Sharon Worcester

BOSTON – Around-the-clock availability of a neurologist for acute stroke treatment significantly reduced door-to-needle times at a community-based primary stroke center serving as a regional tertiary referral center for western North Carolina.

Ryan McVay/Thinkstock

sworcester@frontlinemedcom.com

BOSTON – Around-the-clock availability of a neurologist for acute stroke treatment significantly reduced door-to-needle times at a community-based primary stroke center serving as a regional tertiary referral center for western North Carolina.

Ryan McVay/Thinkstock

sworcester@frontlinemedcom.com

BOSTON – Around-the-clock availability of a neurologist for acute stroke treatment significantly reduced door-to-needle times at a community-based primary stroke center serving as a regional tertiary referral center for western North Carolina.

Ryan McVay/Thinkstock

sworcester@frontlinemedcom.com

BOSTON – Cannabidiol add-on treatment significantly reduces the frequency of drop seizures in patients with Lennox-Gastaut syndrome, according to findings from the randomized, double-blind, placebo-controlled GWPCARE4 and GWPCARE3 trials.

In GWPCARE4 – the first controlled trial of cannabidiol in Lennox-Gastaut syndrome (LGS) – 171 patients were randomized to receive either placebo or cannabidiol oral solution at a dose of 20 mg/kg per day for 14 weeks, including 2 weeks of titration and 12 weeks of maintenance therapy. The drop seizure frequency decreased by a median of 44% in the cannabidiol group vs. 22% in the placebo group. The difference between the groups was statistically significant and was apparent within the first 4 weeks of the maintenance period, Jacqueline French, MD, director of translational research and clinical trials in epilepsy at New York University Langone Medical Center reported at the annual meeting of the American Academy of Neurology.

Study participants had a mean age of 15 years, and 34% were aged 18 years or older. The median drop seizure frequency was 74 per month at baseline.

“That is a very high seizure burden,” Dr. French said, noting that the median total drop and non-drop seizure frequency was in the mid to high 100s. “So you can see that these children were very afflicted by seizures.”

Interestingly, there was a “very substantial drop” in non-drop seizures, as well, she said.

“And that’s really hard to demonstrate, so that’s impressive to me, at least,” she added.

Patients had taken a median of six antiepileptic drugs (AEDs) in their past and were taking a median of three AEDs in addition to the cannabidiol throughout the study period.

Adverse events were common, occurring in 86% of cannabidiol patients and 69% of placebo patients. The most common were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting, but most were mild or moderate. Treatment-related serious adverse events were reported in nine cannabidiol patients and one placebo patient. All patients who completed the trial entered an open-label extension study, Dr. French said.

GWPCARE4 was followed by GWPCARE3, which compared both 20 mg/kg per day and 10 mg/kg per day doses of cannabidiol with placebo.

In that study, 225 patients with a mean age of 16 years (30% were aged 18 years or older) were randomized, and the median drop in seizure frequency was 42% with 20 mg/kg of cannabidiol and 37% with 10 mg/kg of cannabidiol versus 17% with placebo, Anup D. Patel, MD, reported at the meeting.

Approximately 40% and 36% of patients in the 20 mg/kg and 10 mg/kg groups, respectively, achieved the secondary outcome of a 50% or greater drop in seizure frequency, compared with 15% of placebo patients.

“Overall, 5 patients in the 20 mg/kg per day arm, 3 in the 10 [mg/kg per day arm], and 1 in the placebo arm achieved drop seizure freedom during the maintenance period of our study,” said Dr. Patel, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.

The median monthly drop seizure frequency at baseline was 80-87 in the three groups, and patients had previously failed a median of six to seven AEDs. They took a median of three AEDs during the study.

Adverse events occurred in 94% of patients in the 20-mg/kg cannabidiol group, 84% of those in the 10-mg/kg group, and 72% of placebo patients, and most were mild or moderate. The most common were somnolence and decreased appetite.

Treatment-related serious adverse events were reported in 5, 2, and 0 patients in the groups, respectively. Some elevations in transaminases were seen (in 11 patients in the 20-mg/kg dose group, and 2 in the 10-mg/kg dose group), but no patients met criteria for drug-induced liver injury with concurrent elevated bilirubin, and all cases resolved, Dr. Patel said.

Similar findings were noted in GWPCARE4, and both Dr. Patel and Dr. French noted that most patients with elevated transaminases were also taking valproic acid.

No deaths occurred in either GWPCARE4 or GWPCARE3.

“We feel both doses... produce significantly greater reductions in drop seizures as compared to placebo,” Dr. Patel said.

In an interview, he noted that the two cannabidiol doses were not compared directly to determine if the differences in response rates and adverse events were statistically significant, but said that the rates appeared comparable, and that the adverse event rates were high in all of the groups, reflecting a very sick patient population.

Of the 212 patients who completed GWPCARE3, 99% entered an open-label extension study.

Eligible patients in both trials were children and adults aged 2-55 years with a clinical diagnosis of LGS, at least two drop seizures (including tonic, atonic, and tonic-clonic seizures) each week at baseline, and documented failures on at least one AED.

Patients and caregivers in both trials were more likely to report improvement in overall condition among treated vs. placebo patients, as measured using the Subject/Caregiver Global Impression of Change scale.

The findings provide class 1 evidence that cannabidiol as add-on therapy in LGS is efficacious for reducing seizure frequency, and is generally well tolerated, Dr. French and Dr. Patel said.

Dr. French noted that enthusiasm for the trials was high, with many study sites reporting waiting lists for patient enrollment.

Some of the authors in each study have consulted for, conducted studies funded by, or received honoraria from GW Pharmaceuticals, which funded the GWPCARE4 and GWPCARE3 trials and manufacturers the oral cannabidiol solution. Several authors in each study were employees of GW Pharmaceuticals.

sworcester@frontlinemedcom.com

BOSTON – Cannabidiol add-on treatment significantly reduces the frequency of drop seizures in patients with Lennox-Gastaut syndrome, according to findings from the randomized, double-blind, placebo-controlled GWPCARE4 and GWPCARE3 trials.

In GWPCARE4 – the first controlled trial of cannabidiol in Lennox-Gastaut syndrome (LGS) – 171 patients were randomized to receive either placebo or cannabidiol oral solution at a dose of 20 mg/kg per day for 14 weeks, including 2 weeks of titration and 12 weeks of maintenance therapy. The drop seizure frequency decreased by a median of 44% in the cannabidiol group vs. 22% in the placebo group. The difference between the groups was statistically significant and was apparent within the first 4 weeks of the maintenance period, Jacqueline French, MD, director of translational research and clinical trials in epilepsy at New York University Langone Medical Center reported at the annual meeting of the American Academy of Neurology.

Study participants had a mean age of 15 years, and 34% were aged 18 years or older. The median drop seizure frequency was 74 per month at baseline.

“That is a very high seizure burden,” Dr. French said, noting that the median total drop and non-drop seizure frequency was in the mid to high 100s. “So you can see that these children were very afflicted by seizures.”

Interestingly, there was a “very substantial drop” in non-drop seizures, as well, she said.

“And that’s really hard to demonstrate, so that’s impressive to me, at least,” she added.

Patients had taken a median of six antiepileptic drugs (AEDs) in their past and were taking a median of three AEDs in addition to the cannabidiol throughout the study period.

Adverse events were common, occurring in 86% of cannabidiol patients and 69% of placebo patients. The most common were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting, but most were mild or moderate. Treatment-related serious adverse events were reported in nine cannabidiol patients and one placebo patient. All patients who completed the trial entered an open-label extension study, Dr. French said.

GWPCARE4 was followed by GWPCARE3, which compared both 20 mg/kg per day and 10 mg/kg per day doses of cannabidiol with placebo.

In that study, 225 patients with a mean age of 16 years (30% were aged 18 years or older) were randomized, and the median drop in seizure frequency was 42% with 20 mg/kg of cannabidiol and 37% with 10 mg/kg of cannabidiol versus 17% with placebo, Anup D. Patel, MD, reported at the meeting.

Approximately 40% and 36% of patients in the 20 mg/kg and 10 mg/kg groups, respectively, achieved the secondary outcome of a 50% or greater drop in seizure frequency, compared with 15% of placebo patients.

“Overall, 5 patients in the 20 mg/kg per day arm, 3 in the 10 [mg/kg per day arm], and 1 in the placebo arm achieved drop seizure freedom during the maintenance period of our study,” said Dr. Patel, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.

The median monthly drop seizure frequency at baseline was 80-87 in the three groups, and patients had previously failed a median of six to seven AEDs. They took a median of three AEDs during the study.

Adverse events occurred in 94% of patients in the 20-mg/kg cannabidiol group, 84% of those in the 10-mg/kg group, and 72% of placebo patients, and most were mild or moderate. The most common were somnolence and decreased appetite.

Treatment-related serious adverse events were reported in 5, 2, and 0 patients in the groups, respectively. Some elevations in transaminases were seen (in 11 patients in the 20-mg/kg dose group, and 2 in the 10-mg/kg dose group), but no patients met criteria for drug-induced liver injury with concurrent elevated bilirubin, and all cases resolved, Dr. Patel said.

Similar findings were noted in GWPCARE4, and both Dr. Patel and Dr. French noted that most patients with elevated transaminases were also taking valproic acid.

No deaths occurred in either GWPCARE4 or GWPCARE3.

“We feel both doses... produce significantly greater reductions in drop seizures as compared to placebo,” Dr. Patel said.

In an interview, he noted that the two cannabidiol doses were not compared directly to determine if the differences in response rates and adverse events were statistically significant, but said that the rates appeared comparable, and that the adverse event rates were high in all of the groups, reflecting a very sick patient population.

