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Gabapentin falls short in treating sickle cell pain
NEW ORLEANS – Adding gabapentin to standard therapy did not significantly reduce vaso-occlusive pain in most patients with sickle cell disease enrolled in a phase 2 trial.
In the entire cohort, there were no significant differences in pain response between patients who received gabapentin and those who received placebo. However, patients with the HbSS genotype had a significantly greater decrease in pain score from baseline to discharge if they received gabapentin rather than placebo.
Additional studies are needed to confirm these findings because this trial was limited by a small sample size, according to study investigator Latika Puri, MD, of St. Jude Children’s Research Hospital in Memphis. Dr. Puri presented the trial at the annual meeting of the American Society of Pediatric Hematology/Oncology.
The trial included 86 evaluable patients who had vaso-occlusive pain and a pain score of at least 4. All patients received standard therapy for vaso-occlusive pain and were randomized to receive placebo (n = 44) or a single oral dose of gabapentin at 15 mg/kg (n = 42).
Baseline characteristics were similar between the treatment arms. For the entire cohort, the mean age was 11.8 years (range, 1-21 years), and 51% of patients were male. Forty-four patients had the HbSS genotype, 25 had the HbSC genotype, 8 had HbS/beta0-thalassemia, and 9 had other genotypes.
The mean pain score at baseline was 7.8 for the entire cohort, 8.0 for the gabapentin arm, and 7.7 for the placebo arm.
For the entire cohort, there was no significant difference in pain response between the gabapentin and placebo arms.
The proportion of patients who experienced a greater than 33% decrease in pain from baseline to 3 hours posttreatment was 67% in the gabapentin arm and 59% in the placebo arm (P = .23). The proportion of patients who experienced a greater than 33% decrease from baseline to discharge from the acute care clinic was 75% and 61%, respectively (P = .18).
In the entire cohort, decreases in pain scores from baseline to 3 hours posttreatment were not significantly different between the gabapentin and placebo arms, at 1.3 and 0.7, respectively (P = .74). Likewise, decreases in pain scores from baseline to discharge were not significantly different, at 1.6 and 0.8 (P = .38).
Among patients who had the HbSS genotype, there was a significantly greater decrease in pain score from baseline to discharge in the gabapentin arm than in the placebo arm, 5.9 versus 3.6 (P = .03). However, there were no other significant differences in pain response for the HbSS subgroup.
There were no significant differences in opioid consumption or hospitalization for the HbSS subgroup or the entire cohort. For the entire cohort, the mean morphine equivalent dose from baseline to 3 hours posttreatment was 0.16 mg/kg in the gabapentin arm and 0.17 mg/kg in the placebo arm (P = .89). For the HbSS subgroup, the mean dose was 0.16 mg/kg and 0.15 mg/kg, respectively (P = .93).
In the entire cohort, 24% of patients in the gabapentin arm and 27% of those in the placebo arm were hospitalized (P = .71). In the HbSS subgroup, hospitalizations occurred in 11% and 35% (P = .15).
Dr. Puri pointed out several challenges that led to limitations in this study. Specifically, the investigators had to obtain patient consent while delivering standard treatment, while patients were in pain and distress, and from patients who had already received opioids and were sleepy. Additionally, gabapentin had to be delivered within 1 hour of opioid administration, and a lack of after-hours staff limited enrollment.
“These challenges led to one of our biggest limitations, which was a small sample size, leading to a limited power to observe real differences,” Dr. Puri said. “We also defined a very short time period of evaluation for the primary outcomes; that was 3 hours from the gabapentin dose or placebo dose. This limited our capability to see real differences if they existed.”
Dr. Puri said additional studies with larger sample sizes are needed to confirm these findings. She added that efforts to better characterize pain in sickle cell disease could reveal patients who may benefit from gabapentin because they have a neuropathic component to their pain.
The trial was sponsored by St. Jude Children’s Research Hospital in collaboration with Scan|Design Foundation. Dr. Puri did not provide disclosure information at the meeting.
SOURCE: Puri L et al. ASPHO 2019, Abstract 2011.
NEW ORLEANS – Adding gabapentin to standard therapy did not significantly reduce vaso-occlusive pain in most patients with sickle cell disease enrolled in a phase 2 trial.
In the entire cohort, there were no significant differences in pain response between patients who received gabapentin and those who received placebo. However, patients with the HbSS genotype had a significantly greater decrease in pain score from baseline to discharge if they received gabapentin rather than placebo.
Additional studies are needed to confirm these findings because this trial was limited by a small sample size, according to study investigator Latika Puri, MD, of St. Jude Children’s Research Hospital in Memphis. Dr. Puri presented the trial at the annual meeting of the American Society of Pediatric Hematology/Oncology.
The trial included 86 evaluable patients who had vaso-occlusive pain and a pain score of at least 4. All patients received standard therapy for vaso-occlusive pain and were randomized to receive placebo (n = 44) or a single oral dose of gabapentin at 15 mg/kg (n = 42).
Baseline characteristics were similar between the treatment arms. For the entire cohort, the mean age was 11.8 years (range, 1-21 years), and 51% of patients were male. Forty-four patients had the HbSS genotype, 25 had the HbSC genotype, 8 had HbS/beta0-thalassemia, and 9 had other genotypes.
The mean pain score at baseline was 7.8 for the entire cohort, 8.0 for the gabapentin arm, and 7.7 for the placebo arm.
For the entire cohort, there was no significant difference in pain response between the gabapentin and placebo arms.
The proportion of patients who experienced a greater than 33% decrease in pain from baseline to 3 hours posttreatment was 67% in the gabapentin arm and 59% in the placebo arm (P = .23). The proportion of patients who experienced a greater than 33% decrease from baseline to discharge from the acute care clinic was 75% and 61%, respectively (P = .18).
In the entire cohort, decreases in pain scores from baseline to 3 hours posttreatment were not significantly different between the gabapentin and placebo arms, at 1.3 and 0.7, respectively (P = .74). Likewise, decreases in pain scores from baseline to discharge were not significantly different, at 1.6 and 0.8 (P = .38).
Among patients who had the HbSS genotype, there was a significantly greater decrease in pain score from baseline to discharge in the gabapentin arm than in the placebo arm, 5.9 versus 3.6 (P = .03). However, there were no other significant differences in pain response for the HbSS subgroup.
There were no significant differences in opioid consumption or hospitalization for the HbSS subgroup or the entire cohort. For the entire cohort, the mean morphine equivalent dose from baseline to 3 hours posttreatment was 0.16 mg/kg in the gabapentin arm and 0.17 mg/kg in the placebo arm (P = .89). For the HbSS subgroup, the mean dose was 0.16 mg/kg and 0.15 mg/kg, respectively (P = .93).
In the entire cohort, 24% of patients in the gabapentin arm and 27% of those in the placebo arm were hospitalized (P = .71). In the HbSS subgroup, hospitalizations occurred in 11% and 35% (P = .15).
Dr. Puri pointed out several challenges that led to limitations in this study. Specifically, the investigators had to obtain patient consent while delivering standard treatment, while patients were in pain and distress, and from patients who had already received opioids and were sleepy. Additionally, gabapentin had to be delivered within 1 hour of opioid administration, and a lack of after-hours staff limited enrollment.
“These challenges led to one of our biggest limitations, which was a small sample size, leading to a limited power to observe real differences,” Dr. Puri said. “We also defined a very short time period of evaluation for the primary outcomes; that was 3 hours from the gabapentin dose or placebo dose. This limited our capability to see real differences if they existed.”
Dr. Puri said additional studies with larger sample sizes are needed to confirm these findings. She added that efforts to better characterize pain in sickle cell disease could reveal patients who may benefit from gabapentin because they have a neuropathic component to their pain.
The trial was sponsored by St. Jude Children’s Research Hospital in collaboration with Scan|Design Foundation. Dr. Puri did not provide disclosure information at the meeting.
SOURCE: Puri L et al. ASPHO 2019, Abstract 2011.
NEW ORLEANS – Adding gabapentin to standard therapy did not significantly reduce vaso-occlusive pain in most patients with sickle cell disease enrolled in a phase 2 trial.
In the entire cohort, there were no significant differences in pain response between patients who received gabapentin and those who received placebo. However, patients with the HbSS genotype had a significantly greater decrease in pain score from baseline to discharge if they received gabapentin rather than placebo.
Additional studies are needed to confirm these findings because this trial was limited by a small sample size, according to study investigator Latika Puri, MD, of St. Jude Children’s Research Hospital in Memphis. Dr. Puri presented the trial at the annual meeting of the American Society of Pediatric Hematology/Oncology.
The trial included 86 evaluable patients who had vaso-occlusive pain and a pain score of at least 4. All patients received standard therapy for vaso-occlusive pain and were randomized to receive placebo (n = 44) or a single oral dose of gabapentin at 15 mg/kg (n = 42).
Baseline characteristics were similar between the treatment arms. For the entire cohort, the mean age was 11.8 years (range, 1-21 years), and 51% of patients were male. Forty-four patients had the HbSS genotype, 25 had the HbSC genotype, 8 had HbS/beta0-thalassemia, and 9 had other genotypes.
The mean pain score at baseline was 7.8 for the entire cohort, 8.0 for the gabapentin arm, and 7.7 for the placebo arm.
For the entire cohort, there was no significant difference in pain response between the gabapentin and placebo arms.
The proportion of patients who experienced a greater than 33% decrease in pain from baseline to 3 hours posttreatment was 67% in the gabapentin arm and 59% in the placebo arm (P = .23). The proportion of patients who experienced a greater than 33% decrease from baseline to discharge from the acute care clinic was 75% and 61%, respectively (P = .18).
In the entire cohort, decreases in pain scores from baseline to 3 hours posttreatment were not significantly different between the gabapentin and placebo arms, at 1.3 and 0.7, respectively (P = .74). Likewise, decreases in pain scores from baseline to discharge were not significantly different, at 1.6 and 0.8 (P = .38).
Among patients who had the HbSS genotype, there was a significantly greater decrease in pain score from baseline to discharge in the gabapentin arm than in the placebo arm, 5.9 versus 3.6 (P = .03). However, there were no other significant differences in pain response for the HbSS subgroup.
There were no significant differences in opioid consumption or hospitalization for the HbSS subgroup or the entire cohort. For the entire cohort, the mean morphine equivalent dose from baseline to 3 hours posttreatment was 0.16 mg/kg in the gabapentin arm and 0.17 mg/kg in the placebo arm (P = .89). For the HbSS subgroup, the mean dose was 0.16 mg/kg and 0.15 mg/kg, respectively (P = .93).
In the entire cohort, 24% of patients in the gabapentin arm and 27% of those in the placebo arm were hospitalized (P = .71). In the HbSS subgroup, hospitalizations occurred in 11% and 35% (P = .15).
Dr. Puri pointed out several challenges that led to limitations in this study. Specifically, the investigators had to obtain patient consent while delivering standard treatment, while patients were in pain and distress, and from patients who had already received opioids and were sleepy. Additionally, gabapentin had to be delivered within 1 hour of opioid administration, and a lack of after-hours staff limited enrollment.
“These challenges led to one of our biggest limitations, which was a small sample size, leading to a limited power to observe real differences,” Dr. Puri said. “We also defined a very short time period of evaluation for the primary outcomes; that was 3 hours from the gabapentin dose or placebo dose. This limited our capability to see real differences if they existed.”
