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PK dosing software available in US
Pharmacokinetic (PK) dosing software intended for use in patients with hemophilia A is now available in the US.
This free, web-based, prescription software—myPKFiT for ADVATE—is intended to aid healthcare professionals in personalizing the dose and schedule of ADVATE, a full-length recombinant factor VIII product.
The software was cleared by the US Food and Drug Administration (FDA) for use in hemophilia A patients age 16 and older who weigh at least 45 kg and are receiving prophylaxis with ADVATE.
The myPKFiT software generates ADVATE dosage amount and frequency recommendations using a patient’s age and body weight information, as well as local laboratory factor VIII one-stage clotting activity measurements of sparse samples collected from the patient.
A minimum of 2 sparse sampling points are required at the recommended 3 to 4 hours (± 30 minutes) and at 24 to 32 hours (±1 hour) post-infusion.
The software output may be used to guide ADVATE use to maintain factor VIII activity levels at or above a user-specified minimum of 1% to 3% above natural baseline, in accordance with the FDA-approved dosing recommendations for ADVATE.
myPKFiT should only be used to evaluate prophylactic dosing regimens for hemophilia A patients treated with ADVATE.
The software should not be used for patients who have developed neutralizing antibodies to factor VIII products and is not indicated for use in patients with von Willebrand disease.
“A version of myPKFiT has already been widely adopted in Europe since 2014, and we’ve seen how important it has been in helping physicians develop personalized dosing regimens tailored to the specific needs of their patients,” said Andreas Busch, global head of research and development at Shire, the company behind myPKFiT for ADVATE.
“As part of our commitment to precision medicine, we are pleased to bring this innovative application to physicians and patients in the United States.”
More information on the myPKFiT software is available on the ADVATE website and the myPKFiT site.
Pharmacokinetic (PK) dosing software intended for use in patients with hemophilia A is now available in the US.
This free, web-based, prescription software—myPKFiT for ADVATE—is intended to aid healthcare professionals in personalizing the dose and schedule of ADVATE, a full-length recombinant factor VIII product.
The software was cleared by the US Food and Drug Administration (FDA) for use in hemophilia A patients age 16 and older who weigh at least 45 kg and are receiving prophylaxis with ADVATE.
The myPKFiT software generates ADVATE dosage amount and frequency recommendations using a patient’s age and body weight information, as well as local laboratory factor VIII one-stage clotting activity measurements of sparse samples collected from the patient.
A minimum of 2 sparse sampling points are required at the recommended 3 to 4 hours (± 30 minutes) and at 24 to 32 hours (±1 hour) post-infusion.
The software output may be used to guide ADVATE use to maintain factor VIII activity levels at or above a user-specified minimum of 1% to 3% above natural baseline, in accordance with the FDA-approved dosing recommendations for ADVATE.
myPKFiT should only be used to evaluate prophylactic dosing regimens for hemophilia A patients treated with ADVATE.
The software should not be used for patients who have developed neutralizing antibodies to factor VIII products and is not indicated for use in patients with von Willebrand disease.
“A version of myPKFiT has already been widely adopted in Europe since 2014, and we’ve seen how important it has been in helping physicians develop personalized dosing regimens tailored to the specific needs of their patients,” said Andreas Busch, global head of research and development at Shire, the company behind myPKFiT for ADVATE.
“As part of our commitment to precision medicine, we are pleased to bring this innovative application to physicians and patients in the United States.”
More information on the myPKFiT software is available on the ADVATE website and the myPKFiT site.
Pharmacokinetic (PK) dosing software intended for use in patients with hemophilia A is now available in the US.
This free, web-based, prescription software—myPKFiT for ADVATE—is intended to aid healthcare professionals in personalizing the dose and schedule of ADVATE, a full-length recombinant factor VIII product.
The software was cleared by the US Food and Drug Administration (FDA) for use in hemophilia A patients age 16 and older who weigh at least 45 kg and are receiving prophylaxis with ADVATE.
The myPKFiT software generates ADVATE dosage amount and frequency recommendations using a patient’s age and body weight information, as well as local laboratory factor VIII one-stage clotting activity measurements of sparse samples collected from the patient.
A minimum of 2 sparse sampling points are required at the recommended 3 to 4 hours (± 30 minutes) and at 24 to 32 hours (±1 hour) post-infusion.
The software output may be used to guide ADVATE use to maintain factor VIII activity levels at or above a user-specified minimum of 1% to 3% above natural baseline, in accordance with the FDA-approved dosing recommendations for ADVATE.
myPKFiT should only be used to evaluate prophylactic dosing regimens for hemophilia A patients treated with ADVATE.
The software should not be used for patients who have developed neutralizing antibodies to factor VIII products and is not indicated for use in patients with von Willebrand disease.
“A version of myPKFiT has already been widely adopted in Europe since 2014, and we’ve seen how important it has been in helping physicians develop personalized dosing regimens tailored to the specific needs of their patients,” said Andreas Busch, global head of research and development at Shire, the company behind myPKFiT for ADVATE.
“As part of our commitment to precision medicine, we are pleased to bring this innovative application to physicians and patients in the United States.”
More information on the myPKFiT software is available on the ADVATE website and the myPKFiT site.
Agent can reveal HSC engraftment faster
An imaging agent can safely show engraftment of hematopoietic stem cells (HSCs) just days after transplant, according to research published in The Lancet Haematology.
The agent is 18F-fluorothymidine (18F-FLT), a radio-labeled analogue of thymidine.
Past studies have shown that 18F-FLT is incorporated into HSCs.
With the current study, researchers wanted to determine if 18F-FLT could allow them to safely visualize transplanted HSCs.
Kirsten M. Williams, MD, of Children’s National Health System in Washington, DC, and her colleagues tested 18F-FLT in 23 patients undergoing HSC transplant to treat high-risk hematologic malignancies.
The patients first underwent total body irradiation to destroy their own HSCs and then received donor HSCs.
The patients underwent PET/CT scans 1 day before they were infused with HSCs as well as post-transplant at 5 or 9 days, 28 days, and 1 year.
Results
All patients engrafted, a finding that was reflected in blood tests conducted 2 to 4 weeks after transplant. However, imaging results revealed more details.
“Through the images we took, these patients could see the new cells growing in their bodies,” Dr Williams said. “They loved that.”
The researchers and the patients saw the HSCs take a complex journey as they engrafted.
First, HSCs migrated to the patients’ livers and spleens. Next, the cells went to the thoracic spine, the axial spine, the sternum, and the arms and legs.
By 1 year, most of the HSCs were concentrated in the bones that make up the trunk of the body, including the hip, where most biopsies to assess marrow function take place.
This pathway is the same one HSCs take in the fetus when they first form.
The researchers also found the radiation in 18F-FLT did not adversely affect engraftment.
And imaging could reveal successful engraftment at 5 days post-transplant, “which was up to 20 days before engraftment became clinically evident,” according to the researchers.
Dr Williams and her colleagues believe use of 18F-FLT could potentially help patients avoid bone marrow biopsies or, at the very least, help target those biopsies.
And the agent might be helpful for taking stock of HSCs in conditions such as aplastic anemia.
“What happens with HSCs always has been a mystery,” Dr Williams said. “Now, we can start to open that black box.”
