Bleeding Disorders

PARIS – A strategy of switching from prasugrel or ticagrelor to clopidogrel 1 month after percutaneous coronary intervention for acute coronary syndrome is superior to the guideline-recommended full 12 months of dual-antiplatelet therapy with either of the newer P2Y12 inhibitors, according to Thomas Cuisset, MD.

In the randomized TOPIC (Timing of Platelet Inhibition After Acute Coronary Syndrome) trial, this switch strategy resulted in a marked reduction in bleeding without an increased risk of ischemic events, compared with a full 12 months of standard dual-antiplatelet therapy (DAPT) using prasugrel (Effient) or ticagrelor (Brilinta).

Bruce Jancin/Frontline Medical News

PARIS – A strategy of switching from prasugrel or ticagrelor to clopidogrel 1 month after percutaneous coronary intervention for acute coronary syndrome is superior to the guideline-recommended full 12 months of dual-antiplatelet therapy with either of the newer P2Y12 inhibitors, according to Thomas Cuisset, MD.

In the randomized TOPIC (Timing of Platelet Inhibition After Acute Coronary Syndrome) trial, this switch strategy resulted in a marked reduction in bleeding without an increased risk of ischemic events, compared with a full 12 months of standard dual-antiplatelet therapy (DAPT) using prasugrel (Effient) or ticagrelor (Brilinta).

Bruce Jancin/Frontline Medical News

PARIS – A strategy of switching from prasugrel or ticagrelor to clopidogrel 1 month after percutaneous coronary intervention for acute coronary syndrome is superior to the guideline-recommended full 12 months of dual-antiplatelet therapy with either of the newer P2Y12 inhibitors, according to Thomas Cuisset, MD.

In the randomized TOPIC (Timing of Platelet Inhibition After Acute Coronary Syndrome) trial, this switch strategy resulted in a marked reduction in bleeding without an increased risk of ischemic events, compared with a full 12 months of standard dual-antiplatelet therapy (DAPT) using prasugrel (Effient) or ticagrelor (Brilinta).

Bruce Jancin/Frontline Medical News

BOSTON – Intensive systolic blood pressure reduction did not significantly reduce hematoma expansion, compared with standard systolic blood pressure reduction in the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial, but, in a post hoc analysis, it did show a strong trend toward reducing hematoma expansion in those with a larger initial hematoma volume.

In 450 patients randomized to receive intensive treatment and 426 randomized to receive standard treatment in the large, international, phase III randomized trial, the proportion of patients with any hematoma expansion was 46.4% and 52.3% , respectively (relative risk, 0.89; 95% confidence interval, 0.73-1.07). The proportion with hematoma expansion with an increase of greater than 33% was 18.9% and 24.4%, respectively (RR, 0.77; 95% CI, 0.58-1.03), Joshua N. Goldstein, MD, reported at the annual meeting of the American Academy of Neurology.

The confidence intervals suggested only a trend toward improvement, as the difference between the groups did not reach statistical significance, he said.

To determine if intensive systolic blood pressure reduction might have more of an impact among higher-risk patients, the investigators conducted a post hoc, secondary analysis in those with relatively larger hematomas. Among patients with an initial hematoma volume of at least 10 mL (at least half of the study population had smaller hematomas), the proportion with any hematoma expansion was 53.8% in the intensive treatment group and 61.3% in the standard treatment group (RR, 0.88; 95% CI, 0.67-1.13), and the proportion of patients with hematoma expansion of greater than 33% was 18% and 27.6%, respectively (RR, 0.67; 95% CI, 0.45-1.00), said Dr. Goldstein of Massachusetts General Hospital, Boston.

In those with an expansion greater than 33% and a hematoma volume of at least 6 cc, the finding was similar.

“The trend looks a little bit more aggressive,” he said, but the 95% confidence interval in those with larger hematomas reached 1.

Study subjects had elevated blood pressure at arrival, a Glasgow coma scale score of at least 5, and a hematoma volume of less than 60 cc. They were enrolled and randomized within 4.5 hours of symptom onset. Those in the intensive treatment group were treated with a goal of achieving between 110 and 139 mm Hg within 24 hours, and those in the standard treatment group were treated with a goal of achieving between 140 mm Hg and 179 mm Hg within 24 hours. They underwent baseline and 24-hour computed tomography scans, which were analyzed centrally by blinded investigators who recorded any increase of 0.5 mL or more, an increase of more than 33% , an increase of more than 33% or more than 6 mL, and an intraventricular hemorrhage volume greater than 2 mL.

These measures were correlated with death and disability, and hematoma enlargement was shown to be significantly associated with those outcomes at 3 months after randomization (RR, 1.59; 95% CI, 1.25-2.02), Dr. Goldstein said.

Previous studies have suggested that intensive lowering of systolic BP in patients with intracerebral hemorrhage can reduce the rate of hematoma expansion. As such, the hypothesis of the current study was that the intensive treatment of elevated blood pressures – arriving systolic blood pressure of greater than 180 mm Hg – would reduce the likelihood of death and disability at 3 months, Dr. Goldstein said,

The question is whether the biomarker – hematoma expansion – is really linked to clinical outcome, he said, “because a lot of our attempts to treat hematoma expansion are based on the assumption that, if we reduce hematoma expansion, we’re going to improve clinical outcomes.”

“In this trial ... the expanders had more death and disability than nonexpanders, and this was statistically significant, so hematoma expansion does seem to be a statistically significant predictor of poor outcome,” he said.

Thus, the strong trend toward a reduced risk of hematoma expansion with intensive blood pressure lowering in patients with larger hematoma volumes at baseline in this analysis is noteworthy, he said.

