The Diagnosis: Crusted Scabies

Approximately 1 year prior to presentation the patient completed a course of therapy comprised of repeat doses of ivermectin and permethrin for crusted scabies. He stated that the crusts had recurred shortly after treatment (Figure 1). The initial differential diagnosis included crusted scabies, pityriasis rubra pilaris, and psoriasis. Scraping from the interdigital web space (Figure 2) revealed multiple scabies mites, scabella, and ova (Figure 3). The patient was diagnosed with crusted scabies. Laboratory test results revealed a normal white blood cell count of 7300/μL, with an elevated eosinophil count of 1900/μL (reference range, <500/μL). Human T-lymphotropic virus 1 (HTLV-1) was found to be positive. Serum protein electrophoresis showed a moderate polyclonal increase in gamma globulins. Treatment was promptly initiated with permethrin cream 5% applied to the whole body for a total of 2 treatments that were administered 7 days apart. Ivermectin also was started at 200 μg/kg and was given on days 1, 7, 14, and 29. Salicylic acid cream 25% was applied daily to help hasten resolution of the crusts.

Human T-lymphotropic virus 1 is endemic to Japan, Central and South America, the Middle East, and regions of Africa and the Caribbean.¹ Multiple cases of HTLV-1 associated with crusted scabies have been reported in endemic areas.^2-6 In the present case, we encountered a patient with crusted scabies and HTLV-1 in a nonendemic area.

Cases of HTLV-1 and crusted scabies have been reported in Brazil, Peru, and Central Australia.^3,4,7 A retrospective study in Brazil showed a notable association between HTLV-1 infection and crusted scabies; of 23 patients with crusted scabies, 21 were HTLV-1 positive.³ In another small study from Peru, 23 patients with crusted scabies were tested for HTLV-1 and 16 (70%) were seropositive.⁴ Neither study had a control group for comparison; however, interestingly, the estimated seroprevalence in the general population (based on blood donors) is only 0.04% to 1% and 1.2% to 1.7% in Brazil and Peru, respectively, thus reinforcing the association between HTLV-1 and crusted scabies.¹ Crusted scabies and HTLV-1 seropositivity acting as a predictor for adult T-cell leukemia/lymphoma (ATL) has been reported⁸ but not consistently.³ Our patient had abnormal serum protein electrophoresis findings. Although the results were not diagnostic of ATL, patients with HTLV-1 are at increased risk for ATL and the pres-ence of this virus is important to document when there is a high index of suspicion for ATL, as with crusted scabies.

Our patient resided in the northeastern United States and there was no evidence in support of underlying immunosuppression. This case of crusted scabies is unique because the patient was HTLV-1 positive without other underlying immunocompromise and he resided in a region where HTLV-1 is nonendemic. In light of these findings, the present case serves as a reminder to check for HTLV-1 infection in those patients with severe or crusted scabies and without an identifiable reason for immunosuppression, even if the patient resides in an area that is nonendemic for HTLV-1.

The Diagnosis: Crusted Scabies

Approximately 1 year prior to presentation the patient completed a course of therapy comprised of repeat doses of ivermectin and permethrin for crusted scabies. He stated that the crusts had recurred shortly after treatment (Figure 1). The initial differential diagnosis included crusted scabies, pityriasis rubra pilaris, and psoriasis. Scraping from the interdigital web space (Figure 2) revealed multiple scabies mites, scabella, and ova (Figure 3). The patient was diagnosed with crusted scabies. Laboratory test results revealed a normal white blood cell count of 7300/μL, with an elevated eosinophil count of 1900/μL (reference range, <500/μL). Human T-lymphotropic virus 1 (HTLV-1) was found to be positive. Serum protein electrophoresis showed a moderate polyclonal increase in gamma globulins. Treatment was promptly initiated with permethrin cream 5% applied to the whole body for a total of 2 treatments that were administered 7 days apart. Ivermectin also was started at 200 μg/kg and was given on days 1, 7, 14, and 29. Salicylic acid cream 25% was applied daily to help hasten resolution of the crusts.

Human T-lymphotropic virus 1 is endemic to Japan, Central and South America, the Middle East, and regions of Africa and the Caribbean.¹ Multiple cases of HTLV-1 associated with crusted scabies have been reported in endemic areas.^2-6 In the present case, we encountered a patient with crusted scabies and HTLV-1 in a nonendemic area.

Cases of HTLV-1 and crusted scabies have been reported in Brazil, Peru, and Central Australia.^3,4,7 A retrospective study in Brazil showed a notable association between HTLV-1 infection and crusted scabies; of 23 patients with crusted scabies, 21 were HTLV-1 positive.³ In another small study from Peru, 23 patients with crusted scabies were tested for HTLV-1 and 16 (70%) were seropositive.⁴ Neither study had a control group for comparison; however, interestingly, the estimated seroprevalence in the general population (based on blood donors) is only 0.04% to 1% and 1.2% to 1.7% in Brazil and Peru, respectively, thus reinforcing the association between HTLV-1 and crusted scabies.¹ Crusted scabies and HTLV-1 seropositivity acting as a predictor for adult T-cell leukemia/lymphoma (ATL) has been reported⁸ but not consistently.³ Our patient had abnormal serum protein electrophoresis findings. Although the results were not diagnostic of ATL, patients with HTLV-1 are at increased risk for ATL and the pres-ence of this virus is important to document when there is a high index of suspicion for ATL, as with crusted scabies.

Our patient resided in the northeastern United States and there was no evidence in support of underlying immunosuppression. This case of crusted scabies is unique because the patient was HTLV-1 positive without other underlying immunocompromise and he resided in a region where HTLV-1 is nonendemic. In light of these findings, the present case serves as a reminder to check for HTLV-1 infection in those patients with severe or crusted scabies and without an identifiable reason for immunosuppression, even if the patient resides in an area that is nonendemic for HTLV-1.

The Diagnosis: Crusted Scabies

Approximately 1 year prior to presentation the patient completed a course of therapy comprised of repeat doses of ivermectin and permethrin for crusted scabies. He stated that the crusts had recurred shortly after treatment (Figure 1). The initial differential diagnosis included crusted scabies, pityriasis rubra pilaris, and psoriasis. Scraping from the interdigital web space (Figure 2) revealed multiple scabies mites, scabella, and ova (Figure 3). The patient was diagnosed with crusted scabies. Laboratory test results revealed a normal white blood cell count of 7300/μL, with an elevated eosinophil count of 1900/μL (reference range, <500/μL). Human T-lymphotropic virus 1 (HTLV-1) was found to be positive. Serum protein electrophoresis showed a moderate polyclonal increase in gamma globulins. Treatment was promptly initiated with permethrin cream 5% applied to the whole body for a total of 2 treatments that were administered 7 days apart. Ivermectin also was started at 200 μg/kg and was given on days 1, 7, 14, and 29. Salicylic acid cream 25% was applied daily to help hasten resolution of the crusts.

Human T-lymphotropic virus 1 is endemic to Japan, Central and South America, the Middle East, and regions of Africa and the Caribbean.¹ Multiple cases of HTLV-1 associated with crusted scabies have been reported in endemic areas.^2-6 In the present case, we encountered a patient with crusted scabies and HTLV-1 in a nonendemic area.

Cases of HTLV-1 and crusted scabies have been reported in Brazil, Peru, and Central Australia.^3,4,7 A retrospective study in Brazil showed a notable association between HTLV-1 infection and crusted scabies; of 23 patients with crusted scabies, 21 were HTLV-1 positive.³ In another small study from Peru, 23 patients with crusted scabies were tested for HTLV-1 and 16 (70%) were seropositive.⁴ Neither study had a control group for comparison; however, interestingly, the estimated seroprevalence in the general population (based on blood donors) is only 0.04% to 1% and 1.2% to 1.7% in Brazil and Peru, respectively, thus reinforcing the association between HTLV-1 and crusted scabies.¹ Crusted scabies and HTLV-1 seropositivity acting as a predictor for adult T-cell leukemia/lymphoma (ATL) has been reported⁸ but not consistently.³ Our patient had abnormal serum protein electrophoresis findings. Although the results were not diagnostic of ATL, patients with HTLV-1 are at increased risk for ATL and the pres-ence of this virus is important to document when there is a high index of suspicion for ATL, as with crusted scabies.

Our patient resided in the northeastern United States and there was no evidence in support of underlying immunosuppression. This case of crusted scabies is unique because the patient was HTLV-1 positive without other underlying immunocompromise and he resided in a region where HTLV-1 is nonendemic. In light of these findings, the present case serves as a reminder to check for HTLV-1 infection in those patients with severe or crusted scabies and without an identifiable reason for immunosuppression, even if the patient resides in an area that is nonendemic for HTLV-1.

NEW YORK - Inflammation may contribute to impaired cerebral vasoregulation in type 2 diabetes, research suggests.

In a two-year study, participants with type 2 diabetes experienced diminished regional and global vasoreactivity in the brain, as well as a decline in cognitive function and the ability to perform daily tasks.

Higher blood levels of inflammatory markers were correlated with decreases in cerebral vasoreactivity and vasodilation in the diabetic subjects, but not in controls.

"Normal blood flow regulation allows the brain to redistribute blood to areas of the brain that have increased activity while performing certain tasks," senior author Dr. Vera Novak, of Beth Israel Deaconess Medical Center in Boston, said in a news release. "People with type 2 diabetes have impaired blood flow regulation. Our results suggest that diabetes and high blood sugar impose a chronic negative effect on cognitive and decision-making skills."

The study's final analysis involved 40 people, average age 69, including 19 with diabetes and 21 controls. The diabetes patients had been treated for the disease an average of 13 years. Smokers were excluded.

The researchers administered a number of cognition and memory tests, magnetic resonance imaging (MRI) scans and blood tests at the beginning of the study and at 24 months.

At the two-year visit, the diabetics had lower global gray matter volume, lower composite scores on learning and memory, lower regional and global cerebral vasoreactivity, and worse glycemic control, compared to baseline.

Among the diabetics, impaired cerebral vasoreactivity at baseline correlated with worse performance of daily activities. In addition, worsening vasodilation correlated with greater decreases in executive function, independent of age, education, and other factors.

