented their findings at Heart Failure 2017 and the 4th World Congress on Acute Heart Failure (abstract 697).
The study included 1,362,569 subjects from 11 prospective cohorts, described in 9 articles. There were a total of 23,154 cardiovascular events.
The investigators analyzed the association between blood group and all coronary events, combined cardiovascular events, and fatal coronary events.
The analysis of all coronary events included 771,113 subjects with a non-O blood group and 519,743 with an O blood group, of whom 11,437 (1.5%) and 7220 (1.4%), respectively, suffered a coronary event.
The odds ratio (OR) for all coronary events was significantly higher in subjects with a non-O blood group, at 1.09 (95% confidence interval [CI], 1.06-1.13, P<0.00001).
The analysis of combined cardiovascular events included 708,276 subjects with a non-O blood group and 476,868 with an O blood group, of whom 17,449 (2.5%) and 10,916 (2.3%), respectively, had an event.
The OR for combined cardiovascular events was significantly higher in subjects with non-O blood groups, at 1.09 (95% CI, 1.06-1.11, P=0.006).
The analysis of fatal coronary events did not show a significant difference between people with O and non-O blood groups. The OR was 1.00 (95% CI, 0.85-1.18, P=0.98).
“We demonstrate that having a non-O blood group is associated with a 9% increased risk of coronary events and a 9% increased risk of cardiovascular events, especially myocardial infarction,” Kole said.
“More research is needed to identify the cause of the apparent increased cardiovascular risk in people with a non-O blood group. Obtaining more information about risk in each non-O blood group (A, B, and AB) might provide further explanations of the causes.”
“In future, blood group should be considered in risk assessment for cardiovascular prevention, together with cholesterol, age, sex, and systolic blood pressure. It could be that people with an A blood group should have a lower treatment threshold for dyslipidemia or hypertension, for example. We need further studies to validate if the excess cardiovascular risk in non-O blood group carriers may be amenable to treatment.”
PARIS—Having a blood type other than O is associated with a higher risk of heart attack, according to a meta-analysis.
“It has been suggested that people with non-O blood groups (A, B, AB) are at higher risk for heart attacks and overall cardiovascular mortality, but this suggestion comes from case-control studies, which have a low level of evidence,” said Tessa Kole, a student at the University Medical Centre Groningen in the Netherlands.
Therefore, Kole and her fellow investigators conducted a meta-analysis of prospective studies reporting on blood groups and incident cardiovascular events.
The team presented their findings at Heart Failure 2017 and the 4th World Congress on Acute Heart Failure (abstract 697).
The study included 1,362,569 subjects from 11 prospective cohorts, described in 9 articles. There were a total of 23,154 cardiovascular events.
The investigators analyzed the association between blood group and all coronary events, combined cardiovascular events, and fatal coronary events.
The analysis of all coronary events included 771,113 subjects with a non-O blood group and 519,743 with an O blood group, of whom 11,437 (1.5%) and 7220 (1.4%), respectively, suffered a coronary event.
The odds ratio (OR) for all coronary events was significantly higher in subjects with a non-O blood group, at 1.09 (95% confidence interval [CI], 1.06-1.13, P<0.00001).
The analysis of combined cardiovascular events included 708,276 subjects with a non-O blood group and 476,868 with an O blood group, of whom 17,449 (2.5%) and 10,916 (2.3%), respectively, had an event.
The OR for combined cardiovascular events was significantly higher in subjects with non-O blood groups, at 1.09 (95% CI, 1.06-1.11, P=0.006).
The analysis of fatal coronary events did not show a significant difference between people with O and non-O blood groups. The OR was 1.00 (95% CI, 0.85-1.18, P=0.98).
“We demonstrate that having a non-O blood group is associated with a 9% increased risk of coronary events and a 9% increased risk of cardiovascular events, especially myocardial infarction,” Kole said.