“It appears that the treatment is affecting the biomarker, that the treatment is affecting hematoma expansion ... and hematoma expansion was a significant predictor of death and disability ... so why didn’t we get the result we wanted from the trial?” he asked.

It may be that a greater magnitude of reduction in the risk of hematoma expansion was necessary, he said.

“In other words, even if our treatment is having an effect, it’s just not having a big enough effect to change outcomes,” he said, adding that future trials probably need to involve a much bigger impact on the risk of expansion to translate to a change in clinical outcomes.”

This study was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Goldstein reported having no disclosures.

[email protected]

BOSTON – Intensive systolic blood pressure reduction did not significantly reduce hematoma expansion, compared with standard systolic blood pressure reduction in the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial, but, in a post hoc analysis, it did show a strong trend toward reducing hematoma expansion in those with a larger initial hematoma volume.

In 450 patients randomized to receive intensive treatment and 426 randomized to receive standard treatment in the large, international, phase III randomized trial, the proportion of patients with any hematoma expansion was 46.4% and 52.3% , respectively (relative risk, 0.89; 95% confidence interval, 0.73-1.07). The proportion with hematoma expansion with an increase of greater than 33% was 18.9% and 24.4%, respectively (RR, 0.77; 95% CI, 0.58-1.03), Joshua N. Goldstein, MD, reported at the annual meeting of the American Academy of Neurology.

The confidence intervals suggested only a trend toward improvement, as the difference between the groups did not reach statistical significance, he said.

To determine if intensive systolic blood pressure reduction might have more of an impact among higher-risk patients, the investigators conducted a post hoc, secondary analysis in those with relatively larger hematomas. Among patients with an initial hematoma volume of at least 10 mL (at least half of the study population had smaller hematomas), the proportion with any hematoma expansion was 53.8% in the intensive treatment group and 61.3% in the standard treatment group (RR, 0.88; 95% CI, 0.67-1.13), and the proportion of patients with hematoma expansion of greater than 33% was 18% and 27.6%, respectively (RR, 0.67; 95% CI, 0.45-1.00), said Dr. Goldstein of Massachusetts General Hospital, Boston.

In those with an expansion greater than 33% and a hematoma volume of at least 6 cc, the finding was similar.

“The trend looks a little bit more aggressive,” he said, but the 95% confidence interval in those with larger hematomas reached 1.

Study subjects had elevated blood pressure at arrival, a Glasgow coma scale score of at least 5, and a hematoma volume of less than 60 cc. They were enrolled and randomized within 4.5 hours of symptom onset. Those in the intensive treatment group were treated with a goal of achieving between 110 and 139 mm Hg within 24 hours, and those in the standard treatment group were treated with a goal of achieving between 140 mm Hg and 179 mm Hg within 24 hours. They underwent baseline and 24-hour computed tomography scans, which were analyzed centrally by blinded investigators who recorded any increase of 0.5 mL or more, an increase of more than 33% , an increase of more than 33% or more than 6 mL, and an intraventricular hemorrhage volume greater than 2 mL.

These measures were correlated with death and disability, and hematoma enlargement was shown to be significantly associated with those outcomes at 3 months after randomization (RR, 1.59; 95% CI, 1.25-2.02), Dr. Goldstein said.

Previous studies have suggested that intensive lowering of systolic BP in patients with intracerebral hemorrhage can reduce the rate of hematoma expansion. As such, the hypothesis of the current study was that the intensive treatment of elevated blood pressures – arriving systolic blood pressure of greater than 180 mm Hg – would reduce the likelihood of death and disability at 3 months, Dr. Goldstein said,

The question is whether the biomarker – hematoma expansion – is really linked to clinical outcome, he said, “because a lot of our attempts to treat hematoma expansion are based on the assumption that, if we reduce hematoma expansion, we’re going to improve clinical outcomes.”

“In this trial ... the expanders had more death and disability than nonexpanders, and this was statistically significant, so hematoma expansion does seem to be a statistically significant predictor of poor outcome,” he said.

Thus, the strong trend toward a reduced risk of hematoma expansion with intensive blood pressure lowering in patients with larger hematoma volumes at baseline in this analysis is noteworthy, he said.

“It appears that the treatment is affecting the biomarker, that the treatment is affecting hematoma expansion ... and hematoma expansion was a significant predictor of death and disability ... so why didn’t we get the result we wanted from the trial?” he asked.

It may be that a greater magnitude of reduction in the risk of hematoma expansion was necessary, he said.

“In other words, even if our treatment is having an effect, it’s just not having a big enough effect to change outcomes,” he said, adding that future trials probably need to involve a much bigger impact on the risk of expansion to translate to a change in clinical outcomes.”

This study was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Goldstein reported having no disclosures.

[email protected]

BOSTON – Intensive systolic blood pressure reduction did not significantly reduce hematoma expansion, compared with standard systolic blood pressure reduction in the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial, but, in a post hoc analysis, it did show a strong trend toward reducing hematoma expansion in those with a larger initial hematoma volume.

In 450 patients randomized to receive intensive treatment and 426 randomized to receive standard treatment in the large, international, phase III randomized trial, the proportion of patients with any hematoma expansion was 46.4% and 52.3% , respectively (relative risk, 0.89; 95% confidence interval, 0.73-1.07). The proportion with hematoma expansion with an increase of greater than 33% was 18.9% and 24.4%, respectively (RR, 0.77; 95% CI, 0.58-1.03), Joshua N. Goldstein, MD, reported at the annual meeting of the American Academy of Neurology.

The confidence intervals suggested only a trend toward improvement, as the difference between the groups did not reach statistical significance, he said.