"Higher serum soluble intercellular and vascular adhesion molecules, higher cortisol, and higher C-reactive protein levels at baseline were associated with greater decreases in cerebral vasoreactivity and vasodilation only in the (diabetes) group, independent of diabetes control and 24-hour blood pressure," the researchers wrote online July 8 in Neurology.

"Inflammation may further impair cerebral vasoregulation, which consequently accelerates decline in executive function and daily activities performance in older people with (diabetes)," they said.

"Early detection and monitoring of blood flow regulation may be an important predictor of accelerated changes in cognitive and decision-making skills," Dr. Novak said in the news release. She called for additional studies in a greater number of people and for a longer duration.

"We are currently starting a Phase 2-3 clinical trial to see if intranasal insulin could prevent/slow down cognitive decline," she told Reuters Health by email.

She also noted that while no specific treatment exists to prevent cognitive decline, healthy life styles help people to have less decline.

Large clinical trials have shown that even strict control of blood sugar does not prevent cognitive decline. The high fluctuation in blood glucose that occurs with diabetes damages the nerves of the brain, she said.

The study was funded by the National Institute on Aging, American Diabetes Association, Harvard Clinical and Translational Science Center and National Center for Research Resources.

NEW YORK - Inflammation may contribute to impaired cerebral vasoregulation in type 2 diabetes, research suggests.

In a two-year study, participants with type 2 diabetes experienced diminished regional and global vasoreactivity in the brain, as well as a decline in cognitive function and the ability to perform daily tasks.

Higher blood levels of inflammatory markers were correlated with decreases in cerebral vasoreactivity and vasodilation in the diabetic subjects, but not in controls.

"Normal blood flow regulation allows the brain to redistribute blood to areas of the brain that have increased activity while performing certain tasks," senior author Dr. Vera Novak, of Beth Israel Deaconess Medical Center in Boston, said in a news release. "People with type 2 diabetes have impaired blood flow regulation. Our results suggest that diabetes and high blood sugar impose a chronic negative effect on cognitive and decision-making skills."

The study's final analysis involved 40 people, average age 69, including 19 with diabetes and 21 controls. The diabetes patients had been treated for the disease an average of 13 years. Smokers were excluded.

The researchers administered a number of cognition and memory tests, magnetic resonance imaging (MRI) scans and blood tests at the beginning of the study and at 24 months.

At the two-year visit, the diabetics had lower global gray matter volume, lower composite scores on learning and memory, lower regional and global cerebral vasoreactivity, and worse glycemic control, compared to baseline.

Among the diabetics, impaired cerebral vasoreactivity at baseline correlated with worse performance of daily activities. In addition, worsening vasodilation correlated with greater decreases in executive function, independent of age, education, and other factors.

"Higher serum soluble intercellular and vascular adhesion molecules, higher cortisol, and higher C-reactive protein levels at baseline were associated with greater decreases in cerebral vasoreactivity and vasodilation only in the (diabetes) group, independent of diabetes control and 24-hour blood pressure," the researchers wrote online July 8 in Neurology.

"Inflammation may further impair cerebral vasoregulation, which consequently accelerates decline in executive function and daily activities performance in older people with (diabetes)," they said.

"Early detection and monitoring of blood flow regulation may be an important predictor of accelerated changes in cognitive and decision-making skills," Dr. Novak said in the news release. She called for additional studies in a greater number of people and for a longer duration.

"We are currently starting a Phase 2-3 clinical trial to see if intranasal insulin could prevent/slow down cognitive decline," she told Reuters Health by email.

She also noted that while no specific treatment exists to prevent cognitive decline, healthy life styles help people to have less decline.

Large clinical trials have shown that even strict control of blood sugar does not prevent cognitive decline. The high fluctuation in blood glucose that occurs with diabetes damages the nerves of the brain, she said.

The study was funded by the National Institute on Aging, American Diabetes Association, Harvard Clinical and Translational Science Center and National Center for Research Resources.

NEW YORK - Inflammation may contribute to impaired cerebral vasoregulation in type 2 diabetes, research suggests.

In a two-year study, participants with type 2 diabetes experienced diminished regional and global vasoreactivity in the brain, as well as a decline in cognitive function and the ability to perform daily tasks.

Higher blood levels of inflammatory markers were correlated with decreases in cerebral vasoreactivity and vasodilation in the diabetic subjects, but not in controls.

"Normal blood flow regulation allows the brain to redistribute blood to areas of the brain that have increased activity while performing certain tasks," senior author Dr. Vera Novak, of Beth Israel Deaconess Medical Center in Boston, said in a news release. "People with type 2 diabetes have impaired blood flow regulation. Our results suggest that diabetes and high blood sugar impose a chronic negative effect on cognitive and decision-making skills."

The study's final analysis involved 40 people, average age 69, including 19 with diabetes and 21 controls. The diabetes patients had been treated for the disease an average of 13 years. Smokers were excluded.

The researchers administered a number of cognition and memory tests, magnetic resonance imaging (MRI) scans and blood tests at the beginning of the study and at 24 months.

At the two-year visit, the diabetics had lower global gray matter volume, lower composite scores on learning and memory, lower regional and global cerebral vasoreactivity, and worse glycemic control, compared to baseline.

Among the diabetics, impaired cerebral vasoreactivity at baseline correlated with worse performance of daily activities. In addition, worsening vasodilation correlated with greater decreases in executive function, independent of age, education, and other factors.

"Higher serum soluble intercellular and vascular adhesion molecules, higher cortisol, and higher C-reactive protein levels at baseline were associated with greater decreases in cerebral vasoreactivity and vasodilation only in the (diabetes) group, independent of diabetes control and 24-hour blood pressure," the researchers wrote online July 8 in Neurology.

"Inflammation may further impair cerebral vasoregulation, which consequently accelerates decline in executive function and daily activities performance in older people with (diabetes)," they said.

"Early detection and monitoring of blood flow regulation may be an important predictor of accelerated changes in cognitive and decision-making skills," Dr. Novak said in the news release. She called for additional studies in a greater number of people and for a longer duration.

"We are currently starting a Phase 2-3 clinical trial to see if intranasal insulin could prevent/slow down cognitive decline," she told Reuters Health by email.

She also noted that while no specific treatment exists to prevent cognitive decline, healthy life styles help people to have less decline.

Large clinical trials have shown that even strict control of blood sugar does not prevent cognitive decline. The high fluctuation in blood glucose that occurs with diabetes damages the nerves of the brain, she said.

The study was funded by the National Institute on Aging, American Diabetes Association, Harvard Clinical and Translational Science Center and National Center for Research Resources.

DALLAS—Results of 3 studies suggest the full-length recombinant factor VIII product BAY 81-8973 can be safe and effective in children, adolescents, and adults with severe hemophilia A.

Patients who received BAY 81-8973 as routine prophylaxis had low annualized bleeding rates (ABRs)—significantly lower than patients who received on-demand treatment.

None of the patients developed inhibitors, and no adverse event occurred in more than 10% of patients.

These results were presented in posters at the National Hemophilia Foundation’s 67th Annual Meeting. All 3 trials were sponsored by Bayer Healthcare AG, the company developing BAY 81-8973.

LEOPOLD trials

The 3 trials are part of the LEOPOLD Clinical Development Program, which was designed to evaluate BAY 81-8973 in patients with severe hemophilia A.

The first trial, LEOPOLD I, included male patients ages 12 to 65 who had at least 150 previous exposure days with a factor VIII product. For this study, they received BAY 81-8973 at 20-50 IU/kg 2 or 3 times a week (according to investigator decision) for 12 months.

The second trial, LEOPOLD II, also enrolled previously treated (≥ 150 previous exposure days) male subjects ages 12 to 65. The subjects were randomized to receive BAY 81-8973 as a low-dose prophylaxis regimen (20-30 IU/kg) twice a week, high-dose prophylaxis (30-40 IU/kg) 3 times a week, or on-demand.

In the third trial, LEOPOLD Kids, researchers evaluated BAY 81-8973 in previously treated children ages 12 and younger. Patients received BAY 81-8973 at 20-50 IU/kg twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days.

Another part of LEOPOLD KIDS, in which researchers are evaluating BAY 81-8973 in previously untreated children, is ongoing.

Efficacy results

The ABR was the primary efficacy endpoint in LEOPOLD I and II. In LEOPOLD KIDS, the primary efficacy endpoint was the ABR for total bleeds occurring within 48 hours of previous prophylaxis treatment, but the researchers also analyzed the ABR independent of the time of injection.

For all 3 trials, 193 patients were evaluable for efficacy. One hundred and forty patients received BAY 81-8973 for 12 months or more. The median exposure days were 155 for LEOPOLD I and 153 for LEOPOLD II.

In LEOPOLD I (n=62), the median ABR was 1.0 for all patients who received prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.

Sixteen patients did not experience any bleeds while on study—6 patients on the twice-weekly prophylaxis regimen and 10 on the thrice-weekly prophylaxis regimen.

LEOPOLD II included 28 patients who received twice-weekly prophylaxis, 31 who received thrice-weekly prophylaxis, and 21 who received on-demand treatment.

The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.

Again, 16 patients who received prophylaxis did not have any bleeds during the study period. This included 8 patients on the twice-weekly prophylaxis regimen and 8 on the thrice-weekly prophylaxis regimen.

In LEOPOLD KIDS (n=51), the median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.

Twenty-three patients did not have any bleeds during the 6-month treatment period—10 children younger than 6 and 13 children ages 6 to 12.

Safety results

For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with

at least a reasonable suspected causal relationship to BAY 81-8973.

The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.

The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).

None of the patients developed factor VIII inhibitors.

DALLAS—Results of 3 studies suggest the full-length recombinant factor VIII product BAY 81-8973 can be safe and effective in children, adolescents, and adults with severe hemophilia A.

Patients who received BAY 81-8973 as routine prophylaxis had low annualized bleeding rates (ABRs)—significantly lower than patients who received on-demand treatment.

None of the patients developed inhibitors, and no adverse event occurred in more than 10% of patients.

These results were presented in posters at the National Hemophilia Foundation’s 67th Annual Meeting. All 3 trials were sponsored by Bayer Healthcare AG, the company developing BAY 81-8973.

LEOPOLD trials

The 3 trials are part of the LEOPOLD Clinical Development Program, which was designed to evaluate BAY 81-8973 in patients with severe hemophilia A.