“More research is needed to identify the cause of the apparent increased cardiovascular risk in people with a non-O blood group. Obtaining more information about risk in each non-O blood group (A, B, and AB) might provide further explanations of the causes.”
“In future, blood group should be considered in risk assessment for cardiovascular prevention, together with cholesterol, age, sex, and systolic blood pressure. It could be that people with an A blood group should have a lower treatment threshold for dyslipidemia or hypertension, for example. We need further studies to validate if the excess cardiovascular risk in non-O blood group carriers may be amenable to treatment.”
Drug receives orphan designation for AML
The US Food and Drug Administration (FDA) has granted orphan drug designation for PTX-200 for the treatment of acute myeloid leukemia (AML).
PTX-200, or triciribine phosphate monohydrate, is a small-molecule Akt inhibitor being developed by Prescient Therapeutics Ltd.
PTX-200 is currently being tested in combination with cytarabine in a phase 1b/2 trial of patients with relapsed or refractory AML.
PTX-200 was previously tested as monotherapy in a phase 1 trial of patients with relapsed or refractory hematologic malignancies.
Results from this trial were published in Leukemia Research in November 2013.
The trial included 41 patients who received at least 1 dose of PTX-200. The patients’ median age was 70 (range, of 23–83), and most (77%) were male.
Thirty-six patients (84%) had AML, 3 had myelodysplastic syndromes/chronic myelomonocytic leukemia (CMML), 2 had chronic lymphocytic leukemia, and 2 had acute lymphoblastic leukemia.
The patients had received a median of 2 prior therapies (range, 0–11), and they received a median of 1 cycle (range, 0–3) of PTX-200 at varying doses.
The maximum-tolerated dose of PTX-200 was 55 mg/m2. Two dose-limiting toxicities (DLTs) occurred in 3 patients in the 65 mg/m2 cohort (2 cases of lipase elevation and 1 case of triglyceride elevation).
One dose-limiting toxicity (mucositis) occurred in the 35 mg/m2 cohort. All DLTs resolved after patients stopped taking PTX-200.
Common treatment-emergent grade 3/4 adverse events included infection/febrile neutropenia (24%), bleeding (2%), mucositis (2%), and elevated lipase (5%).
Thirty-two patients were evaluable for response. There were no responses, but 17 patients had stable disease. The remaining 15 patients progressed.
Three patients with stable disease (all with AML) achieved at least a 50% reduction in bone marrow blasts, and a patient with CMML experienced spleen reduction and resolution of leukocytosis.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.
Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation for PTX-200 for the treatment of acute myeloid leukemia (AML).
PTX-200, or triciribine phosphate monohydrate, is a small-molecule Akt inhibitor being developed by Prescient Therapeutics Ltd.
PTX-200 is currently being tested in combination with cytarabine in a phase 1b/2 trial of patients with relapsed or refractory AML.
PTX-200 was previously tested as monotherapy in a phase 1 trial of patients with relapsed or refractory hematologic malignancies.
Results from this trial were published in Leukemia Research in November 2013.
The trial included 41 patients who received at least 1 dose of PTX-200. The patients’ median age was 70 (range, of 23–83), and most (77%) were male.
Thirty-six patients (84%) had AML, 3 had myelodysplastic syndromes/chronic myelomonocytic leukemia (CMML), 2 had chronic lymphocytic leukemia, and 2 had acute lymphoblastic leukemia.
The patients had received a median of 2 prior therapies (range, 0–11), and they received a median of 1 cycle (range, 0–3) of PTX-200 at varying doses.
The maximum-tolerated dose of PTX-200 was 55 mg/m2. Two dose-limiting toxicities (DLTs) occurred in 3 patients in the 65 mg/m2 cohort (2 cases of lipase elevation and 1 case of triglyceride elevation).
One dose-limiting toxicity (mucositis) occurred in the 35 mg/m2 cohort. All DLTs resolved after patients stopped taking PTX-200.
