Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Serum levels of both albumin and creatinine proved to be independent biomarkers of disease severity in men and women with amyotrophic lateral sclerosis, with lower levels denoting more serious disease and a shorter survival time, according to a report published online July 21 in JAMA Neurology.

To identify any potential correlations between hematologic biomarkers and ALS severity, researchers analyzed data concerning 638 patients from a regional registry of people diagnosed during 2007-2011 in the Piemonte and Valle d’Aosta areas of Italy. The 352 men and 286 women underwent complete physical examinations at the time of diagnosis, which included tests for 17 serum biomarkers. The only two serum biomarkers found to correlate with ALS severity were albumin level, which reflected inflammation, and creatinine, which reflected muscle wasting, said Dr. Adriano Chio, professor of neuroscience, University of Torino, Turin, Italy, and his associates.

Both biomarkers showed an inverse dose-response relationship with clinical function at diagnosis in men and women. Both had sensitivity and specificity values at predicting 1-year mortality that were similar to those of "the best established prognostic factors" for ALS, such as forced vital capacity, age, and scores on the ALS Functional Rating Scale-Revised, the investigators said (JAMA Neurol. 2014 July 21 [doi:10.1001/jamaneurol.2014.1129]).

Dr. Chio and his colleagues performed a validation study in a cohort of 122 patients (54 men, 68 women) at all stages of ALS who were treated at an ALS tertiary care center in another area of Italy. This study confirmed the findings from the discovery cohort. "Both creatinine and albumin are reliable and easily detectable blood markers of the severity of motor dysfunction in ALS and could be used in defining patients’ prognosis at the time of diagnosis," they said.

This study was supported by the Italian Ministry of Health and the European Community’s Health Seventh Framework Programme. Dr. Chio reported serving on scientific advisory board for Biogen Idec and Cytokinetics

Serum levels of both albumin and creatinine proved to be independent biomarkers of disease severity in men and women with amyotrophic lateral sclerosis, with lower levels denoting more serious disease and a shorter survival time, according to a report published online July 21 in JAMA Neurology.

To identify any potential correlations between hematologic biomarkers and ALS severity, researchers analyzed data concerning 638 patients from a regional registry of people diagnosed during 2007-2011 in the Piemonte and Valle d’Aosta areas of Italy. The 352 men and 286 women underwent complete physical examinations at the time of diagnosis, which included tests for 17 serum biomarkers. The only two serum biomarkers found to correlate with ALS severity were albumin level, which reflected inflammation, and creatinine, which reflected muscle wasting, said Dr. Adriano Chio, professor of neuroscience, University of Torino, Turin, Italy, and his associates.

Both biomarkers showed an inverse dose-response relationship with clinical function at diagnosis in men and women. Both had sensitivity and specificity values at predicting 1-year mortality that were similar to those of "the best established prognostic factors" for ALS, such as forced vital capacity, age, and scores on the ALS Functional Rating Scale-Revised, the investigators said (JAMA Neurol. 2014 July 21 [doi:10.1001/jamaneurol.2014.1129]).

Dr. Chio and his colleagues performed a validation study in a cohort of 122 patients (54 men, 68 women) at all stages of ALS who were treated at an ALS tertiary care center in another area of Italy. This study confirmed the findings from the discovery cohort. "Both creatinine and albumin are reliable and easily detectable blood markers of the severity of motor dysfunction in ALS and could be used in defining patients’ prognosis at the time of diagnosis," they said.

This study was supported by the Italian Ministry of Health and the European Community’s Health Seventh Framework Programme. Dr. Chio reported serving on scientific advisory board for Biogen Idec and Cytokinetics

Serum levels of both albumin and creatinine proved to be independent biomarkers of disease severity in men and women with amyotrophic lateral sclerosis, with lower levels denoting more serious disease and a shorter survival time, according to a report published online July 21 in JAMA Neurology.

To identify any potential correlations between hematologic biomarkers and ALS severity, researchers analyzed data concerning 638 patients from a regional registry of people diagnosed during 2007-2011 in the Piemonte and Valle d’Aosta areas of Italy. The 352 men and 286 women underwent complete physical examinations at the time of diagnosis, which included tests for 17 serum biomarkers. The only two serum biomarkers found to correlate with ALS severity were albumin level, which reflected inflammation, and creatinine, which reflected muscle wasting, said Dr. Adriano Chio, professor of neuroscience, University of Torino, Turin, Italy, and his associates.