Dr. Puri said additional studies with larger sample sizes are needed to confirm these findings. She added that efforts to better characterize pain in sickle cell disease could reveal patients who may benefit from gabapentin because they have a neuropathic component to their pain.
The trial was sponsored by St. Jude Children’s Research Hospital in collaboration with Scan|Design Foundation. Dr. Puri did not provide disclosure information at the meeting.
SOURCE: Puri L et al. ASPHO 2019, Abstract 2011.
REPORTING FROM THE 2019 ASPHO CONFERENCE
Key clinical point:
Major finding: The proportion of patients who experienced a greater than 33% decrease in pain from baseline to 3 hours posttreatment was 67% in the gabapentin arm and 59% in the placebo arm (P = .23).
Study details: A phase 2 trial of 86 evaluable patients.
Disclosures: The trial was sponsored by St. Jude Children’s Research Hospital in collaboration with Scan|Design Foundation. The speaker did not provide disclosure information at the meeting.
Source: Puri L et al. 2019 ASPHO Conference, Abstract 2011.
LentiGlobin reduces transfusion dependence in young thalassemia patients
NEW ORLEANS – The gene therapy LentiGlobin can reduce transfusion dependence in children and young adults with non-beta0/beta0 thalassemia, according to two trials.
In a phase 1/2 trial, 8 of 10 of patients achieved transfusion independence at a median follow-up of 36.0 months. In a phase 3 trial, transfusion independence was achieved by 2 of 3 patients with follow-up of at least 12 months.
Timothy S. Olson, MD, PhD, of Children’s Hospital of Philadelphia, presented results from the phase 1/2 HGB-204 trial and the phase 3 HGB-207 trial at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Treatment
In both trials, patients received granulocyte colony-stimulating factor and plerixafor for hematopoietic stem cell mobilization. Their cells were collected via apheresis and transduced with the betibeglogene darolentivec (BB305) lentiviral vector. The patients received busulfan (for an average of 4 days) as conditioning and were infused with the transduced cells.
The manufacturing process for LentiGlobin was refined in the HGB-207 trial, which translated to a product with a higher vector copy number and higher proportion of CD34+ cells transduced, Dr. Olson said.
The median vector copy number was 3.1 in the HGB-207 trial and 0.7 in the HGB-204 trial. The median proportion of CD34+ cells transfused was 81% and 29%, respectively. The median cell dose was 7.7 x 106 CD34+ cells/kg and 7.1 x 106 CD34+ cells/kg, respectively.
HGB-204 patients and efficacy
The HGB-204 trial included 10 patients with non-beta0/beta0 genotypes – 6 with betaE/beta0, 1 with beta+/beta0, 2 with beta+/beta+, and 1 with an “other” genotype.
The patients’ median age at consent was 19.5 years (range, 16-34). The annualized median prestudy red blood cell (RBC) transfusion volume was 151 mL/kg per year.
At a median follow-up of 36 months, 8 of the 10 patients achieved transfusion independence. The median duration of transfusion independence was 38 months. The median weighted average hemoglobin during transfusion independence was 10.2 g/dL.
“Two patients did not achieve transfusion independence, and both patients were on the lower end of the spectrum both in terms of vector copy number per cell and the percentage of CD34+ cells that were successfully transduced,” Dr. Olson said. “Both patients actually experienced a reduction in the annualized transfusion volume requirements of between 43% and 77%.”
HGB-207 patients and efficacy
The HGB-207 trial included 16 patients with non-beta0/beta0 genotypes – 6 with betaE/beta0, 7 with beta+/beta0, and 3 with the beta+/beta+ genotype.
The patients’ median age at consent was 19 years . The annualized median prestudy RBC transfusion volume was 192 mL/kg per year.
The median follow-up in this trial is 9.3 months. Ten of 11 patients with at least 3 months of follow-up are transfusion-free with hemoglobin levels greater than 11 g/dL.
Two patients have achieved transfusion independence according to the protocol definition, which is weighted average hemoglobin of 9 g/dL or greater without any RBC transfusions for at least 12 months.
“In the one patient in this study who did not achieve transfusion independence, the vector-derived hemoglobin was quite low, and this correlated with a very low vector copy number seen in circulating peripheral blood mononuclear cells,” Dr. Olson said.
It isn’t clear why this occurred, however, as the vector copy number wasn’t especially low in the LentiGlobin product the patient received. Therefore, the researchers are still investigating why this patient failed to achieve transfusion independence.
Safety in both trials
“Very importantly, there were no deaths, there were no engraftment failures, there was no evidence of vector-mediated replication-competent lentivirus, and integration site analysis revealed no evidence of clonal dominance,” Dr. Olson said.
He added that most of the grade 3 or greater adverse events seen in both trials were directly attributable to busulfan-based myeloablative conditioning, including four episodes of veno-occlusive disease.
Nonhematologic grade 3 or higher adverse events in HGB-204 included stomatitis (n = 8), febrile neutropenia (n = 6), irregular menstruation (n = 3), pharyngeal inflammation (n = 2), and veno-occlusive liver disease (n = 1).
Nonhematologic grade 3 or higher adverse events in HGB-207 included stomatitis (n = 9), febrile neutropenia (n = 4), pharyngeal inflammation (n = 2), epistaxis (n = 3), pyrexia (n = 3), veno-occlusive liver disease (n = 3), ALT increase (n = 2), bilirubin increase (n = 2), and hypoxia (n = 2).
One patient in HGB-207 had grade 3 thrombocytopenia considered possibly related to LentiGlobin.
Dr. Olson reported advisory board engagement with bluebird bio, which sponsored both trials.
SOURCE: Olson TS et al. ASPHO 2019. Abstract 2002.
NEW ORLEANS – The gene therapy LentiGlobin can reduce transfusion dependence in children and young adults with non-beta0/beta0 thalassemia, according to two trials.
In a phase 1/2 trial, 8 of 10 of patients achieved transfusion independence at a median follow-up of 36.0 months. In a phase 3 trial, transfusion independence was achieved by 2 of 3 patients with follow-up of at least 12 months.
Timothy S. Olson, MD, PhD, of Children’s Hospital of Philadelphia, presented results from the phase 1/2 HGB-204 trial and the phase 3 HGB-207 trial at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Treatment
In both trials, patients received granulocyte colony-stimulating factor and plerixafor for hematopoietic stem cell mobilization. Their cells were collected via apheresis and transduced with the betibeglogene darolentivec (BB305) lentiviral vector. The patients received busulfan (for an average of 4 days) as conditioning and were infused with the transduced cells.
The manufacturing process for LentiGlobin was refined in the HGB-207 trial, which translated to a product with a higher vector copy number and higher proportion of CD34+ cells transduced, Dr. Olson said.
The median vector copy number was 3.1 in the HGB-207 trial and 0.7 in the HGB-204 trial. The median proportion of CD34+ cells transfused was 81% and 29%, respectively. The median cell dose was 7.7 x 106 CD34+ cells/kg and 7.1 x 106 CD34+ cells/kg, respectively.
HGB-204 patients and efficacy
The HGB-204 trial included 10 patients with non-beta0/beta0 genotypes – 6 with betaE/beta0, 1 with beta+/beta0, 2 with beta+/beta+, and 1 with an “other” genotype.
The patients’ median age at consent was 19.5 years (range, 16-34). The annualized median prestudy red blood cell (RBC) transfusion volume was 151 mL/kg per year.
At a median follow-up of 36 months, 8 of the 10 patients achieved transfusion independence. The median duration of transfusion independence was 38 months. The median weighted average hemoglobin during transfusion independence was 10.2 g/dL.
“Two patients did not achieve transfusion independence, and both patients were on the lower end of the spectrum both in terms of vector copy number per cell and the percentage of CD34+ cells that were successfully transduced,” Dr. Olson said. “Both patients actually experienced a reduction in the annualized transfusion volume requirements of between 43% and 77%.”
HGB-207 patients and efficacy
The HGB-207 trial included 16 patients with non-beta0/beta0 genotypes – 6 with betaE/beta0, 7 with beta+/beta0, and 3 with the beta+/beta+ genotype.
The patients’ median age at consent was 19 years . The annualized median prestudy RBC transfusion volume was 192 mL/kg per year.
The median follow-up in this trial is 9.3 months. Ten of 11 patients with at least 3 months of follow-up are transfusion-free with hemoglobin levels greater than 11 g/dL.
Two patients have achieved transfusion independence according to the protocol definition, which is weighted average hemoglobin of 9 g/dL or greater without any RBC transfusions for at least 12 months.
“In the one patient in this study who did not achieve transfusion independence, the vector-derived hemoglobin was quite low, and this correlated with a very low vector copy number seen in circulating peripheral blood mononuclear cells,” Dr. Olson said.
It isn’t clear why this occurred, however, as the vector copy number wasn’t especially low in the LentiGlobin product the patient received. Therefore, the researchers are still investigating why this patient failed to achieve transfusion independence.
Safety in both trials
“Very importantly, there were no deaths, there were no engraftment failures, there was no evidence of vector-mediated replication-competent lentivirus, and integration site analysis revealed no evidence of clonal dominance,” Dr. Olson said.
He added that most of the grade 3 or greater adverse events seen in both trials were directly attributable to busulfan-based myeloablative conditioning, including four episodes of veno-occlusive disease.
Nonhematologic grade 3 or higher adverse events in HGB-204 included stomatitis (n = 8), febrile neutropenia (n = 6), irregular menstruation (n = 3), pharyngeal inflammation (n = 2), and veno-occlusive liver disease (n = 1).
Nonhematologic grade 3 or higher adverse events in HGB-207 included stomatitis (n = 9), febrile neutropenia (n = 4), pharyngeal inflammation (n = 2), epistaxis (n = 3), pyrexia (n = 3), veno-occlusive liver disease (n = 3), ALT increase (n = 2), bilirubin increase (n = 2), and hypoxia (n = 2).
One patient in HGB-207 had grade 3 thrombocytopenia considered possibly related to LentiGlobin.
Dr. Olson reported advisory board engagement with bluebird bio, which sponsored both trials.
SOURCE: Olson TS et al. ASPHO 2019. Abstract 2002.
NEW ORLEANS – The gene therapy LentiGlobin can reduce transfusion dependence in children and young adults with non-beta0/beta0 thalassemia, according to two trials.
In a phase 1/2 trial, 8 of 10 of patients achieved transfusion independence at a median follow-up of 36.0 months. In a phase 3 trial, transfusion independence was achieved by 2 of 3 patients with follow-up of at least 12 months.
Timothy S. Olson, MD, PhD, of Children’s Hospital of Philadelphia, presented results from the phase 1/2 HGB-204 trial and the phase 3 HGB-207 trial at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Treatment
In both trials, patients received granulocyte colony-stimulating factor and plerixafor for hematopoietic stem cell mobilization. Their cells were collected via apheresis and transduced with the betibeglogene darolentivec (BB305) lentiviral vector. The patients received busulfan (for an average of 4 days) as conditioning and were infused with the transduced cells.
The manufacturing process for LentiGlobin was refined in the HGB-207 trial, which translated to a product with a higher vector copy number and higher proportion of CD34+ cells transduced, Dr. Olson said.
The median vector copy number was 3.1 in the HGB-207 trial and 0.7 in the HGB-204 trial. The median proportion of CD34+ cells transfused was 81% and 29%, respectively. The median cell dose was 7.7 x 106 CD34+ cells/kg and 7.1 x 106 CD34+ cells/kg, respectively.