The first trial, LEOPOLD I, included male patients ages 12 to 65 who had at least 150 previous exposure days with a factor VIII product. For this study, they received BAY 81-8973 at 20-50 IU/kg 2 or 3 times a week (according to investigator decision) for 12 months.

The second trial, LEOPOLD II, also enrolled previously treated (≥ 150 previous exposure days) male subjects ages 12 to 65. The subjects were randomized to receive BAY 81-8973 as a low-dose prophylaxis regimen (20-30 IU/kg) twice a week, high-dose prophylaxis (30-40 IU/kg) 3 times a week, or on-demand.

In the third trial, LEOPOLD Kids, researchers evaluated BAY 81-8973 in previously treated children ages 12 and younger. Patients received BAY 81-8973 at 20-50 IU/kg twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days.

Another part of LEOPOLD KIDS, in which researchers are evaluating BAY 81-8973 in previously untreated children, is ongoing.

Efficacy results

The ABR was the primary efficacy endpoint in LEOPOLD I and II. In LEOPOLD KIDS, the primary efficacy endpoint was the ABR for total bleeds occurring within 48 hours of previous prophylaxis treatment, but the researchers also analyzed the ABR independent of the time of injection.

For all 3 trials, 193 patients were evaluable for efficacy. One hundred and forty patients received BAY 81-8973 for 12 months or more. The median exposure days were 155 for LEOPOLD I and 153 for LEOPOLD II.

In LEOPOLD I (n=62), the median ABR was 1.0 for all patients who received prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.

Sixteen patients did not experience any bleeds while on study—6 patients on the twice-weekly prophylaxis regimen and 10 on the thrice-weekly prophylaxis regimen.

LEOPOLD II included 28 patients who received twice-weekly prophylaxis, 31 who received thrice-weekly prophylaxis, and 21 who received on-demand treatment.

The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.

Again, 16 patients who received prophylaxis did not have any bleeds during the study period. This included 8 patients on the twice-weekly prophylaxis regimen and 8 on the thrice-weekly prophylaxis regimen.

In LEOPOLD KIDS (n=51), the median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.

Twenty-three patients did not have any bleeds during the 6-month treatment period—10 children younger than 6 and 13 children ages 6 to 12.

Safety results

For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with

at least a reasonable suspected causal relationship to BAY 81-8973.

The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.

The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).

None of the patients developed factor VIII inhibitors.

DALLAS—Results of 3 studies suggest the full-length recombinant factor VIII product BAY 81-8973 can be safe and effective in children, adolescents, and adults with severe hemophilia A.

Patients who received BAY 81-8973 as routine prophylaxis had low annualized bleeding rates (ABRs)—significantly lower than patients who received on-demand treatment.

None of the patients developed inhibitors, and no adverse event occurred in more than 10% of patients.

These results were presented in posters at the National Hemophilia Foundation’s 67th Annual Meeting. All 3 trials were sponsored by Bayer Healthcare AG, the company developing BAY 81-8973.

LEOPOLD trials

The 3 trials are part of the LEOPOLD Clinical Development Program, which was designed to evaluate BAY 81-8973 in patients with severe hemophilia A.

The first trial, LEOPOLD I, included male patients ages 12 to 65 who had at least 150 previous exposure days with a factor VIII product. For this study, they received BAY 81-8973 at 20-50 IU/kg 2 or 3 times a week (according to investigator decision) for 12 months.

The second trial, LEOPOLD II, also enrolled previously treated (≥ 150 previous exposure days) male subjects ages 12 to 65. The subjects were randomized to receive BAY 81-8973 as a low-dose prophylaxis regimen (20-30 IU/kg) twice a week, high-dose prophylaxis (30-40 IU/kg) 3 times a week, or on-demand.

In the third trial, LEOPOLD Kids, researchers evaluated BAY 81-8973 in previously treated children ages 12 and younger. Patients received BAY 81-8973 at 20-50 IU/kg twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days.

Another part of LEOPOLD KIDS, in which researchers are evaluating BAY 81-8973 in previously untreated children, is ongoing.

Efficacy results

The ABR was the primary efficacy endpoint in LEOPOLD I and II. In LEOPOLD KIDS, the primary efficacy endpoint was the ABR for total bleeds occurring within 48 hours of previous prophylaxis treatment, but the researchers also analyzed the ABR independent of the time of injection.

For all 3 trials, 193 patients were evaluable for efficacy. One hundred and forty patients received BAY 81-8973 for 12 months or more. The median exposure days were 155 for LEOPOLD I and 153 for LEOPOLD II.

In LEOPOLD I (n=62), the median ABR was 1.0 for all patients who received prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.

Sixteen patients did not experience any bleeds while on study—6 patients on the twice-weekly prophylaxis regimen and 10 on the thrice-weekly prophylaxis regimen.

LEOPOLD II included 28 patients who received twice-weekly prophylaxis, 31 who received thrice-weekly prophylaxis, and 21 who received on-demand treatment.

The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.

Again, 16 patients who received prophylaxis did not have any bleeds during the study period. This included 8 patients on the twice-weekly prophylaxis regimen and 8 on the thrice-weekly prophylaxis regimen.

In LEOPOLD KIDS (n=51), the median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.

Twenty-three patients did not have any bleeds during the 6-month treatment period—10 children younger than 6 and 13 children ages 6 to 12.

Safety results

For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with

at least a reasonable suspected causal relationship to BAY 81-8973.

The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.

The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).

None of the patients developed factor VIII inhibitors.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has expanded the approved indication for a human von Willebrand factor/coagulation factor VIII complex (Wilate) to include prevention of excessive bleeding during and after minor and major surgery in adult and pediatric patients with von Willebrand disease (VWD).

The product was previously approved for the treatment of spontaneous and trauma-induced bleeding episodes in patients with severe VWD, as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.

About Wilate

Wilate is a plasma-derived, highly purified concentrate of freeze-dried human von Willebrand factor and coagulation factor VIII. Two virus-inactivation steps are incorporated into the manufacturing process of the product: a solvent/detergent and terminal dry-heat treatment.

Investigators evaluated Wilate’s safety and efficacy in surgical procedures in a single-arm, phase 3 study known as WONDERS. The investigators enrolled 41 patients, 30 of whom completed the trial.

The patients had type 1, type 2 or type 3 VWD. They had a median age of 39.7, and most were female. All patients underwent surgery—21 major and 9 minor surgeries.

The hemostatic efficacy of Wilate was assessed intra-operatively by the surgeon and post-operatively by investigators. The overall hemostatic efficacy—success or failure—of Wilate was based on both assessments, using a 4-point ordinal efficacy scale.

In the 29 evaluable surgeries, the success rate was 96.7%. Wilate was successful in 100% of minor surgeries (n=9) and 95.2% of major surgeries (n=20).

There were 2 serious adverse events—erosive gastritis and vaginal hemorrhage. Nonserious events included nausea (7 cases in 6 patients), vomiting (n=6), pain (n=4), pyrexia (n=4), procedural pain (10 cases in 8 patients), decrease in hemoglobin (6 cases in 4 patients), and hypertension (n=4).

Wilate is under development by Octapharma. For more information on the product, visit www.WILATEusa.com.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has expanded the approved indication for a human von Willebrand factor/coagulation factor VIII complex (Wilate) to include prevention of excessive bleeding during and after minor and major surgery in adult and pediatric patients with von Willebrand disease (VWD).

The product was previously approved for the treatment of spontaneous and trauma-induced bleeding episodes in patients with severe VWD, as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.

About Wilate

Wilate is a plasma-derived, highly purified concentrate of freeze-dried human von Willebrand factor and coagulation factor VIII. Two virus-inactivation steps are incorporated into the manufacturing process of the product: a solvent/detergent and terminal dry-heat treatment.

Investigators evaluated Wilate’s safety and efficacy in surgical procedures in a single-arm, phase 3 study known as WONDERS. The investigators enrolled 41 patients, 30 of whom completed the trial.

The patients had type 1, type 2 or type 3 VWD. They had a median age of 39.7, and most were female. All patients underwent surgery—21 major and 9 minor surgeries.

The hemostatic efficacy of Wilate was assessed intra-operatively by the surgeon and post-operatively by investigators. The overall hemostatic efficacy—success or failure—of Wilate was based on both assessments, using a 4-point ordinal efficacy scale.

In the 29 evaluable surgeries, the success rate was 96.7%. Wilate was successful in 100% of minor surgeries (n=9) and 95.2% of major surgeries (n=20).

There were 2 serious adverse events—erosive gastritis and vaginal hemorrhage. Nonserious events included nausea (7 cases in 6 patients), vomiting (n=6), pain (n=4), pyrexia (n=4), procedural pain (10 cases in 8 patients), decrease in hemoglobin (6 cases in 4 patients), and hypertension (n=4).

Wilate is under development by Octapharma. For more information on the product, visit www.WILATEusa.com.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has expanded the approved indication for a human von Willebrand factor/coagulation factor VIII complex (Wilate) to include prevention of excessive bleeding during and after minor and major surgery in adult and pediatric patients with von Willebrand disease (VWD).

The product was previously approved for the treatment of spontaneous and trauma-induced bleeding episodes in patients with severe VWD, as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.

About Wilate

Wilate is a plasma-derived, highly purified concentrate of freeze-dried human von Willebrand factor and coagulation factor VIII. Two virus-inactivation steps are incorporated into the manufacturing process of the product: a solvent/detergent and terminal dry-heat treatment.

Investigators evaluated Wilate’s safety and efficacy in surgical procedures in a single-arm, phase 3 study known as WONDERS. The investigators enrolled 41 patients, 30 of whom completed the trial.

The patients had type 1, type 2 or type 3 VWD. They had a median age of 39.7, and most were female. All patients underwent surgery—21 major and 9 minor surgeries.

The hemostatic efficacy of Wilate was assessed intra-operatively by the surgeon and post-operatively by investigators. The overall hemostatic efficacy—success or failure—of Wilate was based on both assessments, using a 4-point ordinal efficacy scale.

In the 29 evaluable surgeries, the success rate was 96.7%. Wilate was successful in 100% of minor surgeries (n=9) and 95.2% of major surgeries (n=20).