Of the 212 patients who completed GWPCARE3, 99% entered an open-label extension study.

Eligible patients in both trials were children and adults aged 2-55 years with a clinical diagnosis of LGS, at least two drop seizures (including tonic, atonic, and tonic-clonic seizures) each week at baseline, and documented failures on at least one AED.

Patients and caregivers in both trials were more likely to report improvement in overall condition among treated vs. placebo patients, as measured using the Subject/Caregiver Global Impression of Change scale.

The findings provide class 1 evidence that cannabidiol as add-on therapy in LGS is efficacious for reducing seizure frequency, and is generally well tolerated, Dr. French and Dr. Patel said.

Dr. French noted that enthusiasm for the trials was high, with many study sites reporting waiting lists for patient enrollment.

Some of the authors in each study have consulted for, conducted studies funded by, or received honoraria from GW Pharmaceuticals, which funded the GWPCARE4 and GWPCARE3 trials and manufacturers the oral cannabidiol solution. Several authors in each study were employees of GW Pharmaceuticals.

sworcester@frontlinemedcom.com

BOSTON – Cannabidiol add-on treatment significantly reduces the frequency of drop seizures in patients with Lennox-Gastaut syndrome, according to findings from the randomized, double-blind, placebo-controlled GWPCARE4 and GWPCARE3 trials.

In GWPCARE4 – the first controlled trial of cannabidiol in Lennox-Gastaut syndrome (LGS) – 171 patients were randomized to receive either placebo or cannabidiol oral solution at a dose of 20 mg/kg per day for 14 weeks, including 2 weeks of titration and 12 weeks of maintenance therapy. The drop seizure frequency decreased by a median of 44% in the cannabidiol group vs. 22% in the placebo group. The difference between the groups was statistically significant and was apparent within the first 4 weeks of the maintenance period, Jacqueline French, MD, director of translational research and clinical trials in epilepsy at New York University Langone Medical Center reported at the annual meeting of the American Academy of Neurology.

Study participants had a mean age of 15 years, and 34% were aged 18 years or older. The median drop seizure frequency was 74 per month at baseline.

“That is a very high seizure burden,” Dr. French said, noting that the median total drop and non-drop seizure frequency was in the mid to high 100s. “So you can see that these children were very afflicted by seizures.”

Interestingly, there was a “very substantial drop” in non-drop seizures, as well, she said.

“And that’s really hard to demonstrate, so that’s impressive to me, at least,” she added.

Patients had taken a median of six antiepileptic drugs (AEDs) in their past and were taking a median of three AEDs in addition to the cannabidiol throughout the study period.

Adverse events were common, occurring in 86% of cannabidiol patients and 69% of placebo patients. The most common were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting, but most were mild or moderate. Treatment-related serious adverse events were reported in nine cannabidiol patients and one placebo patient. All patients who completed the trial entered an open-label extension study, Dr. French said.

GWPCARE4 was followed by GWPCARE3, which compared both 20 mg/kg per day and 10 mg/kg per day doses of cannabidiol with placebo.

In that study, 225 patients with a mean age of 16 years (30% were aged 18 years or older) were randomized, and the median drop in seizure frequency was 42% with 20 mg/kg of cannabidiol and 37% with 10 mg/kg of cannabidiol versus 17% with placebo, Anup D. Patel, MD, reported at the meeting.

Approximately 40% and 36% of patients in the 20 mg/kg and 10 mg/kg groups, respectively, achieved the secondary outcome of a 50% or greater drop in seizure frequency, compared with 15% of placebo patients.

“Overall, 5 patients in the 20 mg/kg per day arm, 3 in the 10 [mg/kg per day arm], and 1 in the placebo arm achieved drop seizure freedom during the maintenance period of our study,” said Dr. Patel, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.

The median monthly drop seizure frequency at baseline was 80-87 in the three groups, and patients had previously failed a median of six to seven AEDs. They took a median of three AEDs during the study.

Adverse events occurred in 94% of patients in the 20-mg/kg cannabidiol group, 84% of those in the 10-mg/kg group, and 72% of placebo patients, and most were mild or moderate. The most common were somnolence and decreased appetite.

Treatment-related serious adverse events were reported in 5, 2, and 0 patients in the groups, respectively. Some elevations in transaminases were seen (in 11 patients in the 20-mg/kg dose group, and 2 in the 10-mg/kg dose group), but no patients met criteria for drug-induced liver injury with concurrent elevated bilirubin, and all cases resolved, Dr. Patel said.

Similar findings were noted in GWPCARE4, and both Dr. Patel and Dr. French noted that most patients with elevated transaminases were also taking valproic acid.

No deaths occurred in either GWPCARE4 or GWPCARE3.

“We feel both doses... produce significantly greater reductions in drop seizures as compared to placebo,” Dr. Patel said.

In an interview, he noted that the two cannabidiol doses were not compared directly to determine if the differences in response rates and adverse events were statistically significant, but said that the rates appeared comparable, and that the adverse event rates were high in all of the groups, reflecting a very sick patient population.

Of the 212 patients who completed GWPCARE3, 99% entered an open-label extension study.

Eligible patients in both trials were children and adults aged 2-55 years with a clinical diagnosis of LGS, at least two drop seizures (including tonic, atonic, and tonic-clonic seizures) each week at baseline, and documented failures on at least one AED.

Patients and caregivers in both trials were more likely to report improvement in overall condition among treated vs. placebo patients, as measured using the Subject/Caregiver Global Impression of Change scale.

The findings provide class 1 evidence that cannabidiol as add-on therapy in LGS is efficacious for reducing seizure frequency, and is generally well tolerated, Dr. French and Dr. Patel said.

Dr. French noted that enthusiasm for the trials was high, with many study sites reporting waiting lists for patient enrollment.

Some of the authors in each study have consulted for, conducted studies funded by, or received honoraria from GW Pharmaceuticals, which funded the GWPCARE4 and GWPCARE3 trials and manufacturers the oral cannabidiol solution. Several authors in each study were employees of GW Pharmaceuticals.

sworcester@frontlinemedcom.com

BOSTON – Adjunctive treatment with cannabidiol significantly reduced convulsive seizure frequency in Dravet syndrome patients in a randomized, double-blind, placebo-controlled trial.

Over a 14-week treatment period, including 2 weeks of titration and 12 weeks of maintenance, convulsive seizure frequency in 61 treated children and adolescents decreased from a median of 12.4 to 5.9 per month (median reduction of 39%), compared with a decrease from a median of 14.9 to 14.1 per month (median reduction of 13%) in 59 patients who received placebo, J. Helen Cross, MD, reported at the annual meeting of the American Academy of Neurology.

The proportion of patients with at least a 50% reduction in convulsive seizures was 42.6% with cannabidiol vs. 27.1% with placebo (odds ratio, 2.0), but this difference did not reach statistical significance, said Dr. Cross of the University College London Great Ormond Street Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust, London.

In a video interview, Dr. Cross discussed the findings and the importance of improving seizure control in patients with Dravet syndrome, a rare infantile-onset developmental and epileptic encephalopathy with very poor prognosis for long-term seizure control and neurodevelopmental outcomes.

Participants in the study (GWPCARE1) had a mean age of 10 years, but nearly a third were younger than 6 years. All had Dravet syndrome and drug-resistant seizures; the median number of antiepilepsy drugs previously tried was four, and the median number being used was three. Those randomized to the treatment group received cannabidiol oral solution up to 20 mg/kg per day.

Adverse events were common, occurring in 93.4% and 74.6% of treatment group and placebo group patients, respectively. But adverse events reported in the treatment group were mild or moderate in 84% of patients, and treatment was generally well tolerated.

“These are very complex patients with a high seizure burden... and therefore, to have another medication that looks as if it can be of benefit is really very exciting for this population,” Dr. Cross said, noting that cannabidiol was also shown in other studies presented at the AAN meeting (GWPCARE3 and GWPCARE4) to reduce seizure frequency in patients with Lennox-Gastaut syndrome.

GW Research sponsored the study. Dr. Cross is a member of the advisory boards for Eisai, GW Pharmaceuticals, Shire, and Zogenix.

sworcester@frontlinemedcom.com

BOSTON – Adjunctive treatment with cannabidiol significantly reduced convulsive seizure frequency in Dravet syndrome patients in a randomized, double-blind, placebo-controlled trial.

Over a 14-week treatment period, including 2 weeks of titration and 12 weeks of maintenance, convulsive seizure frequency in 61 treated children and adolescents decreased from a median of 12.4 to 5.9 per month (median reduction of 39%), compared with a decrease from a median of 14.9 to 14.1 per month (median reduction of 13%) in 59 patients who received placebo, J. Helen Cross, MD, reported at the annual meeting of the American Academy of Neurology.

The proportion of patients with at least a 50% reduction in convulsive seizures was 42.6% with cannabidiol vs. 27.1% with placebo (odds ratio, 2.0), but this difference did not reach statistical significance, said Dr. Cross of the University College London Great Ormond Street Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust, London.

In a video interview, Dr. Cross discussed the findings and the importance of improving seizure control in patients with Dravet syndrome, a rare infantile-onset developmental and epileptic encephalopathy with very poor prognosis for long-term seizure control and neurodevelopmental outcomes.

Participants in the study (GWPCARE1) had a mean age of 10 years, but nearly a third were younger than 6 years. All had Dravet syndrome and drug-resistant seizures; the median number of antiepilepsy drugs previously tried was four, and the median number being used was three. Those randomized to the treatment group received cannabidiol oral solution up to 20 mg/kg per day.