Common treatment-emergent grade 3/4 adverse events included infection/febrile neutropenia (24%), bleeding (2%), mucositis (2%), and elevated lipase (5%).
Thirty-two patients were evaluable for response. There were no responses, but 17 patients had stable disease. The remaining 15 patients progressed.
Three patients with stable disease (all with AML) achieved at least a 50% reduction in bone marrow blasts, and a patient with CMML experienced spleen reduction and resolution of leukocytosis.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.
Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation for PTX-200 for the treatment of acute myeloid leukemia (AML).
PTX-200, or triciribine phosphate monohydrate, is a small-molecule Akt inhibitor being developed by Prescient Therapeutics Ltd.
PTX-200 is currently being tested in combination with cytarabine in a phase 1b/2 trial of patients with relapsed or refractory AML.
PTX-200 was previously tested as monotherapy in a phase 1 trial of patients with relapsed or refractory hematologic malignancies.
Results from this trial were published in Leukemia Research in November 2013.
The trial included 41 patients who received at least 1 dose of PTX-200. The patients’ median age was 70 (range, of 23–83), and most (77%) were male.
Thirty-six patients (84%) had AML, 3 had myelodysplastic syndromes/chronic myelomonocytic leukemia (CMML), 2 had chronic lymphocytic leukemia, and 2 had acute lymphoblastic leukemia.
The patients had received a median of 2 prior therapies (range, 0–11), and they received a median of 1 cycle (range, 0–3) of PTX-200 at varying doses.
The maximum-tolerated dose of PTX-200 was 55 mg/m2. Two dose-limiting toxicities (DLTs) occurred in 3 patients in the 65 mg/m2 cohort (2 cases of lipase elevation and 1 case of triglyceride elevation).
One dose-limiting toxicity (mucositis) occurred in the 35 mg/m2 cohort. All DLTs resolved after patients stopped taking PTX-200.
Common treatment-emergent grade 3/4 adverse events included infection/febrile neutropenia (24%), bleeding (2%), mucositis (2%), and elevated lipase (5%).
Thirty-two patients were evaluable for response. There were no responses, but 17 patients had stable disease. The remaining 15 patients progressed.
Three patients with stable disease (all with AML) achieved at least a 50% reduction in bone marrow blasts, and a patient with CMML experienced spleen reduction and resolution of leukocytosis.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.
Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.
Simplifying consent forms doesn’t affect patient comprehension
Simplifying consent documents does not affect how well potential participants understand a clinical trial, according to new research.
The study showed no significant difference in comprehension between patients who read a concise consent document and those who read a longer document written at a more advanced reading level.
However, researchers did find that mailing consent forms to patients in advance and explaining the study to patients in person did improve their comprehension.
Christine Grady, PhD, of the NIH Clinical Center in Bethesda, Maryland, and her colleagues reported these findings in PLOS ONE.
The team noted that informed consent is a central tenet of ethical clinical research. However, over time, the documents used to obtain informed consent have grown longer, more complex, and harder to read.
So the researchers developed a concise alternative to consent documents used in the multinational START trial.
The new document was shorter than the old document by almost 70%, at 1821 words. The new document also contained bullet points and tables and had a simpler reading level.
Dr Grady and her colleagues tested the old and new documents with 4229 HIV-positive patients treated at 77 sites seeking enrollment in the START trial between 2009 and 2013.
The sites were randomly allocated to either the concise or the standard consent documents for participants to review.
There was no significant difference in comprehension scores between patients who received the concise form and those who received the standard form (P>0.1). Likewise, there was no significant difference in patient satisfaction or willingness to volunteer (P>0.1).
However, patients who received the concise form were significantly less likely to say the form was too long or too detailed (P<0.001).
The researchers did find several factors that were associated with significantly better comprehension.
Patients had significantly (P<0.05) better comprehension scores if they had a higher education level, were white, were treated at sites with more previous HIV studies, and were treated at sites where staff explained the study and thought patients understood the study very well.