There were 2 serious adverse events—erosive gastritis and vaginal hemorrhage. Nonserious events included nausea (7 cases in 6 patients), vomiting (n=6), pain (n=4), pyrexia (n=4), procedural pain (10 cases in 8 patients), decrease in hemoglobin (6 cases in 4 patients), and hypertension (n=4).

Wilate is under development by Octapharma. For more information on the product, visit www.WILATEusa.com.

Warfarin tablets

Routine use of warfarin is associated with clinical benefits in ischemic stroke patients with atrial fibrillation (AF), according to research published in BMJ.

When compared to patients who did not receive anticoagulant therapy, patients who received warfarin at hospital discharge had a lower incidence of major adverse cardiovascular events (MACE), less time spent in an institutional care facility, and a lower risk of all-cause mortality.

Warfarin seemed particularly beneficial for patients older than 80 years of age, women, and patients with more severe strokes.

Ying Xian, MD, PhD, of the Duke Clinical Research Institute in Durham, North Carolina, and his colleagues conducted this research, analyzing the association between warfarin treatment and longitudinal outcomes after ischemic stroke among AF patients.

The researchers evaluated 12,552 warfarin-naive AF patients who were admitted to 1487 hospitals across the US and were discharged between 2009 and 2011. Each patient had at least 1 year of follow-up after discharge.

In all, 11,039 (87.9%) were treated with warfarin at discharge. These patients were slightly younger and  less likely to have a history of previous stroke or coronary artery disease than patients who did not receive warfarin.

Unadjusted results

At 2 years of follow-up, the incidence of MACE was significantly lower in patients treated with warfarin than in untreated patients—54.7% and 66.8%, respectively (P<0.001).

In addition, on average, patients who received warfarin had 86 more days alive and out of institutional care in the 2-year follow-up period than patients who did not receive warfarin (P<0.001).

The incidence of readmission due to ischemic stroke was significantly lower among warfarin-treated patients than untreated patients—7.9% and 11.8%, respectively (P<0.001)—but there was no significant difference in readmission due to hemorrhagic stroke—1.4% and 1.1%, respectively (P=0.50).

The incidence of all-cause mortality was significantly lower among warfarin-treated patients—32.4% and 50%, respectively (P<0.001).

Adjusted results

In adjusted analysis (weighting by the inverse probability of treatment and control for other discharge drugs), patients treated with warfarin at discharge had a significantly lower risk of MACE over 2 years. The adjusted hazard ratio (aHR) was 0.87.

Warfarin-treated patients were also more likely to spend more days alive and out of institutional care. The adjusted home-time difference was 47.6 days.

Patients on warfarin had a lower risk of all-cause mortality (aHR=0.72) and ischemic stroke readmission (aHR=0.63), but there was no significant difference between treated and untreated patients with regard to hemorrhagic stroke readmission (aHR=1.37).

The researchers said the benefits associated with warfarin were consistent across clinically relevant groups by age, sex, stroke severity, and history of stroke and coronary artery disease.

Patients aged 80 and older, women, and those with more severe stroke seemed to enjoy greater benefits from warfarin treatment, even though these groups were less likely to receive warfarin.

The researchers speculated that this might result from clinicians’ misperception of warfarin’s risks and benefits for these patient groups.

Warfarin tablets

Routine use of warfarin is associated with clinical benefits in ischemic stroke patients with atrial fibrillation (AF), according to research published in BMJ.

When compared to patients who did not receive anticoagulant therapy, patients who received warfarin at hospital discharge had a lower incidence of major adverse cardiovascular events (MACE), less time spent in an institutional care facility, and a lower risk of all-cause mortality.

Warfarin seemed particularly beneficial for patients older than 80 years of age, women, and patients with more severe strokes.

Ying Xian, MD, PhD, of the Duke Clinical Research Institute in Durham, North Carolina, and his colleagues conducted this research, analyzing the association between warfarin treatment and longitudinal outcomes after ischemic stroke among AF patients.

The researchers evaluated 12,552 warfarin-naive AF patients who were admitted to 1487 hospitals across the US and were discharged between 2009 and 2011. Each patient had at least 1 year of follow-up after discharge.

In all, 11,039 (87.9%) were treated with warfarin at discharge. These patients were slightly younger and  less likely to have a history of previous stroke or coronary artery disease than patients who did not receive warfarin.

Unadjusted results

At 2 years of follow-up, the incidence of MACE was significantly lower in patients treated with warfarin than in untreated patients—54.7% and 66.8%, respectively (P<0.001).

In addition, on average, patients who received warfarin had 86 more days alive and out of institutional care in the 2-year follow-up period than patients who did not receive warfarin (P<0.001).

The incidence of readmission due to ischemic stroke was significantly lower among warfarin-treated patients than untreated patients—7.9% and 11.8%, respectively (P<0.001)—but there was no significant difference in readmission due to hemorrhagic stroke—1.4% and 1.1%, respectively (P=0.50).

The incidence of all-cause mortality was significantly lower among warfarin-treated patients—32.4% and 50%, respectively (P<0.001).

Adjusted results

In adjusted analysis (weighting by the inverse probability of treatment and control for other discharge drugs), patients treated with warfarin at discharge had a significantly lower risk of MACE over 2 years. The adjusted hazard ratio (aHR) was 0.87.

Warfarin-treated patients were also more likely to spend more days alive and out of institutional care. The adjusted home-time difference was 47.6 days.

Patients on warfarin had a lower risk of all-cause mortality (aHR=0.72) and ischemic stroke readmission (aHR=0.63), but there was no significant difference between treated and untreated patients with regard to hemorrhagic stroke readmission (aHR=1.37).

The researchers said the benefits associated with warfarin were consistent across clinically relevant groups by age, sex, stroke severity, and history of stroke and coronary artery disease.

Patients aged 80 and older, women, and those with more severe stroke seemed to enjoy greater benefits from warfarin treatment, even though these groups were less likely to receive warfarin.

The researchers speculated that this might result from clinicians’ misperception of warfarin’s risks and benefits for these patient groups.

Warfarin tablets

Routine use of warfarin is associated with clinical benefits in ischemic stroke patients with atrial fibrillation (AF), according to research published in BMJ.

When compared to patients who did not receive anticoagulant therapy, patients who received warfarin at hospital discharge had a lower incidence of major adverse cardiovascular events (MACE), less time spent in an institutional care facility, and a lower risk of all-cause mortality.

Warfarin seemed particularly beneficial for patients older than 80 years of age, women, and patients with more severe strokes.

Ying Xian, MD, PhD, of the Duke Clinical Research Institute in Durham, North Carolina, and his colleagues conducted this research, analyzing the association between warfarin treatment and longitudinal outcomes after ischemic stroke among AF patients.

The researchers evaluated 12,552 warfarin-naive AF patients who were admitted to 1487 hospitals across the US and were discharged between 2009 and 2011. Each patient had at least 1 year of follow-up after discharge.

In all, 11,039 (87.9%) were treated with warfarin at discharge. These patients were slightly younger and  less likely to have a history of previous stroke or coronary artery disease than patients who did not receive warfarin.

Unadjusted results

At 2 years of follow-up, the incidence of MACE was significantly lower in patients treated with warfarin than in untreated patients—54.7% and 66.8%, respectively (P<0.001).

In addition, on average, patients who received warfarin had 86 more days alive and out of institutional care in the 2-year follow-up period than patients who did not receive warfarin (P<0.001).

The incidence of readmission due to ischemic stroke was significantly lower among warfarin-treated patients than untreated patients—7.9% and 11.8%, respectively (P<0.001)—but there was no significant difference in readmission due to hemorrhagic stroke—1.4% and 1.1%, respectively (P=0.50).

The incidence of all-cause mortality was significantly lower among warfarin-treated patients—32.4% and 50%, respectively (P<0.001).

Adjusted results

In adjusted analysis (weighting by the inverse probability of treatment and control for other discharge drugs), patients treated with warfarin at discharge had a significantly lower risk of MACE over 2 years. The adjusted hazard ratio (aHR) was 0.87.

Warfarin-treated patients were also more likely to spend more days alive and out of institutional care. The adjusted home-time difference was 47.6 days.

Patients on warfarin had a lower risk of all-cause mortality (aHR=0.72) and ischemic stroke readmission (aHR=0.63), but there was no significant difference between treated and untreated patients with regard to hemorrhagic stroke readmission (aHR=1.37).

The researchers said the benefits associated with warfarin were consistent across clinically relevant groups by age, sex, stroke severity, and history of stroke and coronary artery disease.

Patients aged 80 and older, women, and those with more severe stroke seemed to enjoy greater benefits from warfarin treatment, even though these groups were less likely to receive warfarin.

The researchers speculated that this might result from clinicians’ misperception of warfarin’s risks and benefits for these patient groups.

Twelve weeks of estradiol or progesterone yielded distinct cognitive benefits in recently menopausal women, compared with placebo, according to a randomized, double-blind study reported in Psychoneuroendocrinology.

“Despite uncertainty about the potential cognitive benefits of postmenopausal hormone use, as women continue to live longer and healthier lives beyond the end of their reproductive years, hormones will continue to be prescribed for symptomatic indications,” said Dr. Alison Berent-Spillson of the University of Michigan, Ann Arbor, and her associates. “In contrast to previous studies that have found negative cognitive effects of treatment with synthetic progestins, our results point to potential cognitive benefits of both estrogen and progesterone.”

Few studies have examined unopposed progesterone treatment in postmenopausal women, and none have included functional neuroimaging (fMRI), even though fMRI can detect neurobiologic differences before patients exhibit measurable behavioral changes on task assessments, the investigators said. Past studies of postmenopausal hormone therapy and cognition have reported inconsistent results, they noted. Therefore, the investigators carried out a pilot study of 29 women who were within 38 months of their final menstrual period, and thus were inside the “critical window” when hormone therapy is thought to offer maximum benefit. Participants were randomized to 12 weeks of 1 mg oral estradiol or 200 mg oral progesterone. Each therapy was counterbalanced with placebo for the same amount of time, separated by a 12-week washout period. At the end of each 12-week treatment period, the women underwent verbal and visual cognitive function and working memory tests, as well as functional MRI of verbal and visual working memory processing (Psychoneuroendocrinology 2015; 59:25-36).