HGB-204 patients and efficacy
The HGB-204 trial included 10 patients with non-beta0/beta0 genotypes – 6 with betaE/beta0, 1 with beta+/beta0, 2 with beta+/beta+, and 1 with an “other” genotype.
The patients’ median age at consent was 19.5 years (range, 16-34). The annualized median prestudy red blood cell (RBC) transfusion volume was 151 mL/kg per year.
At a median follow-up of 36 months, 8 of the 10 patients achieved transfusion independence. The median duration of transfusion independence was 38 months. The median weighted average hemoglobin during transfusion independence was 10.2 g/dL.
“Two patients did not achieve transfusion independence, and both patients were on the lower end of the spectrum both in terms of vector copy number per cell and the percentage of CD34+ cells that were successfully transduced,” Dr. Olson said. “Both patients actually experienced a reduction in the annualized transfusion volume requirements of between 43% and 77%.”
HGB-207 patients and efficacy
The HGB-207 trial included 16 patients with non-beta0/beta0 genotypes – 6 with betaE/beta0, 7 with beta+/beta0, and 3 with the beta+/beta+ genotype.
The patients’ median age at consent was 19 years . The annualized median prestudy RBC transfusion volume was 192 mL/kg per year.
The median follow-up in this trial is 9.3 months. Ten of 11 patients with at least 3 months of follow-up are transfusion-free with hemoglobin levels greater than 11 g/dL.
Two patients have achieved transfusion independence according to the protocol definition, which is weighted average hemoglobin of 9 g/dL or greater without any RBC transfusions for at least 12 months.
“In the one patient in this study who did not achieve transfusion independence, the vector-derived hemoglobin was quite low, and this correlated with a very low vector copy number seen in circulating peripheral blood mononuclear cells,” Dr. Olson said.
It isn’t clear why this occurred, however, as the vector copy number wasn’t especially low in the LentiGlobin product the patient received. Therefore, the researchers are still investigating why this patient failed to achieve transfusion independence.
Safety in both trials
“Very importantly, there were no deaths, there were no engraftment failures, there was no evidence of vector-mediated replication-competent lentivirus, and integration site analysis revealed no evidence of clonal dominance,” Dr. Olson said.
He added that most of the grade 3 or greater adverse events seen in both trials were directly attributable to busulfan-based myeloablative conditioning, including four episodes of veno-occlusive disease.
Nonhematologic grade 3 or higher adverse events in HGB-204 included stomatitis (n = 8), febrile neutropenia (n = 6), irregular menstruation (n = 3), pharyngeal inflammation (n = 2), and veno-occlusive liver disease (n = 1).
Nonhematologic grade 3 or higher adverse events in HGB-207 included stomatitis (n = 9), febrile neutropenia (n = 4), pharyngeal inflammation (n = 2), epistaxis (n = 3), pyrexia (n = 3), veno-occlusive liver disease (n = 3), ALT increase (n = 2), bilirubin increase (n = 2), and hypoxia (n = 2).
One patient in HGB-207 had grade 3 thrombocytopenia considered possibly related to LentiGlobin.
Dr. Olson reported advisory board engagement with bluebird bio, which sponsored both trials.
SOURCE: Olson TS et al. ASPHO 2019. Abstract 2002.
REPORTING FROM 2019 ASPHO CONFERENCE
ICYMI: NIH renames, streamlines gene therapy committee
The National Institutes of Health has released an amended guideline on research involving gene therapy.
As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.
We previously covered this story; find our coverage at the link below.
The National Institutes of Health has released an amended guideline on research involving gene therapy.
As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.
We previously covered this story; find our coverage at the link below.
The National Institutes of Health has released an amended guideline on research involving gene therapy.
As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.
We previously covered this story; find our coverage at the link below.
CDC warns against misuse of opioid-prescribing guideline
Officials at the Centers for Disease Control and Prevention are warning against the misapplication of the agency’s 2016 guidelines on opioid prescribing, as well as clarifying dosage recommendations for patients starting or stopping pain medications.
In a perspective published in the New England Journal of Medicine on April 24, lead author Deborah Dowell, MD, chief medical officer for the CDC’s National Center for Injury Prevention and Control, conveyed concern that some policies and practices derived from the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain are inconsistent with the recommendations and often go beyond their scope.
Misapplication examples include inappropriately applying the guideline to patients in active cancer treatment, patients experiencing acute sickle cell crises, or patients experiencing postsurgical pain, Dr. Dowell wrote.
The guideline offers guidance to clinicians treating chronic pain in adults who are already receiving opioids long-term at high dosages, she noted. It includes advice on maximizing nonopioid treatment, reviewing risks associated with continuing high-dose opioids, and collaborating with patients who agree to taper dosage, among other guidance.
Any application of the guideline’s dosage recommendation that results in hard limits or “cutting off” opioids is also an incorrect use of the recommendations, according to Dr. Dowell.
While the guideline advises clinicians to start opioids at the lowest effective dosage and avoid increasing dosage to 90 morphine milligram equivalents per day or more, that statement does not suggest discontinuation of opioids already prescribed at high dosages, according to the CDC’s clarification.
The guidance also does not apply to patients receiving or starting medication-assisted treatment for opioid use disorder.
The commentary comes after a trio of organizations raised concerns that insurers are inappropriately applying the recommendations to active cancer patients when making coverage determinations.
The American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the American Society of Hematology, raised the issue in a letter to the CDC in February. In response, Dr. Dowell clarified that the recommendations are not intended to deny clinically appropriate opioid therapy to any patients who suffer chronic pain, but rather to ensure that physicians and patients consider all safe and effective treatment options.
In the perspective, Dr. Dowell wrote that the CDC is evaluating the intended and unintended impact of the 2016 opioid-prescribing guideline on clinician and patient outcomes and that the agency is committed to updating the recommendations when new evidence is available.
Officials at the Centers for Disease Control and Prevention are warning against the misapplication of the agency’s 2016 guidelines on opioid prescribing, as well as clarifying dosage recommendations for patients starting or stopping pain medications.
In a perspective published in the New England Journal of Medicine on April 24, lead author Deborah Dowell, MD, chief medical officer for the CDC’s National Center for Injury Prevention and Control, conveyed concern that some policies and practices derived from the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain are inconsistent with the recommendations and often go beyond their scope.
Misapplication examples include inappropriately applying the guideline to patients in active cancer treatment, patients experiencing acute sickle cell crises, or patients experiencing postsurgical pain, Dr. Dowell wrote.
The guideline offers guidance to clinicians treating chronic pain in adults who are already receiving opioids long-term at high dosages, she noted. It includes advice on maximizing nonopioid treatment, reviewing risks associated with continuing high-dose opioids, and collaborating with patients who agree to taper dosage, among other guidance.
Any application of the guideline’s dosage recommendation that results in hard limits or “cutting off” opioids is also an incorrect use of the recommendations, according to Dr. Dowell.
While the guideline advises clinicians to start opioids at the lowest effective dosage and avoid increasing dosage to 90 morphine milligram equivalents per day or more, that statement does not suggest discontinuation of opioids already prescribed at high dosages, according to the CDC’s clarification.
The guidance also does not apply to patients receiving or starting medication-assisted treatment for opioid use disorder.
The commentary comes after a trio of organizations raised concerns that insurers are inappropriately applying the recommendations to active cancer patients when making coverage determinations.
The American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the American Society of Hematology, raised the issue in a letter to the CDC in February. In response, Dr. Dowell clarified that the recommendations are not intended to deny clinically appropriate opioid therapy to any patients who suffer chronic pain, but rather to ensure that physicians and patients consider all safe and effective treatment options.
In the perspective, Dr. Dowell wrote that the CDC is evaluating the intended and unintended impact of the 2016 opioid-prescribing guideline on clinician and patient outcomes and that the agency is committed to updating the recommendations when new evidence is available.
Officials at the Centers for Disease Control and Prevention are warning against the misapplication of the agency’s 2016 guidelines on opioid prescribing, as well as clarifying dosage recommendations for patients starting or stopping pain medications.
In a perspective published in the New England Journal of Medicine on April 24, lead author Deborah Dowell, MD, chief medical officer for the CDC’s National Center for Injury Prevention and Control, conveyed concern that some policies and practices derived from the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain are inconsistent with the recommendations and often go beyond their scope.
Misapplication examples include inappropriately applying the guideline to patients in active cancer treatment, patients experiencing acute sickle cell crises, or patients experiencing postsurgical pain, Dr. Dowell wrote.
The guideline offers guidance to clinicians treating chronic pain in adults who are already receiving opioids long-term at high dosages, she noted. It includes advice on maximizing nonopioid treatment, reviewing risks associated with continuing high-dose opioids, and collaborating with patients who agree to taper dosage, among other guidance.
Any application of the guideline’s dosage recommendation that results in hard limits or “cutting off” opioids is also an incorrect use of the recommendations, according to Dr. Dowell.
While the guideline advises clinicians to start opioids at the lowest effective dosage and avoid increasing dosage to 90 morphine milligram equivalents per day or more, that statement does not suggest discontinuation of opioids already prescribed at high dosages, according to the CDC’s clarification.
The guidance also does not apply to patients receiving or starting medication-assisted treatment for opioid use disorder.
The commentary comes after a trio of organizations raised concerns that insurers are inappropriately applying the recommendations to active cancer patients when making coverage determinations.
The American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the American Society of Hematology, raised the issue in a letter to the CDC in February. In response, Dr. Dowell clarified that the recommendations are not intended to deny clinically appropriate opioid therapy to any patients who suffer chronic pain, but rather to ensure that physicians and patients consider all safe and effective treatment options.
In the perspective, Dr. Dowell wrote that the CDC is evaluating the intended and unintended impact of the 2016 opioid-prescribing guideline on clinician and patient outcomes and that the agency is committed to updating the recommendations when new evidence is available.
C3 inhibitor shows potential in PNH and AIHA
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
REPORTING FROM BSH 2019
CDC clarifies opioid prescribing guidelines in cancer, sickle cell disease
Officials at the Centers for Disease Control and Prevention have clarified the agency’s guidelines on opioid prescribing after a trio of organizations raised concerns that insurers were inappropriately applying the recommendations to active cancer patients when making coverage determinations.
The CDC guidelines, released in March 2016, address when to initiate or continue opioids for chronic pain, opioid selection, dosage, duration, follow-up, and discontinuation, and assess risk and harms of opioid use. Although the guidelines clearly state they are intended for clinicians prescribing opioids outside of active cancer treatment, insurance companies are still applying the guidelines to opioid coverage decisions for patients with active cancer, according to a Feb. 13, 2019, letter sent to the CDC from leaders at the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the American Society of Hematology.
Additionally, the associations wrote that the CDC’s recommendations pose coverage problems for sickle cell patients and select groups of cancer survivors who may benefit from opioids for pain management. The groups asked the CDC to issue a clarification to ensure appropriate implementation of the opioid recommendations.
In a Feb. 28, 2019, letter to ASCO, NCCN, and ASH, Deborah Dowell, MD, chief medical officer for the CDC’s National Center for Injury Prevention and Control took note of the concerns, clarifying that the recommendations are not intended to deny clinically appropriate opioid therapy to any patients who suffer chronic pain, but rather to ensure that physicians and patients consider all safe and effective treatment options.