To determine if intensive systolic blood pressure reduction might have more of an impact among higher-risk patients, the investigators conducted a post hoc, secondary analysis in those with relatively larger hematomas. Among patients with an initial hematoma volume of at least 10 mL (at least half of the study population had smaller hematomas), the proportion with any hematoma expansion was 53.8% in the intensive treatment group and 61.3% in the standard treatment group (RR, 0.88; 95% CI, 0.67-1.13), and the proportion of patients with hematoma expansion of greater than 33% was 18% and 27.6%, respectively (RR, 0.67; 95% CI, 0.45-1.00), said Dr. Goldstein of Massachusetts General Hospital, Boston.

In those with an expansion greater than 33% and a hematoma volume of at least 6 cc, the finding was similar.

“The trend looks a little bit more aggressive,” he said, but the 95% confidence interval in those with larger hematomas reached 1.

Study subjects had elevated blood pressure at arrival, a Glasgow coma scale score of at least 5, and a hematoma volume of less than 60 cc. They were enrolled and randomized within 4.5 hours of symptom onset. Those in the intensive treatment group were treated with a goal of achieving between 110 and 139 mm Hg within 24 hours, and those in the standard treatment group were treated with a goal of achieving between 140 mm Hg and 179 mm Hg within 24 hours. They underwent baseline and 24-hour computed tomography scans, which were analyzed centrally by blinded investigators who recorded any increase of 0.5 mL or more, an increase of more than 33% , an increase of more than 33% or more than 6 mL, and an intraventricular hemorrhage volume greater than 2 mL.

These measures were correlated with death and disability, and hematoma enlargement was shown to be significantly associated with those outcomes at 3 months after randomization (RR, 1.59; 95% CI, 1.25-2.02), Dr. Goldstein said.

Previous studies have suggested that intensive lowering of systolic BP in patients with intracerebral hemorrhage can reduce the rate of hematoma expansion. As such, the hypothesis of the current study was that the intensive treatment of elevated blood pressures – arriving systolic blood pressure of greater than 180 mm Hg – would reduce the likelihood of death and disability at 3 months, Dr. Goldstein said,

The question is whether the biomarker – hematoma expansion – is really linked to clinical outcome, he said, “because a lot of our attempts to treat hematoma expansion are based on the assumption that, if we reduce hematoma expansion, we’re going to improve clinical outcomes.”

“In this trial ... the expanders had more death and disability than nonexpanders, and this was statistically significant, so hematoma expansion does seem to be a statistically significant predictor of poor outcome,” he said.

Thus, the strong trend toward a reduced risk of hematoma expansion with intensive blood pressure lowering in patients with larger hematoma volumes at baseline in this analysis is noteworthy, he said.

“It appears that the treatment is affecting the biomarker, that the treatment is affecting hematoma expansion ... and hematoma expansion was a significant predictor of death and disability ... so why didn’t we get the result we wanted from the trial?” he asked.

It may be that a greater magnitude of reduction in the risk of hematoma expansion was necessary, he said.

“In other words, even if our treatment is having an effect, it’s just not having a big enough effect to change outcomes,” he said, adding that future trials probably need to involve a much bigger impact on the risk of expansion to translate to a change in clinical outcomes.”

This study was sponsored by the National Institute of Neurological Disorders and Stroke. Dr. Goldstein reported having no disclosures.

[email protected]

Red blood cells

The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).

This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.

APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).

Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.

In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.

In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days. 

Red blood cells

The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).

This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.

APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).

Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.

In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.

In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days. 

Red blood cells

The European Medicines Agency (EMA) has recommended orphan drug designation for the complement C3 inhibitor APL-2 as a treatment for paroxysmal nocturnal hemoglobinuria (PNH).

APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).

This comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH, according to Apellis Pharmaceuticals, Inc., the company developing APL-2.

APL-2 has been evaluated in a pair of phase 1 studies of healthy volunteers. Results from these studies were presented at the 2016 ASH Annual Meeting (abstract 1251).

Now, Apellis is evaluating APL-2 in PNH patients in a pair of phase 1b trials.

In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.

In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.

About orphan designation

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days. 

MONTREAL – Clinicians who manage the care of children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) have to decide whether to treat patients early and possibly increase risk for chronic ITP down the road or to leave well enough alone and treat only as needed.

Evidence from a retrospective study suggests that, for most patients, early treatment of acute ITP does not appear to increase the risk for chronic ITP in the future, reported Chelsea L. Grama, a fourth-year medical student, and her colleagues from Penn State Health Children’s Hospital in Hershey, Pennsylvania.

“It’s controversial whether to treat or not. Some people think steroids are the best way to go, some think IVIG [intravenous immunoglobulin] is the best way to go, and some think that no treatment could be the best option. There is really no consensus in the literature to say what the ideal treatment for ITP is,” she commented in an interview at the annual meeting of the American Society of Pediatric Hematology/Oncology.

That lack of consensus is the result of the fact that serious consequences of ITP, such as intracranial hemorrhage, are rare, making it difficult for investigators to compare clinical outcomes with various forms of treatment. It’s also unclear whether early interventions could lead to later chronic disease.

In hopes of answering this question, Ms. Grama and her coinvestigators, led by Andrew S. Freiberg, MD, took a retrospective look at data on 249 patients with ITP diagnosed from birth through age 21 from 1994 to 2011.

They looked at demographic variables, treatments received, and subsequent platelet counts. Outcomes included intracranial hemorrhage and long-term improvements in platelet counts. They defined chronic ITP as a platelet count below 140,000/mcL for at least 6 months following diagnosis.