Compared with placebo, postmenopausal progesterone therapy was associated with a greater verbal working memory composite score and with greater fMRI activation of the right prefrontal cortex during the verbal working memory task (P = .014), the investigators reported. Women on progesterone also had significantly greater activation of the left prefrontal cortex (P = .001) and the right hippocampus (P = .003) during the visual working memory tasks, compared with the placebo group. Estradiol therapy and placebo did not differ significantly in terms of verbal or visual learning, recall, or working memory composite scores. However, estradiol was associated with increased activation of the left prefrontal cortex (P = .006) and the left hippocampus (P = .037) compared with placebo during the verbal working memory tasks, the researchers said.

Progesterone might affect the hippocampus by promoting neurogenesis and neuron survival, although its effects on the postmenopausal brain remain largely unstudied, the investigators said. Estrogen seems to offer cognitive effects during menopause through its actions on the hippocampus, but a longer treatment period might be needed for such benefits to emerge during testing, they said. “While we did not detect differences in verbal ability between the estrogen and placebo treatment arms, we saw increased activation after estrogen treatment in the left prefrontal cortex during the verbal processing task, a region associated with verbal processing,” they emphasized. “This may reflect more efficient encoding, as women remembered more words from the verbal task after estrogen than placebo, although this difference did not reach statistical significance.”

Although the study was small, its crossover design maximized the statistical power, said the researchers. They recommended larger studies with longer treatment durations in order to better detect emergent differences in cognitive ability between treatment groups and relationships between performance on tasks and regional brain activation patterns.

The National Institutes of Health and the Phil F. Jenkins Foundation funded the study. The investigators declared no conflicts of interest.

Twelve weeks of estradiol or progesterone yielded distinct cognitive benefits in recently menopausal women, compared with placebo, according to a randomized, double-blind study reported in Psychoneuroendocrinology.

“Despite uncertainty about the potential cognitive benefits of postmenopausal hormone use, as women continue to live longer and healthier lives beyond the end of their reproductive years, hormones will continue to be prescribed for symptomatic indications,” said Dr. Alison Berent-Spillson of the University of Michigan, Ann Arbor, and her associates. “In contrast to previous studies that have found negative cognitive effects of treatment with synthetic progestins, our results point to potential cognitive benefits of both estrogen and progesterone.”

Few studies have examined unopposed progesterone treatment in postmenopausal women, and none have included functional neuroimaging (fMRI), even though fMRI can detect neurobiologic differences before patients exhibit measurable behavioral changes on task assessments, the investigators said. Past studies of postmenopausal hormone therapy and cognition have reported inconsistent results, they noted. Therefore, the investigators carried out a pilot study of 29 women who were within 38 months of their final menstrual period, and thus were inside the “critical window” when hormone therapy is thought to offer maximum benefit. Participants were randomized to 12 weeks of 1 mg oral estradiol or 200 mg oral progesterone. Each therapy was counterbalanced with placebo for the same amount of time, separated by a 12-week washout period. At the end of each 12-week treatment period, the women underwent verbal and visual cognitive function and working memory tests, as well as functional MRI of verbal and visual working memory processing (Psychoneuroendocrinology 2015; 59:25-36).

Compared with placebo, postmenopausal progesterone therapy was associated with a greater verbal working memory composite score and with greater fMRI activation of the right prefrontal cortex during the verbal working memory task (P = .014), the investigators reported. Women on progesterone also had significantly greater activation of the left prefrontal cortex (P = .001) and the right hippocampus (P = .003) during the visual working memory tasks, compared with the placebo group. Estradiol therapy and placebo did not differ significantly in terms of verbal or visual learning, recall, or working memory composite scores. However, estradiol was associated with increased activation of the left prefrontal cortex (P = .006) and the left hippocampus (P = .037) compared with placebo during the verbal working memory tasks, the researchers said.

Progesterone might affect the hippocampus by promoting neurogenesis and neuron survival, although its effects on the postmenopausal brain remain largely unstudied, the investigators said. Estrogen seems to offer cognitive effects during menopause through its actions on the hippocampus, but a longer treatment period might be needed for such benefits to emerge during testing, they said. “While we did not detect differences in verbal ability between the estrogen and placebo treatment arms, we saw increased activation after estrogen treatment in the left prefrontal cortex during the verbal processing task, a region associated with verbal processing,” they emphasized. “This may reflect more efficient encoding, as women remembered more words from the verbal task after estrogen than placebo, although this difference did not reach statistical significance.”

Although the study was small, its crossover design maximized the statistical power, said the researchers. They recommended larger studies with longer treatment durations in order to better detect emergent differences in cognitive ability between treatment groups and relationships between performance on tasks and regional brain activation patterns.

The National Institutes of Health and the Phil F. Jenkins Foundation funded the study. The investigators declared no conflicts of interest.

Twelve weeks of estradiol or progesterone yielded distinct cognitive benefits in recently menopausal women, compared with placebo, according to a randomized, double-blind study reported in Psychoneuroendocrinology.

“Despite uncertainty about the potential cognitive benefits of postmenopausal hormone use, as women continue to live longer and healthier lives beyond the end of their reproductive years, hormones will continue to be prescribed for symptomatic indications,” said Dr. Alison Berent-Spillson of the University of Michigan, Ann Arbor, and her associates. “In contrast to previous studies that have found negative cognitive effects of treatment with synthetic progestins, our results point to potential cognitive benefits of both estrogen and progesterone.”

Few studies have examined unopposed progesterone treatment in postmenopausal women, and none have included functional neuroimaging (fMRI), even though fMRI can detect neurobiologic differences before patients exhibit measurable behavioral changes on task assessments, the investigators said. Past studies of postmenopausal hormone therapy and cognition have reported inconsistent results, they noted. Therefore, the investigators carried out a pilot study of 29 women who were within 38 months of their final menstrual period, and thus were inside the “critical window” when hormone therapy is thought to offer maximum benefit. Participants were randomized to 12 weeks of 1 mg oral estradiol or 200 mg oral progesterone. Each therapy was counterbalanced with placebo for the same amount of time, separated by a 12-week washout period. At the end of each 12-week treatment period, the women underwent verbal and visual cognitive function and working memory tests, as well as functional MRI of verbal and visual working memory processing (Psychoneuroendocrinology 2015; 59:25-36).

Compared with placebo, postmenopausal progesterone therapy was associated with a greater verbal working memory composite score and with greater fMRI activation of the right prefrontal cortex during the verbal working memory task (P = .014), the investigators reported. Women on progesterone also had significantly greater activation of the left prefrontal cortex (P = .001) and the right hippocampus (P = .003) during the visual working memory tasks, compared with the placebo group. Estradiol therapy and placebo did not differ significantly in terms of verbal or visual learning, recall, or working memory composite scores. However, estradiol was associated with increased activation of the left prefrontal cortex (P = .006) and the left hippocampus (P = .037) compared with placebo during the verbal working memory tasks, the researchers said.

Progesterone might affect the hippocampus by promoting neurogenesis and neuron survival, although its effects on the postmenopausal brain remain largely unstudied, the investigators said. Estrogen seems to offer cognitive effects during menopause through its actions on the hippocampus, but a longer treatment period might be needed for such benefits to emerge during testing, they said. “While we did not detect differences in verbal ability between the estrogen and placebo treatment arms, we saw increased activation after estrogen treatment in the left prefrontal cortex during the verbal processing task, a region associated with verbal processing,” they emphasized. “This may reflect more efficient encoding, as women remembered more words from the verbal task after estrogen than placebo, although this difference did not reach statistical significance.”

Although the study was small, its crossover design maximized the statistical power, said the researchers. They recommended larger studies with longer treatment durations in order to better detect emergent differences in cognitive ability between treatment groups and relationships between performance on tasks and regional brain activation patterns.

The National Institutes of Health and the Phil F. Jenkins Foundation funded the study. The investigators declared no conflicts of interest.

Diagnosis: Staphylococcal scalded skin syndrome (SSSS)

Staphylococcal scalded skin syndrome (SSSS), also known as Ritter’s disease and pemphigus neonatorum, is a blistering skin disease seen most commonly in neonates and young children, but it can be seen in older children and rarely in adults¹. The severity of SSSS can range from mild localized bullae to severe generalized erythroderma and exfoliation. 

The most common early symptoms in neonates and children are fever, malaise, irritability, and skin tenderness followed by erythema at the site of infection, usually in the perioral, periorbital, or umbilical areas¹. The erythema becomes well demarcated, and more erythematous patches develop and spread over the body and subsequently coalesce. One to two days later, fragile bullae form over the erythematous skin, most commonly in intertriginous areas; these bullae rupture easily, leaving behind denuded, erythematous skin, giving the scalded appearance for which the disease is named. 

The causative factor is an exfoliating (epidermolytic) toxin (ET) produced by phage II Staphylococcus aureus2. There are two types of ETs, ETA and ETB. In western countries, the vast majority of toxin-producing strains of S. aureus produce ETA. Both ETA and ETB target and destroy desmoglein-1, a molecule found in desmosomes that plays an important role in cell-cell adhesion in the stratum granulosum of the epidermis². This compromise in the structural integrity of the superficial epidermis is responsible for the fragile nature of the bullae seen in SSSS and the positive Nikolsky sign.

Differential diagnosis

The differential diagnosis includes toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and staphylococcal toxic-shock syndrome (STSS)³. 

TEN is a severe condition, most commonly caused by adverse drug reactions. Unlike in TEN, SSSS patients the lack mucosal involvement and have more superficial epidermal peeling⁴. 

DRESS is also a medication-induced reaction, commonly associated with anticonvulsants and sulfonamides. Only severe cases of DRESS can present similarly to SSSS with exfoliation and erythroderma, but there is often mucosal involvement and signs of visceral organ involvement, most commonly the liver⁵. 

The additional findings inSTSS that help distinguish it from SSSS include petechiae and preferential desquamation of the palms and soles⁶. 

SSSS can usually be diagnosed clinically, but biopsies are important in differentiating difficult cases. Sampling the crusted areas as well as the nasal, periumbilical, and perianal sites for culture and sensitivities is recommended prior to starting antibiotic therapy.

Treatment

For neonates and children with severe disease, inpatient treatment in an intensive care or burn unit setting is sometimes required. SSSS can be caused by both methicillin-sensitive and -resistant strains of S. aureus, so antibiotic treatment must be tailored to the sensitivity. 