The CDC guidance may apply to cancer survivors in certain conditions, Dr. Dowell wrote, namely when survivors experience chronic pain after cancer treatment completion, are in clinical remission, and are under cancer surveillance only. However, she agreed that, for select groups of cancer survivors with persistent pain caused by past cancer, the ratio of opioid benefits to risks for chronic pain is unique. She referred health providers to guidelines by ASCO on chronic pain management for adult cancer survivors and NCCN guidance on managing adult cancer pain when considering opioids for pain control in such populations.
Special considerations in sickle cell disease may also change the balance of opioid risks to benefits for pain management, Dr. Dowell wrote, referring providers and insurers to additional guidance on sickle cell disease from the National Institute of Health when making treatment and reimbursement decisions.
“Clinical decision making should be based on the relationship between the clinician and patient, with an understanding of the patient’s clinical situation, functioning, and life context, as well as careful consideration of the benefits and risk of all treatment options, including opioid therapy,” Dr. Dowell wrote. “CDC encourages physicians to continue using their clinical judgment and base treatment on what they know about their patients, including the use of opioids if determined to be the best course of treatment.”
Clifford A. Hudis, MD, CEO of ASCO, praised the clarification, calling the letter necessary to clear up confusion and prevent inappropriate coverage decisions.
“This clarification from CDC is critically important because, while the agency’s guideline clearly states that it is not intended to apply to patients during active cancer and sickle cell disease treatment, many payers have been inappropriately using it to make opioid coverage determinations for those exact populations,” Dr. Hudis said in a statement.
Sickle cell patients suffer from severe, chronic pain, which is debilitating on its own without the added burden of having to constantly appeal coverage denials, added ASH President Roy Silverstein, MD.
“We appreciate CDC’s acknowledgment that the challenges of managing severe and chronic pain in conditions, such as sickle cell disease, require special consideration, and we hope payers will take the CDC’s clarification into account to ensure that patients’ pain management needs are covered,” he said in the same statement.
Officials at the Centers for Disease Control and Prevention have clarified the agency’s guidelines on opioid prescribing after a trio of organizations raised concerns that insurers were inappropriately applying the recommendations to active cancer patients when making coverage determinations.
The CDC guidelines, released in March 2016, address when to initiate or continue opioids for chronic pain, opioid selection, dosage, duration, follow-up, and discontinuation, and assess risk and harms of opioid use. Although the guidelines clearly state they are intended for clinicians prescribing opioids outside of active cancer treatment, insurance companies are still applying the guidelines to opioid coverage decisions for patients with active cancer, according to a Feb. 13, 2019, letter sent to the CDC from leaders at the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the American Society of Hematology.
Additionally, the associations wrote that the CDC’s recommendations pose coverage problems for sickle cell patients and select groups of cancer survivors who may benefit from opioids for pain management. The groups asked the CDC to issue a clarification to ensure appropriate implementation of the opioid recommendations.
In a Feb. 28, 2019, letter to ASCO, NCCN, and ASH, Deborah Dowell, MD, chief medical officer for the CDC’s National Center for Injury Prevention and Control took note of the concerns, clarifying that the recommendations are not intended to deny clinically appropriate opioid therapy to any patients who suffer chronic pain, but rather to ensure that physicians and patients consider all safe and effective treatment options.
The CDC guidance may apply to cancer survivors in certain conditions, Dr. Dowell wrote, namely when survivors experience chronic pain after cancer treatment completion, are in clinical remission, and are under cancer surveillance only. However, she agreed that, for select groups of cancer survivors with persistent pain caused by past cancer, the ratio of opioid benefits to risks for chronic pain is unique. She referred health providers to guidelines by ASCO on chronic pain management for adult cancer survivors and NCCN guidance on managing adult cancer pain when considering opioids for pain control in such populations.
Special considerations in sickle cell disease may also change the balance of opioid risks to benefits for pain management, Dr. Dowell wrote, referring providers and insurers to additional guidance on sickle cell disease from the National Institute of Health when making treatment and reimbursement decisions.
“Clinical decision making should be based on the relationship between the clinician and patient, with an understanding of the patient’s clinical situation, functioning, and life context, as well as careful consideration of the benefits and risk of all treatment options, including opioid therapy,” Dr. Dowell wrote. “CDC encourages physicians to continue using their clinical judgment and base treatment on what they know about their patients, including the use of opioids if determined to be the best course of treatment.”
Clifford A. Hudis, MD, CEO of ASCO, praised the clarification, calling the letter necessary to clear up confusion and prevent inappropriate coverage decisions.
“This clarification from CDC is critically important because, while the agency’s guideline clearly states that it is not intended to apply to patients during active cancer and sickle cell disease treatment, many payers have been inappropriately using it to make opioid coverage determinations for those exact populations,” Dr. Hudis said in a statement.
Sickle cell patients suffer from severe, chronic pain, which is debilitating on its own without the added burden of having to constantly appeal coverage denials, added ASH President Roy Silverstein, MD.
“We appreciate CDC’s acknowledgment that the challenges of managing severe and chronic pain in conditions, such as sickle cell disease, require special consideration, and we hope payers will take the CDC’s clarification into account to ensure that patients’ pain management needs are covered,” he said in the same statement.
Officials at the Centers for Disease Control and Prevention have clarified the agency’s guidelines on opioid prescribing after a trio of organizations raised concerns that insurers were inappropriately applying the recommendations to active cancer patients when making coverage determinations.
The CDC guidelines, released in March 2016, address when to initiate or continue opioids for chronic pain, opioid selection, dosage, duration, follow-up, and discontinuation, and assess risk and harms of opioid use. Although the guidelines clearly state they are intended for clinicians prescribing opioids outside of active cancer treatment, insurance companies are still applying the guidelines to opioid coverage decisions for patients with active cancer, according to a Feb. 13, 2019, letter sent to the CDC from leaders at the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the American Society of Hematology.
Additionally, the associations wrote that the CDC’s recommendations pose coverage problems for sickle cell patients and select groups of cancer survivors who may benefit from opioids for pain management. The groups asked the CDC to issue a clarification to ensure appropriate implementation of the opioid recommendations.
In a Feb. 28, 2019, letter to ASCO, NCCN, and ASH, Deborah Dowell, MD, chief medical officer for the CDC’s National Center for Injury Prevention and Control took note of the concerns, clarifying that the recommendations are not intended to deny clinically appropriate opioid therapy to any patients who suffer chronic pain, but rather to ensure that physicians and patients consider all safe and effective treatment options.
The CDC guidance may apply to cancer survivors in certain conditions, Dr. Dowell wrote, namely when survivors experience chronic pain after cancer treatment completion, are in clinical remission, and are under cancer surveillance only. However, she agreed that, for select groups of cancer survivors with persistent pain caused by past cancer, the ratio of opioid benefits to risks for chronic pain is unique. She referred health providers to guidelines by ASCO on chronic pain management for adult cancer survivors and NCCN guidance on managing adult cancer pain when considering opioids for pain control in such populations.
Special considerations in sickle cell disease may also change the balance of opioid risks to benefits for pain management, Dr. Dowell wrote, referring providers and insurers to additional guidance on sickle cell disease from the National Institute of Health when making treatment and reimbursement decisions.
“Clinical decision making should be based on the relationship between the clinician and patient, with an understanding of the patient’s clinical situation, functioning, and life context, as well as careful consideration of the benefits and risk of all treatment options, including opioid therapy,” Dr. Dowell wrote. “CDC encourages physicians to continue using their clinical judgment and base treatment on what they know about their patients, including the use of opioids if determined to be the best course of treatment.”
Clifford A. Hudis, MD, CEO of ASCO, praised the clarification, calling the letter necessary to clear up confusion and prevent inappropriate coverage decisions.
“This clarification from CDC is critically important because, while the agency’s guideline clearly states that it is not intended to apply to patients during active cancer and sickle cell disease treatment, many payers have been inappropriately using it to make opioid coverage determinations for those exact populations,” Dr. Hudis said in a statement.
Sickle cell patients suffer from severe, chronic pain, which is debilitating on its own without the added burden of having to constantly appeal coverage denials, added ASH President Roy Silverstein, MD.
“We appreciate CDC’s acknowledgment that the challenges of managing severe and chronic pain in conditions, such as sickle cell disease, require special consideration, and we hope payers will take the CDC’s clarification into account to ensure that patients’ pain management needs are covered,” he said in the same statement.
In sickle cell disease, opioid prescribing starts early, study finds
MILWAUKEE – A new study of for them.
The Medicaid claims database analysis looked at a one-year snapshot of prescriptions filled for a variety of opioids among children and young adults in North Carolina, said Nancy Crego, PhD, in an interview at a poster session of the scientific meeting of the American Pain Society.
Dr. Crego and her colleagues at Duke University School of Nursing, Durham, N.C., studied 1,560 children and young adults aged 0-22 years with sickle cell disease who received Medicaid; in all, 586 (38%) had an opioid prescription filled during the year-long study period.
Among adolescents and young adults with sickle cell disease, outpatient opioid prescriptions were common, with increasing prescription fills seen through the middle years and young adulthood. “Opioid prescription claims were prevalent across all age groups,” wrote Dr. Crego and her associates.
Though 20% of preschoolers (87 of 428) had had a prescription filled for opioids, the rates of opioid prescribing increased with age. Of adolescents aged 15-18 years, 54% (154 of 284) had filled an opioid prescription, as had 50% (110 of 221) of those aged 19-22 years.
For the 366 school-aged children aged 6-10 years, 117 (32%) had an opioid prescription filled. The number of prescriptions filled per patient on an annual basis for this age group ranged from one to 10.
There was a wide variation in the number of prescriptions filled in all other age groups over the study period as well. For school-aged children, the range was 1 to 10, and 1 to 18 for middle schoolers aged 11-14 years. Adolescents filled from 1-30 prescriptions, and for young adults, the range was 1-24.
Though the rates of opioid prescribing increased with age, the number of doses per prescription actually fell throughout the adolescent and young adult years. In an interview at the poster presentation, Dr. Crego speculated that this decrease observed with increasing age might reflect provider concern about opioid misuse and diversion, though the study methodology didn’t allow them to examine this.
Dr. Crego said that she was surprised by the high numbers of children who were receiving opioid prescriptions in the preschool years. “I wonder what their parents are being taught about how to administer these medications” to this very young age group, she commented.
Opioids included in the claims database analysis included morphine, hydromorphone, hydrocodone, oxycodone, oxymorphone, methadone, fentanyl, codeine, and tramadol.
Children with sickle cell disease are exposed to opioids in early childhood,” Dr. Crego and her colleagues wrote in the poster, but they acknowledged that “it is unknown if this early exposure increases the risk of opioid misuse later in life in this population ... Prescribers should incorporate continuous assessments for potential misuse and abuse in all age groups.”
“Most of the data that we have on opioid prescription claims in children usually exclude chronically ill children; they’re almost all of acutely ill children, and quite a bit of it is on postoperative care,” Dr. Crego said. The current study captures early-life prescribing “for somebody who’s going to be on opioids for a lot of their life,” she noted.
The studies of opioids used for acute pain, she said, showed that parents would often “administer opioids for inappropriate indications.” She is now conducting a qualitative study investigating pharmacologic and non-pharmacologic pain interventions for children with sickle cell disease. She’s also investigating how parents decide to administer opioids: “What did they see in their child that would prompt them to give an opioid versus giving another type of analgesic?”
There are some limitations to working with a claims database, acknowledged Dr. Crego: “We don’t know about their actual use, because we don’t know how often they are taking it, but we know it’s a filled opioid prescription.”