An imaging agent can safely show engraftment of hematopoietic stem cells (HSCs) just days after transplant, according to research published in The Lancet Haematology.
The agent is 18F-fluorothymidine (18F-FLT), a radio-labeled analogue of thymidine.
Past studies have shown that 18F-FLT is incorporated into HSCs.
With the current study, researchers wanted to determine if 18F-FLT could allow them to safely visualize transplanted HSCs.
Kirsten M. Williams, MD, of Children’s National Health System in Washington, DC, and her colleagues tested 18F-FLT in 23 patients undergoing HSC transplant to treat high-risk hematologic malignancies.
The patients first underwent total body irradiation to destroy their own HSCs and then received donor HSCs.
The patients underwent PET/CT scans 1 day before they were infused with HSCs as well as post-transplant at 5 or 9 days, 28 days, and 1 year.
Results
All patients engrafted, a finding that was reflected in blood tests conducted 2 to 4 weeks after transplant. However, imaging results revealed more details.
“Through the images we took, these patients could see the new cells growing in their bodies,” Dr Williams said. “They loved that.”
The researchers and the patients saw the HSCs take a complex journey as they engrafted.
First, HSCs migrated to the patients’ livers and spleens. Next, the cells went to the thoracic spine, the axial spine, the sternum, and the arms and legs.
By 1 year, most of the HSCs were concentrated in the bones that make up the trunk of the body, including the hip, where most biopsies to assess marrow function take place.
This pathway is the same one HSCs take in the fetus when they first form.
The researchers also found the radiation in 18F-FLT did not adversely affect engraftment.
And imaging could reveal successful engraftment at 5 days post-transplant, “which was up to 20 days before engraftment became clinically evident,” according to the researchers.
Dr Williams and her colleagues believe use of 18F-FLT could potentially help patients avoid bone marrow biopsies or, at the very least, help target those biopsies.
And the agent might be helpful for taking stock of HSCs in conditions such as aplastic anemia.
“What happens with HSCs always has been a mystery,” Dr Williams said. “Now, we can start to open that black box.”
An imaging agent can safely show engraftment of hematopoietic stem cells (HSCs) just days after transplant, according to research published in The Lancet Haematology.
The agent is 18F-fluorothymidine (18F-FLT), a radio-labeled analogue of thymidine.
Past studies have shown that 18F-FLT is incorporated into HSCs.
With the current study, researchers wanted to determine if 18F-FLT could allow them to safely visualize transplanted HSCs.
Kirsten M. Williams, MD, of Children’s National Health System in Washington, DC, and her colleagues tested 18F-FLT in 23 patients undergoing HSC transplant to treat high-risk hematologic malignancies.
The patients first underwent total body irradiation to destroy their own HSCs and then received donor HSCs.
The patients underwent PET/CT scans 1 day before they were infused with HSCs as well as post-transplant at 5 or 9 days, 28 days, and 1 year.
Results
All patients engrafted, a finding that was reflected in blood tests conducted 2 to 4 weeks after transplant. However, imaging results revealed more details.
“Through the images we took, these patients could see the new cells growing in their bodies,” Dr Williams said. “They loved that.”
The researchers and the patients saw the HSCs take a complex journey as they engrafted.
First, HSCs migrated to the patients’ livers and spleens. Next, the cells went to the thoracic spine, the axial spine, the sternum, and the arms and legs.
By 1 year, most of the HSCs were concentrated in the bones that make up the trunk of the body, including the hip, where most biopsies to assess marrow function take place.
This pathway is the same one HSCs take in the fetus when they first form.
The researchers also found the radiation in 18F-FLT did not adversely affect engraftment.
And imaging could reveal successful engraftment at 5 days post-transplant, “which was up to 20 days before engraftment became clinically evident,” according to the researchers.
Dr Williams and her colleagues believe use of 18F-FLT could potentially help patients avoid bone marrow biopsies or, at the very least, help target those biopsies.
And the agent might be helpful for taking stock of HSCs in conditions such as aplastic anemia.
“What happens with HSCs always has been a mystery,” Dr Williams said. “Now, we can start to open that black box.”
Drug approved to treat newly diagnosed MM in China
The China Food and Drug Administration (CFDA) has approved lenalidomide (Revlimid®) to treat patients with newly diagnosed multiple myeloma (MM).
The drug is now approved for use in combination with dexamethasone to treat adults with previously untreated MM who are not eligible for transplant.
Lenalidomide was first approved by the CFDA in 2013 for use in combination with dexamethasone to treat adults with MM who had received at least one prior therapy.
“In China, where the incidence of multiple myeloma is on the rise due to an aging population and improved diagnosis, we are hopeful that newly diagnosed patients will have a meaningful long-term benefit from this approval,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene, the company marketing lenalidomide as Revlimid in China under an exclusive license from Celgene Corporation.
Trial results
The CFDA’s decision to expand the approval of lenalidomide is based on results from the phase 3 FIRST trial. Updated results from this study were published in the Journal of Clinical Oncology in November 2016.
The trial included 1623 patients with newly diagnosed MM who were not eligible for stem cell transplant.
Patients were randomized to receive:
- Lenalidomide and low-dose dexamethasone (Rd) in 28-day cycles until disease progression (n=535), known as the “continuous Rd group”
- 18 cycles of Rd (Rd18) for 72 weeks (n=541), known as the “Rd18 group”
- Melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).
In the intent-to-treat population, the overall response rate was 81% for the continuous Rd group, 79% for the Rd18 group, and 67% in the MPT group. The complete response rates were 21%, 20%, and 12%, respectively.
The median progression-free survival was 26.0 months in the continuous Rd group, 21.0 months in the Rd18 group, and 21.9 months in the MPT group. At 4 years, progression-free survival rates were 33%, 14%, and 13%, respectively.
The median overall survival was 58.9 months in the continuous Rd group, 56.7 months in the Rd18 group, and 48.5 months in the MPT group. At 4 years, overall survival rates were 60%, 57%, and 51%, respectively.
The most frequent grade 3/4 hematologic treatment-emergent adverse events were neutropenia and anemia. The rate of grade 3/4 neutropenia was higher in the MPT group than the continuous Rd or Rd18 groups.
Infections were the most common grade 3/4 non-hematologic treatment-emergent adverse events. The rate of grade 3/4 infections was higher in the Rd groups than the MPT group.
The China Food and Drug Administration (CFDA) has approved lenalidomide (Revlimid®) to treat patients with newly diagnosed multiple myeloma (MM).
The drug is now approved for use in combination with dexamethasone to treat adults with previously untreated MM who are not eligible for transplant.
Lenalidomide was first approved by the CFDA in 2013 for use in combination with dexamethasone to treat adults with MM who had received at least one prior therapy.
“In China, where the incidence of multiple myeloma is on the rise due to an aging population and improved diagnosis, we are hopeful that newly diagnosed patients will have a meaningful long-term benefit from this approval,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene, the company marketing lenalidomide as Revlimid in China under an exclusive license from Celgene Corporation.
Trial results
The CFDA’s decision to expand the approval of lenalidomide is based on results from the phase 3 FIRST trial. Updated results from this study were published in the Journal of Clinical Oncology in November 2016.
The trial included 1623 patients with newly diagnosed MM who were not eligible for stem cell transplant.