In either case, beginning broad-spectrum antibiotic treatment early is essential. For methicillin-sensitive strains, penicillinase-resistant penicillins like flucloxacillin, nafcillin, or oxacillin are the drugs of choice^3,7.

In known MRSA infections or in areas with a high prevalence of resistance and suspected MRSA, clindamycin or vancomycin should be used^3,8. Supportive care in an inpatient setting also is important, especially in younger or sick children because they are more susceptible to sepsis and pneumonia and are at risk for complications because of problems with temperature, fluid, and electrolyte regulation while their skin barrier function is compromised⁷.

References

1. Arch Dis Child. 1998;78(1):85-8. 
2. N Engl J Med. 2006;355(17):1800-10. 
3. J Eur Acad Dermatol Venereol. 2014;28(11):1418-23.  
4. JAAD. 2013;69(2):173.e1-173.e13. 
5. JAAD. 2013;68(5):693.e1-693.e14. 
6. Clin Infect Dis. 2006;42(2):181-5. 
7. Am J Clin Dermatol. 2003;4(3):165-75. 
8. Pediatr Dermatol. 2014;31(3):305-08.

Dr. Matiz is assistant professor of dermatology at Rady Children's Hospital San Diego-University of California San Diego and Mr. Ginsberg is a research associate at the hospital. Dr. Matiz and Mr. Ginsberg said they have no relevant financial disclosures. 

Diagnosis: Staphylococcal scalded skin syndrome (SSSS)

Staphylococcal scalded skin syndrome (SSSS), also known as Ritter’s disease and pemphigus neonatorum, is a blistering skin disease seen most commonly in neonates and young children, but it can be seen in older children and rarely in adults¹. The severity of SSSS can range from mild localized bullae to severe generalized erythroderma and exfoliation. 

The most common early symptoms in neonates and children are fever, malaise, irritability, and skin tenderness followed by erythema at the site of infection, usually in the perioral, periorbital, or umbilical areas¹. The erythema becomes well demarcated, and more erythematous patches develop and spread over the body and subsequently coalesce. One to two days later, fragile bullae form over the erythematous skin, most commonly in intertriginous areas; these bullae rupture easily, leaving behind denuded, erythematous skin, giving the scalded appearance for which the disease is named. 

The causative factor is an exfoliating (epidermolytic) toxin (ET) produced by phage II Staphylococcus aureus2. There are two types of ETs, ETA and ETB. In western countries, the vast majority of toxin-producing strains of S. aureus produce ETA. Both ETA and ETB target and destroy desmoglein-1, a molecule found in desmosomes that plays an important role in cell-cell adhesion in the stratum granulosum of the epidermis². This compromise in the structural integrity of the superficial epidermis is responsible for the fragile nature of the bullae seen in SSSS and the positive Nikolsky sign.

Differential diagnosis

The differential diagnosis includes toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and staphylococcal toxic-shock syndrome (STSS)³. 

TEN is a severe condition, most commonly caused by adverse drug reactions. Unlike in TEN, SSSS patients the lack mucosal involvement and have more superficial epidermal peeling⁴. 

DRESS is also a medication-induced reaction, commonly associated with anticonvulsants and sulfonamides. Only severe cases of DRESS can present similarly to SSSS with exfoliation and erythroderma, but there is often mucosal involvement and signs of visceral organ involvement, most commonly the liver⁵. 

The additional findings inSTSS that help distinguish it from SSSS include petechiae and preferential desquamation of the palms and soles⁶. 

SSSS can usually be diagnosed clinically, but biopsies are important in differentiating difficult cases. Sampling the crusted areas as well as the nasal, periumbilical, and perianal sites for culture and sensitivities is recommended prior to starting antibiotic therapy.

Treatment

For neonates and children with severe disease, inpatient treatment in an intensive care or burn unit setting is sometimes required. SSSS can be caused by both methicillin-sensitive and -resistant strains of S. aureus, so antibiotic treatment must be tailored to the sensitivity. 

In either case, beginning broad-spectrum antibiotic treatment early is essential. For methicillin-sensitive strains, penicillinase-resistant penicillins like flucloxacillin, nafcillin, or oxacillin are the drugs of choice^3,7.

In known MRSA infections or in areas with a high prevalence of resistance and suspected MRSA, clindamycin or vancomycin should be used^3,8. Supportive care in an inpatient setting also is important, especially in younger or sick children because they are more susceptible to sepsis and pneumonia and are at risk for complications because of problems with temperature, fluid, and electrolyte regulation while their skin barrier function is compromised⁷.

References

1. Arch Dis Child. 1998;78(1):85-8. 
2. N Engl J Med. 2006;355(17):1800-10. 
3. J Eur Acad Dermatol Venereol. 2014;28(11):1418-23.  
4. JAAD. 2013;69(2):173.e1-173.e13. 
5. JAAD. 2013;68(5):693.e1-693.e14. 
6. Clin Infect Dis. 2006;42(2):181-5. 
7. Am J Clin Dermatol. 2003;4(3):165-75. 
8. Pediatr Dermatol. 2014;31(3):305-08.

Dr. Matiz is assistant professor of dermatology at Rady Children's Hospital San Diego-University of California San Diego and Mr. Ginsberg is a research associate at the hospital. Dr. Matiz and Mr. Ginsberg said they have no relevant financial disclosures. 

Diagnosis: Staphylococcal scalded skin syndrome (SSSS)

Staphylococcal scalded skin syndrome (SSSS), also known as Ritter’s disease and pemphigus neonatorum, is a blistering skin disease seen most commonly in neonates and young children, but it can be seen in older children and rarely in adults¹. The severity of SSSS can range from mild localized bullae to severe generalized erythroderma and exfoliation. 

The most common early symptoms in neonates and children are fever, malaise, irritability, and skin tenderness followed by erythema at the site of infection, usually in the perioral, periorbital, or umbilical areas¹. The erythema becomes well demarcated, and more erythematous patches develop and spread over the body and subsequently coalesce. One to two days later, fragile bullae form over the erythematous skin, most commonly in intertriginous areas; these bullae rupture easily, leaving behind denuded, erythematous skin, giving the scalded appearance for which the disease is named. 

The causative factor is an exfoliating (epidermolytic) toxin (ET) produced by phage II Staphylococcus aureus2. There are two types of ETs, ETA and ETB. In western countries, the vast majority of toxin-producing strains of S. aureus produce ETA. Both ETA and ETB target and destroy desmoglein-1, a molecule found in desmosomes that plays an important role in cell-cell adhesion in the stratum granulosum of the epidermis². This compromise in the structural integrity of the superficial epidermis is responsible for the fragile nature of the bullae seen in SSSS and the positive Nikolsky sign.

Differential diagnosis

The differential diagnosis includes toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and staphylococcal toxic-shock syndrome (STSS)³. 

TEN is a severe condition, most commonly caused by adverse drug reactions. Unlike in TEN, SSSS patients the lack mucosal involvement and have more superficial epidermal peeling⁴. 

DRESS is also a medication-induced reaction, commonly associated with anticonvulsants and sulfonamides. Only severe cases of DRESS can present similarly to SSSS with exfoliation and erythroderma, but there is often mucosal involvement and signs of visceral organ involvement, most commonly the liver⁵. 

The additional findings inSTSS that help distinguish it from SSSS include petechiae and preferential desquamation of the palms and soles⁶. 

SSSS can usually be diagnosed clinically, but biopsies are important in differentiating difficult cases. Sampling the crusted areas as well as the nasal, periumbilical, and perianal sites for culture and sensitivities is recommended prior to starting antibiotic therapy.

Treatment

For neonates and children with severe disease, inpatient treatment in an intensive care or burn unit setting is sometimes required. SSSS can be caused by both methicillin-sensitive and -resistant strains of S. aureus, so antibiotic treatment must be tailored to the sensitivity. 

In either case, beginning broad-spectrum antibiotic treatment early is essential. For methicillin-sensitive strains, penicillinase-resistant penicillins like flucloxacillin, nafcillin, or oxacillin are the drugs of choice^3,7.

In known MRSA infections or in areas with a high prevalence of resistance and suspected MRSA, clindamycin or vancomycin should be used^3,8. Supportive care in an inpatient setting also is important, especially in younger or sick children because they are more susceptible to sepsis and pneumonia and are at risk for complications because of problems with temperature, fluid, and electrolyte regulation while their skin barrier function is compromised⁷.

References

1. Arch Dis Child. 1998;78(1):85-8. 
2. N Engl J Med. 2006;355(17):1800-10. 
3. J Eur Acad Dermatol Venereol. 2014;28(11):1418-23.  
4. JAAD. 2013;69(2):173.e1-173.e13. 
5. JAAD. 2013;68(5):693.e1-693.e14. 
6. Clin Infect Dis. 2006;42(2):181-5. 
7. Am J Clin Dermatol. 2003;4(3):165-75. 
8. Pediatr Dermatol. 2014;31(3):305-08.

Dr. Matiz is assistant professor of dermatology at Rady Children's Hospital San Diego-University of California San Diego and Mr. Ginsberg is a research associate at the hospital. Dr. Matiz and Mr. Ginsberg said they have no relevant financial disclosures. 

Diagnosis: Systemic sclerosis

Systemic sclerosis, or scleroderma, is a rare connective tissue disorder in which excessive collagen is deposited in the skin and internal organs. This disease predominantly affects women (3-6:1) between the ages of 20 and 60 years with no apparent racial predominance. Effective treatment is critical, as scleroderma carries a poor prognosis, with a mortality rate of up to 50% at 5 years in severe cases. The pathogenesis of systemic sclerosis is unknown, but three pathways are implicated, including immune deregulation, vascular abnormalities, and abnormal fibroblast activation.

Clinical presentation is variable because of the involvement of multiple organ systems. Common features include cutaneous pruritus, skin thickening, Raynaud's phenomenon, difficulty swallowing, shortness of breath, palpitations, nonproductive cough, and joint pain and swelling, as well as muscle pain and weakness. Laboratory findings may include elevated erythrocyte sedimentation rate, thrombocytopenia, hypergammaglobulinemia, increased urea and creatinine levels, and elevated C-reactive protein. Antinuclear antibodies are usually elevated, especially Scl-70, antimitochondrial, and anticentromere antibodies. Cardiac and pulmonary function should be assessed upon diagnosis. A Doppler echocardiogram may detect cardiac abnormalities, and chest x-ray or high-resolution CT is used to assess for pulmonary fibrosis.