Dr. Crego said that more work is needed to examine how parents administer opioids to their children with sickle cell disease, and to learn more about what parents are told – and what they understand – about how their child’s pain should be managed. Also, she added, more research is needed on non-pharmacologic pain management for pediatric patients with sickle cell disease.
The study was funded by the Agency for Healthcare Research and Quality. Dr. Crego and her coauthors reported no conflicts of interest.
SOURCE: Crego, N. et al. APS 2019.
MILWAUKEE – A new study of for them.
The Medicaid claims database analysis looked at a one-year snapshot of prescriptions filled for a variety of opioids among children and young adults in North Carolina, said Nancy Crego, PhD, in an interview at a poster session of the scientific meeting of the American Pain Society.
Dr. Crego and her colleagues at Duke University School of Nursing, Durham, N.C., studied 1,560 children and young adults aged 0-22 years with sickle cell disease who received Medicaid; in all, 586 (38%) had an opioid prescription filled during the year-long study period.
Among adolescents and young adults with sickle cell disease, outpatient opioid prescriptions were common, with increasing prescription fills seen through the middle years and young adulthood. “Opioid prescription claims were prevalent across all age groups,” wrote Dr. Crego and her associates.
Though 20% of preschoolers (87 of 428) had had a prescription filled for opioids, the rates of opioid prescribing increased with age. Of adolescents aged 15-18 years, 54% (154 of 284) had filled an opioid prescription, as had 50% (110 of 221) of those aged 19-22 years.
For the 366 school-aged children aged 6-10 years, 117 (32%) had an opioid prescription filled. The number of prescriptions filled per patient on an annual basis for this age group ranged from one to 10.
There was a wide variation in the number of prescriptions filled in all other age groups over the study period as well. For school-aged children, the range was 1 to 10, and 1 to 18 for middle schoolers aged 11-14 years. Adolescents filled from 1-30 prescriptions, and for young adults, the range was 1-24.
Though the rates of opioid prescribing increased with age, the number of doses per prescription actually fell throughout the adolescent and young adult years. In an interview at the poster presentation, Dr. Crego speculated that this decrease observed with increasing age might reflect provider concern about opioid misuse and diversion, though the study methodology didn’t allow them to examine this.
Dr. Crego said that she was surprised by the high numbers of children who were receiving opioid prescriptions in the preschool years. “I wonder what their parents are being taught about how to administer these medications” to this very young age group, she commented.
Opioids included in the claims database analysis included morphine, hydromorphone, hydrocodone, oxycodone, oxymorphone, methadone, fentanyl, codeine, and tramadol.
Children with sickle cell disease are exposed to opioids in early childhood,” Dr. Crego and her colleagues wrote in the poster, but they acknowledged that “it is unknown if this early exposure increases the risk of opioid misuse later in life in this population ... Prescribers should incorporate continuous assessments for potential misuse and abuse in all age groups.”
“Most of the data that we have on opioid prescription claims in children usually exclude chronically ill children; they’re almost all of acutely ill children, and quite a bit of it is on postoperative care,” Dr. Crego said. The current study captures early-life prescribing “for somebody who’s going to be on opioids for a lot of their life,” she noted.
The studies of opioids used for acute pain, she said, showed that parents would often “administer opioids for inappropriate indications.” She is now conducting a qualitative study investigating pharmacologic and non-pharmacologic pain interventions for children with sickle cell disease. She’s also investigating how parents decide to administer opioids: “What did they see in their child that would prompt them to give an opioid versus giving another type of analgesic?”
There are some limitations to working with a claims database, acknowledged Dr. Crego: “We don’t know about their actual use, because we don’t know how often they are taking it, but we know it’s a filled opioid prescription.”
Dr. Crego said that more work is needed to examine how parents administer opioids to their children with sickle cell disease, and to learn more about what parents are told – and what they understand – about how their child’s pain should be managed. Also, she added, more research is needed on non-pharmacologic pain management for pediatric patients with sickle cell disease.
The study was funded by the Agency for Healthcare Research and Quality. Dr. Crego and her coauthors reported no conflicts of interest.
SOURCE: Crego, N. et al. APS 2019.
MILWAUKEE – A new study of for them.
The Medicaid claims database analysis looked at a one-year snapshot of prescriptions filled for a variety of opioids among children and young adults in North Carolina, said Nancy Crego, PhD, in an interview at a poster session of the scientific meeting of the American Pain Society.
Dr. Crego and her colleagues at Duke University School of Nursing, Durham, N.C., studied 1,560 children and young adults aged 0-22 years with sickle cell disease who received Medicaid; in all, 586 (38%) had an opioid prescription filled during the year-long study period.
Among adolescents and young adults with sickle cell disease, outpatient opioid prescriptions were common, with increasing prescription fills seen through the middle years and young adulthood. “Opioid prescription claims were prevalent across all age groups,” wrote Dr. Crego and her associates.
Though 20% of preschoolers (87 of 428) had had a prescription filled for opioids, the rates of opioid prescribing increased with age. Of adolescents aged 15-18 years, 54% (154 of 284) had filled an opioid prescription, as had 50% (110 of 221) of those aged 19-22 years.
For the 366 school-aged children aged 6-10 years, 117 (32%) had an opioid prescription filled. The number of prescriptions filled per patient on an annual basis for this age group ranged from one to 10.
There was a wide variation in the number of prescriptions filled in all other age groups over the study period as well. For school-aged children, the range was 1 to 10, and 1 to 18 for middle schoolers aged 11-14 years. Adolescents filled from 1-30 prescriptions, and for young adults, the range was 1-24.
Though the rates of opioid prescribing increased with age, the number of doses per prescription actually fell throughout the adolescent and young adult years. In an interview at the poster presentation, Dr. Crego speculated that this decrease observed with increasing age might reflect provider concern about opioid misuse and diversion, though the study methodology didn’t allow them to examine this.
Dr. Crego said that she was surprised by the high numbers of children who were receiving opioid prescriptions in the preschool years. “I wonder what their parents are being taught about how to administer these medications” to this very young age group, she commented.
Opioids included in the claims database analysis included morphine, hydromorphone, hydrocodone, oxycodone, oxymorphone, methadone, fentanyl, codeine, and tramadol.
Children with sickle cell disease are exposed to opioids in early childhood,” Dr. Crego and her colleagues wrote in the poster, but they acknowledged that “it is unknown if this early exposure increases the risk of opioid misuse later in life in this population ... Prescribers should incorporate continuous assessments for potential misuse and abuse in all age groups.”
“Most of the data that we have on opioid prescription claims in children usually exclude chronically ill children; they’re almost all of acutely ill children, and quite a bit of it is on postoperative care,” Dr. Crego said. The current study captures early-life prescribing “for somebody who’s going to be on opioids for a lot of their life,” she noted.
The studies of opioids used for acute pain, she said, showed that parents would often “administer opioids for inappropriate indications.” She is now conducting a qualitative study investigating pharmacologic and non-pharmacologic pain interventions for children with sickle cell disease. She’s also investigating how parents decide to administer opioids: “What did they see in their child that would prompt them to give an opioid versus giving another type of analgesic?”
There are some limitations to working with a claims database, acknowledged Dr. Crego: “We don’t know about their actual use, because we don’t know how often they are taking it, but we know it’s a filled opioid prescription.”
Dr. Crego said that more work is needed to examine how parents administer opioids to their children with sickle cell disease, and to learn more about what parents are told – and what they understand – about how their child’s pain should be managed. Also, she added, more research is needed on non-pharmacologic pain management for pediatric patients with sickle cell disease.
The study was funded by the Agency for Healthcare Research and Quality. Dr. Crego and her coauthors reported no conflicts of interest.
SOURCE: Crego, N. et al. APS 2019.
REPORTING FROM APS 2019
Novel transplant protocol improves engraftment in severe hemoglobinopathies
Doubling total body irradiation improved rates of engraftment without altering safety in patients with severe hemoglobinopathies undergoing haploidentical hematopoietic cell transplantation, new findings suggest.
“[A]lthough our previous study showed cures in most patients and low toxicity, the graft failure rate – albeit all with full host recovery – was 50%,” Francisco Javier Bolaños-Meade, MD, of Johns Hopkins University, Baltimore, and his colleagues wrote in the Lancet Haematology. The present study set out to decrease graft failure in these patients.
The researchers conducted a single-center study of 17 consecutive patients who underwent haploidentical hematopoietic cell transplantation for a severe hemoglobinopathy. A total of 12 patients had sickle cell disease and 5 had beta-thalassemia major.
Study participants received a nonmyeloablative conditioning regimen consisting of haploidentical related donors and postprocedure cyclophosphamide.
“The primary endpoint of the study was modified to evaluate engraftment by measurement of blood chimerism,” they wrote.
After analysis, Dr. Bolaños-Meade and his colleagues found that increasing total body irradiation dose from 200 cGy to 400 cGy lowered graft failure without raising toxicity. In particular, only one participant had primary graft failure, but experienced recovery of host hematopoiesis.
Of the 17 patients, 13 patients (76%) achieved full donor chimerism and 3 patients (18%) had mixed donor-host chimerism. Three patients remained on immunosuppression, the researchers reported.
With respect to safety, five patients developed acute GVHD, which varied from grade 2 to 4; chronic GVHD was seen in three patients.
“The results of our study warrant further investigation to determine whether the curative potential of allogeneic bone marrow transplantation can extend beyond the traditionally small fraction of patients with severe hemoglobinopathies who have matched donors and are healthy enough to receive myeloablative conditioning,” they wrote.
The study was funded by the National Institutes of Health and the Maryland Stem Cell Research Fund. The researchers reported financial disclosures related to Aduro Biotech, Amgen, Alexion Pharmaceuticals, Celgene, Takeda, and others.
SOURCE: Bolaños-Meade FJ et al. Lancet Haematol. 2019 Mar 13. doi: 10.1016/S2352-3026(19)30031-6.
Doubling total body irradiation improved rates of engraftment without altering safety in patients with severe hemoglobinopathies undergoing haploidentical hematopoietic cell transplantation, new findings suggest.
“[A]lthough our previous study showed cures in most patients and low toxicity, the graft failure rate – albeit all with full host recovery – was 50%,” Francisco Javier Bolaños-Meade, MD, of Johns Hopkins University, Baltimore, and his colleagues wrote in the Lancet Haematology. The present study set out to decrease graft failure in these patients.
The researchers conducted a single-center study of 17 consecutive patients who underwent haploidentical hematopoietic cell transplantation for a severe hemoglobinopathy. A total of 12 patients had sickle cell disease and 5 had beta-thalassemia major.
Study participants received a nonmyeloablative conditioning regimen consisting of haploidentical related donors and postprocedure cyclophosphamide.
“The primary endpoint of the study was modified to evaluate engraftment by measurement of blood chimerism,” they wrote.
After analysis, Dr. Bolaños-Meade and his colleagues found that increasing total body irradiation dose from 200 cGy to 400 cGy lowered graft failure without raising toxicity. In particular, only one participant had primary graft failure, but experienced recovery of host hematopoiesis.
Of the 17 patients, 13 patients (76%) achieved full donor chimerism and 3 patients (18%) had mixed donor-host chimerism. Three patients remained on immunosuppression, the researchers reported.
With respect to safety, five patients developed acute GVHD, which varied from grade 2 to 4; chronic GVHD was seen in three patients.
“The results of our study warrant further investigation to determine whether the curative potential of allogeneic bone marrow transplantation can extend beyond the traditionally small fraction of patients with severe hemoglobinopathies who have matched donors and are healthy enough to receive myeloablative conditioning,” they wrote.