Patients were randomized to receive:
- Lenalidomide and low-dose dexamethasone (Rd) in 28-day cycles until disease progression (n=535), known as the “continuous Rd group”
- 18 cycles of Rd (Rd18) for 72 weeks (n=541), known as the “Rd18 group”
- Melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).
In the intent-to-treat population, the overall response rate was 81% for the continuous Rd group, 79% for the Rd18 group, and 67% in the MPT group. The complete response rates were 21%, 20%, and 12%, respectively.
The median progression-free survival was 26.0 months in the continuous Rd group, 21.0 months in the Rd18 group, and 21.9 months in the MPT group. At 4 years, progression-free survival rates were 33%, 14%, and 13%, respectively.
The median overall survival was 58.9 months in the continuous Rd group, 56.7 months in the Rd18 group, and 48.5 months in the MPT group. At 4 years, overall survival rates were 60%, 57%, and 51%, respectively.
The most frequent grade 3/4 hematologic treatment-emergent adverse events were neutropenia and anemia. The rate of grade 3/4 neutropenia was higher in the MPT group than the continuous Rd or Rd18 groups.
Infections were the most common grade 3/4 non-hematologic treatment-emergent adverse events. The rate of grade 3/4 infections was higher in the Rd groups than the MPT group.
The China Food and Drug Administration (CFDA) has approved lenalidomide (Revlimid®) to treat patients with newly diagnosed multiple myeloma (MM).
The drug is now approved for use in combination with dexamethasone to treat adults with previously untreated MM who are not eligible for transplant.
Lenalidomide was first approved by the CFDA in 2013 for use in combination with dexamethasone to treat adults with MM who had received at least one prior therapy.
“In China, where the incidence of multiple myeloma is on the rise due to an aging population and improved diagnosis, we are hopeful that newly diagnosed patients will have a meaningful long-term benefit from this approval,” said John V. Oyler, founder, chief executive officer, and chairman of BeiGene, the company marketing lenalidomide as Revlimid in China under an exclusive license from Celgene Corporation.
Trial results
The CFDA’s decision to expand the approval of lenalidomide is based on results from the phase 3 FIRST trial. Updated results from this study were published in the Journal of Clinical Oncology in November 2016.
The trial included 1623 patients with newly diagnosed MM who were not eligible for stem cell transplant.
Patients were randomized to receive:
- Lenalidomide and low-dose dexamethasone (Rd) in 28-day cycles until disease progression (n=535), known as the “continuous Rd group”
- 18 cycles of Rd (Rd18) for 72 weeks (n=541), known as the “Rd18 group”
- Melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).
In the intent-to-treat population, the overall response rate was 81% for the continuous Rd group, 79% for the Rd18 group, and 67% in the MPT group. The complete response rates were 21%, 20%, and 12%, respectively.
The median progression-free survival was 26.0 months in the continuous Rd group, 21.0 months in the Rd18 group, and 21.9 months in the MPT group. At 4 years, progression-free survival rates were 33%, 14%, and 13%, respectively.
The median overall survival was 58.9 months in the continuous Rd group, 56.7 months in the Rd18 group, and 48.5 months in the MPT group. At 4 years, overall survival rates were 60%, 57%, and 51%, respectively.
The most frequent grade 3/4 hematologic treatment-emergent adverse events were neutropenia and anemia. The rate of grade 3/4 neutropenia was higher in the MPT group than the continuous Rd or Rd18 groups.
Infections were the most common grade 3/4 non-hematologic treatment-emergent adverse events. The rate of grade 3/4 infections was higher in the Rd groups than the MPT group.
Potential link between varicose veins and VTE, PAD
People with varicose veins may have an increased risk of venous thromboembolism (VTE) and peripheral artery disease (PAD), according to a new study.
The data suggested patients with varicose veins had a 5-fold higher risk of deep vein thrombosis (DVT) and roughly twice the risk of pulmonary embolism (PE) and PAD as patients without varicose veins.
Investigators said these results suggest an increased risk of DVT among patients with varicose veins, but “the findings for PE and PAD are less clear due to the potential for confounding.”
Pei-Chun Chen, PhD, of China Medical University in Taichung, Taiwan, and colleagues reported these findings in JAMA.
The team conducted this research using claims data in Taiwan’s National Health Insurance program. They assessed the risk of DVT, PE, and PAD in 212,984 patients with varicose veins and 212,984 control subjects. Patients and controls were matched by age, sex, and calendar year.
All study subjects were enrolled from 2001 to 2013 and followed through 2014.
Among the patients with varicose veins, the median duration of follow-up was 7.5 years for DVT, 7.8 years for PE, and 7.3 years for PAD. For controls, the median follow-up was 7.6 years for DVT, 7.7 years for PE, and 7.4 years for PAD.
Results
The incidence rate for DVT was 6.55 per 1000 person-years for patients with varicose veins (n=10,360) and 1.23 per 1000 person-years for controls (n=1980). The absolute risk difference (ARD) was 5.32.
The incidence rate for PE was 0.48 per 1000 person-years for patients with varicose veins (n=793) and 0.28 per 1000 person-years for controls (n=451). The ARD was 0.20.
The incidence rate for PAD was 10.73 per 1000 person-years for patients with varicose veins (n=16,615) and 6.22 for controls (n=9709). The ARD was 4.51.
The hazard ratios (for the varicose-veins group compared to controls) were 5.30 for DVT, 1.73 for PE, and 1.72 for PAD.
The investigators also calculated hazard ratios in a model adjusted for sex, age, index year, number of outpatient visits during the year before index date, and comorbidities. Comorbidities included hypertension, diabetes, chronic obstructive pulmonary disease, hyperlipidemia, malignancy, heart failure, ischemic heart disease, stroke, and chronic renal insufficiency.
In this adjusted model, the hazard ratios were 5.39 for DVT, 1.75 for PE, and 1.76 for PAD.
Limitations
The investigators said this study had several limitations.
First, the data did not include information for patients who didn’t seek medical care for varicose veins. Therefore, the results may reflect only the risk of VTE and PAD among patients with more severe varicose veins.
And the investigators were not able to examine whether the severity of varicose veins played a role in the risk of VTE or PAD.
In addition, information on some potential confounders, such as smoking and obesity, was not available. And the magnitude of the association between varicose veins and PE/PAD was small, so the association the investigators observed could be due to residual or unmeasured confounding.
The investigators also noted that diagnostic evaluations for PAD are more likely to occur in patients with varicose veins, which could partially explain the observed association between varicose veins and PAD.
Furthermore, cases of DVT, PE, and PAD could have been misclassified.
People with varicose veins may have an increased risk of venous thromboembolism (VTE) and peripheral artery disease (PAD), according to a new study.
The data suggested patients with varicose veins had a 5-fold higher risk of deep vein thrombosis (DVT) and roughly twice the risk of pulmonary embolism (PE) and PAD as patients without varicose veins.
Investigators said these results suggest an increased risk of DVT among patients with varicose veins, but “the findings for PE and PAD are less clear due to the potential for confounding.”
Pei-Chun Chen, PhD, of China Medical University in Taichung, Taiwan, and colleagues reported these findings in JAMA.