Both biomarkers showed an inverse dose-response relationship with clinical function at diagnosis in men and women. Both had sensitivity and specificity values at predicting 1-year mortality that were similar to those of "the best established prognostic factors" for ALS, such as forced vital capacity, age, and scores on the ALS Functional Rating Scale-Revised, the investigators said (JAMA Neurol. 2014 July 21 [doi:10.1001/jamaneurol.2014.1129]).

Dr. Chio and his colleagues performed a validation study in a cohort of 122 patients (54 men, 68 women) at all stages of ALS who were treated at an ALS tertiary care center in another area of Italy. This study confirmed the findings from the discovery cohort. "Both creatinine and albumin are reliable and easily detectable blood markers of the severity of motor dysfunction in ALS and could be used in defining patients’ prognosis at the time of diagnosis," they said.

This study was supported by the Italian Ministry of Health and the European Community’s Health Seventh Framework Programme. Dr. Chio reported serving on scientific advisory board for Biogen Idec and Cytokinetics

MILAN – The investigational Bcl-2 inhibitor ABT-199 continues to impress with substantial activity as single-agent or combination therapy in relapsed or refractory chronic lymphocytic leukemia, following dose-scheduling modifications to address the risk of tumor lysis syndrome.

ABT-199 monotherapy

Updated data from all 105 CLL patients in the phase I trial show the overall response rate remains high at 77%, with 23% of patients achieving complete remission.

Seven of 11 complete responders assessed had no detectable minimal residual disease, Dr. John F. Seymour said at the annual congress of the European Hematology Association.

Overall response rates were sustained in the 75%-80% range for high-risk patients with deletion 17p, fludarabine-refractory, or immunoglobulin heavy-chain variable (IGHV)-unmutated CLL; and complete response rates in these subgroups also did not differ from the overall group at 22% to 29%.

Prior results from the first-in-human trial dazzled the leukemia community, but tumor lysis syndrome (TLS) complications, including two fatal events, temporarily halted ABT-199 clinical trials and gave the advantage to its closest competitor, the recently approved and more tolerable CLL drug ibrutinib (Imbruvica).

Use of a modified, ramp-up dosing scheme and aggressive TLS prophylaxis appear to have ameliorated the risk of TLS, with no further clinically significant or grade 3 or 4 events reported in the 49 patients treated with this schema, said Dr. Seymour, director of hematology and cancer medicine at the Peter MacCallum Cancer Centre, East Melbourne, Australia.

Rather than using a 3-week schedule and 50-mg starting dose, the safety expansion cohort received once-daily oral ABT-199 beginning at 20 mg, with weekly adjustments to 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks.

The 400-mg dose has been identified as the phase II dose, with 59% of patients free of progression at 18 months and beyond on this dose, he said.

As of April 2014, 37 of the 105 patients discontinued treatment, 22 due to progressive disease and 12 for adverse events; in addition, two proceeded to allogeneic hematopoietic cell transplantation, and one needed Coumadin, which is not permitted on protocol.

The median duration of response has not yet been reached for patients treated at doses of 400 mg or above, he said.

The most common treatment-emergent adverse events of any grade were diarrhea (40% of patients), neutropenia (36%), and nausea (35%).

Neutropenia was the only grade 3/4 event occurring in more than 10% of patients (33%), followed by anemia in 10%.

Combination ABT-199

Of substantial interest to many was a second phase Ib study presented in the same session, evaluating the role of ABT-199 with the anti-CD20 antibody rituximab (Rituxan) in relapsed or refractory CLL.

After a median time on study of just 7.5 months, the overall response rate was 84% among 25 evaluable patients, including 9 complete responses (36%) and 12 partial responses (48%), said Dr. Andrew W. Roberts, with the Royal Melbourne (Australia) Hospital and Walter and Eliza Hall Institute of Medical Research.

Six of eight complete responders tested were negative for minimal residual disease by flow cytometry.

Preliminary pharmacokinetic results suggest no apparent effect of rituximab on ABT-199 exposure, he said.

Three patients discontinued ABT-199 after achieving a complete remission, including one with fludarabine-refractory disease, and all remain in complete remission at 8.6, 8.8, and 11.6 months after cessation.