The study was funded by the National Institutes of Health and the Maryland Stem Cell Research Fund. The researchers reported financial disclosures related to Aduro Biotech, Amgen, Alexion Pharmaceuticals, Celgene, Takeda, and others.
SOURCE: Bolaños-Meade FJ et al. Lancet Haematol. 2019 Mar 13. doi: 10.1016/S2352-3026(19)30031-6.
Doubling total body irradiation improved rates of engraftment without altering safety in patients with severe hemoglobinopathies undergoing haploidentical hematopoietic cell transplantation, new findings suggest.
“[A]lthough our previous study showed cures in most patients and low toxicity, the graft failure rate – albeit all with full host recovery – was 50%,” Francisco Javier Bolaños-Meade, MD, of Johns Hopkins University, Baltimore, and his colleagues wrote in the Lancet Haematology. The present study set out to decrease graft failure in these patients.
The researchers conducted a single-center study of 17 consecutive patients who underwent haploidentical hematopoietic cell transplantation for a severe hemoglobinopathy. A total of 12 patients had sickle cell disease and 5 had beta-thalassemia major.
Study participants received a nonmyeloablative conditioning regimen consisting of haploidentical related donors and postprocedure cyclophosphamide.
“The primary endpoint of the study was modified to evaluate engraftment by measurement of blood chimerism,” they wrote.
After analysis, Dr. Bolaños-Meade and his colleagues found that increasing total body irradiation dose from 200 cGy to 400 cGy lowered graft failure without raising toxicity. In particular, only one participant had primary graft failure, but experienced recovery of host hematopoiesis.
Of the 17 patients, 13 patients (76%) achieved full donor chimerism and 3 patients (18%) had mixed donor-host chimerism. Three patients remained on immunosuppression, the researchers reported.
With respect to safety, five patients developed acute GVHD, which varied from grade 2 to 4; chronic GVHD was seen in three patients.
“The results of our study warrant further investigation to determine whether the curative potential of allogeneic bone marrow transplantation can extend beyond the traditionally small fraction of patients with severe hemoglobinopathies who have matched donors and are healthy enough to receive myeloablative conditioning,” they wrote.
The study was funded by the National Institutes of Health and the Maryland Stem Cell Research Fund. The researchers reported financial disclosures related to Aduro Biotech, Amgen, Alexion Pharmaceuticals, Celgene, Takeda, and others.
SOURCE: Bolaños-Meade FJ et al. Lancet Haematol. 2019 Mar 13. doi: 10.1016/S2352-3026(19)30031-6.
FROM LANCET HAEMATOLOGY
A new era of TTP treatment
Earlier this year, the Food and Drug Administration approved Cablivi (caplacizumab-yhdp) (Sanofi Genzyme, Cambridge, Mass.) for the treatment of acquired thrombotic thrombocytopenic purpura (TTP), making it the first medication specifically indicated for the treatment of TTP.
The approval of caplacizumab and the clinical trial results that approval is based on are the most promising developments in the treatment of TTP since the introduction of plasma exchange (PE) therapy. However, many questions remain about how to best administer caplacizumab, specifically, which patients should receive it? Should all TTP patients start on caplacizumab therapy or should it be limited to patients with histories of TTP or those slow to respond to standard therapy with PE and immunosuppression?
TTP is a rare thrombotic microangiopathy characterized by thrombocytopenia and microangiopathic hemolytic anemia caused by the inhibition of ADAMTS13, a metalloproteinase, which cleaves large-molecular-weight von Willebrand factor (vWF) multimers. Caplacizumab is a humanized bivalent, variable domain-only immunoglobulin fragment. The drug targets the A1 domain of vWF and inhibits the binding between vWF and the platelet glycoprotein Ib-IX-V receptor, preventing the formation of the microvascular thrombi and platelet loss associated with TTP.
FDA approval of caplacizumab came shortly after the publication of the results of the HERCULES trial in the New England Journal of Medicine by Marie Scully, MD, and her colleagues (N Engl J Med. 2019; 380[4]: 335-46).
HERCULES was an international phase 3, double blinded, placebo-controlled, randomized study designed to evaluate the efficacy and safety of caplacizumab. In total, 145 patients participated in the trial. Caplacizumab or placebo were given in addition to standard therapy of plasma exchange (PE) and immunosuppression. Caplacizumab or placebo were administered as an intravenous loading dose prior to the first PE after randomization and subcutaneously once daily until 30 days after the last PE. All patients received daily PE until 2 days after platelet count normalization.
The primary measure of the study was the time to platelet count response of greater than 150 x 109/L following the cessation of daily PE. Secondary measures included TTP-related death; TTP relapse; major thromboembolic events; proportion of subjects with refractory TTP; normalization of organ damage markers including lactate dehydrogenase, cardiac troponin I, and serum creatinine; and other adverse events.
The authors found that the median time of normalization of the platelet count was shorter in the caplacizumab group, compared with placebo, with the caplacizumab group being 1.55 times more likely to have a normalized platelet count at any given time point in the study. While statistically significant differences were identified in the rate of platelet normalization, the median number of days of PE until normalization was only 2 days less in the caplacizumab group (five treatments) than in the placebo group (seven treatments), which may not be clinically significant for the treating physician.
In fact, the secondary endpoints of the study seem much more clinically promising in the treatment of TTP. The composite rate of TTP-related death, TTP recurrence, or major thromboembolic events during the treatment period was significantly lower in the caplacizumab group (12%) versus placebo (49%). No TTP-related deaths occurred in the caplacizumab group. The caplacizumab group was also statistically less likely to have a TTP exacerbation, defined as disease recurrence within 30 days from the last PE, than the placebo group.
End organ damage serum markers also improved faster in the caplacizumab group, although there was no significant difference between groups. Overall hospitalization (median of 9 vs. 12 days) and ICU stays (median of 3 vs. 5 days) were shorter in the caplacizumab group, compared with the placebo group.
While several relapses, defined as disease recurrence after 30 days from the last PE, occurred in the caplacizumab group, the relapses were only found in patients with ADAMTS13 activity of less than 10% at the end of the treatment period. Mild side effects, such as mucocutaneous bleeding were more frequent in the caplacizumab group. No major bleeding complications were observed.
The HERCULES trial generates more questions about the role of ADAMTS13 activity testing to monitor treatment response and to make therapy decisions. Extremely low ADAMTS13 activity levels at the cessation of therapy may be a sign of treatment inadequacy and may warrant closer follow-up of at-risk patients on caplacizumab.
Sanofi Genzyme estimates that the U.S. list price will be approximately $270,000 for a standard treatment course, according to a news release from the company. Whether payers will add it to formularies remains uncertain, but the high drug cost may be countered by potential savings in the reduction of hospital and ICU days with caplacizumab therapy. Sanofi Genzyme will also have a patient support program for eligible patients.
Caplacizumab has been approved in Europe since August 2018, but is not readily available in the United States. Given the dearth of clinical experience with the drug outside of the TITAN and HERCULES trials, strong recommendations for when and how to initiate therapy remain elusive.
As caplacizumab is further introduced into clinical practice, more studies are needed to identify which patient groups will benefit most from therapy. The current data for caplacizumab shows that it will be used as an adjunct to standard PE therapy, rather than as a replacement. How the drug is used in combination with current TTP treatments – such as corticosteroids, rituximab, bortezomib, vincristine, N-acetylcysteine, and splenectomy – should be evaluated to identify which treatment combinations not only improve platelet counts, but also reduce mortality and morbidity while remaining cost effective.
Dr. Ricci is a staff physician and Apheresis Director at the Taussig Cancer Institute at the Cleveland Clinic. She reported having no conflicts of interest.
Earlier this year, the Food and Drug Administration approved Cablivi (caplacizumab-yhdp) (Sanofi Genzyme, Cambridge, Mass.) for the treatment of acquired thrombotic thrombocytopenic purpura (TTP), making it the first medication specifically indicated for the treatment of TTP.
The approval of caplacizumab and the clinical trial results that approval is based on are the most promising developments in the treatment of TTP since the introduction of plasma exchange (PE) therapy. However, many questions remain about how to best administer caplacizumab, specifically, which patients should receive it? Should all TTP patients start on caplacizumab therapy or should it be limited to patients with histories of TTP or those slow to respond to standard therapy with PE and immunosuppression?
TTP is a rare thrombotic microangiopathy characterized by thrombocytopenia and microangiopathic hemolytic anemia caused by the inhibition of ADAMTS13, a metalloproteinase, which cleaves large-molecular-weight von Willebrand factor (vWF) multimers. Caplacizumab is a humanized bivalent, variable domain-only immunoglobulin fragment. The drug targets the A1 domain of vWF and inhibits the binding between vWF and the platelet glycoprotein Ib-IX-V receptor, preventing the formation of the microvascular thrombi and platelet loss associated with TTP.
FDA approval of caplacizumab came shortly after the publication of the results of the HERCULES trial in the New England Journal of Medicine by Marie Scully, MD, and her colleagues (N Engl J Med. 2019; 380[4]: 335-46).
HERCULES was an international phase 3, double blinded, placebo-controlled, randomized study designed to evaluate the efficacy and safety of caplacizumab. In total, 145 patients participated in the trial. Caplacizumab or placebo were given in addition to standard therapy of plasma exchange (PE) and immunosuppression. Caplacizumab or placebo were administered as an intravenous loading dose prior to the first PE after randomization and subcutaneously once daily until 30 days after the last PE. All patients received daily PE until 2 days after platelet count normalization.
The primary measure of the study was the time to platelet count response of greater than 150 x 109/L following the cessation of daily PE. Secondary measures included TTP-related death; TTP relapse; major thromboembolic events; proportion of subjects with refractory TTP; normalization of organ damage markers including lactate dehydrogenase, cardiac troponin I, and serum creatinine; and other adverse events.
The authors found that the median time of normalization of the platelet count was shorter in the caplacizumab group, compared with placebo, with the caplacizumab group being 1.55 times more likely to have a normalized platelet count at any given time point in the study. While statistically significant differences were identified in the rate of platelet normalization, the median number of days of PE until normalization was only 2 days less in the caplacizumab group (five treatments) than in the placebo group (seven treatments), which may not be clinically significant for the treating physician.
In fact, the secondary endpoints of the study seem much more clinically promising in the treatment of TTP. The composite rate of TTP-related death, TTP recurrence, or major thromboembolic events during the treatment period was significantly lower in the caplacizumab group (12%) versus placebo (49%). No TTP-related deaths occurred in the caplacizumab group. The caplacizumab group was also statistically less likely to have a TTP exacerbation, defined as disease recurrence within 30 days from the last PE, than the placebo group.
End organ damage serum markers also improved faster in the caplacizumab group, although there was no significant difference between groups. Overall hospitalization (median of 9 vs. 12 days) and ICU stays (median of 3 vs. 5 days) were shorter in the caplacizumab group, compared with the placebo group.
While several relapses, defined as disease recurrence after 30 days from the last PE, occurred in the caplacizumab group, the relapses were only found in patients with ADAMTS13 activity of less than 10% at the end of the treatment period. Mild side effects, such as mucocutaneous bleeding were more frequent in the caplacizumab group. No major bleeding complications were observed.
The HERCULES trial generates more questions about the role of ADAMTS13 activity testing to monitor treatment response and to make therapy decisions. Extremely low ADAMTS13 activity levels at the cessation of therapy may be a sign of treatment inadequacy and may warrant closer follow-up of at-risk patients on caplacizumab.