The team conducted this research using claims data in Taiwan’s National Health Insurance program. They assessed the risk of DVT, PE, and PAD in 212,984 patients with varicose veins and 212,984 control subjects. Patients and controls were matched by age, sex, and calendar year.
All study subjects were enrolled from 2001 to 2013 and followed through 2014.
Among the patients with varicose veins, the median duration of follow-up was 7.5 years for DVT, 7.8 years for PE, and 7.3 years for PAD. For controls, the median follow-up was 7.6 years for DVT, 7.7 years for PE, and 7.4 years for PAD.
Results
The incidence rate for DVT was 6.55 per 1000 person-years for patients with varicose veins (n=10,360) and 1.23 per 1000 person-years for controls (n=1980). The absolute risk difference (ARD) was 5.32.
The incidence rate for PE was 0.48 per 1000 person-years for patients with varicose veins (n=793) and 0.28 per 1000 person-years for controls (n=451). The ARD was 0.20.
The incidence rate for PAD was 10.73 per 1000 person-years for patients with varicose veins (n=16,615) and 6.22 for controls (n=9709). The ARD was 4.51.
The hazard ratios (for the varicose-veins group compared to controls) were 5.30 for DVT, 1.73 for PE, and 1.72 for PAD.
The investigators also calculated hazard ratios in a model adjusted for sex, age, index year, number of outpatient visits during the year before index date, and comorbidities. Comorbidities included hypertension, diabetes, chronic obstructive pulmonary disease, hyperlipidemia, malignancy, heart failure, ischemic heart disease, stroke, and chronic renal insufficiency.
In this adjusted model, the hazard ratios were 5.39 for DVT, 1.75 for PE, and 1.76 for PAD.
Limitations
The investigators said this study had several limitations.
First, the data did not include information for patients who didn’t seek medical care for varicose veins. Therefore, the results may reflect only the risk of VTE and PAD among patients with more severe varicose veins.
And the investigators were not able to examine whether the severity of varicose veins played a role in the risk of VTE or PAD.
In addition, information on some potential confounders, such as smoking and obesity, was not available. And the magnitude of the association between varicose veins and PE/PAD was small, so the association the investigators observed could be due to residual or unmeasured confounding.
The investigators also noted that diagnostic evaluations for PAD are more likely to occur in patients with varicose veins, which could partially explain the observed association between varicose veins and PAD.
Furthermore, cases of DVT, PE, and PAD could have been misclassified.
People with varicose veins may have an increased risk of venous thromboembolism (VTE) and peripheral artery disease (PAD), according to a new study.
The data suggested patients with varicose veins had a 5-fold higher risk of deep vein thrombosis (DVT) and roughly twice the risk of pulmonary embolism (PE) and PAD as patients without varicose veins.
Investigators said these results suggest an increased risk of DVT among patients with varicose veins, but “the findings for PE and PAD are less clear due to the potential for confounding.”
Pei-Chun Chen, PhD, of China Medical University in Taichung, Taiwan, and colleagues reported these findings in JAMA.
The team conducted this research using claims data in Taiwan’s National Health Insurance program. They assessed the risk of DVT, PE, and PAD in 212,984 patients with varicose veins and 212,984 control subjects. Patients and controls were matched by age, sex, and calendar year.
All study subjects were enrolled from 2001 to 2013 and followed through 2014.
Among the patients with varicose veins, the median duration of follow-up was 7.5 years for DVT, 7.8 years for PE, and 7.3 years for PAD. For controls, the median follow-up was 7.6 years for DVT, 7.7 years for PE, and 7.4 years for PAD.
Results
The incidence rate for DVT was 6.55 per 1000 person-years for patients with varicose veins (n=10,360) and 1.23 per 1000 person-years for controls (n=1980). The absolute risk difference (ARD) was 5.32.
The incidence rate for PE was 0.48 per 1000 person-years for patients with varicose veins (n=793) and 0.28 per 1000 person-years for controls (n=451). The ARD was 0.20.
The incidence rate for PAD was 10.73 per 1000 person-years for patients with varicose veins (n=16,615) and 6.22 for controls (n=9709). The ARD was 4.51.
The hazard ratios (for the varicose-veins group compared to controls) were 5.30 for DVT, 1.73 for PE, and 1.72 for PAD.
The investigators also calculated hazard ratios in a model adjusted for sex, age, index year, number of outpatient visits during the year before index date, and comorbidities. Comorbidities included hypertension, diabetes, chronic obstructive pulmonary disease, hyperlipidemia, malignancy, heart failure, ischemic heart disease, stroke, and chronic renal insufficiency.
In this adjusted model, the hazard ratios were 5.39 for DVT, 1.75 for PE, and 1.76 for PAD.
Limitations
The investigators said this study had several limitations.
First, the data did not include information for patients who didn’t seek medical care for varicose veins. Therefore, the results may reflect only the risk of VTE and PAD among patients with more severe varicose veins.
And the investigators were not able to examine whether the severity of varicose veins played a role in the risk of VTE or PAD.
In addition, information on some potential confounders, such as smoking and obesity, was not available. And the magnitude of the association between varicose veins and PE/PAD was small, so the association the investigators observed could be due to residual or unmeasured confounding.
The investigators also noted that diagnostic evaluations for PAD are more likely to occur in patients with varicose veins, which could partially explain the observed association between varicose veins and PAD.
Furthermore, cases of DVT, PE, and PAD could have been misclassified.
HSCT approach provides ‘excellent’ survival in FA
SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.
All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).
None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.
Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*
“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”
“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”
The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.
This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.
Patients
The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.
Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).
Eighteen patients had a history of transfusions, and 3 had a history of androgen use.
Treatment
The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m2/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).
Busulfan doses were adjusted according to age and disease status.
Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.
“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”
All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.
The median number of CD34+ cells/kg was 23.9 x 106 (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 104 (range, 0.003-3.1).
T-cell depletion was the only GVHD prophylaxis used.
Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.
Toxicity
There were no cases of acute or chronic GVHD.
Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).
There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).
Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”
“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.
“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”
Response and survival
All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).
Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).
The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.
The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.
“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.
“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”
*Data in the abstract differ from the presentation.
**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.
SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.
All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).
None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.
Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*
“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”
“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”
The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.
This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.
Patients
The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.
Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).
Eighteen patients had a history of transfusions, and 3 had a history of androgen use.
Treatment
The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m2/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).
Busulfan doses were adjusted according to age and disease status.
Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.
“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”
All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.
The median number of CD34+ cells/kg was 23.9 x 106 (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 104 (range, 0.003-3.1).
T-cell depletion was the only GVHD prophylaxis used.
Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.
Toxicity
There were no cases of acute or chronic GVHD.
Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).
There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).
Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”
“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.
“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”
Response and survival
All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).
Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).
The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.
The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.
“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.
“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”
*Data in the abstract differ from the presentation.
**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.
SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.
All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).
None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.
Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*
“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”
“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”
The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.
This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.
Patients
The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.
Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).
Eighteen patients had a history of transfusions, and 3 had a history of androgen use.
Treatment
The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m2/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).
Busulfan doses were adjusted according to age and disease status.
Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.
“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”
All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.
The median number of CD34+ cells/kg was 23.9 x 106 (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 104 (range, 0.003-3.1).
T-cell depletion was the only GVHD prophylaxis used.
Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.