Adverse events were common, occurring in 93.4% and 74.6% of treatment group and placebo group patients, respectively. But adverse events reported in the treatment group were mild or moderate in 84% of patients, and treatment was generally well tolerated.

“These are very complex patients with a high seizure burden... and therefore, to have another medication that looks as if it can be of benefit is really very exciting for this population,” Dr. Cross said, noting that cannabidiol was also shown in other studies presented at the AAN meeting (GWPCARE3 and GWPCARE4) to reduce seizure frequency in patients with Lennox-Gastaut syndrome.

GW Research sponsored the study. Dr. Cross is a member of the advisory boards for Eisai, GW Pharmaceuticals, Shire, and Zogenix.

sworcester@frontlinemedcom.com

BOSTON – Adjunctive treatment with cannabidiol significantly reduced convulsive seizure frequency in Dravet syndrome patients in a randomized, double-blind, placebo-controlled trial.

Over a 14-week treatment period, including 2 weeks of titration and 12 weeks of maintenance, convulsive seizure frequency in 61 treated children and adolescents decreased from a median of 12.4 to 5.9 per month (median reduction of 39%), compared with a decrease from a median of 14.9 to 14.1 per month (median reduction of 13%) in 59 patients who received placebo, J. Helen Cross, MD, reported at the annual meeting of the American Academy of Neurology.

The proportion of patients with at least a 50% reduction in convulsive seizures was 42.6% with cannabidiol vs. 27.1% with placebo (odds ratio, 2.0), but this difference did not reach statistical significance, said Dr. Cross of the University College London Great Ormond Street Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust, London.

In a video interview, Dr. Cross discussed the findings and the importance of improving seizure control in patients with Dravet syndrome, a rare infantile-onset developmental and epileptic encephalopathy with very poor prognosis for long-term seizure control and neurodevelopmental outcomes.

Participants in the study (GWPCARE1) had a mean age of 10 years, but nearly a third were younger than 6 years. All had Dravet syndrome and drug-resistant seizures; the median number of antiepilepsy drugs previously tried was four, and the median number being used was three. Those randomized to the treatment group received cannabidiol oral solution up to 20 mg/kg per day.

Adverse events were common, occurring in 93.4% and 74.6% of treatment group and placebo group patients, respectively. But adverse events reported in the treatment group were mild or moderate in 84% of patients, and treatment was generally well tolerated.

“These are very complex patients with a high seizure burden... and therefore, to have another medication that looks as if it can be of benefit is really very exciting for this population,” Dr. Cross said, noting that cannabidiol was also shown in other studies presented at the AAN meeting (GWPCARE3 and GWPCARE4) to reduce seizure frequency in patients with Lennox-Gastaut syndrome.

GW Research sponsored the study. Dr. Cross is a member of the advisory boards for Eisai, GW Pharmaceuticals, Shire, and Zogenix.

sworcester@frontlinemedcom.com

Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.

The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD, of the University of Chicago and her colleagues said in The Lancet Haematology.

In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.

The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred (Lancet Haematol. 2017 Apr;4:e176-82).

Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.

Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.

“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.

The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.

“Both ... trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.

Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.

“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.

The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.

“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.

The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.

sworcester@frontlinemedcom.com

Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.

The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD, of the University of Chicago and her colleagues said in The Lancet Haematology.

In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.

The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred (Lancet Haematol. 2017 Apr;4:e176-82).

Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.

Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.

“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.

The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.

“Both ... trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.

Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.

“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.

The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.

“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.

The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.

sworcester@frontlinemedcom.com

Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.

The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD, of the University of Chicago and her colleagues said in The Lancet Haematology.

In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.

The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred (Lancet Haematol. 2017 Apr;4:e176-82).

Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.

Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.

“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.

The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.

“Both ... trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.

Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.

“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.

The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.

“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.

The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.

sworcester@frontlinemedcom.com

BOSTON – Generalized tonic-clonic seizures (GTCS) are a major risk factor for sudden unexpected death in epilepsy (SUDEP), which underscores the importance of advising people with epilepsy about controlling such seizures, according to a new practice guideline from the American Academy of Neurology and the American Epilepsy Society.

Though SUDEP is rare, with an incidence rate of 0.22/1,000 patient-years in children with epilepsy and 1.2/1,000 patient-years in adults with epilepsy, the guideline committee found that people with three or more GTCS per year are 15 times more likely to die suddenly than are those without this seizure type. The risk increases with increasing GTCS frequency. This translates to an absolute risk of up to 18 deaths per 1,000 patient-years for people with epilepsy who have frequent GTCS.

Sharon Worcester/Frontline Medical News

Sharon Worcester/Frontline Medical News

sworcester@frontlinemedcom.com

BOSTON – Generalized tonic-clonic seizures (GTCS) are a major risk factor for sudden unexpected death in epilepsy (SUDEP), which underscores the importance of advising people with epilepsy about controlling such seizures, according to a new practice guideline from the American Academy of Neurology and the American Epilepsy Society.

Though SUDEP is rare, with an incidence rate of 0.22/1,000 patient-years in children with epilepsy and 1.2/1,000 patient-years in adults with epilepsy, the guideline committee found that people with three or more GTCS per year are 15 times more likely to die suddenly than are those without this seizure type. The risk increases with increasing GTCS frequency. This translates to an absolute risk of up to 18 deaths per 1,000 patient-years for people with epilepsy who have frequent GTCS.

Sharon Worcester/Frontline Medical News

Sharon Worcester/Frontline Medical News

sworcester@frontlinemedcom.com

BOSTON – Generalized tonic-clonic seizures (GTCS) are a major risk factor for sudden unexpected death in epilepsy (SUDEP), which underscores the importance of advising people with epilepsy about controlling such seizures, according to a new practice guideline from the American Academy of Neurology and the American Epilepsy Society.

Though SUDEP is rare, with an incidence rate of 0.22/1,000 patient-years in children with epilepsy and 1.2/1,000 patient-years in adults with epilepsy, the guideline committee found that people with three or more GTCS per year are 15 times more likely to die suddenly than are those without this seizure type. The risk increases with increasing GTCS frequency. This translates to an absolute risk of up to 18 deaths per 1,000 patient-years for people with epilepsy who have frequent GTCS.

Sharon Worcester/Frontline Medical News

Sharon Worcester/Frontline Medical News

sworcester@frontlinemedcom.com

BOSTON – Ultra-fast door-to-needle times of 10 minutes or less for intravenous acute ischemic stroke thrombolysis can be safely achieved in carefully selected cases, according to a review of cases at an Austrian teaching hospital.

Raffi Topakian, MD, and his colleagues at the Academic Teaching Hospital Wels-Grieskirchen in Wels, Austria, followed a multidisciplinary intervention to reinforce key components of the well-known Helsinki model of acute stroke care to improve the intravenous thrombolysis rate and the median door-to-needle time (DNT) at the teaching hospital and analyzed data from 361 patients who underwent intravenous thrombolysis (IVT) for stroke there between July 2014 and September 2016. The IVT rate increased from 19% to about 27% after intervention, and the DNT during the study period was 60 minutes or less in 316 patients (87.5%), 30 minutes or less in 181 patients (50.1%), and 10 minutes or less in 63 patients (17.5%).

“Over the study period, we reduced the DNT time from 49 minutes to 25 minutes. This was significant, and the door-to-needle times were astonishingly similar for the in-hours service and the out-of-hour service,” he said at the annual meeting of the American Academy of Neurology.

Further, the rate of prenotifications from emergency medical services rose from about 30% to 63% during the study period.

Patients with ultra-fast DNT vs. those with slower DNT were older, had more chronic heart failure, had more severe stroke (National Institutes of Health Stroke Scale score of 10 vs. 5), had more anterior circulation stroke and cardioembolic stroke, and had clear onset of stroke. Independent predictors of ultra-fast DNT included prenotification by EMS, anterior circulation syndrome, chronic heart failure, and having a stroke neurologist on duty, Dr. Topakian said.

“Ultra short DNTs can be achieved safely. The key is that we are prenotified by the EMS, that we can get all the relevant history details during transport, that there is a dedicated multidisciplinary stroke team and EMS staff, and that we have a seemingly unequivocal clinical scenario,” he said. “Out-of-hours DNT matched in-hours DNT, but the caveat is we’re talking about highly selected candidates; safety must not be sacrificed for the sake of speed, in all of our patients.”

Dr. Topakian has received personal compensation for activities with Novartis and Shire-Baxalta as an advisory board member; from Novartis, Pfizer, AbbVie, and Bayer for conference support; and from Pfizer as a speaker.

sworcester@frontlinemedcom.com

BOSTON – Ultra-fast door-to-needle times of 10 minutes or less for intravenous acute ischemic stroke thrombolysis can be safely achieved in carefully selected cases, according to a review of cases at an Austrian teaching hospital.

Raffi Topakian, MD, and his colleagues at the Academic Teaching Hospital Wels-Grieskirchen in Wels, Austria, followed a multidisciplinary intervention to reinforce key components of the well-known Helsinki model of acute stroke care to improve the intravenous thrombolysis rate and the median door-to-needle time (DNT) at the teaching hospital and analyzed data from 361 patients who underwent intravenous thrombolysis (IVT) for stroke there between July 2014 and September 2016. The IVT rate increased from 19% to about 27% after intervention, and the DNT during the study period was 60 minutes or less in 316 patients (87.5%), 30 minutes or less in 181 patients (50.1%), and 10 minutes or less in 63 patients (17.5%).

“Over the study period, we reduced the DNT time from 49 minutes to 25 minutes. This was significant, and the door-to-needle times were astonishingly similar for the in-hours service and the out-of-hour service,” he said at the annual meeting of the American Academy of Neurology.

Further, the rate of prenotifications from emergency medical services rose from about 30% to 63% during the study period.