Despite the severity of the disease, there are no Food and Drug Administration-approved disease-modifying agents for the treatment of scleroderma, and management often focuses on symptom relief. For example, patients with kidney involvement should be placed on an ACE inhibitor or angiotensin II inhibitor therapy, and patients with gastrointestinal tract involvement should use proton pump inhibitors and H2 blockers to control reflux. Bosentan and pentoxifylline, which target vascular abnormalities, also may help improve skin fibrosis. Steroids show benefits in the early stages of the disease, but carry a risk of scleroderma renal crisis with doses greater than 15 mg of prednisone daily. Mycophenolate mofetil and sirolimus have immunomodulatory and antifibrotic properties, which may be of benefit in this disease.

Cyclophosphamide is reserved for more severe cases. Other treatment modalities include rituximab, intravenous immunoglobulin, and autologous stem cell transplantation.

Diagnosis: Systemic sclerosis

Systemic sclerosis, or scleroderma, is a rare connective tissue disorder in which excessive collagen is deposited in the skin and internal organs. This disease predominantly affects women (3-6:1) between the ages of 20 and 60 years with no apparent racial predominance. Effective treatment is critical, as scleroderma carries a poor prognosis, with a mortality rate of up to 50% at 5 years in severe cases. The pathogenesis of systemic sclerosis is unknown, but three pathways are implicated, including immune deregulation, vascular abnormalities, and abnormal fibroblast activation.

Clinical presentation is variable because of the involvement of multiple organ systems. Common features include cutaneous pruritus, skin thickening, Raynaud's phenomenon, difficulty swallowing, shortness of breath, palpitations, nonproductive cough, and joint pain and swelling, as well as muscle pain and weakness. Laboratory findings may include elevated erythrocyte sedimentation rate, thrombocytopenia, hypergammaglobulinemia, increased urea and creatinine levels, and elevated C-reactive protein. Antinuclear antibodies are usually elevated, especially Scl-70, antimitochondrial, and anticentromere antibodies. Cardiac and pulmonary function should be assessed upon diagnosis. A Doppler echocardiogram may detect cardiac abnormalities, and chest x-ray or high-resolution CT is used to assess for pulmonary fibrosis.

Despite the severity of the disease, there are no Food and Drug Administration-approved disease-modifying agents for the treatment of scleroderma, and management often focuses on symptom relief. For example, patients with kidney involvement should be placed on an ACE inhibitor or angiotensin II inhibitor therapy, and patients with gastrointestinal tract involvement should use proton pump inhibitors and H2 blockers to control reflux. Bosentan and pentoxifylline, which target vascular abnormalities, also may help improve skin fibrosis. Steroids show benefits in the early stages of the disease, but carry a risk of scleroderma renal crisis with doses greater than 15 mg of prednisone daily. Mycophenolate mofetil and sirolimus have immunomodulatory and antifibrotic properties, which may be of benefit in this disease.

Cyclophosphamide is reserved for more severe cases. Other treatment modalities include rituximab, intravenous immunoglobulin, and autologous stem cell transplantation.

Diagnosis: Systemic sclerosis

Systemic sclerosis, or scleroderma, is a rare connective tissue disorder in which excessive collagen is deposited in the skin and internal organs. This disease predominantly affects women (3-6:1) between the ages of 20 and 60 years with no apparent racial predominance. Effective treatment is critical, as scleroderma carries a poor prognosis, with a mortality rate of up to 50% at 5 years in severe cases. The pathogenesis of systemic sclerosis is unknown, but three pathways are implicated, including immune deregulation, vascular abnormalities, and abnormal fibroblast activation.

Clinical presentation is variable because of the involvement of multiple organ systems. Common features include cutaneous pruritus, skin thickening, Raynaud's phenomenon, difficulty swallowing, shortness of breath, palpitations, nonproductive cough, and joint pain and swelling, as well as muscle pain and weakness. Laboratory findings may include elevated erythrocyte sedimentation rate, thrombocytopenia, hypergammaglobulinemia, increased urea and creatinine levels, and elevated C-reactive protein. Antinuclear antibodies are usually elevated, especially Scl-70, antimitochondrial, and anticentromere antibodies. Cardiac and pulmonary function should be assessed upon diagnosis. A Doppler echocardiogram may detect cardiac abnormalities, and chest x-ray or high-resolution CT is used to assess for pulmonary fibrosis.

Despite the severity of the disease, there are no Food and Drug Administration-approved disease-modifying agents for the treatment of scleroderma, and management often focuses on symptom relief. For example, patients with kidney involvement should be placed on an ACE inhibitor or angiotensin II inhibitor therapy, and patients with gastrointestinal tract involvement should use proton pump inhibitors and H2 blockers to control reflux. Bosentan and pentoxifylline, which target vascular abnormalities, also may help improve skin fibrosis. Steroids show benefits in the early stages of the disease, but carry a risk of scleroderma renal crisis with doses greater than 15 mg of prednisone daily. Mycophenolate mofetil and sirolimus have immunomodulatory and antifibrotic properties, which may be of benefit in this disease.

Cyclophosphamide is reserved for more severe cases. Other treatment modalities include rituximab, intravenous immunoglobulin, and autologous stem cell transplantation.

Micrograph showing MF

Researchers have reported results of the phase 3 JAKARTA trial, in which they evaluated the selective JAK2 inhibitor fedratinib in patients with myelofibrosis (MF).

Fedratinib was being developed as a treatment for myeloproliferative neoplasms (MPNs), but Sanofi Oncology stopped clinical development of the drug in 2013, after it was linked to a neurological condition known as Wernicke encephalopathy.

There were 4 confirmed cases of Wernicke encephalopathy in the JAKARTA trial, in addition to other adverse events (AEs). However, fedratinib also lessened the severity of MF symptoms in about 35% to 40% of patients.

These results have been published in JAMA Oncology alongside an invited commentary. The study was sponsored by Sanofi.

Treatment and response

The study enrolled 289 adult patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. Patients were randomized to receive fedratinib at 400 mg once a day, fedratinib at 500 mg once a day, or placebo for at least 6 consecutive, 4-week cycles.

The study’s primary endpoint was spleen response, or a 35% or greater reduction in spleen volume from baseline (determined by MRI or CT) at week 24 and confirmed 4 weeks later.

Thirty-six percent (35/96) of patients in the 400 mg arm and 40% (39/97) in the 500 mg arm achieved the primary endpoint, compared to 1% (1/96) of patients in the placebo arm (P<0.001).

The main secondary endpoint was symptom response, or a 50% or greater reduction in total symptom score (assessed using the modified Myelofibrosis Symptom Assessment Form).

At week 24, symptom response rates were 36% (33/91) in the 400 mg arm, 34% (31/91) in the 500 mg arm, and 7% (6/85) in the placebo arm (P<0.001).

Safety data

Treatment-emergent AEs occurred in 100% of patients in the 400 mg arm, 98% in the 500 mg arm, and 94% in the placebo arm. Serious AEs occurred in 27%, 31%, and 23%, respectively. AEs leading to discontinuation occurred in 14%, 25%, and 8%, respectively.

Infections occurred in 42% of patients in the 400 mg arm, 39% of patients in the 500 mg arm, and 27% of patients of patients in the placebo arm.

Nonhematologic AEs occurring in at least 10% of patients in any group were diarrhea (66%, 56%, and 16%, respectively), vomiting (42%, 55%, and 5%, respectively), nausea (64%, 51%, and 15%, respectively), constipation (10%, 18%, and 7%, respectively), asthenia (9%, 16%, and 6%, respectively), abdominal pain (15%, 12%, and 16%, respectively), fatigue (16%, 10%, and 10%, respectively), dyspnea (8%, 10%, and 6%, respectively), and weight loss (4%, 10%, and 5%, respectively).

Hematologic AEs occurring in at least 10% of patients in any group were anemia (99%, 98%, and 91%, respectively), thrombocytopenia (63%, 57%, and 51%, respectively), lymphopenia (57%, 66%, and 54%, respectively), leukopenia (47%, 53%, and 19%, respectively), and neutropenia (28%, 44%, and 15%, respectively).

One patient in each fedratinib arm and 2 in the placebo arm transformed to acute myeloid leukemia.

There were 24 deaths during the first 24 weeks of the study—4 in the 400 mg arm, 10 in the 500 mg arm, and 10 in the placebo arm. Nine of the deaths were attributed to AEs—1, 4, and 4, respectively.

Wernicke encephalopathy

There were 4 cases of Wernicke encephalopathy, all in women who received fedratinib at 500 mg. All of these cases were confirmed by an independent expert safety panel, 3 on the basis of clinical features and MRI results, and 1 on the basis of clinical symptoms alone.

The patients developed symptoms 6 weeks to 44 weeks after beginning fedratinib treatment, and all discontinued treatment permanently.

Cognitive symptoms manifested in the context of persistent vomiting, malnutrition, and cachexia in 1 patient, vomiting and hyponatremia in 1 patient, and renal failure with mild hyponatremia in 1 patient.

All of the patients received intravenous thiamine and showed responses to the treatment, but all had persistent cognitive defects at last follow-up.

Micrograph showing MF

Researchers have reported results of the phase 3 JAKARTA trial, in which they evaluated the selective JAK2 inhibitor fedratinib in patients with myelofibrosis (MF).

Fedratinib was being developed as a treatment for myeloproliferative neoplasms (MPNs), but Sanofi Oncology stopped clinical development of the drug in 2013, after it was linked to a neurological condition known as Wernicke encephalopathy.

There were 4 confirmed cases of Wernicke encephalopathy in the JAKARTA trial, in addition to other adverse events (AEs). However, fedratinib also lessened the severity of MF symptoms in about 35% to 40% of patients.

These results have been published in JAMA Oncology alongside an invited commentary. The study was sponsored by Sanofi.

Treatment and response

The study enrolled 289 adult patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. Patients were randomized to receive fedratinib at 400 mg once a day, fedratinib at 500 mg once a day, or placebo for at least 6 consecutive, 4-week cycles.

The study’s primary endpoint was spleen response, or a 35% or greater reduction in spleen volume from baseline (determined by MRI or CT) at week 24 and confirmed 4 weeks later.