Toxicity
There were no cases of acute or chronic GVHD.
Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).
There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).
Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”
“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.
“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”
Response and survival
All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).
Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).
The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.
The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.
“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.
“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”
*Data in the abstract differ from the presentation.
**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.
EC approves emicizumab for hemophilia A with inhibitors
The European Commission (EC) has granted marketing authorization for emicizumab (Hemlibra®), a bispecific factor IXa- and factor X-directed antibody.
This means emicizumab is approved for use in the European Union for routine prophylaxis of bleeding episodes in patients of all ages who have hemophilia A and factor VIII inhibitors.
The recommended dose of emicizumab is 3 mg/kg once a week for the first 4 weeks, followed by 1.5 mg/kg once a week.
Emicizumab is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for patients with hemophilia A.
Emicizumab was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche, and Genentech.
The EC’s decision to authorize marketing of emicizumab is based on results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.
Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.
HAVEN 1
This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).
Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
HAVEN 2
In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.
Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).
There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.
The European Commission (EC) has granted marketing authorization for emicizumab (Hemlibra®), a bispecific factor IXa- and factor X-directed antibody.
This means emicizumab is approved for use in the European Union for routine prophylaxis of bleeding episodes in patients of all ages who have hemophilia A and factor VIII inhibitors.
The recommended dose of emicizumab is 3 mg/kg once a week for the first 4 weeks, followed by 1.5 mg/kg once a week.
Emicizumab is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for patients with hemophilia A.
Emicizumab was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche, and Genentech.
The EC’s decision to authorize marketing of emicizumab is based on results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.
Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.
HAVEN 1
This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).
Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
HAVEN 2
In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.
Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).
There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.
The European Commission (EC) has granted marketing authorization for emicizumab (Hemlibra®), a bispecific factor IXa- and factor X-directed antibody.
This means emicizumab is approved for use in the European Union for routine prophylaxis of bleeding episodes in patients of all ages who have hemophilia A and factor VIII inhibitors.
The recommended dose of emicizumab is 3 mg/kg once a week for the first 4 weeks, followed by 1.5 mg/kg once a week.
Emicizumab is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for patients with hemophilia A.
Emicizumab was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche, and Genentech.
The EC’s decision to authorize marketing of emicizumab is based on results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.
Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.
HAVEN 1
This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).
Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
HAVEN 2
In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.
Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).
There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.
Use of RBC, plasma transfusions may be declining in US
A study of US hospital discharges revealed a decrease in the use of red blood cell (RBC) and plasma transfusions—but not platelet transfusions—in recent years.
Researchers examined a sample of US hospital inpatient discharges from 1993 to 2014.
Overall, platelet, plasma, and RBC transfusions increased from 1993 to 2010.
However, from 2011 to 2014, there was a significant decrease in both plasma and RBC transfusions. Platelet transfusions remained stable over that period.
Aaron A. R. Tobian, MD, PhD, of Johns Hopkins University in Baltimore, Maryland, and his colleagues reported these findings in a letter to JAMA.
The researchers analyzed data from the National Inpatient Sample, which uses a stratified probability sample of 20% of all inpatient discharges in the US.
The team looked at transfusion trends from 1993 to 2014 but focused on trends from 2011 to 2014 because there was an inflection point in RBC transfusion in 2011. They used multivariable Poisson regression to estimate adjusted risk ratios (aRRs) comparing the risk of transfusion in 2011 and 2014.
The researchers found that RBC transfusions decreased from 6.8% in 2011 to 5.7% in 2014 (aRR=0.83; 95% confidence interval [CI], 0.78-0.88; P<0.001).
Plasma transfusions decreased from 1.0% to 0.87% (aRR=0.87; 95% CI, 0.80-0.95; P=0.003). And platelet transfusions remained stable (aRR=0.99; 95% CI, 0.89-1.10; P=0.93).
The researchers also conducted subgroup analyses to explore trends in RBC transfusion. They found that, from 2011 to 2014, there were significant reductions in RBC transfusions regardless of patients’ sex, race/ethnicity, risk severity, payer type, and admission type.
However, there was no significant reduction in RBC transfusions among patients younger than 18 years of age or in private investor–owned hospitals.
The researchers said the diagnostic coding used for this study was carried out primarily for billing purposes, and it was not possible to verify its accuracy. They also noted that the study only covered inpatient transfusions, so the results may not be generalizable to outpatient transfusions.
A study of US hospital discharges revealed a decrease in the use of red blood cell (RBC) and plasma transfusions—but not platelet transfusions—in recent years.
Researchers examined a sample of US hospital inpatient discharges from 1993 to 2014.
Overall, platelet, plasma, and RBC transfusions increased from 1993 to 2010.
However, from 2011 to 2014, there was a significant decrease in both plasma and RBC transfusions. Platelet transfusions remained stable over that period.
Aaron A. R. Tobian, MD, PhD, of Johns Hopkins University in Baltimore, Maryland, and his colleagues reported these findings in a letter to JAMA.
The researchers analyzed data from the National Inpatient Sample, which uses a stratified probability sample of 20% of all inpatient discharges in the US.
The team looked at transfusion trends from 1993 to 2014 but focused on trends from 2011 to 2014 because there was an inflection point in RBC transfusion in 2011. They used multivariable Poisson regression to estimate adjusted risk ratios (aRRs) comparing the risk of transfusion in 2011 and 2014.
The researchers found that RBC transfusions decreased from 6.8% in 2011 to 5.7% in 2014 (aRR=0.83; 95% confidence interval [CI], 0.78-0.88; P<0.001).
Plasma transfusions decreased from 1.0% to 0.87% (aRR=0.87; 95% CI, 0.80-0.95; P=0.003). And platelet transfusions remained stable (aRR=0.99; 95% CI, 0.89-1.10; P=0.93).
The researchers also conducted subgroup analyses to explore trends in RBC transfusion. They found that, from 2011 to 2014, there were significant reductions in RBC transfusions regardless of patients’ sex, race/ethnicity, risk severity, payer type, and admission type.
However, there was no significant reduction in RBC transfusions among patients younger than 18 years of age or in private investor–owned hospitals.
The researchers said the diagnostic coding used for this study was carried out primarily for billing purposes, and it was not possible to verify its accuracy. They also noted that the study only covered inpatient transfusions, so the results may not be generalizable to outpatient transfusions.
A study of US hospital discharges revealed a decrease in the use of red blood cell (RBC) and plasma transfusions—but not platelet transfusions—in recent years.
Researchers examined a sample of US hospital inpatient discharges from 1993 to 2014.
Overall, platelet, plasma, and RBC transfusions increased from 1993 to 2010.
However, from 2011 to 2014, there was a significant decrease in both plasma and RBC transfusions. Platelet transfusions remained stable over that period.
Aaron A. R. Tobian, MD, PhD, of Johns Hopkins University in Baltimore, Maryland, and his colleagues reported these findings in a letter to JAMA.
The researchers analyzed data from the National Inpatient Sample, which uses a stratified probability sample of 20% of all inpatient discharges in the US.
The team looked at transfusion trends from 1993 to 2014 but focused on trends from 2011 to 2014 because there was an inflection point in RBC transfusion in 2011. They used multivariable Poisson regression to estimate adjusted risk ratios (aRRs) comparing the risk of transfusion in 2011 and 2014.