Of the 249 patients, 126 (66 boys and 60 girls) progressed to chronic ITP. The incidence of chronic ITP among treated patients was 51.1% and, in untreated patients, 49.3%.

However, in two subgroups, there was a significant association between treatment and chronic ITP. Among girls from birth through age 3 years, 58% of those treated went on to chronic ITP, compared with 0% for untreated patients (P = .008). When the age cohort was expanded to girls younger than 6 years, a similar pattern emerged, with chronic ITP rates of 45% for treated patients, compared with 0% for untreated patients. There were only 44 total patients in this age and sex subgroup, however, making it difficult to draw strong inferences about a potential relationship between treatment and chronic ITP, Ms. Grama noted.

Only three patients had cerebral hemorrhage. Two had hemorrhage as their initial ITP presentation, and the third had bleeding despite being on treatment. The sample size was too small to correlate the outcome with treatment, the authors noted.

In multivariate analysis controlling for demographic, clinical, and treatment factors, only age and platelet count at presentation independently predicted chronic thrombocytopenia (P less than .0001 for each). Steroid therapy was the only independent predictor for acute ITP (P = .0001).

Although their data suggest that there could be a benefit to treating patients who first present with acute ITP at age 12 years or older, “I do think it’s reasonable to wait and watch these patients,” Ms. Grama said.

“The incidence of brain bleeds, which is the really scary complication, was so low in these patients that I think watchful waiting would be a better way to go, just monitoring patients very closely. Hopefully, they will resolve without having treatment,” she added.

The study was internally supported. The authors reported no relevant disclosures.

MONTREAL – Clinicians who manage the care of children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) have to decide whether to treat patients early and possibly increase risk for chronic ITP down the road or to leave well enough alone and treat only as needed.

Evidence from a retrospective study suggests that, for most patients, early treatment of acute ITP does not appear to increase the risk for chronic ITP in the future, reported Chelsea L. Grama, a fourth-year medical student, and her colleagues from Penn State Health Children’s Hospital in Hershey, Pennsylvania.

“It’s controversial whether to treat or not. Some people think steroids are the best way to go, some think IVIG [intravenous immunoglobulin] is the best way to go, and some think that no treatment could be the best option. There is really no consensus in the literature to say what the ideal treatment for ITP is,” she commented in an interview at the annual meeting of the American Society of Pediatric Hematology/Oncology.

That lack of consensus is the result of the fact that serious consequences of ITP, such as intracranial hemorrhage, are rare, making it difficult for investigators to compare clinical outcomes with various forms of treatment. It’s also unclear whether early interventions could lead to later chronic disease.

In hopes of answering this question, Ms. Grama and her coinvestigators, led by Andrew S. Freiberg, MD, took a retrospective look at data on 249 patients with ITP diagnosed from birth through age 21 from 1994 to 2011.

They looked at demographic variables, treatments received, and subsequent platelet counts. Outcomes included intracranial hemorrhage and long-term improvements in platelet counts. They defined chronic ITP as a platelet count below 140,000/mcL for at least 6 months following diagnosis.

Of the 249 patients, 126 (66 boys and 60 girls) progressed to chronic ITP. The incidence of chronic ITP among treated patients was 51.1% and, in untreated patients, 49.3%.

However, in two subgroups, there was a significant association between treatment and chronic ITP. Among girls from birth through age 3 years, 58% of those treated went on to chronic ITP, compared with 0% for untreated patients (P = .008). When the age cohort was expanded to girls younger than 6 years, a similar pattern emerged, with chronic ITP rates of 45% for treated patients, compared with 0% for untreated patients. There were only 44 total patients in this age and sex subgroup, however, making it difficult to draw strong inferences about a potential relationship between treatment and chronic ITP, Ms. Grama noted.

Only three patients had cerebral hemorrhage. Two had hemorrhage as their initial ITP presentation, and the third had bleeding despite being on treatment. The sample size was too small to correlate the outcome with treatment, the authors noted.

In multivariate analysis controlling for demographic, clinical, and treatment factors, only age and platelet count at presentation independently predicted chronic thrombocytopenia (P less than .0001 for each). Steroid therapy was the only independent predictor for acute ITP (P = .0001).

Although their data suggest that there could be a benefit to treating patients who first present with acute ITP at age 12 years or older, “I do think it’s reasonable to wait and watch these patients,” Ms. Grama said.

“The incidence of brain bleeds, which is the really scary complication, was so low in these patients that I think watchful waiting would be a better way to go, just monitoring patients very closely. Hopefully, they will resolve without having treatment,” she added.

The study was internally supported. The authors reported no relevant disclosures.

MONTREAL – Clinicians who manage the care of children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) have to decide whether to treat patients early and possibly increase risk for chronic ITP down the road or to leave well enough alone and treat only as needed.

Evidence from a retrospective study suggests that, for most patients, early treatment of acute ITP does not appear to increase the risk for chronic ITP in the future, reported Chelsea L. Grama, a fourth-year medical student, and her colleagues from Penn State Health Children’s Hospital in Hershey, Pennsylvania.

“It’s controversial whether to treat or not. Some people think steroids are the best way to go, some think IVIG [intravenous immunoglobulin] is the best way to go, and some think that no treatment could be the best option. There is really no consensus in the literature to say what the ideal treatment for ITP is,” she commented in an interview at the annual meeting of the American Society of Pediatric Hematology/Oncology.

That lack of consensus is the result of the fact that serious consequences of ITP, such as intracranial hemorrhage, are rare, making it difficult for investigators to compare clinical outcomes with various forms of treatment. It’s also unclear whether early interventions could lead to later chronic disease.