Sanofi Genzyme estimates that the U.S. list price will be approximately $270,000 for a standard treatment course, according to a news release from the company. Whether payers will add it to formularies remains uncertain, but the high drug cost may be countered by potential savings in the reduction of hospital and ICU days with caplacizumab therapy. Sanofi Genzyme will also have a patient support program for eligible patients.
Caplacizumab has been approved in Europe since August 2018, but is not readily available in the United States. Given the dearth of clinical experience with the drug outside of the TITAN and HERCULES trials, strong recommendations for when and how to initiate therapy remain elusive.
As caplacizumab is further introduced into clinical practice, more studies are needed to identify which patient groups will benefit most from therapy. The current data for caplacizumab shows that it will be used as an adjunct to standard PE therapy, rather than as a replacement. How the drug is used in combination with current TTP treatments – such as corticosteroids, rituximab, bortezomib, vincristine, N-acetylcysteine, and splenectomy – should be evaluated to identify which treatment combinations not only improve platelet counts, but also reduce mortality and morbidity while remaining cost effective.
Dr. Ricci is a staff physician and Apheresis Director at the Taussig Cancer Institute at the Cleveland Clinic. She reported having no conflicts of interest.
Earlier this year, the Food and Drug Administration approved Cablivi (caplacizumab-yhdp) (Sanofi Genzyme, Cambridge, Mass.) for the treatment of acquired thrombotic thrombocytopenic purpura (TTP), making it the first medication specifically indicated for the treatment of TTP.
The approval of caplacizumab and the clinical trial results that approval is based on are the most promising developments in the treatment of TTP since the introduction of plasma exchange (PE) therapy. However, many questions remain about how to best administer caplacizumab, specifically, which patients should receive it? Should all TTP patients start on caplacizumab therapy or should it be limited to patients with histories of TTP or those slow to respond to standard therapy with PE and immunosuppression?
TTP is a rare thrombotic microangiopathy characterized by thrombocytopenia and microangiopathic hemolytic anemia caused by the inhibition of ADAMTS13, a metalloproteinase, which cleaves large-molecular-weight von Willebrand factor (vWF) multimers. Caplacizumab is a humanized bivalent, variable domain-only immunoglobulin fragment. The drug targets the A1 domain of vWF and inhibits the binding between vWF and the platelet glycoprotein Ib-IX-V receptor, preventing the formation of the microvascular thrombi and platelet loss associated with TTP.
FDA approval of caplacizumab came shortly after the publication of the results of the HERCULES trial in the New England Journal of Medicine by Marie Scully, MD, and her colleagues (N Engl J Med. 2019; 380[4]: 335-46).
HERCULES was an international phase 3, double blinded, placebo-controlled, randomized study designed to evaluate the efficacy and safety of caplacizumab. In total, 145 patients participated in the trial. Caplacizumab or placebo were given in addition to standard therapy of plasma exchange (PE) and immunosuppression. Caplacizumab or placebo were administered as an intravenous loading dose prior to the first PE after randomization and subcutaneously once daily until 30 days after the last PE. All patients received daily PE until 2 days after platelet count normalization.
The primary measure of the study was the time to platelet count response of greater than 150 x 109/L following the cessation of daily PE. Secondary measures included TTP-related death; TTP relapse; major thromboembolic events; proportion of subjects with refractory TTP; normalization of organ damage markers including lactate dehydrogenase, cardiac troponin I, and serum creatinine; and other adverse events.
The authors found that the median time of normalization of the platelet count was shorter in the caplacizumab group, compared with placebo, with the caplacizumab group being 1.55 times more likely to have a normalized platelet count at any given time point in the study. While statistically significant differences were identified in the rate of platelet normalization, the median number of days of PE until normalization was only 2 days less in the caplacizumab group (five treatments) than in the placebo group (seven treatments), which may not be clinically significant for the treating physician.
In fact, the secondary endpoints of the study seem much more clinically promising in the treatment of TTP. The composite rate of TTP-related death, TTP recurrence, or major thromboembolic events during the treatment period was significantly lower in the caplacizumab group (12%) versus placebo (49%). No TTP-related deaths occurred in the caplacizumab group. The caplacizumab group was also statistically less likely to have a TTP exacerbation, defined as disease recurrence within 30 days from the last PE, than the placebo group.
End organ damage serum markers also improved faster in the caplacizumab group, although there was no significant difference between groups. Overall hospitalization (median of 9 vs. 12 days) and ICU stays (median of 3 vs. 5 days) were shorter in the caplacizumab group, compared with the placebo group.
While several relapses, defined as disease recurrence after 30 days from the last PE, occurred in the caplacizumab group, the relapses were only found in patients with ADAMTS13 activity of less than 10% at the end of the treatment period. Mild side effects, such as mucocutaneous bleeding were more frequent in the caplacizumab group. No major bleeding complications were observed.
The HERCULES trial generates more questions about the role of ADAMTS13 activity testing to monitor treatment response and to make therapy decisions. Extremely low ADAMTS13 activity levels at the cessation of therapy may be a sign of treatment inadequacy and may warrant closer follow-up of at-risk patients on caplacizumab.
Sanofi Genzyme estimates that the U.S. list price will be approximately $270,000 for a standard treatment course, according to a news release from the company. Whether payers will add it to formularies remains uncertain, but the high drug cost may be countered by potential savings in the reduction of hospital and ICU days with caplacizumab therapy. Sanofi Genzyme will also have a patient support program for eligible patients.
Caplacizumab has been approved in Europe since August 2018, but is not readily available in the United States. Given the dearth of clinical experience with the drug outside of the TITAN and HERCULES trials, strong recommendations for when and how to initiate therapy remain elusive.
As caplacizumab is further introduced into clinical practice, more studies are needed to identify which patient groups will benefit most from therapy. The current data for caplacizumab shows that it will be used as an adjunct to standard PE therapy, rather than as a replacement. How the drug is used in combination with current TTP treatments – such as corticosteroids, rituximab, bortezomib, vincristine, N-acetylcysteine, and splenectomy – should be evaluated to identify which treatment combinations not only improve platelet counts, but also reduce mortality and morbidity while remaining cost effective.
Dr. Ricci is a staff physician and Apheresis Director at the Taussig Cancer Institute at the Cleveland Clinic. She reported having no conflicts of interest.
Single-dose tafenoquine appears to prevent malaria relapse
Single-dose tafenoquine therapy safely reduces the risk of Plasmodium vivax relapse in patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity, according to the results of two phase 3, double-blind, randomized controlled trials.
Findings from both studies were published in two separate reports in the New England Journal of Medicine.
In the first study, the Dose and Efficacy Trial Evaluating Chloroquine and Tafenoquine in Vivax Elimination (DETECTIVE), the risk of P. vivax recurrence was approximately 70% lower with tafenoquine versus placebo, wrote Marcus V.G. Lacerda, MD, of Fundação de Medicina Tropical Doutor Heitor Vieira Dourado in Manaus, Brazil, and his colleagues.
The study included 522 patients with confirmed P. vivax infection from Peru, Brazil, Ethiopia, Cambodia, Thailand, and the Philippines. Patients received 3 days of chloroquine therapy (600 mg on days 1 and 2, and 300 mg on day 3) and were randomly assigned on a 2:1:1 basis to receive a single 300-mg dose of tafenoquine on day 1 or 2, primaquine once daily for 14 days, or placebo.
Since primaquine and tafenoquine can cause clinically significant hemolysis in individuals with G6PD deficiency, the study included only patients with normal G6PD activity.
In the intention-to-treat analysis, 62% of tafenoquine recipients were free from P. vivax recurrence (95% confidence interval [CI], 55%-69%) at 6 months, as were 70% of primaquine recipients (95% CI, 60%-77%) and 28% of placebo recipients (95% CI, 20%-37%). Compared with placebo, the reduction in risk of recurrence was 70% with tafenoquine (hazard ratio [HR], 0.30; 95% CI, 0.22-0.40; P less than .001) and 74% with primaquine.
Declines in hemoglobin levels were greatest in the tafenoquine group but were not associated with symptomatic anemia and resolved without intervention, the investigators wrote.
In addition to the quantitative G6PD test, the investigators also evaluated a qualitative test, which “failed to identify 16 patients most at risk for hemolysis,” they reported. “If tafenoquine use is expanded, adoption of reliable quantitative point-of-care G6PD tests will be needed; such tests are not currently available but are in development.”
In the second study, Global Assessment of Tafenoquine Hemolytic Risk (GATHER), Alejandro Llanos-Cuentas, MD, of Universidad Peruana Cayetano Heredia, Lima, Peru, and his colleagues enrolled 251 patients with confirmed P. vivax infection from Peru, Brazil, Columbia, Vietnam, and Thailand. They attempted to recruit women with moderate G6PD levels, but only one participant met this criterion – all others had normal G6PD activity.
Patients received 3-day course of chloroquine and were randomly assigned on a 2:1 basis to either tafenoquine or primaquine at the same doses as in the DETECTIVE trial.
At 6 months, 2% (95% CI, 1%-6%) of tafenoquine recipients and 1% (95% CI, 0.2%-6%) of primaquine recipients had decreased hemoglobin levels, but none consequently needed treatment. The medications also caused a similar degree and time course of hemoglobin decrease, the investigators noted.
A meta-analysis of GATHER and DETECTIVE confirmed that tafenoquine more often led to a decreased hemoglobin level (4% versus 1.5% with primaquine). Tafenoquine also did not meet prespecified criteria for noninferiority compared with primaquine, with respective 6-month recurrence rates of 67% versus 73%.
However, GATHER deployed “extensive” support to help patients adhere to the 15-day primaquine course, Dr. Llanos-Cuentas and his colleagues wrote. “Without such interventions, adherence to primaquine has been reported to be as low as 24% in Southeast Asia, with a corresponding attenuation of efficacy.”
GlaxoSmithKline and Medicines for Malaria Venture funded both studies, and GSK funded and conducted the meta-analysis. Dr. Llanos-Cuentas and several coinvestigators reported ties to GSK, Medicines for Malaria Venture, the Gambia, and LSTMH. Dr. Lacerda reported having no conflicts of interest.
SOURCES: Lacerda MVG et al. N Engl J Med 2019;380:215-28, and Llanos-Cuentas A et al. N Engl J Med 2019;380:229-41.
The studies show that tafenoquine reduces the risk of Plasmodium vivax recurrence in patients with quantitatively confirmed normal glucose-6-phosphate dehydrogenase (G6PD) activity, Nicholas J. White, FRS, wrote in an accompanying editorial.
But the need for this test and current prescribing restrictions will “limit the potential deployment of tafenoquine, at least in the immediate future,” he said. He praised the developers of tafenoquine “for persevering with this potentially valuable antimalarial drug, despite the difficulties,” but cautioned that it’s too soon to conclude that tafenoquine can be used safely and routinely on a large scale “and thus fulfill its promise as a radical improvement in the treatment of malaria.”
Currently, tafenoquine may not be used during pregnancy, lactation, or in patients younger than 16 years, Dr. White noted. Tafenoquine, like primaquine, causes dose-dependent hemolysis in patients with G6PD deficiency, but unlike primaquine, it is given as a single large dose. Hence, pretreatment quantitative G6PD testing is necessary. Point-of-care quantitative G6PD tests have been developed but await extensive field testing, Dr. White said.