Dose modifications were also made in this study following a fatal TLS event in December 2012 after a first dose of ABT-199 at 50 mg. Under the modified step-up dosing, ABT-199 was started at 20 mg, escalating up to 600 mg daily over 5 weeks, with rituximab 375 mg/m² added on day 1 of week 5 and rituximab 500 mg/m² added on day 1 of months 2-6.

The combination was well tolerated, and no new safety concerns were identified, Dr. Roberts said. The most common grade 3/4 adverse events among 45 patients evaluable for safety were neutropenia in 47%, anemia in 16%, thrombocytopenia in 13%, and febrile neutropenia in 7%. Grade 3/4 neutropenia was more common at 600 mg, with the 400-mg dose selected for the ongoing safety expansion cohort. Two serious TLS events occurred, but both were prior to schedule modifications, he said.

One patient in the combination study and 13 in the monotherapy study received treatment for small lymphocytic lymphoma. Response rates and tolerability were similar between CLL and SLL patients in the monotherapy study, Dr. Roberts said in an interview.

During a press briefing at the meeting, Dr. Seymour said ABT-199 potentially could be combined with ibrutinib and that the combination was very potent in laboratory tests in both CLL and some forms of mantle cell lymphoma. Negotiations with the various companies involved are intricate, but there is agreement and commitment "to begin clinical trials of the combination later this year," he added.

ABT-199 is currently being evaluated in a phase II trial as monotherapy in deletion 17p relapsed CLL, as combination therapy with rituximab versus bendamustine plus rituximab in a phase III trial in relapsed/refractory CLL, and in combination trials with bendamustine/rituximab and obinutuzumab in relapsed/refractory CLL.

AbbVie and Genentech sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.

[email protected]

MILAN – The investigational Bcl-2 inhibitor ABT-199 continues to impress with substantial activity as single-agent or combination therapy in relapsed or refractory chronic lymphocytic leukemia, following dose-scheduling modifications to address the risk of tumor lysis syndrome.

ABT-199 monotherapy

Updated data from all 105 CLL patients in the phase I trial show the overall response rate remains high at 77%, with 23% of patients achieving complete remission.

Seven of 11 complete responders assessed had no detectable minimal residual disease, Dr. John F. Seymour said at the annual congress of the European Hematology Association.

Overall response rates were sustained in the 75%-80% range for high-risk patients with deletion 17p, fludarabine-refractory, or immunoglobulin heavy-chain variable (IGHV)-unmutated CLL; and complete response rates in these subgroups also did not differ from the overall group at 22% to 29%.

Prior results from the first-in-human trial dazzled the leukemia community, but tumor lysis syndrome (TLS) complications, including two fatal events, temporarily halted ABT-199 clinical trials and gave the advantage to its closest competitor, the recently approved and more tolerable CLL drug ibrutinib (Imbruvica).

Use of a modified, ramp-up dosing scheme and aggressive TLS prophylaxis appear to have ameliorated the risk of TLS, with no further clinically significant or grade 3 or 4 events reported in the 49 patients treated with this schema, said Dr. Seymour, director of hematology and cancer medicine at the Peter MacCallum Cancer Centre, East Melbourne, Australia.

Rather than using a 3-week schedule and 50-mg starting dose, the safety expansion cohort received once-daily oral ABT-199 beginning at 20 mg, with weekly adjustments to 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks.

The 400-mg dose has been identified as the phase II dose, with 59% of patients free of progression at 18 months and beyond on this dose, he said.

As of April 2014, 37 of the 105 patients discontinued treatment, 22 due to progressive disease and 12 for adverse events; in addition, two proceeded to allogeneic hematopoietic cell transplantation, and one needed Coumadin, which is not permitted on protocol.

The median duration of response has not yet been reached for patients treated at doses of 400 mg or above, he said.

The most common treatment-emergent adverse events of any grade were diarrhea (40% of patients), neutropenia (36%), and nausea (35%).

Neutropenia was the only grade 3/4 event occurring in more than 10% of patients (33%), followed by anemia in 10%.

Combination ABT-199

Of substantial interest to many was a second phase Ib study presented in the same session, evaluating the role of ABT-199 with the anti-CD20 antibody rituximab (Rituxan) in relapsed or refractory CLL.