Patients had significantly lower comprehension scores if they were treated at sites that rarely or never mailed the consent form ahead of the clinic visit (P=0.009).
Simplifying consent documents does not affect how well potential participants understand a clinical trial, according to new research.
The study showed no significant difference in comprehension between patients who read a concise consent document and those who read a longer document written at a more advanced reading level.
However, researchers did find that mailing consent forms to patients in advance and explaining the study to patients in person did improve their comprehension.
Christine Grady, PhD, of the NIH Clinical Center in Bethesda, Maryland, and her colleagues reported these findings in PLOS ONE.
The team noted that informed consent is a central tenet of ethical clinical research. However, over time, the documents used to obtain informed consent have grown longer, more complex, and harder to read.
So the researchers developed a concise alternative to consent documents used in the multinational START trial.
The new document was shorter than the old document by almost 70%, at 1821 words. The new document also contained bullet points and tables and had a simpler reading level.
Dr Grady and her colleagues tested the old and new documents with 4229 HIV-positive patients treated at 77 sites seeking enrollment in the START trial between 2009 and 2013.
The sites were randomly allocated to either the concise or the standard consent documents for participants to review.
There was no significant difference in comprehension scores between patients who received the concise form and those who received the standard form (P>0.1). Likewise, there was no significant difference in patient satisfaction or willingness to volunteer (P>0.1).
However, patients who received the concise form were significantly less likely to say the form was too long or too detailed (P<0.001).
The researchers did find several factors that were associated with significantly better comprehension.
Patients had significantly (P<0.05) better comprehension scores if they had a higher education level, were white, were treated at sites with more previous HIV studies, and were treated at sites where staff explained the study and thought patients understood the study very well.
Patients had significantly lower comprehension scores if they were treated at sites that rarely or never mailed the consent form ahead of the clinic visit (P=0.009).
Simplifying consent documents does not affect how well potential participants understand a clinical trial, according to new research.
The study showed no significant difference in comprehension between patients who read a concise consent document and those who read a longer document written at a more advanced reading level.
However, researchers did find that mailing consent forms to patients in advance and explaining the study to patients in person did improve their comprehension.
Christine Grady, PhD, of the NIH Clinical Center in Bethesda, Maryland, and her colleagues reported these findings in PLOS ONE.
The team noted that informed consent is a central tenet of ethical clinical research. However, over time, the documents used to obtain informed consent have grown longer, more complex, and harder to read.
So the researchers developed a concise alternative to consent documents used in the multinational START trial.
The new document was shorter than the old document by almost 70%, at 1821 words. The new document also contained bullet points and tables and had a simpler reading level.
Dr Grady and her colleagues tested the old and new documents with 4229 HIV-positive patients treated at 77 sites seeking enrollment in the START trial between 2009 and 2013.
The sites were randomly allocated to either the concise or the standard consent documents for participants to review.
There was no significant difference in comprehension scores between patients who received the concise form and those who received the standard form (P>0.1). Likewise, there was no significant difference in patient satisfaction or willingness to volunteer (P>0.1).
However, patients who received the concise form were significantly less likely to say the form was too long or too detailed (P<0.001).
The researchers did find several factors that were associated with significantly better comprehension.
Patients had significantly (P<0.05) better comprehension scores if they had a higher education level, were white, were treated at sites with more previous HIV studies, and were treated at sites where staff explained the study and thought patients understood the study very well.
Patients had significantly lower comprehension scores if they were treated at sites that rarely or never mailed the consent form ahead of the clinic visit (P=0.009).
FDA approves midostaurin to treat FLT3+ AML, advanced SM
The US Food and Drug Administration (FDA) has granted approval for the oral, multi-targeted kinase inhibitor midostaurin (Rydapt).
The drug is now approved for the treatment of adults with advanced systemic mastocytosis (SM), including aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).
Midostaurin is also approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.