In hopes of answering this question, Ms. Grama and her coinvestigators, led by Andrew S. Freiberg, MD, took a retrospective look at data on 249 patients with ITP diagnosed from birth through age 21 from 1994 to 2011.

They looked at demographic variables, treatments received, and subsequent platelet counts. Outcomes included intracranial hemorrhage and long-term improvements in platelet counts. They defined chronic ITP as a platelet count below 140,000/mcL for at least 6 months following diagnosis.

Of the 249 patients, 126 (66 boys and 60 girls) progressed to chronic ITP. The incidence of chronic ITP among treated patients was 51.1% and, in untreated patients, 49.3%.

However, in two subgroups, there was a significant association between treatment and chronic ITP. Among girls from birth through age 3 years, 58% of those treated went on to chronic ITP, compared with 0% for untreated patients (P = .008). When the age cohort was expanded to girls younger than 6 years, a similar pattern emerged, with chronic ITP rates of 45% for treated patients, compared with 0% for untreated patients. There were only 44 total patients in this age and sex subgroup, however, making it difficult to draw strong inferences about a potential relationship between treatment and chronic ITP, Ms. Grama noted.

Only three patients had cerebral hemorrhage. Two had hemorrhage as their initial ITP presentation, and the third had bleeding despite being on treatment. The sample size was too small to correlate the outcome with treatment, the authors noted.

In multivariate analysis controlling for demographic, clinical, and treatment factors, only age and platelet count at presentation independently predicted chronic thrombocytopenia (P less than .0001 for each). Steroid therapy was the only independent predictor for acute ITP (P = .0001).

Although their data suggest that there could be a benefit to treating patients who first present with acute ITP at age 12 years or older, “I do think it’s reasonable to wait and watch these patients,” Ms. Grama said.

“The incidence of brain bleeds, which is the really scary complication, was so low in these patients that I think watchful waiting would be a better way to go, just monitoring patients very closely. Hopefully, they will resolve without having treatment,” she added.

The study was internally supported. The authors reported no relevant disclosures.

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

[email protected]

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

[email protected]

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

[email protected]

The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.

Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.

The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.

[email protected]

The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.

Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.

The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.

[email protected]

The Food and Drug Administration’s 2007 “boxed warning” about serious adverse events associated with the use of erythropoietin-stimulating agents (ESAs) was followed by a substantial reduction in their use among patients recovering from colorectal, breast, or lung cancer, according to a new report.

Boxed warnings are considered one of the strongest mechanisms with which the FDA can communicate concerns about drug safety to the public. However, some critics have questioned the effectiveness of these warnings, and the available evidence “remains inconclusive, largely because almost all of [the data] were drawn from observational studies using pre-post designs without control groups,” said John Bian, PhD, of the University of South Carolina College of Pharmacy and Hollings Cancer Center, Columbia, and his associates.

The study was supported by the National Institutes of Health. Dr. Bian reported having no relevant financial disclosures. His associates reported ties to Quincy Bioscience, Bristol-Myers Squibb, Taiho Pharmaceutical, Mylan, Eli Lilly, Merck, Amgen, and BDI Pharma.

[email protected]

The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation, according to a report published online April 24 in JAMA Internal Medicine.

A recent observational Canadian study suggested that blood from young donors and female donors increased the recipients’ risk of death – a finding which, if confirmed, would have immediate implications for medical practice.

A separate group of Scandinavian researchers attempted to replicate these findings by performing a retrospective cohort study using similar but more nuanced statistical methods. Gustaf Edgren, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates analyzed information collected on 968,264 patients over a 10-year period from a Swedish and Danish transfusion database.

In initial, unadjusted analyses, both extremes of age (young and old) and female sex in the donor were associated with reduced survival in the recipient. However, that association disappeared when the data were adjusted to account for the total number of transfusions a patient received, a marker of their severity of illness. The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99. This pattern also occurred in sensitivity analyses, the investigators noted (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0890).

“When studying associations between ... transfusions with a particular characteristic and the risk of death in the recipient, [the] underlying disease severity ... may still confound the association. However, with meticulous adjustment for total number of transfusions, it should be possible to block the confounding effect of patient disease severity entirely,” they noted.

“We believe that, rather than reflecting true biologic effects, the Canadian results can be explained by residual confounding (i.e., that the observations resulted from incomplete adjustment for the number of transfusions),” Dr. Edgren and his associates said.

“In addition, we believe these data reinforce the importance of extreme caution in assessing epidemiologic analyses in this field, given the tremendous clinical and logistical implications of false-positive findings,” they added.

The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation, according to a report published online April 24 in JAMA Internal Medicine.

A recent observational Canadian study suggested that blood from young donors and female donors increased the recipients’ risk of death – a finding which, if confirmed, would have immediate implications for medical practice.

A separate group of Scandinavian researchers attempted to replicate these findings by performing a retrospective cohort study using similar but more nuanced statistical methods. Gustaf Edgren, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates analyzed information collected on 968,264 patients over a 10-year period from a Swedish and Danish transfusion database.

In initial, unadjusted analyses, both extremes of age (young and old) and female sex in the donor were associated with reduced survival in the recipient. However, that association disappeared when the data were adjusted to account for the total number of transfusions a patient received, a marker of their severity of illness. The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99. This pattern also occurred in sensitivity analyses, the investigators noted (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0890).

“When studying associations between ... transfusions with a particular characteristic and the risk of death in the recipient, [the] underlying disease severity ... may still confound the association. However, with meticulous adjustment for total number of transfusions, it should be possible to block the confounding effect of patient disease severity entirely,” they noted.

“We believe that, rather than reflecting true biologic effects, the Canadian results can be explained by residual confounding (i.e., that the observations resulted from incomplete adjustment for the number of transfusions),” Dr. Edgren and his associates said.