The researchers found that RBC transfusions decreased from 6.8% in 2011 to 5.7% in 2014 (aRR=0.83; 95% confidence interval [CI], 0.78-0.88; P<0.001).
Plasma transfusions decreased from 1.0% to 0.87% (aRR=0.87; 95% CI, 0.80-0.95; P=0.003). And platelet transfusions remained stable (aRR=0.99; 95% CI, 0.89-1.10; P=0.93).
The researchers also conducted subgroup analyses to explore trends in RBC transfusion. They found that, from 2011 to 2014, there were significant reductions in RBC transfusions regardless of patients’ sex, race/ethnicity, risk severity, payer type, and admission type.
However, there was no significant reduction in RBC transfusions among patients younger than 18 years of age or in private investor–owned hospitals.
The researchers said the diagnostic coding used for this study was carried out primarily for billing purposes, and it was not possible to verify its accuracy. They also noted that the study only covered inpatient transfusions, so the results may not be generalizable to outpatient transfusions.
Study confirms higher risk of infection with CB transplant
SALT LAKE CITY—Results of a large, retrospective analysis support the notion that patients who receive cord blood (CB) transplants have a higher risk of infection than other hematopoietic stem cell transplant (HSCT) recipients.
Investigators found that CB recipients had a significantly higher risk of bacterial, viral, and fungal infections in the early post-transplant period than patients who received peripheral blood (PB) or bone marrow (BM) transplants.
In addition, CB recipients had longer hospital stays, higher inpatient costs, and greater inpatient mortality than PB and BM recipients.
Amandeep Godara, MD, of Tufts Medical Center in Boston, Massachusetts, presented these results at the 2018 BMT Tandem Meetings (abstract 30*).
“Infections are considered more common in cord blood transplant recipients based on some prior retrospective analyses,” Dr Godara noted. “But there is limited data comparing these infectious complications between cord blood transplant and peripheral blood/bone marrow stem cell transplants during the inpatient stay for the stem cell transplant.”
With this in mind, Dr Godara and his colleagues analyzed data from the Healthcare Cost and Utilization Project National Inpatient Sample. This database covers 46 US states and contains data from more than 7 million hospital stays each year.
The investigators searched the database for hospital admissions for HSCT from 2002 to 2014. They identified 2979 CB transplants and 56,845 PB or BM transplants.
The CB recipients had a median age of 48, and 55% were male. Fifty-nine percent were white, 18% Hispanic, 13% black, 5% Asian, and 5% “other.” Sixty-six percent of patients had acute leukemia, 18% non-Hodgkin lymphoma, 5% Hodgkin lymphoma, and 11% “other” diseases.
The PB/BM recipients had a median age of 45, and 58% were male. Seventy-nine percent were white, 8% Hispanic, 6% black, 3% Asian, and 4% “other.” Sixty-one percent of patients had acute leukemia, 16% non-Hodgkin lymphoma, 4% Hodgkin lymphoma, and 19% “other” diseases.
Results
Dr Godara and his colleagues compared the rates and types of infection from the time of HSCT to hospital discharge in CB and PB/BM recipients. The team also compared early inpatient mortality, the cost of hospitalization, and the length of hospital stay.
“[W]e observed a higher risk for infections in cord blood transplant patients compared to peripheral blood and bone marrow stem cell transplant patients, and this risk for infection extended through a wide spectrum of pathogens,” Dr Godara said.
“We also observed a higher all-cause inpatient mortality in cord blood transplant compared to peripheral blood and bone marrow transplant, especially in patients who had bacterial sepsis or invasive fungal infection.”
The rate of bacterial sepsis was 34.87% in CB recipients and 20.20% in PB/BM recipients (P<0.0001). Rates of viral infection were 20.05% and 8.19%, respectively (P<0.0001). And rates of invasive fungal infection were 12.87% and 7.89% (P<0.0001).
There was a similar distribution of bacterial infections in CB and PB/BM recipients. The most common was pneumonia (47% and 41%, respectively), followed by abdominal infections (29% and 31%, respectively), urinary tract infections (17% and 21%, respectively), central line-associated bloodstream infections (4% and 6%, respectively), and acute sinusitis (3% and 1%, respectively).
The rate of Clostridium difficile infection was significantly higher in CB recipients than PB/BM recipients—11.75% and 8.90%, respectively (P=0.02). However, there was no significant difference in mortality related to C. difficile—14% and 10%, respectively (P=0.3).
On the other hand, all-cause inpatient mortality was significantly higher in CB recipients than PB/BM recipients—16% and 7%, respectively (P<0.0001).
Inpatient mortality rates were significantly higher for CB recipients with bacterial sepsis (33% vs 23%, P=0.001) and invasive fungal infections (29% vs 16%, P=0.0045) but not viral infections (19% vs 17%, P=0.5).
The median length of hospital stay was 36 days for CB recipients and 25 days for PB/BM recipients. The mean inpatient charges were $448,892 and $250,437 respectively.
*Data in the abstract differ from the presentation.
SALT LAKE CITY—Results of a large, retrospective analysis support the notion that patients who receive cord blood (CB) transplants have a higher risk of infection than other hematopoietic stem cell transplant (HSCT) recipients.
Investigators found that CB recipients had a significantly higher risk of bacterial, viral, and fungal infections in the early post-transplant period than patients who received peripheral blood (PB) or bone marrow (BM) transplants.
In addition, CB recipients had longer hospital stays, higher inpatient costs, and greater inpatient mortality than PB and BM recipients.
Amandeep Godara, MD, of Tufts Medical Center in Boston, Massachusetts, presented these results at the 2018 BMT Tandem Meetings (abstract 30*).
“Infections are considered more common in cord blood transplant recipients based on some prior retrospective analyses,” Dr Godara noted. “But there is limited data comparing these infectious complications between cord blood transplant and peripheral blood/bone marrow stem cell transplants during the inpatient stay for the stem cell transplant.”
With this in mind, Dr Godara and his colleagues analyzed data from the Healthcare Cost and Utilization Project National Inpatient Sample. This database covers 46 US states and contains data from more than 7 million hospital stays each year.
The investigators searched the database for hospital admissions for HSCT from 2002 to 2014. They identified 2979 CB transplants and 56,845 PB or BM transplants.
The CB recipients had a median age of 48, and 55% were male. Fifty-nine percent were white, 18% Hispanic, 13% black, 5% Asian, and 5% “other.” Sixty-six percent of patients had acute leukemia, 18% non-Hodgkin lymphoma, 5% Hodgkin lymphoma, and 11% “other” diseases.
The PB/BM recipients had a median age of 45, and 58% were male. Seventy-nine percent were white, 8% Hispanic, 6% black, 3% Asian, and 4% “other.” Sixty-one percent of patients had acute leukemia, 16% non-Hodgkin lymphoma, 4% Hodgkin lymphoma, and 19% “other” diseases.
Results
Dr Godara and his colleagues compared the rates and types of infection from the time of HSCT to hospital discharge in CB and PB/BM recipients. The team also compared early inpatient mortality, the cost of hospitalization, and the length of hospital stay.
“[W]e observed a higher risk for infections in cord blood transplant patients compared to peripheral blood and bone marrow stem cell transplant patients, and this risk for infection extended through a wide spectrum of pathogens,” Dr Godara said.