Patients with ultra-fast DNT vs. those with slower DNT were older, had more chronic heart failure, had more severe stroke (National Institutes of Health Stroke Scale score of 10 vs. 5), had more anterior circulation stroke and cardioembolic stroke, and had clear onset of stroke. Independent predictors of ultra-fast DNT included prenotification by EMS, anterior circulation syndrome, chronic heart failure, and having a stroke neurologist on duty, Dr. Topakian said.

“Ultra short DNTs can be achieved safely. The key is that we are prenotified by the EMS, that we can get all the relevant history details during transport, that there is a dedicated multidisciplinary stroke team and EMS staff, and that we have a seemingly unequivocal clinical scenario,” he said. “Out-of-hours DNT matched in-hours DNT, but the caveat is we’re talking about highly selected candidates; safety must not be sacrificed for the sake of speed, in all of our patients.”

Dr. Topakian has received personal compensation for activities with Novartis and Shire-Baxalta as an advisory board member; from Novartis, Pfizer, AbbVie, and Bayer for conference support; and from Pfizer as a speaker.

sworcester@frontlinemedcom.com

BOSTON – Ultra-fast door-to-needle times of 10 minutes or less for intravenous acute ischemic stroke thrombolysis can be safely achieved in carefully selected cases, according to a review of cases at an Austrian teaching hospital.

Raffi Topakian, MD, and his colleagues at the Academic Teaching Hospital Wels-Grieskirchen in Wels, Austria, followed a multidisciplinary intervention to reinforce key components of the well-known Helsinki model of acute stroke care to improve the intravenous thrombolysis rate and the median door-to-needle time (DNT) at the teaching hospital and analyzed data from 361 patients who underwent intravenous thrombolysis (IVT) for stroke there between July 2014 and September 2016. The IVT rate increased from 19% to about 27% after intervention, and the DNT during the study period was 60 minutes or less in 316 patients (87.5%), 30 minutes or less in 181 patients (50.1%), and 10 minutes or less in 63 patients (17.5%).

“Over the study period, we reduced the DNT time from 49 minutes to 25 minutes. This was significant, and the door-to-needle times were astonishingly similar for the in-hours service and the out-of-hour service,” he said at the annual meeting of the American Academy of Neurology.

Further, the rate of prenotifications from emergency medical services rose from about 30% to 63% during the study period.

Patients with ultra-fast DNT vs. those with slower DNT were older, had more chronic heart failure, had more severe stroke (National Institutes of Health Stroke Scale score of 10 vs. 5), had more anterior circulation stroke and cardioembolic stroke, and had clear onset of stroke. Independent predictors of ultra-fast DNT included prenotification by EMS, anterior circulation syndrome, chronic heart failure, and having a stroke neurologist on duty, Dr. Topakian said.

“Ultra short DNTs can be achieved safely. The key is that we are prenotified by the EMS, that we can get all the relevant history details during transport, that there is a dedicated multidisciplinary stroke team and EMS staff, and that we have a seemingly unequivocal clinical scenario,” he said. “Out-of-hours DNT matched in-hours DNT, but the caveat is we’re talking about highly selected candidates; safety must not be sacrificed for the sake of speed, in all of our patients.”

Dr. Topakian has received personal compensation for activities with Novartis and Shire-Baxalta as an advisory board member; from Novartis, Pfizer, AbbVie, and Bayer for conference support; and from Pfizer as a speaker.

sworcester@frontlinemedcom.com

Optimum antithymocyte globulin exposure after allogeneic hemopoietic cell transplantation (HTC) is associated with a higher probability of survival as a result of reductions in transplant-related and relapse-related deaths, based on findings from a retrospective multicenter cohort study.

The findings come from a pharmacokinetic-pharmacodynamic analysis of data from 146 patients with acute lymphoid leukemia, acute myeloid leukemia, or myelodysplastic syndrome. All were receiving their first T cell–repleted allogeneic peripheral blood stem cell HCT with antithymocyte globulin (ATG) as part of their nonmyeloablative conditioning regimen. Based on hazard ratios for overall survival, nonrelapse mortality, and relapse-related mortality, the optimum range of ATG exposure was 60-95 arbitrary units per day/mL, Rick Admiraal, MD, of the University Medical Centre Utrecht, Netherlands, and his colleagues reported in the Lancet Haematology (Lancet Haematol. 2017 Apr;4[4]:e183-91).

The estimated 5-year survival was significantly greater with optimum ATG exposure than with below-optimum exposure (69% vs. 32%; hazard ratio, 2.41) or with above-optimum exposure (69% vs. 48%; hazard ratio, 2.11).

Optimum ATG exposure also was associated with a greater likelihood of event-free survival: The hazard ratio was 2.54 for those with below-optimum exposure and 1.83 for those with above-optimum exposure, the researchers said. Further, above-optimum exposure was associated with higher relapse-related mortality (hazard ratio, 2.66). Below-optimum exposure was associated with higher non-relapse mortality (hazard ratio, 4.36) as well as with a higher risk for grade 3-4 acute graft-versus-host disease (hazard ratio, 3.09), but not for chronic graft-versus-host disease (hazard ratio, 2.38).

Optimum target attainment was better with modeled dosing based on absolute lymphocyte counts than with weight-based dosing, the authors said.

The findings underscore the importance of optimum ATG dosing, as “survival after HCT is highly affected by ATG exposure after HCT,” and they suggest that survival chances may be improved with individualized dosing based on lymphocyte counts–a finding that requires assessment in a prospective study, they concluded.

This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no relevant disclosures.

sworcester@frontlinemedcom.com

Optimum antithymocyte globulin exposure after allogeneic hemopoietic cell transplantation (HTC) is associated with a higher probability of survival as a result of reductions in transplant-related and relapse-related deaths, based on findings from a retrospective multicenter cohort study.

The findings come from a pharmacokinetic-pharmacodynamic analysis of data from 146 patients with acute lymphoid leukemia, acute myeloid leukemia, or myelodysplastic syndrome. All were receiving their first T cell–repleted allogeneic peripheral blood stem cell HCT with antithymocyte globulin (ATG) as part of their nonmyeloablative conditioning regimen. Based on hazard ratios for overall survival, nonrelapse mortality, and relapse-related mortality, the optimum range of ATG exposure was 60-95 arbitrary units per day/mL, Rick Admiraal, MD, of the University Medical Centre Utrecht, Netherlands, and his colleagues reported in the Lancet Haematology (Lancet Haematol. 2017 Apr;4[4]:e183-91).

The estimated 5-year survival was significantly greater with optimum ATG exposure than with below-optimum exposure (69% vs. 32%; hazard ratio, 2.41) or with above-optimum exposure (69% vs. 48%; hazard ratio, 2.11).

Optimum ATG exposure also was associated with a greater likelihood of event-free survival: The hazard ratio was 2.54 for those with below-optimum exposure and 1.83 for those with above-optimum exposure, the researchers said. Further, above-optimum exposure was associated with higher relapse-related mortality (hazard ratio, 2.66). Below-optimum exposure was associated with higher non-relapse mortality (hazard ratio, 4.36) as well as with a higher risk for grade 3-4 acute graft-versus-host disease (hazard ratio, 3.09), but not for chronic graft-versus-host disease (hazard ratio, 2.38).

Optimum target attainment was better with modeled dosing based on absolute lymphocyte counts than with weight-based dosing, the authors said.

The findings underscore the importance of optimum ATG dosing, as “survival after HCT is highly affected by ATG exposure after HCT,” and they suggest that survival chances may be improved with individualized dosing based on lymphocyte counts–a finding that requires assessment in a prospective study, they concluded.

This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no relevant disclosures.

sworcester@frontlinemedcom.com

Optimum antithymocyte globulin exposure after allogeneic hemopoietic cell transplantation (HTC) is associated with a higher probability of survival as a result of reductions in transplant-related and relapse-related deaths, based on findings from a retrospective multicenter cohort study.

The findings come from a pharmacokinetic-pharmacodynamic analysis of data from 146 patients with acute lymphoid leukemia, acute myeloid leukemia, or myelodysplastic syndrome. All were receiving their first T cell–repleted allogeneic peripheral blood stem cell HCT with antithymocyte globulin (ATG) as part of their nonmyeloablative conditioning regimen. Based on hazard ratios for overall survival, nonrelapse mortality, and relapse-related mortality, the optimum range of ATG exposure was 60-95 arbitrary units per day/mL, Rick Admiraal, MD, of the University Medical Centre Utrecht, Netherlands, and his colleagues reported in the Lancet Haematology (Lancet Haematol. 2017 Apr;4[4]:e183-91).

The estimated 5-year survival was significantly greater with optimum ATG exposure than with below-optimum exposure (69% vs. 32%; hazard ratio, 2.41) or with above-optimum exposure (69% vs. 48%; hazard ratio, 2.11).

Optimum ATG exposure also was associated with a greater likelihood of event-free survival: The hazard ratio was 2.54 for those with below-optimum exposure and 1.83 for those with above-optimum exposure, the researchers said. Further, above-optimum exposure was associated with higher relapse-related mortality (hazard ratio, 2.66). Below-optimum exposure was associated with higher non-relapse mortality (hazard ratio, 4.36) as well as with a higher risk for grade 3-4 acute graft-versus-host disease (hazard ratio, 3.09), but not for chronic graft-versus-host disease (hazard ratio, 2.38).

Optimum target attainment was better with modeled dosing based on absolute lymphocyte counts than with weight-based dosing, the authors said.

The findings underscore the importance of optimum ATG dosing, as “survival after HCT is highly affected by ATG exposure after HCT,” and they suggest that survival chances may be improved with individualized dosing based on lymphocyte counts–a finding that requires assessment in a prospective study, they concluded.