Dr. White is with Mahidol University, Bangkok, Thailand, and University of Oxford, England. He reported having no financial disclosures. These comments are from his accompanying editorial ( N Engl J Med. 2019;380:285-6 ).
The studies show that tafenoquine reduces the risk of Plasmodium vivax recurrence in patients with quantitatively confirmed normal glucose-6-phosphate dehydrogenase (G6PD) activity, Nicholas J. White, FRS, wrote in an accompanying editorial.
But the need for this test and current prescribing restrictions will “limit the potential deployment of tafenoquine, at least in the immediate future,” he said. He praised the developers of tafenoquine “for persevering with this potentially valuable antimalarial drug, despite the difficulties,” but cautioned that it’s too soon to conclude that tafenoquine can be used safely and routinely on a large scale “and thus fulfill its promise as a radical improvement in the treatment of malaria.”
Currently, tafenoquine may not be used during pregnancy, lactation, or in patients younger than 16 years, Dr. White noted. Tafenoquine, like primaquine, causes dose-dependent hemolysis in patients with G6PD deficiency, but unlike primaquine, it is given as a single large dose. Hence, pretreatment quantitative G6PD testing is necessary. Point-of-care quantitative G6PD tests have been developed but await extensive field testing, Dr. White said.
Dr. White is with Mahidol University, Bangkok, Thailand, and University of Oxford, England. He reported having no financial disclosures. These comments are from his accompanying editorial ( N Engl J Med. 2019;380:285-6 ).
The studies show that tafenoquine reduces the risk of Plasmodium vivax recurrence in patients with quantitatively confirmed normal glucose-6-phosphate dehydrogenase (G6PD) activity, Nicholas J. White, FRS, wrote in an accompanying editorial.
But the need for this test and current prescribing restrictions will “limit the potential deployment of tafenoquine, at least in the immediate future,” he said. He praised the developers of tafenoquine “for persevering with this potentially valuable antimalarial drug, despite the difficulties,” but cautioned that it’s too soon to conclude that tafenoquine can be used safely and routinely on a large scale “and thus fulfill its promise as a radical improvement in the treatment of malaria.”
Currently, tafenoquine may not be used during pregnancy, lactation, or in patients younger than 16 years, Dr. White noted. Tafenoquine, like primaquine, causes dose-dependent hemolysis in patients with G6PD deficiency, but unlike primaquine, it is given as a single large dose. Hence, pretreatment quantitative G6PD testing is necessary. Point-of-care quantitative G6PD tests have been developed but await extensive field testing, Dr. White said.
Dr. White is with Mahidol University, Bangkok, Thailand, and University of Oxford, England. He reported having no financial disclosures. These comments are from his accompanying editorial ( N Engl J Med. 2019;380:285-6 ).
Single-dose tafenoquine therapy safely reduces the risk of Plasmodium vivax relapse in patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity, according to the results of two phase 3, double-blind, randomized controlled trials.
Findings from both studies were published in two separate reports in the New England Journal of Medicine.
In the first study, the Dose and Efficacy Trial Evaluating Chloroquine and Tafenoquine in Vivax Elimination (DETECTIVE), the risk of P. vivax recurrence was approximately 70% lower with tafenoquine versus placebo, wrote Marcus V.G. Lacerda, MD, of Fundação de Medicina Tropical Doutor Heitor Vieira Dourado in Manaus, Brazil, and his colleagues.
The study included 522 patients with confirmed P. vivax infection from Peru, Brazil, Ethiopia, Cambodia, Thailand, and the Philippines. Patients received 3 days of chloroquine therapy (600 mg on days 1 and 2, and 300 mg on day 3) and were randomly assigned on a 2:1:1 basis to receive a single 300-mg dose of tafenoquine on day 1 or 2, primaquine once daily for 14 days, or placebo.
Since primaquine and tafenoquine can cause clinically significant hemolysis in individuals with G6PD deficiency, the study included only patients with normal G6PD activity.
In the intention-to-treat analysis, 62% of tafenoquine recipients were free from P. vivax recurrence (95% confidence interval [CI], 55%-69%) at 6 months, as were 70% of primaquine recipients (95% CI, 60%-77%) and 28% of placebo recipients (95% CI, 20%-37%). Compared with placebo, the reduction in risk of recurrence was 70% with tafenoquine (hazard ratio [HR], 0.30; 95% CI, 0.22-0.40; P less than .001) and 74% with primaquine.
Declines in hemoglobin levels were greatest in the tafenoquine group but were not associated with symptomatic anemia and resolved without intervention, the investigators wrote.
In addition to the quantitative G6PD test, the investigators also evaluated a qualitative test, which “failed to identify 16 patients most at risk for hemolysis,” they reported. “If tafenoquine use is expanded, adoption of reliable quantitative point-of-care G6PD tests will be needed; such tests are not currently available but are in development.”
In the second study, Global Assessment of Tafenoquine Hemolytic Risk (GATHER), Alejandro Llanos-Cuentas, MD, of Universidad Peruana Cayetano Heredia, Lima, Peru, and his colleagues enrolled 251 patients with confirmed P. vivax infection from Peru, Brazil, Columbia, Vietnam, and Thailand. They attempted to recruit women with moderate G6PD levels, but only one participant met this criterion – all others had normal G6PD activity.
Patients received 3-day course of chloroquine and were randomly assigned on a 2:1 basis to either tafenoquine or primaquine at the same doses as in the DETECTIVE trial.
At 6 months, 2% (95% CI, 1%-6%) of tafenoquine recipients and 1% (95% CI, 0.2%-6%) of primaquine recipients had decreased hemoglobin levels, but none consequently needed treatment. The medications also caused a similar degree and time course of hemoglobin decrease, the investigators noted.
A meta-analysis of GATHER and DETECTIVE confirmed that tafenoquine more often led to a decreased hemoglobin level (4% versus 1.5% with primaquine). Tafenoquine also did not meet prespecified criteria for noninferiority compared with primaquine, with respective 6-month recurrence rates of 67% versus 73%.
However, GATHER deployed “extensive” support to help patients adhere to the 15-day primaquine course, Dr. Llanos-Cuentas and his colleagues wrote. “Without such interventions, adherence to primaquine has been reported to be as low as 24% in Southeast Asia, with a corresponding attenuation of efficacy.”
GlaxoSmithKline and Medicines for Malaria Venture funded both studies, and GSK funded and conducted the meta-analysis. Dr. Llanos-Cuentas and several coinvestigators reported ties to GSK, Medicines for Malaria Venture, the Gambia, and LSTMH. Dr. Lacerda reported having no conflicts of interest.
SOURCES: Lacerda MVG et al. N Engl J Med 2019;380:215-28, and Llanos-Cuentas A et al. N Engl J Med 2019;380:229-41.
Single-dose tafenoquine therapy safely reduces the risk of Plasmodium vivax relapse in patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity, according to the results of two phase 3, double-blind, randomized controlled trials.
Findings from both studies were published in two separate reports in the New England Journal of Medicine.
In the first study, the Dose and Efficacy Trial Evaluating Chloroquine and Tafenoquine in Vivax Elimination (DETECTIVE), the risk of P. vivax recurrence was approximately 70% lower with tafenoquine versus placebo, wrote Marcus V.G. Lacerda, MD, of Fundação de Medicina Tropical Doutor Heitor Vieira Dourado in Manaus, Brazil, and his colleagues.
The study included 522 patients with confirmed P. vivax infection from Peru, Brazil, Ethiopia, Cambodia, Thailand, and the Philippines. Patients received 3 days of chloroquine therapy (600 mg on days 1 and 2, and 300 mg on day 3) and were randomly assigned on a 2:1:1 basis to receive a single 300-mg dose of tafenoquine on day 1 or 2, primaquine once daily for 14 days, or placebo.
Since primaquine and tafenoquine can cause clinically significant hemolysis in individuals with G6PD deficiency, the study included only patients with normal G6PD activity.
In the intention-to-treat analysis, 62% of tafenoquine recipients were free from P. vivax recurrence (95% confidence interval [CI], 55%-69%) at 6 months, as were 70% of primaquine recipients (95% CI, 60%-77%) and 28% of placebo recipients (95% CI, 20%-37%). Compared with placebo, the reduction in risk of recurrence was 70% with tafenoquine (hazard ratio [HR], 0.30; 95% CI, 0.22-0.40; P less than .001) and 74% with primaquine.
Declines in hemoglobin levels were greatest in the tafenoquine group but were not associated with symptomatic anemia and resolved without intervention, the investigators wrote.
In addition to the quantitative G6PD test, the investigators also evaluated a qualitative test, which “failed to identify 16 patients most at risk for hemolysis,” they reported. “If tafenoquine use is expanded, adoption of reliable quantitative point-of-care G6PD tests will be needed; such tests are not currently available but are in development.”
In the second study, Global Assessment of Tafenoquine Hemolytic Risk (GATHER), Alejandro Llanos-Cuentas, MD, of Universidad Peruana Cayetano Heredia, Lima, Peru, and his colleagues enrolled 251 patients with confirmed P. vivax infection from Peru, Brazil, Columbia, Vietnam, and Thailand. They attempted to recruit women with moderate G6PD levels, but only one participant met this criterion – all others had normal G6PD activity.
Patients received 3-day course of chloroquine and were randomly assigned on a 2:1 basis to either tafenoquine or primaquine at the same doses as in the DETECTIVE trial.
At 6 months, 2% (95% CI, 1%-6%) of tafenoquine recipients and 1% (95% CI, 0.2%-6%) of primaquine recipients had decreased hemoglobin levels, but none consequently needed treatment. The medications also caused a similar degree and time course of hemoglobin decrease, the investigators noted.
A meta-analysis of GATHER and DETECTIVE confirmed that tafenoquine more often led to a decreased hemoglobin level (4% versus 1.5% with primaquine). Tafenoquine also did not meet prespecified criteria for noninferiority compared with primaquine, with respective 6-month recurrence rates of 67% versus 73%.
However, GATHER deployed “extensive” support to help patients adhere to the 15-day primaquine course, Dr. Llanos-Cuentas and his colleagues wrote. “Without such interventions, adherence to primaquine has been reported to be as low as 24% in Southeast Asia, with a corresponding attenuation of efficacy.”
GlaxoSmithKline and Medicines for Malaria Venture funded both studies, and GSK funded and conducted the meta-analysis. Dr. Llanos-Cuentas and several coinvestigators reported ties to GSK, Medicines for Malaria Venture, the Gambia, and LSTMH. Dr. Lacerda reported having no conflicts of interest.
SOURCES: Lacerda MVG et al. N Engl J Med 2019;380:215-28, and Llanos-Cuentas A et al. N Engl J Med 2019;380:229-41.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: In DETECTIVE, 6-month rates of freedom from recurrence from Plasmodium vivax infection were 62% with tafenoquine, 70% with primaquine, and 28% with placebo.
Study details: Two randomized, phase 3, double-blind controlled trials of patients with confirmed P. vivax infection (DETECTIVE and GATHER) and without deficient G6PD activity.
Disclosures: GlaxoSmithKline and Medicines for Malaria Venture funded both studies, and GSK funded and conducted the meta-analysis. Dr. Llanos-Cuentas and several coinvestigators reported ties to GSK, Medicines for Malaria Venture, the Gambia, and LSTMH. Dr. Lacerda reported having financial disclosures.
Source: Lacerda MVG et al. N Engl J Med 2019;380:215-28, and Llanos-Cuentas A et al. N Engl J Med 2019;380:229-41.