“In addition, we believe these data reinforce the importance of extreme caution in assessing epidemiologic analyses in this field, given the tremendous clinical and logistical implications of false-positive findings,” they added.

The age and sex of blood donors do not affect the recipient’s survival and do not need to be considered in blood allocation, according to a report published online April 24 in JAMA Internal Medicine.

A recent observational Canadian study suggested that blood from young donors and female donors increased the recipients’ risk of death – a finding which, if confirmed, would have immediate implications for medical practice.

A separate group of Scandinavian researchers attempted to replicate these findings by performing a retrospective cohort study using similar but more nuanced statistical methods. Gustaf Edgren, MD, PhD, of the department of medical epidemiology and biostatistics, Karolinska Institutet, Stockholm, and his associates analyzed information collected on 968,264 patients over a 10-year period from a Swedish and Danish transfusion database.

In initial, unadjusted analyses, both extremes of age (young and old) and female sex in the donor were associated with reduced survival in the recipient. However, that association disappeared when the data were adjusted to account for the total number of transfusions a patient received, a marker of their severity of illness. The hazard ratio per transfusion from a donor younger than age 20 was 0.98, and the hazard ratio per transfusion from a female donor was 0.99. This pattern also occurred in sensitivity analyses, the investigators noted (JAMA Intern. Med. 2017 April 24. doi: 10.1001/jamainternmed.2017.0890).

“When studying associations between ... transfusions with a particular characteristic and the risk of death in the recipient, [the] underlying disease severity ... may still confound the association. However, with meticulous adjustment for total number of transfusions, it should be possible to block the confounding effect of patient disease severity entirely,” they noted.

“We believe that, rather than reflecting true biologic effects, the Canadian results can be explained by residual confounding (i.e., that the observations resulted from incomplete adjustment for the number of transfusions),” Dr. Edgren and his associates said.

“In addition, we believe these data reinforce the importance of extreme caution in assessing epidemiologic analyses in this field, given the tremendous clinical and logistical implications of false-positive findings,” they added.

The Food and Drug Administration recently authorized 23andMe to provide consumers with results of germline DNA sequence variants associated with risk for 10 health conditions, among them hereditary hemochromatosis, alpha-1 antitrypsin deficiency, celiac disease, Alzheimer’s disease, and Parkinson’s disease. After they submit a saliva sample and pay a test fee, customers ordering the online test will receive a report delineating their ancestry markers and informing them whether they carry any of the genetic variants associated with selected health risks included on the targeted DNA sequencing panel.

Dr. Stoffel is a gastroenterologist, assistant professor of internal medicine, and director of the cancer genetics clinic at the University of Michigan, Ann Arbor. She has no disclosures.

The Food and Drug Administration recently authorized 23andMe to provide consumers with results of germline DNA sequence variants associated with risk for 10 health conditions, among them hereditary hemochromatosis, alpha-1 antitrypsin deficiency, celiac disease, Alzheimer’s disease, and Parkinson’s disease. After they submit a saliva sample and pay a test fee, customers ordering the online test will receive a report delineating their ancestry markers and informing them whether they carry any of the genetic variants associated with selected health risks included on the targeted DNA sequencing panel.

Dr. Stoffel is a gastroenterologist, assistant professor of internal medicine, and director of the cancer genetics clinic at the University of Michigan, Ann Arbor. She has no disclosures.

The Food and Drug Administration recently authorized 23andMe to provide consumers with results of germline DNA sequence variants associated with risk for 10 health conditions, among them hereditary hemochromatosis, alpha-1 antitrypsin deficiency, celiac disease, Alzheimer’s disease, and Parkinson’s disease. After they submit a saliva sample and pay a test fee, customers ordering the online test will receive a report delineating their ancestry markers and informing them whether they carry any of the genetic variants associated with selected health risks included on the targeted DNA sequencing panel.

Dr. Stoffel is a gastroenterologist, assistant professor of internal medicine, and director of the cancer genetics clinic at the University of Michigan, Ann Arbor. She has no disclosures.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

Researchers have developed and validated a new diagnostic tool – the PLASMIC score – that rapidly predicts severe ADAMTS13 deficiency in patients who present with thrombotic microangiopathy, effectively distinguishing those who have thrombotic thrombocytopenic purpura (TTP) from those with other disorders, according to a report published in Lancet Haematology.

Many disorders or clinical events can present as a thrombotic microangiopathy, including hemolytic uremic syndrome, disseminated intravascular coagulation, and malignant hypertension; this abnormality can even be an adverse effect of hematopoietic stem cell transplantation or solid-organ transplantation. Rapidly differentiating TTP from such disorders facilitates urgent treatment with plasma exchange or plasma transfusion. But testing for elevated ADAMTS13 levels to make this distinction currently requires long turnaround times and is unavailable in some locations, said Pavan K. Bendapudi, MD, of the division of hematology, Massachusetts General Hospital, Boston, and his associates.

The PLASMIC score “is designed specifically to aid practitioners who might have little experience managing thrombotic microangiopathy, and it can distinguish TTP from a broad range of thrombotic microangiopathy subtypes, including those that seem most similar to TTP,” they wrote.

The researchers developed a 7-point scoring system to predict the likelihood of elevated ADAMTS13 levels by analyzing 29 clinical and laboratory variables that would aid in diagnosis, using a cohort of 214 consecutive patients enrolled in a multicenter research registry in 2004-2012. They narrowed their initial finding of 11 key variables down to 5 key variables that best predicted severe ADAMTSD13 deficiency: platelet count lower than 29x10⁹ per liter, creatinine less than 1.8 mg/dL, international normalized ratio (INR) less than 1.3, mean corpuscular volume (MCV) less than 86.5/L, and a combined hemolysis variable based on reticulocyte count, the presence of haptoglobin, and bilirubin level.