This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no relevant disclosures.

sworcester@frontlinemedcom.com

ORLANDO – The use of the CCR5 antagonist maraviroc for 90 days is safe and effective for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation, according to findings from a phase II study.

An earlier study showed that CCR5 blockade using maraviroc for 33 days was associated with a low incidence of acute GVHD, as well as with absence of early liver and gut GVHD – although delayed severe cases of visceral GVHD still occurred.

The current study was performed because the prior findings raised concerns that brief blockade was insufficient for preventing GVHD over a longer period of time. The new findings show that an extended course may indeed provide additional benefits, Ran Reshef, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In 37 high-risk patients who received allogeneic stem cell transplantation from unrelated donors using fludarabine/busulfan (Flu/Bu2) conditioning followed by peripheral blood stem cells, maraviroc was given at a dose of 300 mg twice daily, in addition to standard tacrolimus and methotrexate.

The 180-day rates of grade 2-4 and grade 3-4 acute GVHD (the primary endpoint of the study) in these patients were 27% and 5%, respectively. These rates were very similar to the 24% and 6% rates seen in the first study at 6 months after 30 days of maraviroc treatment, said Dr. Reshef of Columbia University Medical Center, New York.

The earlier results were “driven not so much by a reduction in the rates of skin GVHD, but by low rates of visceral GVHD of the gut and the liver – with a striking absence of gut and liver GVHD in the first 100 days,” he said.

Dr. Reshef also noted that the current study had a less favorable donor mix, as no matched related donors were included because of the earlier study’s very low rates of GVHD – with or without maraviroc – in those with related donors, who composed a third of donors.

Long-term follow-up of results from the earlier study, with comparison of a large contemporary control cohort, showed that “there is in fact an impact ... on grade 2-4 and grade 3-4 [GVHD], although the number of events is small, and the study was not powered enough to reach statistical significance,” Dr. Reshef said. The rates of chronic GVHD did not differ between the study subjects and contemporary controls, he noted.

At 100 days in the current study, there were no cases of liver GVHD, two cases of mild upper-GI GVHD, and one case of severe gut GVHD. At 1 year, the disease relapse rate was “fairly reasonable” at 30%, nonrelapse mortality was 12% with only one case of death from GVHD, and the incidence of chronic GVHD was 8%, which was significantly lower than in the prior study, he said.

The low rate of chronic GVHD led to a GVHD/relapse-free survival (GRFS) rate of 49%.

“To put this in context, the [Center for International Blood & Marrow Transplant Research] data for reduced-intensity transplants ... have shown 25% for acute myeloid leukemia and 12% for myelodysplastic syndrome,” he said. “So, we feel that these are by far improved numbers, compared with this benchmark.”

To determine which patients develop GVHD despite chemotaxis blockade and why, Dr. Reshef and his colleagues developed a pharmacodynamic assay to assess the activity of maraviroc in fresh blood samples. They found that those with insufficient CCR5 blockade on day 0 were those with higher incidence of severe acute GVHD, nonrelapse mortality, GRFS, and overall survival.

The investigators performed pharmacokinetic analysis using combined data from both trials to improve understanding of why some patients have insufficient CCR5 blockade. This showed significant variability in day 0 trough of maraviroc among patients (median of 65 ng/mL, range 12-316 ng/mL); levels above the median were associated with a significantly lower incidence of acute grade 2-4 GVHD and a trend toward improved GRFS.

These studies of maraviroc, which was originally developed for the treatment of HIV infection, were done to test the belief that blocking lymphocyte migration might prevent GVHD without interfering with graft-versus-tumor activity. Based on the earlier findings, Dr. Reshef and his colleagues hypothesized that treatment up to day 90 would decrease the rate to less than 30%, from a historical rate of 52%.

Patients in the study were high risk by virtue of age (median, 64 years), HLA matching (matched unrelated, 84%; mismatched unrelated, 16%), and comorbidities (comorbidity index greater than 2 in 49%). Underlying diseases were acute leukemia (78%), myelodysplastic syndrome (16%), and myeloproliferative neoplasm and cutaneous T-cell lymphomas (3% each).

At a median follow-up of 21 months, the 3-month course of maraviroc was well tolerated. Eight patients did not complete treatment because of disease relapse (five patients), skin reaction (one patient), early infection-related death (one patient), or poor tolerance of oral drugs (one patient). Neutrophil, platelet, and T-cell engraftment were similar to historical controls, and rates of infections were also similar, Dr Reshef noted.

“To conclude, an extended course of maraviroc up to day 90 is feasible and safe in the majority of patients,” he said. “This study confirms the effect of CCR5 blockade on visceral GVHD. I’m still awaiting a randomized study to confirm that further.

“A long course of maraviroc does not necessarily affect the rates of acute GVHD, but may help reduce chronic GVHD and improve GRFS,” Dr. Reshef said. “We should look further into the pharmacodynamic and pharmacokinetic variables.”

Dr. Reshef reported receiving research funding from Pfizer.

sworcester@frontlinemedcom.com

ORLANDO – The use of the CCR5 antagonist maraviroc for 90 days is safe and effective for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation, according to findings from a phase II study.

An earlier study showed that CCR5 blockade using maraviroc for 33 days was associated with a low incidence of acute GVHD, as well as with absence of early liver and gut GVHD – although delayed severe cases of visceral GVHD still occurred.

The current study was performed because the prior findings raised concerns that brief blockade was insufficient for preventing GVHD over a longer period of time. The new findings show that an extended course may indeed provide additional benefits, Ran Reshef, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In 37 high-risk patients who received allogeneic stem cell transplantation from unrelated donors using fludarabine/busulfan (Flu/Bu2) conditioning followed by peripheral blood stem cells, maraviroc was given at a dose of 300 mg twice daily, in addition to standard tacrolimus and methotrexate.

The 180-day rates of grade 2-4 and grade 3-4 acute GVHD (the primary endpoint of the study) in these patients were 27% and 5%, respectively. These rates were very similar to the 24% and 6% rates seen in the first study at 6 months after 30 days of maraviroc treatment, said Dr. Reshef of Columbia University Medical Center, New York.

The earlier results were “driven not so much by a reduction in the rates of skin GVHD, but by low rates of visceral GVHD of the gut and the liver – with a striking absence of gut and liver GVHD in the first 100 days,” he said.

Dr. Reshef also noted that the current study had a less favorable donor mix, as no matched related donors were included because of the earlier study’s very low rates of GVHD – with or without maraviroc – in those with related donors, who composed a third of donors.

Long-term follow-up of results from the earlier study, with comparison of a large contemporary control cohort, showed that “there is in fact an impact ... on grade 2-4 and grade 3-4 [GVHD], although the number of events is small, and the study was not powered enough to reach statistical significance,” Dr. Reshef said. The rates of chronic GVHD did not differ between the study subjects and contemporary controls, he noted.

At 100 days in the current study, there were no cases of liver GVHD, two cases of mild upper-GI GVHD, and one case of severe gut GVHD. At 1 year, the disease relapse rate was “fairly reasonable” at 30%, nonrelapse mortality was 12% with only one case of death from GVHD, and the incidence of chronic GVHD was 8%, which was significantly lower than in the prior study, he said.

The low rate of chronic GVHD led to a GVHD/relapse-free survival (GRFS) rate of 49%.

“To put this in context, the [Center for International Blood & Marrow Transplant Research] data for reduced-intensity transplants ... have shown 25% for acute myeloid leukemia and 12% for myelodysplastic syndrome,” he said. “So, we feel that these are by far improved numbers, compared with this benchmark.”

To determine which patients develop GVHD despite chemotaxis blockade and why, Dr. Reshef and his colleagues developed a pharmacodynamic assay to assess the activity of maraviroc in fresh blood samples. They found that those with insufficient CCR5 blockade on day 0 were those with higher incidence of severe acute GVHD, nonrelapse mortality, GRFS, and overall survival.

The investigators performed pharmacokinetic analysis using combined data from both trials to improve understanding of why some patients have insufficient CCR5 blockade. This showed significant variability in day 0 trough of maraviroc among patients (median of 65 ng/mL, range 12-316 ng/mL); levels above the median were associated with a significantly lower incidence of acute grade 2-4 GVHD and a trend toward improved GRFS.

These studies of maraviroc, which was originally developed for the treatment of HIV infection, were done to test the belief that blocking lymphocyte migration might prevent GVHD without interfering with graft-versus-tumor activity. Based on the earlier findings, Dr. Reshef and his colleagues hypothesized that treatment up to day 90 would decrease the rate to less than 30%, from a historical rate of 52%.

Patients in the study were high risk by virtue of age (median, 64 years), HLA matching (matched unrelated, 84%; mismatched unrelated, 16%), and comorbidities (comorbidity index greater than 2 in 49%). Underlying diseases were acute leukemia (78%), myelodysplastic syndrome (16%), and myeloproliferative neoplasm and cutaneous T-cell lymphomas (3% each).

At a median follow-up of 21 months, the 3-month course of maraviroc was well tolerated. Eight patients did not complete treatment because of disease relapse (five patients), skin reaction (one patient), early infection-related death (one patient), or poor tolerance of oral drugs (one patient). Neutrophil, platelet, and T-cell engraftment were similar to historical controls, and rates of infections were also similar, Dr Reshef noted.

“To conclude, an extended course of maraviroc up to day 90 is feasible and safe in the majority of patients,” he said. “This study confirms the effect of CCR5 blockade on visceral GVHD. I’m still awaiting a randomized study to confirm that further.