After a median time on study of just 7.5 months, the overall response rate was 84% among 25 evaluable patients, including 9 complete responses (36%) and 12 partial responses (48%), said Dr. Andrew W. Roberts, with the Royal Melbourne (Australia) Hospital and Walter and Eliza Hall Institute of Medical Research.

Six of eight complete responders tested were negative for minimal residual disease by flow cytometry.

Preliminary pharmacokinetic results suggest no apparent effect of rituximab on ABT-199 exposure, he said.

Three patients discontinued ABT-199 after achieving a complete remission, including one with fludarabine-refractory disease, and all remain in complete remission at 8.6, 8.8, and 11.6 months after cessation.

Dose modifications were also made in this study following a fatal TLS event in December 2012 after a first dose of ABT-199 at 50 mg. Under the modified step-up dosing, ABT-199 was started at 20 mg, escalating up to 600 mg daily over 5 weeks, with rituximab 375 mg/m² added on day 1 of week 5 and rituximab 500 mg/m² added on day 1 of months 2-6.

The combination was well tolerated, and no new safety concerns were identified, Dr. Roberts said. The most common grade 3/4 adverse events among 45 patients evaluable for safety were neutropenia in 47%, anemia in 16%, thrombocytopenia in 13%, and febrile neutropenia in 7%. Grade 3/4 neutropenia was more common at 600 mg, with the 400-mg dose selected for the ongoing safety expansion cohort. Two serious TLS events occurred, but both were prior to schedule modifications, he said.

One patient in the combination study and 13 in the monotherapy study received treatment for small lymphocytic lymphoma. Response rates and tolerability were similar between CLL and SLL patients in the monotherapy study, Dr. Roberts said in an interview.

During a press briefing at the meeting, Dr. Seymour said ABT-199 potentially could be combined with ibrutinib and that the combination was very potent in laboratory tests in both CLL and some forms of mantle cell lymphoma. Negotiations with the various companies involved are intricate, but there is agreement and commitment "to begin clinical trials of the combination later this year," he added.

ABT-199 is currently being evaluated in a phase II trial as monotherapy in deletion 17p relapsed CLL, as combination therapy with rituximab versus bendamustine plus rituximab in a phase III trial in relapsed/refractory CLL, and in combination trials with bendamustine/rituximab and obinutuzumab in relapsed/refractory CLL.

AbbVie and Genentech sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.

[email protected]

MILAN – The investigational Bcl-2 inhibitor ABT-199 continues to impress with substantial activity as single-agent or combination therapy in relapsed or refractory chronic lymphocytic leukemia, following dose-scheduling modifications to address the risk of tumor lysis syndrome.

ABT-199 monotherapy

Updated data from all 105 CLL patients in the phase I trial show the overall response rate remains high at 77%, with 23% of patients achieving complete remission.

Seven of 11 complete responders assessed had no detectable minimal residual disease, Dr. John F. Seymour said at the annual congress of the European Hematology Association.

Overall response rates were sustained in the 75%-80% range for high-risk patients with deletion 17p, fludarabine-refractory, or immunoglobulin heavy-chain variable (IGHV)-unmutated CLL; and complete response rates in these subgroups also did not differ from the overall group at 22% to 29%.

Prior results from the first-in-human trial dazzled the leukemia community, but tumor lysis syndrome (TLS) complications, including two fatal events, temporarily halted ABT-199 clinical trials and gave the advantage to its closest competitor, the recently approved and more tolerable CLL drug ibrutinib (Imbruvica).

Use of a modified, ramp-up dosing scheme and aggressive TLS prophylaxis appear to have ameliorated the risk of TLS, with no further clinically significant or grade 3 or 4 events reported in the 49 patients treated with this schema, said Dr. Seymour, director of hematology and cancer medicine at the Peter MacCallum Cancer Centre, East Melbourne, Australia.

Rather than using a 3-week schedule and 50-mg starting dose, the safety expansion cohort received once-daily oral ABT-199 beginning at 20 mg, with weekly adjustments to 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks.

The 400-mg dose has been identified as the phase II dose, with 59% of patients free of progression at 18 months and beyond on this dose, he said.

As of April 2014, 37 of the 105 patients discontinued treatment, 22 due to progressive disease and 12 for adverse events; in addition, two proceeded to allogeneic hematopoietic cell transplantation, and one needed Coumadin, which is not permitted on protocol.