The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, for use with midostaurin to test AML patients for the FLT3 mutation.
Midostaurin is a product of Novartis. The companion diagnostic was developed by Novartis and Invivoscribe Technologies, Inc.
Midostaurin in AML
The FDA’s approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.016).
The median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Midostaurin in advanced SM
The FDA’s approval of midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.
Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.
Study 2 included 116 patients, 115 of whom were evaluable for response.
The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.
Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.
Among the 17 patients with SM-AHN, there were 10 response (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.
In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.
The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.
Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
The US Food and Drug Administration (FDA) has granted approval for the oral, multi-targeted kinase inhibitor midostaurin (Rydapt).
The drug is now approved for the treatment of adults with advanced systemic mastocytosis (SM), including aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).
Midostaurin is also approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.
The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, for use with midostaurin to test AML patients for the FLT3 mutation.
Midostaurin is a product of Novartis. The companion diagnostic was developed by Novartis and Invivoscribe Technologies, Inc.
Midostaurin in AML
The FDA’s approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.016).
The median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Midostaurin in advanced SM
The FDA’s approval of midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.
Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.
Study 2 included 116 patients, 115 of whom were evaluable for response.
The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.
Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.
Among the 17 patients with SM-AHN, there were 10 response (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.
In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.
The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.
Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
The US Food and Drug Administration (FDA) has granted approval for the oral, multi-targeted kinase inhibitor midostaurin (Rydapt).
The drug is now approved for the treatment of adults with advanced systemic mastocytosis (SM), including aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL).
Midostaurin is also approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test.
The FDA approved a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, for use with midostaurin to test AML patients for the FLT3 mutation.
Midostaurin is a product of Novartis. The companion diagnostic was developed by Novartis and Invivoscribe Technologies, Inc.
Midostaurin in AML
The FDA’s approval of midostaurin in AML is based on results from the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.
In RATIFY, researchers compared midostaurin plus standard chemotherapy to placebo plus standard chemotherapy in 717 adults younger than age 60 who had FLT3-mutated AML.
Patients in the midostaurin arm experienced a statistically significant improvement in overall survival, with a 23% reduction in risk of death compared to the placebo arm (hazard ratio=0.77, P=0.016).
The median event-free survival was significantly longer in the midostaurin arm than the placebo arm—8.2 months and 3.0 months, respectively (hazard ratio=0.78, P=0.004).
The most frequent adverse events (AEs) in the midostaurin arm (occurring in at least 20% of patients) were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia, and upper respiratory tract infections.
The most frequent grade 3/4 AEs (occurring in at least 10% of patients) were febrile neutropenia, device-related infection, and mucositis. Nine percent of patients in the midostaurin arm stopped treatment due to AEs, as did 6% in the placebo arm.
Midostaurin in advanced SM
The FDA’s approval of midostaurin in advanced SM was based on results from a pair of phase 2, single-arm studies, hereafter referred to as Study 2 and Study 3.
Data from Study 2 were published in NEJM in June 2016, and data from Study 3 were presented at the 2010 ASH Annual Meeting.
Study 2 included 116 patients, 115 of whom were evaluable for response.
The overall response rate (ORR) was 17% in the entire cohort, 31% among patients with ASM, 11% among patients with SM-AHN, and 19% among patients with MCL. The complete response rates were 2%, 6%, 0%, and 5%, respectively.
Study 3 included 26 patients with advanced SM. In 3 of the patients, the subtype of SM was unconfirmed.
Among the 17 patients with SM-AHN, there were 10 response (ORR=59%), including 1 partial response and 9 major responses. In the 6 patients with MCL, there were 2 responses (ORR=33%), which included 1 partial response and 1 major response.
In both studies combined, there were 142 adults with ASM, SM-AHN, or MCL.
The most frequent AEs (excluding laboratory abnormalities) that occurred in at least 20% of these patients were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
The most frequent grade 3 or higher AEs (excluding laboratory abnormalities) that occurred in at least 5% of patients were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency.