“A long course of maraviroc does not necessarily affect the rates of acute GVHD, but may help reduce chronic GVHD and improve GRFS,” Dr. Reshef said. “We should look further into the pharmacodynamic and pharmacokinetic variables.”

Dr. Reshef reported receiving research funding from Pfizer.

sworcester@frontlinemedcom.com

ORLANDO – The use of the CCR5 antagonist maraviroc for 90 days is safe and effective for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation, according to findings from a phase II study.

An earlier study showed that CCR5 blockade using maraviroc for 33 days was associated with a low incidence of acute GVHD, as well as with absence of early liver and gut GVHD – although delayed severe cases of visceral GVHD still occurred.

The current study was performed because the prior findings raised concerns that brief blockade was insufficient for preventing GVHD over a longer period of time. The new findings show that an extended course may indeed provide additional benefits, Ran Reshef, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In 37 high-risk patients who received allogeneic stem cell transplantation from unrelated donors using fludarabine/busulfan (Flu/Bu2) conditioning followed by peripheral blood stem cells, maraviroc was given at a dose of 300 mg twice daily, in addition to standard tacrolimus and methotrexate.

The 180-day rates of grade 2-4 and grade 3-4 acute GVHD (the primary endpoint of the study) in these patients were 27% and 5%, respectively. These rates were very similar to the 24% and 6% rates seen in the first study at 6 months after 30 days of maraviroc treatment, said Dr. Reshef of Columbia University Medical Center, New York.

The earlier results were “driven not so much by a reduction in the rates of skin GVHD, but by low rates of visceral GVHD of the gut and the liver – with a striking absence of gut and liver GVHD in the first 100 days,” he said.

Dr. Reshef also noted that the current study had a less favorable donor mix, as no matched related donors were included because of the earlier study’s very low rates of GVHD – with or without maraviroc – in those with related donors, who composed a third of donors.

Long-term follow-up of results from the earlier study, with comparison of a large contemporary control cohort, showed that “there is in fact an impact ... on grade 2-4 and grade 3-4 [GVHD], although the number of events is small, and the study was not powered enough to reach statistical significance,” Dr. Reshef said. The rates of chronic GVHD did not differ between the study subjects and contemporary controls, he noted.

At 100 days in the current study, there were no cases of liver GVHD, two cases of mild upper-GI GVHD, and one case of severe gut GVHD. At 1 year, the disease relapse rate was “fairly reasonable” at 30%, nonrelapse mortality was 12% with only one case of death from GVHD, and the incidence of chronic GVHD was 8%, which was significantly lower than in the prior study, he said.

The low rate of chronic GVHD led to a GVHD/relapse-free survival (GRFS) rate of 49%.

“To put this in context, the [Center for International Blood & Marrow Transplant Research] data for reduced-intensity transplants ... have shown 25% for acute myeloid leukemia and 12% for myelodysplastic syndrome,” he said. “So, we feel that these are by far improved numbers, compared with this benchmark.”

To determine which patients develop GVHD despite chemotaxis blockade and why, Dr. Reshef and his colleagues developed a pharmacodynamic assay to assess the activity of maraviroc in fresh blood samples. They found that those with insufficient CCR5 blockade on day 0 were those with higher incidence of severe acute GVHD, nonrelapse mortality, GRFS, and overall survival.

The investigators performed pharmacokinetic analysis using combined data from both trials to improve understanding of why some patients have insufficient CCR5 blockade. This showed significant variability in day 0 trough of maraviroc among patients (median of 65 ng/mL, range 12-316 ng/mL); levels above the median were associated with a significantly lower incidence of acute grade 2-4 GVHD and a trend toward improved GRFS.

These studies of maraviroc, which was originally developed for the treatment of HIV infection, were done to test the belief that blocking lymphocyte migration might prevent GVHD without interfering with graft-versus-tumor activity. Based on the earlier findings, Dr. Reshef and his colleagues hypothesized that treatment up to day 90 would decrease the rate to less than 30%, from a historical rate of 52%.

Patients in the study were high risk by virtue of age (median, 64 years), HLA matching (matched unrelated, 84%; mismatched unrelated, 16%), and comorbidities (comorbidity index greater than 2 in 49%). Underlying diseases were acute leukemia (78%), myelodysplastic syndrome (16%), and myeloproliferative neoplasm and cutaneous T-cell lymphomas (3% each).

At a median follow-up of 21 months, the 3-month course of maraviroc was well tolerated. Eight patients did not complete treatment because of disease relapse (five patients), skin reaction (one patient), early infection-related death (one patient), or poor tolerance of oral drugs (one patient). Neutrophil, platelet, and T-cell engraftment were similar to historical controls, and rates of infections were also similar, Dr Reshef noted.

“To conclude, an extended course of maraviroc up to day 90 is feasible and safe in the majority of patients,” he said. “This study confirms the effect of CCR5 blockade on visceral GVHD. I’m still awaiting a randomized study to confirm that further.

“A long course of maraviroc does not necessarily affect the rates of acute GVHD, but may help reduce chronic GVHD and improve GRFS,” Dr. Reshef said. “We should look further into the pharmacodynamic and pharmacokinetic variables.”

Dr. Reshef reported receiving research funding from Pfizer.

sworcester@frontlinemedcom.com

The Centers for Disease Control and Prevention has identified an increase in Shigella isolates with reduced susceptibility to ciprofloxacin, and has released an official health advisory outlining new recommendations for clinical diagnosis, management, and reporting, as well as for laboratories and public health officials.

The Shigella isolates of concern in the United States have minimum inhibitory concentration (MIC) values of 0.12-1 mcg/mL for ciprofloxacin, which is within the range considered susceptible. These strains, however, “often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics,” such as ciprofloxacin, according to the CDC advisory.

Copyright CDC

• Order a stool culture to obtain isolates for antimicrobial susceptibility testing in suspected cases.

• Order antimicrobial susceptibility testing when ordering a stool culture for Shigella.

• Avoid routine prescribing of antibiotic therapy for Shigella infection, instead reserving antibiotics for patients with a clinical indication or when advised by public health officials in an outbreak setting.

• Tailor antibiotic choice (when antibiotics are indicated) to susceptibility results as soon as possible – with special attention given to the MIC for fluoroquinolone antibiotics.

• Obtain follow-up stool cultures in shigellosis patients who have continued or worsening symptoms despite antibiotic therapy.

• Consult local or state health departments for guidance regarding when patients may return to child care, school, or work.

• Counsel patients with active diarrhea on how they can prevent spreading the infection to others, regardless of whether antibiotic treatment is prescribed.

Additionally, the CDC noted that shigellosis is a nationally notifiable condition; all cases should be reported to the local health department. If a patient with shigellosis and a ciprofloxacin MIC of 0.12-1 mcg/mL is identified, this information should be included in the report to facilitate further testing of the isolate.

The CDC reported that it is working with state and local public health departments and clinical partners to determine if outcomes are indeed worse for patients treated with ciprofloxacin for Shigella strains harboring a quinolone resistance gene, and it will continue to monitor trends in susceptibility of Shigella isolates and to perform genetic testing on select strains to confirm the presence and type of resistance genes.

sworcester@frontlinemedcom.com

The Centers for Disease Control and Prevention has identified an increase in Shigella isolates with reduced susceptibility to ciprofloxacin, and has released an official health advisory outlining new recommendations for clinical diagnosis, management, and reporting, as well as for laboratories and public health officials.

The Shigella isolates of concern in the United States have minimum inhibitory concentration (MIC) values of 0.12-1 mcg/mL for ciprofloxacin, which is within the range considered susceptible. These strains, however, “often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics,” such as ciprofloxacin, according to the CDC advisory.

Copyright CDC

• Order a stool culture to obtain isolates for antimicrobial susceptibility testing in suspected cases.

• Order antimicrobial susceptibility testing when ordering a stool culture for Shigella.

• Avoid routine prescribing of antibiotic therapy for Shigella infection, instead reserving antibiotics for patients with a clinical indication or when advised by public health officials in an outbreak setting.

• Tailor antibiotic choice (when antibiotics are indicated) to susceptibility results as soon as possible – with special attention given to the MIC for fluoroquinolone antibiotics.

• Obtain follow-up stool cultures in shigellosis patients who have continued or worsening symptoms despite antibiotic therapy.

• Consult local or state health departments for guidance regarding when patients may return to child care, school, or work.

• Counsel patients with active diarrhea on how they can prevent spreading the infection to others, regardless of whether antibiotic treatment is prescribed.

Additionally, the CDC noted that shigellosis is a nationally notifiable condition; all cases should be reported to the local health department. If a patient with shigellosis and a ciprofloxacin MIC of 0.12-1 mcg/mL is identified, this information should be included in the report to facilitate further testing of the isolate.

The CDC reported that it is working with state and local public health departments and clinical partners to determine if outcomes are indeed worse for patients treated with ciprofloxacin for Shigella strains harboring a quinolone resistance gene, and it will continue to monitor trends in susceptibility of Shigella isolates and to perform genetic testing on select strains to confirm the presence and type of resistance genes.

sworcester@frontlinemedcom.com

The Centers for Disease Control and Prevention has identified an increase in Shigella isolates with reduced susceptibility to ciprofloxacin, and has released an official health advisory outlining new recommendations for clinical diagnosis, management, and reporting, as well as for laboratories and public health officials.

The Shigella isolates of concern in the United States have minimum inhibitory concentration (MIC) values of 0.12-1 mcg/mL for ciprofloxacin, which is within the range considered susceptible. These strains, however, “often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics,” such as ciprofloxacin, according to the CDC advisory.

Copyright CDC

• Order a stool culture to obtain isolates for antimicrobial susceptibility testing in suspected cases.