“We also observed a higher all-cause inpatient mortality in cord blood transplant compared to peripheral blood and bone marrow transplant, especially in patients who had bacterial sepsis or invasive fungal infection.”
The rate of bacterial sepsis was 34.87% in CB recipients and 20.20% in PB/BM recipients (P<0.0001). Rates of viral infection were 20.05% and 8.19%, respectively (P<0.0001). And rates of invasive fungal infection were 12.87% and 7.89% (P<0.0001).
There was a similar distribution of bacterial infections in CB and PB/BM recipients. The most common was pneumonia (47% and 41%, respectively), followed by abdominal infections (29% and 31%, respectively), urinary tract infections (17% and 21%, respectively), central line-associated bloodstream infections (4% and 6%, respectively), and acute sinusitis (3% and 1%, respectively).
The rate of Clostridium difficile infection was significantly higher in CB recipients than PB/BM recipients—11.75% and 8.90%, respectively (P=0.02). However, there was no significant difference in mortality related to C. difficile—14% and 10%, respectively (P=0.3).
On the other hand, all-cause inpatient mortality was significantly higher in CB recipients than PB/BM recipients—16% and 7%, respectively (P<0.0001).
Inpatient mortality rates were significantly higher for CB recipients with bacterial sepsis (33% vs 23%, P=0.001) and invasive fungal infections (29% vs 16%, P=0.0045) but not viral infections (19% vs 17%, P=0.5).
The median length of hospital stay was 36 days for CB recipients and 25 days for PB/BM recipients. The mean inpatient charges were $448,892 and $250,437 respectively.
*Data in the abstract differ from the presentation.
SALT LAKE CITY—Results of a large, retrospective analysis support the notion that patients who receive cord blood (CB) transplants have a higher risk of infection than other hematopoietic stem cell transplant (HSCT) recipients.
Investigators found that CB recipients had a significantly higher risk of bacterial, viral, and fungal infections in the early post-transplant period than patients who received peripheral blood (PB) or bone marrow (BM) transplants.
In addition, CB recipients had longer hospital stays, higher inpatient costs, and greater inpatient mortality than PB and BM recipients.
Amandeep Godara, MD, of Tufts Medical Center in Boston, Massachusetts, presented these results at the 2018 BMT Tandem Meetings (abstract 30*).
“Infections are considered more common in cord blood transplant recipients based on some prior retrospective analyses,” Dr Godara noted. “But there is limited data comparing these infectious complications between cord blood transplant and peripheral blood/bone marrow stem cell transplants during the inpatient stay for the stem cell transplant.”
With this in mind, Dr Godara and his colleagues analyzed data from the Healthcare Cost and Utilization Project National Inpatient Sample. This database covers 46 US states and contains data from more than 7 million hospital stays each year.
The investigators searched the database for hospital admissions for HSCT from 2002 to 2014. They identified 2979 CB transplants and 56,845 PB or BM transplants.
The CB recipients had a median age of 48, and 55% were male. Fifty-nine percent were white, 18% Hispanic, 13% black, 5% Asian, and 5% “other.” Sixty-six percent of patients had acute leukemia, 18% non-Hodgkin lymphoma, 5% Hodgkin lymphoma, and 11% “other” diseases.
The PB/BM recipients had a median age of 45, and 58% were male. Seventy-nine percent were white, 8% Hispanic, 6% black, 3% Asian, and 4% “other.” Sixty-one percent of patients had acute leukemia, 16% non-Hodgkin lymphoma, 4% Hodgkin lymphoma, and 19% “other” diseases.
Results
Dr Godara and his colleagues compared the rates and types of infection from the time of HSCT to hospital discharge in CB and PB/BM recipients. The team also compared early inpatient mortality, the cost of hospitalization, and the length of hospital stay.
“[W]e observed a higher risk for infections in cord blood transplant patients compared to peripheral blood and bone marrow stem cell transplant patients, and this risk for infection extended through a wide spectrum of pathogens,” Dr Godara said.
“We also observed a higher all-cause inpatient mortality in cord blood transplant compared to peripheral blood and bone marrow transplant, especially in patients who had bacterial sepsis or invasive fungal infection.”
The rate of bacterial sepsis was 34.87% in CB recipients and 20.20% in PB/BM recipients (P<0.0001). Rates of viral infection were 20.05% and 8.19%, respectively (P<0.0001). And rates of invasive fungal infection were 12.87% and 7.89% (P<0.0001).
There was a similar distribution of bacterial infections in CB and PB/BM recipients. The most common was pneumonia (47% and 41%, respectively), followed by abdominal infections (29% and 31%, respectively), urinary tract infections (17% and 21%, respectively), central line-associated bloodstream infections (4% and 6%, respectively), and acute sinusitis (3% and 1%, respectively).
The rate of Clostridium difficile infection was significantly higher in CB recipients than PB/BM recipients—11.75% and 8.90%, respectively (P=0.02). However, there was no significant difference in mortality related to C. difficile—14% and 10%, respectively (P=0.3).
On the other hand, all-cause inpatient mortality was significantly higher in CB recipients than PB/BM recipients—16% and 7%, respectively (P<0.0001).
Inpatient mortality rates were significantly higher for CB recipients with bacterial sepsis (33% vs 23%, P=0.001) and invasive fungal infections (29% vs 16%, P=0.0045) but not viral infections (19% vs 17%, P=0.5).
The median length of hospital stay was 36 days for CB recipients and 25 days for PB/BM recipients. The mean inpatient charges were $448,892 and $250,437 respectively.
*Data in the abstract differ from the presentation.
CHMP recommends approval for GO in AML
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for gemtuzumab ozogamicin (GO, Mylotarg™).
The recommendation is for GO to be used in combination with daunorubicin and cytarabine to treat patients age 15 years and older with previously untreated, de novo, CD33-positive acute myeloid leukemia (AML) but not acute promyelocytic leukemia.
The CHMP’s opinion on GO will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
Previous rejection
The CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.
The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.
The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.
Phase 3 trial
The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.
Patients and treatment
ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.
Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m2 on days 1 to 3) and cytarabine (200 mg/m2 on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m2 (up to maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.
Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m2 on day 1 of first consolidation course; 60 mg/m2 on days 1 and 2 of second consolidation course) and cytarabine (1 g/m2 every 12 hours on days 1 to 4) with or without GO at 3 mg/m2 (up to a maximum of 1 vial) on day 1 according to their initial randomization.
Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.
Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.
Results
The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).
There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been provided).
All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.
Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.
Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).
Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for gemtuzumab ozogamicin (GO, Mylotarg™).
The recommendation is for GO to be used in combination with daunorubicin and cytarabine to treat patients age 15 years and older with previously untreated, de novo, CD33-positive acute myeloid leukemia (AML) but not acute promyelocytic leukemia.
The CHMP’s opinion on GO will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
Previous rejection
The CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.
The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.
The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.
Phase 3 trial
The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.
Patients and treatment
ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.
Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m2 on days 1 to 3) and cytarabine (200 mg/m2 on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m2 (up to maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.
Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m2 on day 1 of first consolidation course; 60 mg/m2 on days 1 and 2 of second consolidation course) and cytarabine (1 g/m2 every 12 hours on days 1 to 4) with or without GO at 3 mg/m2 (up to a maximum of 1 vial) on day 1 according to their initial randomization.
Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.
Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.
Results
The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).
There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been provided).
All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.
Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.
Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).
Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for gemtuzumab ozogamicin (GO, Mylotarg™).
The recommendation is for GO to be used in combination with daunorubicin and cytarabine to treat patients age 15 years and older with previously untreated, de novo, CD33-positive acute myeloid leukemia (AML) but not acute promyelocytic leukemia.
The CHMP’s opinion on GO will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP, the commission will grant a centralized marketing authorization that will be valid in the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions on the basis of the EC’s decision.
The EC typically makes a decision within 67 days of the CHMP’s recommendation.
Previous rejection
The CHMP previously issued a negative opinion of GO (first in 2007, confirmed in 2008), saying the drug should not receive marketing authorization.
The proposed indication for GO at that time was as re-induction treatment in adults with CD33-positive AML in first relapse who were not candidates for other intensive re-induction chemotherapy regimens and were either older than 60 or had a duration of first remission lasting less than 12 months.
The CHMP said there was insufficient evidence to establish the effectiveness of GO in AML, and the drug’s benefits did not outweigh its risks.
Phase 3 trial
The current marketing authorization application for GO is supported by data from an investigator-led, phase 3, randomized trial known as ALFA-0701. Updated results from this trial are available in the US prescribing information for GO.
Patients and treatment
ALFA-0701 included 271 patients with newly diagnosed, de novo AML who were 50 to 70 years of age.
Patients were randomized (1:1) to receive induction consisting of daunorubicin (60 mg/m2 on days 1 to 3) and cytarabine (200 mg/m2 on days 1 to 7) with (n=135) or without (n=136) GO at 3 mg/m2 (up to maximum of 1 vial) on days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone.
Patients with a response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m2 on day 1 of first consolidation course; 60 mg/m2 on days 1 and 2 of second consolidation course) and cytarabine (1 g/m2 every 12 hours on days 1 to 4) with or without GO at 3 mg/m2 (up to a maximum of 1 vial) on day 1 according to their initial randomization.
Patients who achieved remission were also eligible for allogeneic transplant. An interval of at least 2 months between the last dose of GO and transplant was recommended.
Baseline characteristics were largely well balanced between the treatment arms, but there was a higher percentage of males in the GO arm than the control arm—55% and 44%, respectively.
Results
The study’s primary endpoint was event-free survival. The median event-free survival was 17.3 months in the GO arm and 9.5 months in the control arm (hazard ratio=0.56; 95% CI: 0.42-0.76; P<0.001).
There was no significant difference in overall survival between the treatment arms. (Updated overall survival data have not been provided).
All patients in this trial developed severe neutropenia, thrombocytopenia, and anemia. However, the incidence of prolonged, grade 3–4 thrombocytopenia in the absence of active leukemia was higher in the GO arm.
Treatment-emergent adverse events (AEs) considered most important for understanding the safety profile of GO were hemorrhage, veno-occlusive liver disease (VOD), and severe infections.
Treatment discontinuation due to any AE occurred in 31% of patients in the GO arm and 7% of those in the control arm. The most frequent AEs leading to discontinuation for patients on GO were thrombocytopenia (15%), VOD (3%), and septic shock (2%).
Fatal AEs occurred in 8 patients (6%) in the GO arm and 3 (2%) in the control arm. In the GO arm, 3 patients died of VOD, 4 died of hemorrhage-related events, and 1 died of a suspected cardiac cause. All 3 fatal AEs in the control arm were sepsis.
Company withdraws application for idelalisib
Gilead Sciences International Ltd. recently withdrew its application for European approval of idelalisib (Zydelig) in combination with rituximab and bendamustine for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL).
Idelalisib is currently approved in the European Union for use in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab) to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment of CLL in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
In seeking expanded approval for idelalisib, Gilead submitted data from a study (NCT01569295) comparing idelalisib plus bendamustine and rituximab to placebo plus bendamustine and rituximab.
Interim results from this study were published in The Lancet Oncology in March 2017.
Gilead withdrew the application for idelalisib after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) had evaluated documentation provided by the company and formulated lists of questions.
Gilead had not responded to the last round of questions at the time of the withdrawal.
At that point, the CHMP was of the provisional opinion that idelalisib should not be approved for use in combination with rituximab and bendamustine in patients with relapsed/refractory CLL.
The CHMP said additional, longer-term data are needed to show the benefits of idelalisib plus rituximab and bendamustine outweigh the risks.
Gilead said its withdrawal of the application was based on the CHMP’s opinion that there was insufficient evidence of a favorable benefit-risk profile.
The company also said the withdrawal does not impact ongoing trials of idelalisib.
Gilead Sciences International Ltd. recently withdrew its application for European approval of idelalisib (Zydelig) in combination with rituximab and bendamustine for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL).
Idelalisib is currently approved in the European Union for use in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab) to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment of CLL in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
In seeking expanded approval for idelalisib, Gilead submitted data from a study (NCT01569295) comparing idelalisib plus bendamustine and rituximab to placebo plus bendamustine and rituximab.
Interim results from this study were published in The Lancet Oncology in March 2017.
Gilead withdrew the application for idelalisib after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) had evaluated documentation provided by the company and formulated lists of questions.
Gilead had not responded to the last round of questions at the time of the withdrawal.
At that point, the CHMP was of the provisional opinion that idelalisib should not be approved for use in combination with rituximab and bendamustine in patients with relapsed/refractory CLL.
The CHMP said additional, longer-term data are needed to show the benefits of idelalisib plus rituximab and bendamustine outweigh the risks.
Gilead said its withdrawal of the application was based on the CHMP’s opinion that there was insufficient evidence of a favorable benefit-risk profile.
The company also said the withdrawal does not impact ongoing trials of idelalisib.
Gilead Sciences International Ltd. recently withdrew its application for European approval of idelalisib (Zydelig) in combination with rituximab and bendamustine for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL).
Idelalisib is currently approved in the European Union for use in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab) to treat adults with CLL who have received at least 1 prior therapy or as first-line treatment of CLL in the presence of 17p deletion or TP53 mutation in patients who are not eligible for any other therapies.
Idelalisib is also approved as monotherapy for adults with follicular lymphoma that is refractory to 2 prior lines of treatment.
In seeking expanded approval for idelalisib, Gilead submitted data from a study (NCT01569295) comparing idelalisib plus bendamustine and rituximab to placebo plus bendamustine and rituximab.
Interim results from this study were published in The Lancet Oncology in March 2017.
Gilead withdrew the application for idelalisib after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) had evaluated documentation provided by the company and formulated lists of questions.
Gilead had not responded to the last round of questions at the time of the withdrawal.
At that point, the CHMP was of the provisional opinion that idelalisib should not be approved for use in combination with rituximab and bendamustine in patients with relapsed/refractory CLL.
The CHMP said additional, longer-term data are needed to show the benefits of idelalisib plus rituximab and bendamustine outweigh the risks.
Gilead said its withdrawal of the application was based on the CHMP’s opinion that there was insufficient evidence of a favorable benefit-risk profile.
The company also said the withdrawal does not impact ongoing trials of idelalisib.