Serious AEs occurred in 68% of patients, most commonly infections and gastrointestinal disorders. Twenty-one percent of patients discontinued treatment due to AEs, the most frequent of which were infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
FDA approves test to detect FLT3 mutations
The US Food and Drug Administration (FDA) has approved use of the LeukoStrat® CDx FLT3 Mutation Assay as a companion diagnostic test.
The LeukoStrat® CDx FLT3 Mutation Assay is a signal ratio assay that identifies both internal tandem duplication and tyrosine kinase domain mutations.
The assay is the first FDA-approved companion diagnostic for acute myeloid leukemia (AML).
It is approved for use in patients newly diagnosed with AML to determine if they have FLT3 mutations and are therefore eligible to receive treatment with midostaurin (Rydapt).
The FDA granted approval for the LeukoStrat® CDx FLT3 Mutation Assay and midostaurin simultaneously.
The assay was developed by Invivoscribe Technologies, Inc. and Novartis. Midostaurin is a product of Novartis.
Under the current labeling, FLT3 mutation testing with the LeukoStrat® CDx FLT3 Mutation Assay is exclusively performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.
Under terms of a previously announced agreement with Thermo Fisher, Invivoscribe will also seek FDA approval of the LeukoStrat® CDx FLT3 Mutation Assay that will allow the sale of kits to other laboratories.
The US Food and Drug Administration (FDA) has approved use of the LeukoStrat® CDx FLT3 Mutation Assay as a companion diagnostic test.
The LeukoStrat® CDx FLT3 Mutation Assay is a signal ratio assay that identifies both internal tandem duplication and tyrosine kinase domain mutations.
The assay is the first FDA-approved companion diagnostic for acute myeloid leukemia (AML).
It is approved for use in patients newly diagnosed with AML to determine if they have FLT3 mutations and are therefore eligible to receive treatment with midostaurin (Rydapt).
The FDA granted approval for the LeukoStrat® CDx FLT3 Mutation Assay and midostaurin simultaneously.
The assay was developed by Invivoscribe Technologies, Inc. and Novartis. Midostaurin is a product of Novartis.
Under the current labeling, FLT3 mutation testing with the LeukoStrat® CDx FLT3 Mutation Assay is exclusively performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.
Under terms of a previously announced agreement with Thermo Fisher, Invivoscribe will also seek FDA approval of the LeukoStrat® CDx FLT3 Mutation Assay that will allow the sale of kits to other laboratories.
The US Food and Drug Administration (FDA) has approved use of the LeukoStrat® CDx FLT3 Mutation Assay as a companion diagnostic test.
The LeukoStrat® CDx FLT3 Mutation Assay is a signal ratio assay that identifies both internal tandem duplication and tyrosine kinase domain mutations.
The assay is the first FDA-approved companion diagnostic for acute myeloid leukemia (AML).
It is approved for use in patients newly diagnosed with AML to determine if they have FLT3 mutations and are therefore eligible to receive treatment with midostaurin (Rydapt).
The FDA granted approval for the LeukoStrat® CDx FLT3 Mutation Assay and midostaurin simultaneously.
The assay was developed by Invivoscribe Technologies, Inc. and Novartis. Midostaurin is a product of Novartis.
Under the current labeling, FLT3 mutation testing with the LeukoStrat® CDx FLT3 Mutation Assay is exclusively performed by The Laboratory for Personalized Molecular Medicine, a subsidiary of Invivoscribe Technologies, Inc.
Under terms of a previously announced agreement with Thermo Fisher, Invivoscribe will also seek FDA approval of the LeukoStrat® CDx FLT3 Mutation Assay that will allow the sale of kits to other laboratories.
Pembrolizumab could change treatment paradigm, team says
The anti-PD-1 therapy pembrolizumab could change the treatment paradigm of relapsed or refractory classic Hodgkin lymphoma (cHL), according to researchers.