• Order antimicrobial susceptibility testing when ordering a stool culture for Shigella.

• Avoid routine prescribing of antibiotic therapy for Shigella infection, instead reserving antibiotics for patients with a clinical indication or when advised by public health officials in an outbreak setting.

• Tailor antibiotic choice (when antibiotics are indicated) to susceptibility results as soon as possible – with special attention given to the MIC for fluoroquinolone antibiotics.

• Obtain follow-up stool cultures in shigellosis patients who have continued or worsening symptoms despite antibiotic therapy.

• Consult local or state health departments for guidance regarding when patients may return to child care, school, or work.

• Counsel patients with active diarrhea on how they can prevent spreading the infection to others, regardless of whether antibiotic treatment is prescribed.

Additionally, the CDC noted that shigellosis is a nationally notifiable condition; all cases should be reported to the local health department. If a patient with shigellosis and a ciprofloxacin MIC of 0.12-1 mcg/mL is identified, this information should be included in the report to facilitate further testing of the isolate.

The CDC reported that it is working with state and local public health departments and clinical partners to determine if outcomes are indeed worse for patients treated with ciprofloxacin for Shigella strains harboring a quinolone resistance gene, and it will continue to monitor trends in susceptibility of Shigella isolates and to perform genetic testing on select strains to confirm the presence and type of resistance genes.

sworcester@frontlinemedcom.com

Pegylated interferon alfa-2a can induce durable hematologic and molecular responses in patients with advanced essential thrombocythemia and polycythemia vera, according to a post hoc analysis of data from a prospective, open-label, phase II trial.

Of 83 patients treated with pegylated interferon alfa-2a, 66 (80%) experienced hematological response, and of 55 of the 83 who were positive for the JAK2 Val617 mutation and who were evaluable for a molecular response, 35 (64%) experienced molecular response. The median response durations were 66 months and 53 months, respectively, wrote Lucia Masarova, MD, and her colleagues at MD Anderson Cancer Center, Houston.

Of the 66 hematological responders, 26 (39%) maintained some response during a median follow-up of 83 months. Among the 40 who lost their response, 19 had dose reductions or had the drug withheld because of intolerance or toxicity, 1 developed concurrent diffuse large B-cell lymphoma, and 20 progressed despite treatment with the highest tolerable dose of pegylated interferon alfa-2a. Of note, 7 (28%) of 25 patients who were treated for at least 46 months (median of 77 months) sustained their hematologic response for a median of 6 months after discontinuation of therapy, the investigators said (Lancet Haematol. 2017 Apr;4:e165-75).

Of the 35 molecular responders, 25 (71%) maintained some response during follow-up. Of the nine evaluable patients who did not maintain response (the 10th patient was taken off the study because of concurrent non-Hodgkin lymphoma) four lost response at a median of 2 years after the drug was withheld, and five lost response while on therapy. Three maintained their complete molecular remission – for 18, 55, and 79 months – after discontinuation of therapy.

“Only one patient who achieved a complete molecular remission has relapsed after stopping therapy for 16 months (complete molecular remission duration, 66 months). The other 9 of 10 patients had durable remissions (median duration 69 months),” the investigators wrote, noting that among the 20 patients with a partial molecular remission, 5 (25%) sustained best partial remission, 7 (28%) are in minor molecular remission, 8 (32%) lost their response, and 3 of 5 (60%) with minor molecular remission sustained that remission.

The study comprised adults over age 18 years who were diagnosed with essential thrombocythemia (40 patients) or polycythemia vera (43) and were enrolled during May 2005 to October 2009. Of the 83 patients, 52 (63%) had received some form of therapy prior to enrollment, including 14 who were treated with standard interferon alfa-2a and 1 who was treated with pegylated interferon alfa-2a. The initial starting dose of pegylated interferon alfa-2a used in the study was 450 mcg delivered subcutaneously once each week, but the dose was decreased in a stepwise manner to a final starting dose of 90 mcg per week due to toxicity; starting doses include 450 mcg in 3 patients, 360 mcg in 3 patients, 270 mcg in 19 patients, 180 mcg in 26 patients, and 90 mcg in 32 patients). Treatment continued as long as clinical benefit continued, and hematological responses were assessed every 3-6 months.

Treatment-related toxicities decreased over time, but five patients had treatment-limiting grade 3 or 4 toxicities after 60 months on therapy; overall 18 patients (22%) discontinued treatment due to toxicity.

The therapeutic approach to essential thrombocythemia and polycythemia vera has mainly focused on control of blood counts and reduction of the risk of thrombosis. Those at high risk for thrombosis generally undergo cytoreductive therapy with hydroxyurea. Recombinant interferon alfa is an alternative to hydroxyurea “given its biological, anti-proliferative, immunomodulating, and anticlonal effects,” the investigators explained.

“However, the widespread use of this biological drug has been limited by high rates of discontinuation due to side effects. Pegylated forms of interferon have a better pharmacological profile than short-acting interferons: they require less frequent injection, lower immunogenicity, and possibly fewer toxic effects,” they said.

Although pegylated interferon-alfa 2a has shown promise in several trials, most had short follow-up. The nearly 7 years of follow-up in the current trial is almost twice as long as in those prior studies.

During the current study, including follow-up, eight major vascular thromboembolic events occurred. One was associated with heart catheterization, one with elective chest surgery, and one with an angiogram. The remaining five occurred with no discernible cause after a median of 38 months of therapy for an incidence of 1.22 unprovoked vascular thromboembolic events per 100 person-years, and three of those were in patients with complete hematologic response. Two of the five patients were under age 60 years and had no history of thrombosis. Another patient had a serious unprovoked cerebrovascular hemorrhage after 3 years on therapy and while in complete hematological response.

In addition, 7 of the 83 patients in the study had disease progression on therapy; 6 progressed to myelofibrosis, and 1 developed acute myeloid leukemia. The median time to transformation in these patients was 40 months.

At the time of publication, 32 patient remained in the study and 24 were receiving treatment. Nineteen were in hematologic response at last follow-up, and most (75%) were on a dose of 90 mcg or less per week.

In addition to showing that some patients achieve durable responses on pegylated interferon alfa-2a, this study provided five important observations, the investigators said: 1) Patients might continue to derive clinical benefit from pegylated interferon alfa-2a even after losing response. 2) Only complete molecular remissions are durable, and some cases can be sustained after therapy discontinuation. 3) Clinical activity of pegylated interferon alfa-2a is not correlated with JAK2 mutation status. 4) Toxic effects unrelated to dose may develop and can be treatment-limiting, even after a long exposure to the drug. 5) Disease-related vascular complications or progression to myelofibrosis can still occur in patients on therapy.

“Our findings suggest that pegylated interferon alfa-2a is a viable treatment option, especially for young patients who want to avoid prolonged cytotoxic therapy. Lower doses minimize side effects while retaining efficacy,” they wrote, suggesting – based on these and other results – a starting dose of 45 mcg weekly to limit adverse events and maximize response.

They also noted that treated patients with a history of autoimmune disease and those with mood disorder should be monitored closely for side effects.

Future studies on pegylated interferon afla-2a alone or in combination with novel immunomodulatory drugs are needed to identify patients who would benefit most from treatment, and additional objective response criteria, such as measurement of spleen size, bone marrow histology, and quality of life should be used to better assess clinical benefit, they said.

The National Cancer Institute funded the study. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

Pegylated interferon alfa-2a can induce durable hematologic and molecular responses in patients with advanced essential thrombocythemia and polycythemia vera, according to a post hoc analysis of data from a prospective, open-label, phase II trial.

Of 83 patients treated with pegylated interferon alfa-2a, 66 (80%) experienced hematological response, and of 55 of the 83 who were positive for the JAK2 Val617 mutation and who were evaluable for a molecular response, 35 (64%) experienced molecular response. The median response durations were 66 months and 53 months, respectively, wrote Lucia Masarova, MD, and her colleagues at MD Anderson Cancer Center, Houston.

Of the 66 hematological responders, 26 (39%) maintained some response during a median follow-up of 83 months. Among the 40 who lost their response, 19 had dose reductions or had the drug withheld because of intolerance or toxicity, 1 developed concurrent diffuse large B-cell lymphoma, and 20 progressed despite treatment with the highest tolerable dose of pegylated interferon alfa-2a. Of note, 7 (28%) of 25 patients who were treated for at least 46 months (median of 77 months) sustained their hematologic response for a median of 6 months after discontinuation of therapy, the investigators said (Lancet Haematol. 2017 Apr;4:e165-75).

Of the 35 molecular responders, 25 (71%) maintained some response during follow-up. Of the nine evaluable patients who did not maintain response (the 10th patient was taken off the study because of concurrent non-Hodgkin lymphoma) four lost response at a median of 2 years after the drug was withheld, and five lost response while on therapy. Three maintained their complete molecular remission – for 18, 55, and 79 months – after discontinuation of therapy.

“Only one patient who achieved a complete molecular remission has relapsed after stopping therapy for 16 months (complete molecular remission duration, 66 months). The other 9 of 10 patients had durable remissions (median duration 69 months),” the investigators wrote, noting that among the 20 patients with a partial molecular remission, 5 (25%) sustained best partial remission, 7 (28%) are in minor molecular remission, 8 (32%) lost their response, and 3 of 5 (60%) with minor molecular remission sustained that remission.