The median duration of response has not yet been reached for patients treated at doses of 400 mg or above, he said.

The most common treatment-emergent adverse events of any grade were diarrhea (40% of patients), neutropenia (36%), and nausea (35%).

Neutropenia was the only grade 3/4 event occurring in more than 10% of patients (33%), followed by anemia in 10%.

Combination ABT-199

Of substantial interest to many was a second phase Ib study presented in the same session, evaluating the role of ABT-199 with the anti-CD20 antibody rituximab (Rituxan) in relapsed or refractory CLL.

After a median time on study of just 7.5 months, the overall response rate was 84% among 25 evaluable patients, including 9 complete responses (36%) and 12 partial responses (48%), said Dr. Andrew W. Roberts, with the Royal Melbourne (Australia) Hospital and Walter and Eliza Hall Institute of Medical Research.

Six of eight complete responders tested were negative for minimal residual disease by flow cytometry.

Preliminary pharmacokinetic results suggest no apparent effect of rituximab on ABT-199 exposure, he said.

Three patients discontinued ABT-199 after achieving a complete remission, including one with fludarabine-refractory disease, and all remain in complete remission at 8.6, 8.8, and 11.6 months after cessation.

Dose modifications were also made in this study following a fatal TLS event in December 2012 after a first dose of ABT-199 at 50 mg. Under the modified step-up dosing, ABT-199 was started at 20 mg, escalating up to 600 mg daily over 5 weeks, with rituximab 375 mg/m² added on day 1 of week 5 and rituximab 500 mg/m² added on day 1 of months 2-6.

The combination was well tolerated, and no new safety concerns were identified, Dr. Roberts said. The most common grade 3/4 adverse events among 45 patients evaluable for safety were neutropenia in 47%, anemia in 16%, thrombocytopenia in 13%, and febrile neutropenia in 7%. Grade 3/4 neutropenia was more common at 600 mg, with the 400-mg dose selected for the ongoing safety expansion cohort. Two serious TLS events occurred, but both were prior to schedule modifications, he said.

One patient in the combination study and 13 in the monotherapy study received treatment for small lymphocytic lymphoma. Response rates and tolerability were similar between CLL and SLL patients in the monotherapy study, Dr. Roberts said in an interview.

During a press briefing at the meeting, Dr. Seymour said ABT-199 potentially could be combined with ibrutinib and that the combination was very potent in laboratory tests in both CLL and some forms of mantle cell lymphoma. Negotiations with the various companies involved are intricate, but there is agreement and commitment "to begin clinical trials of the combination later this year," he added.

ABT-199 is currently being evaluated in a phase II trial as monotherapy in deletion 17p relapsed CLL, as combination therapy with rituximab versus bendamustine plus rituximab in a phase III trial in relapsed/refractory CLL, and in combination trials with bendamustine/rituximab and obinutuzumab in relapsed/refractory CLL.

AbbVie and Genentech sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.

[email protected]

HIV budding from a lymphocyte

Credit: CDC

MELBOURNE—Two men with hematologic malignancies who were also HIV-positive appear to be free of the virus after receiving stem cell transplants.

The patients have undetectable levels of HIV and remain free of their cancers—acute myeloid leukemia and non-Hodgkin lymphoma—more than 3 years after their transplants.

Importantly, the patients’ stem cell donors were not homozygous for CCR5-delta 32, a mutation that affords protection against HIV.

The researchers said these results herald a new direction in HIV research and provide hope for HIV-positive patients with leukemia and lymphoma.

The work was presented at the “Towards an HIV Cure Symposium,” which is part of the 20th International AIDS Conference.

Both patients were treated at St Vincent’s Hospital in partnership with the University of New South Wales’s Kirby Institute in Sydney, Australia.

One patient underwent a transplant in 2010 to treat his non-Hodgkin lymphoma, and his donor had 1 copy of CCR5-delta 32.

The second patient underwent a similar procedure for acute myeloid leukemia in 2011, and his donor did not have any copies of CCR5-delta 32.

Nevertheless, both patients were successfully cleared of HIV, although they remain on antiretroviral therapy as a protective measure.

“We’re so pleased that both patients are doing reasonably well years after the treatment for their cancers and remain free of both the original cancer and the HIV virus,” said David Cooper, MBBS, MD, DSc, of the Kirby Institute and St Vincent’s Hospital.