In a phase 2 trial, pembrolizumab produced an overall response rate (ORR) of 69% and a complete response (CR) rate of 22% in adults with cHL who had failed treatment with brentuximab vedotin (BV), autologous hematopoietic stem cell transplant (auto-HSCT), or both.
The researchers said the safety profile of pembrolizumab was “acceptable” and largely consistent with safety in previous studies of the drug.
Twelve percent of patients temporarily stopped taking pembrolizumab due to treatment-related adverse events (AEs), and 4% stopped taking the drug entirely as a result of AEs.
Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues reported these results, from the KEYNOTE-087 trial, in the Journal of Clinical Oncology.
The trial was sponsored by Merck, the company that markets pembrolizumab as Keytruda.
In KEYNOTE-087, the 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.
Efficacy
Across all 210 enrolled patients, the ORR was 69.0%, and the CR rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%. The CR rate was 21.7%, the partial response (PR) rate was 52.2%, 15.9% of patients had stable disease (SD), and 7.2% progressed. In 82.2% of responders, the response lasted 6 months or more.
In Cohort 2 (n=81), the ORR was 64.2%. The CR rate was 24.7%, the PR rate was 39.5%, 12.3% of patients had SD, and 21.0% progressed. In 70.0% of responders, the response lasted 6 months or more.
In Cohort 3 (n=60), the ORR was 70.0%. Twenty percent of patients had a CR, 50.0% had a PR, 16.7% had SD, and 13.3% progressed. In 75.6% of responders, the response lasted 6 months or more.
Results also included an analysis of patients with primary refractory disease (n=73), which was defined as failure to achieve CR or PR with first-line treatment. In this patient population, the ORR was 79.5%.
An ORR of 67.8% was reported in patients who relapsed after 3 or more lines of prior therapy (99/146).
For the entire study cohort, the median duration of response was not reached, and the median overall survival was not reached. At 9 months, the overall survival rate was 97.5%, and the progression-free survival rate was 63.4%.
Safety
The most common AEs related to pembrolizumab 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%).
Nine patients (4.3%) stopped taking pembrolizumab due to treatment-related AEs, including myocarditis, myelitis, myositis, pneumonitis, infusion-related reactions, and cytokine release syndrome.
Twenty-six patients (12.4%) had treatment interruptions due to pembrolizumab-related AEs.
Two patients died during follow-up, but neither death was considered related to pembrolizumab. One patient died of septic shock and the other of acute graft-versus-host disease.
The anti-PD-1 therapy pembrolizumab could change the treatment paradigm of relapsed or refractory classic Hodgkin lymphoma (cHL), according to researchers.
In a phase 2 trial, pembrolizumab produced an overall response rate (ORR) of 69% and a complete response (CR) rate of 22% in adults with cHL who had failed treatment with brentuximab vedotin (BV), autologous hematopoietic stem cell transplant (auto-HSCT), or both.
The researchers said the safety profile of pembrolizumab was “acceptable” and largely consistent with safety in previous studies of the drug.
Twelve percent of patients temporarily stopped taking pembrolizumab due to treatment-related adverse events (AEs), and 4% stopped taking the drug entirely as a result of AEs.
Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues reported these results, from the KEYNOTE-087 trial, in the Journal of Clinical Oncology.
The trial was sponsored by Merck, the company that markets pembrolizumab as Keytruda.
In KEYNOTE-087, the 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.
Efficacy
Across all 210 enrolled patients, the ORR was 69.0%, and the CR rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%. The CR rate was 21.7%, the partial response (PR) rate was 52.2%, 15.9% of patients had stable disease (SD), and 7.2% progressed. In 82.2% of responders, the response lasted 6 months or more.
In Cohort 2 (n=81), the ORR was 64.2%. The CR rate was 24.7%, the PR rate was 39.5%, 12.3% of patients had SD, and 21.0% progressed. In 70.0% of responders, the response lasted 6 months or more.