The study comprised adults over age 18 years who were diagnosed with essential thrombocythemia (40 patients) or polycythemia vera (43) and were enrolled during May 2005 to October 2009. Of the 83 patients, 52 (63%) had received some form of therapy prior to enrollment, including 14 who were treated with standard interferon alfa-2a and 1 who was treated with pegylated interferon alfa-2a. The initial starting dose of pegylated interferon alfa-2a used in the study was 450 mcg delivered subcutaneously once each week, but the dose was decreased in a stepwise manner to a final starting dose of 90 mcg per week due to toxicity; starting doses include 450 mcg in 3 patients, 360 mcg in 3 patients, 270 mcg in 19 patients, 180 mcg in 26 patients, and 90 mcg in 32 patients). Treatment continued as long as clinical benefit continued, and hematological responses were assessed every 3-6 months.

Treatment-related toxicities decreased over time, but five patients had treatment-limiting grade 3 or 4 toxicities after 60 months on therapy; overall 18 patients (22%) discontinued treatment due to toxicity.

The therapeutic approach to essential thrombocythemia and polycythemia vera has mainly focused on control of blood counts and reduction of the risk of thrombosis. Those at high risk for thrombosis generally undergo cytoreductive therapy with hydroxyurea. Recombinant interferon alfa is an alternative to hydroxyurea “given its biological, anti-proliferative, immunomodulating, and anticlonal effects,” the investigators explained.

“However, the widespread use of this biological drug has been limited by high rates of discontinuation due to side effects. Pegylated forms of interferon have a better pharmacological profile than short-acting interferons: they require less frequent injection, lower immunogenicity, and possibly fewer toxic effects,” they said.

Although pegylated interferon-alfa 2a has shown promise in several trials, most had short follow-up. The nearly 7 years of follow-up in the current trial is almost twice as long as in those prior studies.

During the current study, including follow-up, eight major vascular thromboembolic events occurred. One was associated with heart catheterization, one with elective chest surgery, and one with an angiogram. The remaining five occurred with no discernible cause after a median of 38 months of therapy for an incidence of 1.22 unprovoked vascular thromboembolic events per 100 person-years, and three of those were in patients with complete hematologic response. Two of the five patients were under age 60 years and had no history of thrombosis. Another patient had a serious unprovoked cerebrovascular hemorrhage after 3 years on therapy and while in complete hematological response.

In addition, 7 of the 83 patients in the study had disease progression on therapy; 6 progressed to myelofibrosis, and 1 developed acute myeloid leukemia. The median time to transformation in these patients was 40 months.

At the time of publication, 32 patient remained in the study and 24 were receiving treatment. Nineteen were in hematologic response at last follow-up, and most (75%) were on a dose of 90 mcg or less per week.

In addition to showing that some patients achieve durable responses on pegylated interferon alfa-2a, this study provided five important observations, the investigators said: 1) Patients might continue to derive clinical benefit from pegylated interferon alfa-2a even after losing response. 2) Only complete molecular remissions are durable, and some cases can be sustained after therapy discontinuation. 3) Clinical activity of pegylated interferon alfa-2a is not correlated with JAK2 mutation status. 4) Toxic effects unrelated to dose may develop and can be treatment-limiting, even after a long exposure to the drug. 5) Disease-related vascular complications or progression to myelofibrosis can still occur in patients on therapy.

“Our findings suggest that pegylated interferon alfa-2a is a viable treatment option, especially for young patients who want to avoid prolonged cytotoxic therapy. Lower doses minimize side effects while retaining efficacy,” they wrote, suggesting – based on these and other results – a starting dose of 45 mcg weekly to limit adverse events and maximize response.

They also noted that treated patients with a history of autoimmune disease and those with mood disorder should be monitored closely for side effects.

Future studies on pegylated interferon afla-2a alone or in combination with novel immunomodulatory drugs are needed to identify patients who would benefit most from treatment, and additional objective response criteria, such as measurement of spleen size, bone marrow histology, and quality of life should be used to better assess clinical benefit, they said.

The National Cancer Institute funded the study. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

Pegylated interferon alfa-2a can induce durable hematologic and molecular responses in patients with advanced essential thrombocythemia and polycythemia vera, according to a post hoc analysis of data from a prospective, open-label, phase II trial.

Of 83 patients treated with pegylated interferon alfa-2a, 66 (80%) experienced hematological response, and of 55 of the 83 who were positive for the JAK2 Val617 mutation and who were evaluable for a molecular response, 35 (64%) experienced molecular response. The median response durations were 66 months and 53 months, respectively, wrote Lucia Masarova, MD, and her colleagues at MD Anderson Cancer Center, Houston.

Of the 66 hematological responders, 26 (39%) maintained some response during a median follow-up of 83 months. Among the 40 who lost their response, 19 had dose reductions or had the drug withheld because of intolerance or toxicity, 1 developed concurrent diffuse large B-cell lymphoma, and 20 progressed despite treatment with the highest tolerable dose of pegylated interferon alfa-2a. Of note, 7 (28%) of 25 patients who were treated for at least 46 months (median of 77 months) sustained their hematologic response for a median of 6 months after discontinuation of therapy, the investigators said (Lancet Haematol. 2017 Apr;4:e165-75).

Of the 35 molecular responders, 25 (71%) maintained some response during follow-up. Of the nine evaluable patients who did not maintain response (the 10th patient was taken off the study because of concurrent non-Hodgkin lymphoma) four lost response at a median of 2 years after the drug was withheld, and five lost response while on therapy. Three maintained their complete molecular remission – for 18, 55, and 79 months – after discontinuation of therapy.

“Only one patient who achieved a complete molecular remission has relapsed after stopping therapy for 16 months (complete molecular remission duration, 66 months). The other 9 of 10 patients had durable remissions (median duration 69 months),” the investigators wrote, noting that among the 20 patients with a partial molecular remission, 5 (25%) sustained best partial remission, 7 (28%) are in minor molecular remission, 8 (32%) lost their response, and 3 of 5 (60%) with minor molecular remission sustained that remission.

The study comprised adults over age 18 years who were diagnosed with essential thrombocythemia (40 patients) or polycythemia vera (43) and were enrolled during May 2005 to October 2009. Of the 83 patients, 52 (63%) had received some form of therapy prior to enrollment, including 14 who were treated with standard interferon alfa-2a and 1 who was treated with pegylated interferon alfa-2a. The initial starting dose of pegylated interferon alfa-2a used in the study was 450 mcg delivered subcutaneously once each week, but the dose was decreased in a stepwise manner to a final starting dose of 90 mcg per week due to toxicity; starting doses include 450 mcg in 3 patients, 360 mcg in 3 patients, 270 mcg in 19 patients, 180 mcg in 26 patients, and 90 mcg in 32 patients). Treatment continued as long as clinical benefit continued, and hematological responses were assessed every 3-6 months.

Treatment-related toxicities decreased over time, but five patients had treatment-limiting grade 3 or 4 toxicities after 60 months on therapy; overall 18 patients (22%) discontinued treatment due to toxicity.

The therapeutic approach to essential thrombocythemia and polycythemia vera has mainly focused on control of blood counts and reduction of the risk of thrombosis. Those at high risk for thrombosis generally undergo cytoreductive therapy with hydroxyurea. Recombinant interferon alfa is an alternative to hydroxyurea “given its biological, anti-proliferative, immunomodulating, and anticlonal effects,” the investigators explained.

“However, the widespread use of this biological drug has been limited by high rates of discontinuation due to side effects. Pegylated forms of interferon have a better pharmacological profile than short-acting interferons: they require less frequent injection, lower immunogenicity, and possibly fewer toxic effects,” they said.

Although pegylated interferon-alfa 2a has shown promise in several trials, most had short follow-up. The nearly 7 years of follow-up in the current trial is almost twice as long as in those prior studies.

During the current study, including follow-up, eight major vascular thromboembolic events occurred. One was associated with heart catheterization, one with elective chest surgery, and one with an angiogram. The remaining five occurred with no discernible cause after a median of 38 months of therapy for an incidence of 1.22 unprovoked vascular thromboembolic events per 100 person-years, and three of those were in patients with complete hematologic response. Two of the five patients were under age 60 years and had no history of thrombosis. Another patient had a serious unprovoked cerebrovascular hemorrhage after 3 years on therapy and while in complete hematological response.

In addition, 7 of the 83 patients in the study had disease progression on therapy; 6 progressed to myelofibrosis, and 1 developed acute myeloid leukemia. The median time to transformation in these patients was 40 months.

At the time of publication, 32 patient remained in the study and 24 were receiving treatment. Nineteen were in hematologic response at last follow-up, and most (75%) were on a dose of 90 mcg or less per week.

In addition to showing that some patients achieve durable responses on pegylated interferon alfa-2a, this study provided five important observations, the investigators said: 1) Patients might continue to derive clinical benefit from pegylated interferon alfa-2a even after losing response. 2) Only complete molecular remissions are durable, and some cases can be sustained after therapy discontinuation. 3) Clinical activity of pegylated interferon alfa-2a is not correlated with JAK2 mutation status. 4) Toxic effects unrelated to dose may develop and can be treatment-limiting, even after a long exposure to the drug. 5) Disease-related vascular complications or progression to myelofibrosis can still occur in patients on therapy.

“Our findings suggest that pegylated interferon alfa-2a is a viable treatment option, especially for young patients who want to avoid prolonged cytotoxic therapy. Lower doses minimize side effects while retaining efficacy,” they wrote, suggesting – based on these and other results – a starting dose of 45 mcg weekly to limit adverse events and maximize response.

They also noted that treated patients with a history of autoimmune disease and those with mood disorder should be monitored closely for side effects.

Future studies on pegylated interferon afla-2a alone or in combination with novel immunomodulatory drugs are needed to identify patients who would benefit most from treatment, and additional objective response criteria, such as measurement of spleen size, bone marrow histology, and quality of life should be used to better assess clinical benefit, they said.

The National Cancer Institute funded the study. The authors reported having no disclosures.

sworcester@frontlinemedcom.com