Thirty-six percent (35/96) of patients in the 400 mg arm and 40% (39/97) in the 500 mg arm achieved the primary endpoint, compared to 1% (1/96) of patients in the placebo arm (P<0.001).

The main secondary endpoint was symptom response, or a 50% or greater reduction in total symptom score (assessed using the modified Myelofibrosis Symptom Assessment Form).

At week 24, symptom response rates were 36% (33/91) in the 400 mg arm, 34% (31/91) in the 500 mg arm, and 7% (6/85) in the placebo arm (P<0.001).

Safety data

Treatment-emergent AEs occurred in 100% of patients in the 400 mg arm, 98% in the 500 mg arm, and 94% in the placebo arm. Serious AEs occurred in 27%, 31%, and 23%, respectively. AEs leading to discontinuation occurred in 14%, 25%, and 8%, respectively.

Infections occurred in 42% of patients in the 400 mg arm, 39% of patients in the 500 mg arm, and 27% of patients of patients in the placebo arm.

Nonhematologic AEs occurring in at least 10% of patients in any group were diarrhea (66%, 56%, and 16%, respectively), vomiting (42%, 55%, and 5%, respectively), nausea (64%, 51%, and 15%, respectively), constipation (10%, 18%, and 7%, respectively), asthenia (9%, 16%, and 6%, respectively), abdominal pain (15%, 12%, and 16%, respectively), fatigue (16%, 10%, and 10%, respectively), dyspnea (8%, 10%, and 6%, respectively), and weight loss (4%, 10%, and 5%, respectively).

Hematologic AEs occurring in at least 10% of patients in any group were anemia (99%, 98%, and 91%, respectively), thrombocytopenia (63%, 57%, and 51%, respectively), lymphopenia (57%, 66%, and 54%, respectively), leukopenia (47%, 53%, and 19%, respectively), and neutropenia (28%, 44%, and 15%, respectively).

One patient in each fedratinib arm and 2 in the placebo arm transformed to acute myeloid leukemia.

There were 24 deaths during the first 24 weeks of the study—4 in the 400 mg arm, 10 in the 500 mg arm, and 10 in the placebo arm. Nine of the deaths were attributed to AEs—1, 4, and 4, respectively.

Wernicke encephalopathy

There were 4 cases of Wernicke encephalopathy, all in women who received fedratinib at 500 mg. All of these cases were confirmed by an independent expert safety panel, 3 on the basis of clinical features and MRI results, and 1 on the basis of clinical symptoms alone.

The patients developed symptoms 6 weeks to 44 weeks after beginning fedratinib treatment, and all discontinued treatment permanently.

Cognitive symptoms manifested in the context of persistent vomiting, malnutrition, and cachexia in 1 patient, vomiting and hyponatremia in 1 patient, and renal failure with mild hyponatremia in 1 patient.

All of the patients received intravenous thiamine and showed responses to the treatment, but all had persistent cognitive defects at last follow-up.

Micrograph showing MF

Researchers have reported results of the phase 3 JAKARTA trial, in which they evaluated the selective JAK2 inhibitor fedratinib in patients with myelofibrosis (MF).

Fedratinib was being developed as a treatment for myeloproliferative neoplasms (MPNs), but Sanofi Oncology stopped clinical development of the drug in 2013, after it was linked to a neurological condition known as Wernicke encephalopathy.

There were 4 confirmed cases of Wernicke encephalopathy in the JAKARTA trial, in addition to other adverse events (AEs). However, fedratinib also lessened the severity of MF symptoms in about 35% to 40% of patients.

These results have been published in JAMA Oncology alongside an invited commentary. The study was sponsored by Sanofi.

Treatment and response

The study enrolled 289 adult patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. Patients were randomized to receive fedratinib at 400 mg once a day, fedratinib at 500 mg once a day, or placebo for at least 6 consecutive, 4-week cycles.

The study’s primary endpoint was spleen response, or a 35% or greater reduction in spleen volume from baseline (determined by MRI or CT) at week 24 and confirmed 4 weeks later.

Thirty-six percent (35/96) of patients in the 400 mg arm and 40% (39/97) in the 500 mg arm achieved the primary endpoint, compared to 1% (1/96) of patients in the placebo arm (P<0.001).

The main secondary endpoint was symptom response, or a 50% or greater reduction in total symptom score (assessed using the modified Myelofibrosis Symptom Assessment Form).

At week 24, symptom response rates were 36% (33/91) in the 400 mg arm, 34% (31/91) in the 500 mg arm, and 7% (6/85) in the placebo arm (P<0.001).

Safety data

Treatment-emergent AEs occurred in 100% of patients in the 400 mg arm, 98% in the 500 mg arm, and 94% in the placebo arm. Serious AEs occurred in 27%, 31%, and 23%, respectively. AEs leading to discontinuation occurred in 14%, 25%, and 8%, respectively.

Infections occurred in 42% of patients in the 400 mg arm, 39% of patients in the 500 mg arm, and 27% of patients of patients in the placebo arm.

Nonhematologic AEs occurring in at least 10% of patients in any group were diarrhea (66%, 56%, and 16%, respectively), vomiting (42%, 55%, and 5%, respectively), nausea (64%, 51%, and 15%, respectively), constipation (10%, 18%, and 7%, respectively), asthenia (9%, 16%, and 6%, respectively), abdominal pain (15%, 12%, and 16%, respectively), fatigue (16%, 10%, and 10%, respectively), dyspnea (8%, 10%, and 6%, respectively), and weight loss (4%, 10%, and 5%, respectively).

Hematologic AEs occurring in at least 10% of patients in any group were anemia (99%, 98%, and 91%, respectively), thrombocytopenia (63%, 57%, and 51%, respectively), lymphopenia (57%, 66%, and 54%, respectively), leukopenia (47%, 53%, and 19%, respectively), and neutropenia (28%, 44%, and 15%, respectively).

One patient in each fedratinib arm and 2 in the placebo arm transformed to acute myeloid leukemia.

There were 24 deaths during the first 24 weeks of the study—4 in the 400 mg arm, 10 in the 500 mg arm, and 10 in the placebo arm. Nine of the deaths were attributed to AEs—1, 4, and 4, respectively.

Wernicke encephalopathy

There were 4 cases of Wernicke encephalopathy, all in women who received fedratinib at 500 mg. All of these cases were confirmed by an independent expert safety panel, 3 on the basis of clinical features and MRI results, and 1 on the basis of clinical symptoms alone.

The patients developed symptoms 6 weeks to 44 weeks after beginning fedratinib treatment, and all discontinued treatment permanently.

Cognitive symptoms manifested in the context of persistent vomiting, malnutrition, and cachexia in 1 patient, vomiting and hyponatremia in 1 patient, and renal failure with mild hyponatremia in 1 patient.

All of the patients received intravenous thiamine and showed responses to the treatment, but all had persistent cognitive defects at last follow-up.

In the last 12 months, 12 actively recruiting trials examining chronic myeloid leukemia have been listed at clinicaltrials.gov.

Most of these trials examine the efficacy of various tyrosine kinase inhibitors (TKIs), but one trial called The LAST Study seeks to determine what happens to patients after TKIs – those patients who have undetectable BCR-ABL by polymerase chain reaction (PCR) test for at least 2 years. The goal of this study is to improve decision making for TKI discontinuation, and patients will be closely monitored for molecular recurrence, testing them monthly for 6 months, then every other month for 24 months, and quarterly until 36 months. Patients who have molecular chronic myelogenous leukemia recurrence will restart TKIs and will continue to be monitored for disease status and patient-reported health status.

All study participants must currently be taking a TKI for at least 3 years and have documented undetectable BCR-ABL by PCR for at least 2 years. Two screening PCRs must have been completed with results less than MR4.5. Participation is not limited by the number of TKIs, but no participant can be resistant to any TKI, and patients need to have been compliant with therapy. Patients with prior stem cell transplants are excluded, as are patients with less than 36 months life expectancy and pregnant or lactating women.

Click here to learn more about The LAST Study.

[email protected]

In the last 12 months, 12 actively recruiting trials examining chronic myeloid leukemia have been listed at clinicaltrials.gov.

Most of these trials examine the efficacy of various tyrosine kinase inhibitors (TKIs), but one trial called The LAST Study seeks to determine what happens to patients after TKIs – those patients who have undetectable BCR-ABL by polymerase chain reaction (PCR) test for at least 2 years. The goal of this study is to improve decision making for TKI discontinuation, and patients will be closely monitored for molecular recurrence, testing them monthly for 6 months, then every other month for 24 months, and quarterly until 36 months. Patients who have molecular chronic myelogenous leukemia recurrence will restart TKIs and will continue to be monitored for disease status and patient-reported health status.

All study participants must currently be taking a TKI for at least 3 years and have documented undetectable BCR-ABL by PCR for at least 2 years. Two screening PCRs must have been completed with results less than MR4.5. Participation is not limited by the number of TKIs, but no participant can be resistant to any TKI, and patients need to have been compliant with therapy. Patients with prior stem cell transplants are excluded, as are patients with less than 36 months life expectancy and pregnant or lactating women.

Click here to learn more about The LAST Study.

[email protected]

In the last 12 months, 12 actively recruiting trials examining chronic myeloid leukemia have been listed at clinicaltrials.gov.

Most of these trials examine the efficacy of various tyrosine kinase inhibitors (TKIs), but one trial called The LAST Study seeks to determine what happens to patients after TKIs – those patients who have undetectable BCR-ABL by polymerase chain reaction (PCR) test for at least 2 years. The goal of this study is to improve decision making for TKI discontinuation, and patients will be closely monitored for molecular recurrence, testing them monthly for 6 months, then every other month for 24 months, and quarterly until 36 months. Patients who have molecular chronic myelogenous leukemia recurrence will restart TKIs and will continue to be monitored for disease status and patient-reported health status.

All study participants must currently be taking a TKI for at least 3 years and have documented undetectable BCR-ABL by PCR for at least 2 years. Two screening PCRs must have been completed with results less than MR4.5. Participation is not limited by the number of TKIs, but no participant can be resistant to any TKI, and patients need to have been compliant with therapy. Patients with prior stem cell transplants are excluded, as are patients with less than 36 months life expectancy and pregnant or lactating women.

Click here to learn more about The LAST Study.

[email protected]