In Cohort 3 (n=60), the ORR was 70.0%. Twenty percent of patients had a CR, 50.0% had a PR, 16.7% had SD, and 13.3% progressed. In 75.6% of responders, the response lasted 6 months or more.
Results also included an analysis of patients with primary refractory disease (n=73), which was defined as failure to achieve CR or PR with first-line treatment. In this patient population, the ORR was 79.5%.
An ORR of 67.8% was reported in patients who relapsed after 3 or more lines of prior therapy (99/146).
For the entire study cohort, the median duration of response was not reached, and the median overall survival was not reached. At 9 months, the overall survival rate was 97.5%, and the progression-free survival rate was 63.4%.
Safety
The most common AEs related to pembrolizumab 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%).
Nine patients (4.3%) stopped taking pembrolizumab due to treatment-related AEs, including myocarditis, myelitis, myositis, pneumonitis, infusion-related reactions, and cytokine release syndrome.
Twenty-six patients (12.4%) had treatment interruptions due to pembrolizumab-related AEs.
Two patients died during follow-up, but neither death was considered related to pembrolizumab. One patient died of septic shock and the other of acute graft-versus-host disease.
The anti-PD-1 therapy pembrolizumab could change the treatment paradigm of relapsed or refractory classic Hodgkin lymphoma (cHL), according to researchers.
In a phase 2 trial, pembrolizumab produced an overall response rate (ORR) of 69% and a complete response (CR) rate of 22% in adults with cHL who had failed treatment with brentuximab vedotin (BV), autologous hematopoietic stem cell transplant (auto-HSCT), or both.
The researchers said the safety profile of pembrolizumab was “acceptable” and largely consistent with safety in previous studies of the drug.
Twelve percent of patients temporarily stopped taking pembrolizumab due to treatment-related adverse events (AEs), and 4% stopped taking the drug entirely as a result of AEs.
Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues reported these results, from the KEYNOTE-087 trial, in the Journal of Clinical Oncology.
The trial was sponsored by Merck, the company that markets pembrolizumab as Keytruda.
In KEYNOTE-087, the 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.
Efficacy
Across all 210 enrolled patients, the ORR was 69.0%, and the CR rate was 22.4%.
In Cohort 1 (n=69), the ORR was 73.9%. The CR rate was 21.7%, the partial response (PR) rate was 52.2%, 15.9% of patients had stable disease (SD), and 7.2% progressed. In 82.2% of responders, the response lasted 6 months or more.
In Cohort 2 (n=81), the ORR was 64.2%. The CR rate was 24.7%, the PR rate was 39.5%, 12.3% of patients had SD, and 21.0% progressed. In 70.0% of responders, the response lasted 6 months or more.
In Cohort 3 (n=60), the ORR was 70.0%. Twenty percent of patients had a CR, 50.0% had a PR, 16.7% had SD, and 13.3% progressed. In 75.6% of responders, the response lasted 6 months or more.
Results also included an analysis of patients with primary refractory disease (n=73), which was defined as failure to achieve CR or PR with first-line treatment. In this patient population, the ORR was 79.5%.
An ORR of 67.8% was reported in patients who relapsed after 3 or more lines of prior therapy (99/146).
For the entire study cohort, the median duration of response was not reached, and the median overall survival was not reached. At 9 months, the overall survival rate was 97.5%, and the progression-free survival rate was 63.4%.
Safety
The most common AEs related to pembrolizumab 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%).
Nine patients (4.3%) stopped taking pembrolizumab due to treatment-related AEs, including myocarditis, myelitis, myositis, pneumonitis, infusion-related reactions, and cytokine release syndrome.
Twenty-six patients (12.4%) had treatment interruptions due to pembrolizumab-related AEs.
Two patients died during follow-up, but neither death was considered related to pembrolizumab. One patient died of septic shock and the other of acute graft-versus-host disease.