Until now, the only person considered to have cleared HIV is an American man, Timothy Ray Brown, who underwent 2 stem cell transplants in Berlin (in 2007 and 2008).

The cells in his second transplant included both copies of CCR5-delta 32, which affords protection against HIV and is found in less than 1% of the population. The man is no longer on antiretroviral therapy and remains free of HIV.

In Boston, 2 other patients underwent similar transplants in 2012, but the donor cells did not contain CCR5-delta 32. In both cases, HIV returned after antiretroviral treatment was stopped.

“It is very difficult to find a match for bone marrow donors and even more so to find one that affords protective immunity against HIV,” Dr Cooper said.

While his group’s results are a significant development, the researchers stressed that transplants are not a general functional “cure” for the up to 38.8 million people infected with HIV worldwide.

“This is a terrific, unexpected result for people with malignancy and HIV,” said Sam Milliken, MBBS, of St Vincent’s Hospital. “It may well give us a whole new insight into HIV, using the principles of stem cell transplantation.”

“It is important to caution that, at this stage, this form of treatment is far too dangerous for treating patients with HIV alone, but there may be potential for using transplants as an effective treatment modality for HIV down the track.”

The researchers said the 2 Sydney patients will be the subject of investigations to determine where any residual virus might be hiding and how it can be controlled. And the patients’ results point to a new direction for HIV research.

“We still don’t know why these patients have undetectable viral loads,” said Kersten Koelsch, MD, of the Kirby Institute. “One theory is that the induction therapy helps to destroy the cells in which the virus is hiding and that any remaining infected cells are destroyed by the patient’s new immune system.”

“We need more research to establish why and how bone marrow transplantation clears the virus. We also want to explore the predictors of sustained viral clearance and how this might be able to be exploited without the need for bone marrow transplantation.”

For the time being, the results mean that more patients who are eligible for transplant might be able to participate in clinical trials to determine the value of this procedure in HIV.

HIV budding from a lymphocyte

Credit: CDC

MELBOURNE—Two men with hematologic malignancies who were also HIV-positive appear to be free of the virus after receiving stem cell transplants.

The patients have undetectable levels of HIV and remain free of their cancers—acute myeloid leukemia and non-Hodgkin lymphoma—more than 3 years after their transplants.

Importantly, the patients’ stem cell donors were not homozygous for CCR5-delta 32, a mutation that affords protection against HIV.

The researchers said these results herald a new direction in HIV research and provide hope for HIV-positive patients with leukemia and lymphoma.

The work was presented at the “Towards an HIV Cure Symposium,” which is part of the 20th International AIDS Conference.

Both patients were treated at St Vincent’s Hospital in partnership with the University of New South Wales’s Kirby Institute in Sydney, Australia.

One patient underwent a transplant in 2010 to treat his non-Hodgkin lymphoma, and his donor had 1 copy of CCR5-delta 32.

The second patient underwent a similar procedure for acute myeloid leukemia in 2011, and his donor did not have any copies of CCR5-delta 32.

Nevertheless, both patients were successfully cleared of HIV, although they remain on antiretroviral therapy as a protective measure.

“We’re so pleased that both patients are doing reasonably well years after the treatment for their cancers and remain free of both the original cancer and the HIV virus,” said David Cooper, MBBS, MD, DSc, of the Kirby Institute and St Vincent’s Hospital.

Until now, the only person considered to have cleared HIV is an American man, Timothy Ray Brown, who underwent 2 stem cell transplants in Berlin (in 2007 and 2008).

The cells in his second transplant included both copies of CCR5-delta 32, which affords protection against HIV and is found in less than 1% of the population. The man is no longer on antiretroviral therapy and remains free of HIV.

In Boston, 2 other patients underwent similar transplants in 2012, but the donor cells did not contain CCR5-delta 32. In both cases, HIV returned after antiretroviral treatment was stopped.

“It is very difficult to find a match for bone marrow donors and even more so to find one that affords protective immunity against HIV,” Dr Cooper said.

While his group’s results are a significant development, the researchers stressed that transplants are not a general functional “cure” for the up to 38.8 million people infected with HIV worldwide.

“This is a terrific, unexpected result for people with malignancy and HIV,” said Sam Milliken, MBBS, of St Vincent’s Hospital. “It may well give us a whole new insight into HIV, using the principles of stem cell transplantation.”