Two additional variables – cancer diagnosed during the preceding year and the absence of stem cell or organ transplantation – were absent in all patients who had severe ADAMTS13 deficiency in this derivation cohort and were included in the PLASMIC score because of their high negative predictive value. Thus, the diagnostic score was named for its seven components: platelet count, combined hemolysis variable, absence of active cancer; absence of stem cell or solid-organ transplant, MCV, INR, and creatinine. Each component was assigned 1 point on the 7-point scale.

None of the 84 patients in this derivation cohort with a PLASMIC score of 0-4 had severe ADAMTS13 deficiency, while 81% of those with a score of 6 or 7 did have a severe ADAMTS13 deficiency. Patients who were eventually diagnosed as having TTP had a median score of 7. In contrast, patients with thrombotic microangiopathy traced to rheumatologic disorders had a median score of 5, those with drug-associated thrombotic microangiopathy had a median score of 4, and those with disseminated intravascular coagulation had a median score of 4. The PLASMIC score also appeared to discriminate among TTP, typical hemolytic uremia syndrome, and atypical hemolytic uremia syndrome, which have “strikingly similar clinical presentations,” Dr. Bendapudi and his associates said.

Unlike TTP, the disorders with lower PLASMIC scores tended to carry a much poorer prognosis. In this cohort, patients with higher PLASMIC scores had significantly better survival time (median survival not yet reached), compared with those who had a score of 5 (median survival, 1,670 days) and those with a score of 1-4 (median survival, 287 days).

The investigators then validated their findings in two independent cohorts: 154 people with thrombotic microangiopathy from the same patient registry but from more recent years (2012-2015), and 152 patients from an Alabama registry. In the first validation cohort, none of the 89 patients assigned a score of 0-4 had severe ADAMTS13 deficiency, while 62% of those given a score of 6 or 7 had a severe deficiency. In the second validation cohort, only two patients (4%) with scores of 0-4 had a severe ADAMTS13 deficiency, while 82% of those with a score of 6 or 7 had a severe deficiency.

Based on these findings, a PLASMIC score of 0-4 denotes low risk for ADAMTS13 deficiency, a score of 5 denotes intermediate risk, and a score of 6 or 7 denotes high risk and thus probable TTP, Dr. Bendapudi and his associates said (Lancet Haematol. 2017;4:e157-64).

The PLASMIC score was superior to both a two-component prediction tool currently used in France and to a clinical consensus score, “further demonstrating the real-world utility of our prediction tool,” the researchers wrote.

Researchers have developed and validated a new diagnostic tool – the PLASMIC score – that rapidly predicts severe ADAMTS13 deficiency in patients who present with thrombotic microangiopathy, effectively distinguishing those who have thrombotic thrombocytopenic purpura (TTP) from those with other disorders, according to a report published in Lancet Haematology.

Many disorders or clinical events can present as a thrombotic microangiopathy, including hemolytic uremic syndrome, disseminated intravascular coagulation, and malignant hypertension; this abnormality can even be an adverse effect of hematopoietic stem cell transplantation or solid-organ transplantation. Rapidly differentiating TTP from such disorders facilitates urgent treatment with plasma exchange or plasma transfusion. But testing for elevated ADAMTS13 levels to make this distinction currently requires long turnaround times and is unavailable in some locations, said Pavan K. Bendapudi, MD, of the division of hematology, Massachusetts General Hospital, Boston, and his associates.

The PLASMIC score “is designed specifically to aid practitioners who might have little experience managing thrombotic microangiopathy, and it can distinguish TTP from a broad range of thrombotic microangiopathy subtypes, including those that seem most similar to TTP,” they wrote.

The researchers developed a 7-point scoring system to predict the likelihood of elevated ADAMTS13 levels by analyzing 29 clinical and laboratory variables that would aid in diagnosis, using a cohort of 214 consecutive patients enrolled in a multicenter research registry in 2004-2012. They narrowed their initial finding of 11 key variables down to 5 key variables that best predicted severe ADAMTSD13 deficiency: platelet count lower than 29x10⁹ per liter, creatinine less than 1.8 mg/dL, international normalized ratio (INR) less than 1.3, mean corpuscular volume (MCV) less than 86.5/L, and a combined hemolysis variable based on reticulocyte count, the presence of haptoglobin, and bilirubin level.

Two additional variables – cancer diagnosed during the preceding year and the absence of stem cell or organ transplantation – were absent in all patients who had severe ADAMTS13 deficiency in this derivation cohort and were included in the PLASMIC score because of their high negative predictive value. Thus, the diagnostic score was named for its seven components: platelet count, combined hemolysis variable, absence of active cancer; absence of stem cell or solid-organ transplant, MCV, INR, and creatinine. Each component was assigned 1 point on the 7-point scale.

None of the 84 patients in this derivation cohort with a PLASMIC score of 0-4 had severe ADAMTS13 deficiency, while 81% of those with a score of 6 or 7 did have a severe ADAMTS13 deficiency. Patients who were eventually diagnosed as having TTP had a median score of 7. In contrast, patients with thrombotic microangiopathy traced to rheumatologic disorders had a median score of 5, those with drug-associated thrombotic microangiopathy had a median score of 4, and those with disseminated intravascular coagulation had a median score of 4. The PLASMIC score also appeared to discriminate among TTP, typical hemolytic uremia syndrome, and atypical hemolytic uremia syndrome, which have “strikingly similar clinical presentations,” Dr. Bendapudi and his associates said.