“It is important to caution that, at this stage, this form of treatment is far too dangerous for treating patients with HIV alone, but there may be potential for using transplants as an effective treatment modality for HIV down the track.”

The researchers said the 2 Sydney patients will be the subject of investigations to determine where any residual virus might be hiding and how it can be controlled. And the patients’ results point to a new direction for HIV research.

“We still don’t know why these patients have undetectable viral loads,” said Kersten Koelsch, MD, of the Kirby Institute. “One theory is that the induction therapy helps to destroy the cells in which the virus is hiding and that any remaining infected cells are destroyed by the patient’s new immune system.”

“We need more research to establish why and how bone marrow transplantation clears the virus. We also want to explore the predictors of sustained viral clearance and how this might be able to be exploited without the need for bone marrow transplantation.”

For the time being, the results mean that more patients who are eligible for transplant might be able to participate in clinical trials to determine the value of this procedure in HIV.

HIV budding from a lymphocyte

Credit: CDC

MELBOURNE—Two men with hematologic malignancies who were also HIV-positive appear to be free of the virus after receiving stem cell transplants.

The patients have undetectable levels of HIV and remain free of their cancers—acute myeloid leukemia and non-Hodgkin lymphoma—more than 3 years after their transplants.

Importantly, the patients’ stem cell donors were not homozygous for CCR5-delta 32, a mutation that affords protection against HIV.

The researchers said these results herald a new direction in HIV research and provide hope for HIV-positive patients with leukemia and lymphoma.

The work was presented at the “Towards an HIV Cure Symposium,” which is part of the 20th International AIDS Conference.

Both patients were treated at St Vincent’s Hospital in partnership with the University of New South Wales’s Kirby Institute in Sydney, Australia.

One patient underwent a transplant in 2010 to treat his non-Hodgkin lymphoma, and his donor had 1 copy of CCR5-delta 32.

The second patient underwent a similar procedure for acute myeloid leukemia in 2011, and his donor did not have any copies of CCR5-delta 32.

Nevertheless, both patients were successfully cleared of HIV, although they remain on antiretroviral therapy as a protective measure.

“We’re so pleased that both patients are doing reasonably well years after the treatment for their cancers and remain free of both the original cancer and the HIV virus,” said David Cooper, MBBS, MD, DSc, of the Kirby Institute and St Vincent’s Hospital.

Until now, the only person considered to have cleared HIV is an American man, Timothy Ray Brown, who underwent 2 stem cell transplants in Berlin (in 2007 and 2008).

The cells in his second transplant included both copies of CCR5-delta 32, which affords protection against HIV and is found in less than 1% of the population. The man is no longer on antiretroviral therapy and remains free of HIV.

In Boston, 2 other patients underwent similar transplants in 2012, but the donor cells did not contain CCR5-delta 32. In both cases, HIV returned after antiretroviral treatment was stopped.

“It is very difficult to find a match for bone marrow donors and even more so to find one that affords protective immunity against HIV,” Dr Cooper said.

While his group’s results are a significant development, the researchers stressed that transplants are not a general functional “cure” for the up to 38.8 million people infected with HIV worldwide.

“This is a terrific, unexpected result for people with malignancy and HIV,” said Sam Milliken, MBBS, of St Vincent’s Hospital. “It may well give us a whole new insight into HIV, using the principles of stem cell transplantation.”

“It is important to caution that, at this stage, this form of treatment is far too dangerous for treating patients with HIV alone, but there may be potential for using transplants as an effective treatment modality for HIV down the track.”

The researchers said the 2 Sydney patients will be the subject of investigations to determine where any residual virus might be hiding and how it can be controlled. And the patients’ results point to a new direction for HIV research.

“We still don’t know why these patients have undetectable viral loads,” said Kersten Koelsch, MD, of the Kirby Institute. “One theory is that the induction therapy helps to destroy the cells in which the virus is hiding and that any remaining infected cells are destroyed by the patient’s new immune system.”

“We need more research to establish why and how bone marrow transplantation clears the virus. We also want to explore the predictors of sustained viral clearance and how this might be able to be exploited without the need for bone marrow transplantation.”

For the time being, the results mean that more patients who are eligible for transplant might be able to participate in clinical trials to determine the value of this procedure in HIV.