Unlike TTP, the disorders with lower PLASMIC scores tended to carry a much poorer prognosis. In this cohort, patients with higher PLASMIC scores had significantly better survival time (median survival not yet reached), compared with those who had a score of 5 (median survival, 1,670 days) and those with a score of 1-4 (median survival, 287 days).

The investigators then validated their findings in two independent cohorts: 154 people with thrombotic microangiopathy from the same patient registry but from more recent years (2012-2015), and 152 patients from an Alabama registry. In the first validation cohort, none of the 89 patients assigned a score of 0-4 had severe ADAMTS13 deficiency, while 62% of those given a score of 6 or 7 had a severe deficiency. In the second validation cohort, only two patients (4%) with scores of 0-4 had a severe ADAMTS13 deficiency, while 82% of those with a score of 6 or 7 had a severe deficiency.

Based on these findings, a PLASMIC score of 0-4 denotes low risk for ADAMTS13 deficiency, a score of 5 denotes intermediate risk, and a score of 6 or 7 denotes high risk and thus probable TTP, Dr. Bendapudi and his associates said (Lancet Haematol. 2017;4:e157-64).

The PLASMIC score was superior to both a two-component prediction tool currently used in France and to a clinical consensus score, “further demonstrating the real-world utility of our prediction tool,” the researchers wrote.

Researchers have developed and validated a new diagnostic tool – the PLASMIC score – that rapidly predicts severe ADAMTS13 deficiency in patients who present with thrombotic microangiopathy, effectively distinguishing those who have thrombotic thrombocytopenic purpura (TTP) from those with other disorders, according to a report published in Lancet Haematology.

Many disorders or clinical events can present as a thrombotic microangiopathy, including hemolytic uremic syndrome, disseminated intravascular coagulation, and malignant hypertension; this abnormality can even be an adverse effect of hematopoietic stem cell transplantation or solid-organ transplantation. Rapidly differentiating TTP from such disorders facilitates urgent treatment with plasma exchange or plasma transfusion. But testing for elevated ADAMTS13 levels to make this distinction currently requires long turnaround times and is unavailable in some locations, said Pavan K. Bendapudi, MD, of the division of hematology, Massachusetts General Hospital, Boston, and his associates.

The PLASMIC score “is designed specifically to aid practitioners who might have little experience managing thrombotic microangiopathy, and it can distinguish TTP from a broad range of thrombotic microangiopathy subtypes, including those that seem most similar to TTP,” they wrote.

The researchers developed a 7-point scoring system to predict the likelihood of elevated ADAMTS13 levels by analyzing 29 clinical and laboratory variables that would aid in diagnosis, using a cohort of 214 consecutive patients enrolled in a multicenter research registry in 2004-2012. They narrowed their initial finding of 11 key variables down to 5 key variables that best predicted severe ADAMTSD13 deficiency: platelet count lower than 29x10⁹ per liter, creatinine less than 1.8 mg/dL, international normalized ratio (INR) less than 1.3, mean corpuscular volume (MCV) less than 86.5/L, and a combined hemolysis variable based on reticulocyte count, the presence of haptoglobin, and bilirubin level.

Two additional variables – cancer diagnosed during the preceding year and the absence of stem cell or organ transplantation – were absent in all patients who had severe ADAMTS13 deficiency in this derivation cohort and were included in the PLASMIC score because of their high negative predictive value. Thus, the diagnostic score was named for its seven components: platelet count, combined hemolysis variable, absence of active cancer; absence of stem cell or solid-organ transplant, MCV, INR, and creatinine. Each component was assigned 1 point on the 7-point scale.

None of the 84 patients in this derivation cohort with a PLASMIC score of 0-4 had severe ADAMTS13 deficiency, while 81% of those with a score of 6 or 7 did have a severe ADAMTS13 deficiency. Patients who were eventually diagnosed as having TTP had a median score of 7. In contrast, patients with thrombotic microangiopathy traced to rheumatologic disorders had a median score of 5, those with drug-associated thrombotic microangiopathy had a median score of 4, and those with disseminated intravascular coagulation had a median score of 4. The PLASMIC score also appeared to discriminate among TTP, typical hemolytic uremia syndrome, and atypical hemolytic uremia syndrome, which have “strikingly similar clinical presentations,” Dr. Bendapudi and his associates said.

Unlike TTP, the disorders with lower PLASMIC scores tended to carry a much poorer prognosis. In this cohort, patients with higher PLASMIC scores had significantly better survival time (median survival not yet reached), compared with those who had a score of 5 (median survival, 1,670 days) and those with a score of 1-4 (median survival, 287 days).

The investigators then validated their findings in two independent cohorts: 154 people with thrombotic microangiopathy from the same patient registry but from more recent years (2012-2015), and 152 patients from an Alabama registry. In the first validation cohort, none of the 89 patients assigned a score of 0-4 had severe ADAMTS13 deficiency, while 62% of those given a score of 6 or 7 had a severe deficiency. In the second validation cohort, only two patients (4%) with scores of 0-4 had a severe ADAMTS13 deficiency, while 82% of those with a score of 6 or 7 had a severe deficiency.

Based on these findings, a PLASMIC score of 0-4 denotes low risk for ADAMTS13 deficiency, a score of 5 denotes intermediate risk, and a score of 6 or 7 denotes high risk and thus probable TTP, Dr. Bendapudi and his associates said (Lancet Haematol. 2017;4:e157-64).

The PLASMIC score was superior to both a two-component prediction tool currently used in France and to a clinical consensus score, “further demonstrating the real-world utility of our prediction tool,” the researchers wrote.