Drug vials

Credit: Bill Branson

The US Food and Drug Administration (FDA) is alerting healthcare professionals and consumers not to use sterile drugs produced by Downing Labs LLC, also known as NuVision Pharmacy, as the products may be contaminated.

Healthcare professionals should immediately check their medical supplies and quarantine any sterile products from NuVision.

Administration of a non-sterile drug product may result in serious and potentially life-threatening infections or death.

NuVision’s products were distributed nationwide. Most of the product labels say, “NuVision Pharmacy, Dallas TX, 75244 1-800-914-7435.”

FDA investigators inspected NuVision and observed unsanitary conditions that result in a lack of sterility assurance of purportedly sterile products, which puts patients at risk.

The inspection revealed sterility failures in 19 lots of products intended to be sterile, endotoxin failures in 3 lots of products, and inadequate or no investigation of these failures. Endotoxins are substances found in certain bacteria that cause a variety of serious reactions such as fever, shock, and changes in blood pressure and other circulatory functions.

The FDA is not aware of recent reports of illness associated with the use of these products.

Patients who have received any product produced by NuVision and have concerns should contact their healthcare professional.

Healthcare professionals and consumers can report adverse events associated with the use of NuVision’s products to the FDA’s MedWatch Adverse Event Reporting Program.

Drug vials

Credit: Bill Branson

The US Food and Drug Administration (FDA) is alerting healthcare professionals and consumers not to use sterile drugs produced by Downing Labs LLC, also known as NuVision Pharmacy, as the products may be contaminated.

Healthcare professionals should immediately check their medical supplies and quarantine any sterile products from NuVision.

Administration of a non-sterile drug product may result in serious and potentially life-threatening infections or death.

NuVision’s products were distributed nationwide. Most of the product labels say, “NuVision Pharmacy, Dallas TX, 75244 1-800-914-7435.”

FDA investigators inspected NuVision and observed unsanitary conditions that result in a lack of sterility assurance of purportedly sterile products, which puts patients at risk.

The inspection revealed sterility failures in 19 lots of products intended to be sterile, endotoxin failures in 3 lots of products, and inadequate or no investigation of these failures. Endotoxins are substances found in certain bacteria that cause a variety of serious reactions such as fever, shock, and changes in blood pressure and other circulatory functions.

The FDA is not aware of recent reports of illness associated with the use of these products.

Patients who have received any product produced by NuVision and have concerns should contact their healthcare professional.

Healthcare professionals and consumers can report adverse events associated with the use of NuVision’s products to the FDA’s MedWatch Adverse Event Reporting Program.

Drug vials

Credit: Bill Branson

The US Food and Drug Administration (FDA) is alerting healthcare professionals and consumers not to use sterile drugs produced by Downing Labs LLC, also known as NuVision Pharmacy, as the products may be contaminated.

Healthcare professionals should immediately check their medical supplies and quarantine any sterile products from NuVision.

Administration of a non-sterile drug product may result in serious and potentially life-threatening infections or death.

NuVision’s products were distributed nationwide. Most of the product labels say, “NuVision Pharmacy, Dallas TX, 75244 1-800-914-7435.”

FDA investigators inspected NuVision and observed unsanitary conditions that result in a lack of sterility assurance of purportedly sterile products, which puts patients at risk.

The inspection revealed sterility failures in 19 lots of products intended to be sterile, endotoxin failures in 3 lots of products, and inadequate or no investigation of these failures. Endotoxins are substances found in certain bacteria that cause a variety of serious reactions such as fever, shock, and changes in blood pressure and other circulatory functions.

The FDA is not aware of recent reports of illness associated with the use of these products.

Patients who have received any product produced by NuVision and have concerns should contact their healthcare professional.

Healthcare professionals and consumers can report adverse events associated with the use of NuVision’s products to the FDA’s MedWatch Adverse Event Reporting Program.

Malaria-carrying mosquito

Credit: James Gathany

Scientists have proposed that gene drives might be used to combat malaria and other insect-borne diseases, control invasive species, and promote sustainable agriculture.

Engineered gene drives are genetic systems that circumvent traditional rules of sexual reproduction and greatly increase the odds that the drive will be passed on to offspring.

This enables the spread of specified genetic alterations through targeted wild populations over many generations.

Gene drives represent a potentially powerful tool to confront regional or global challenges, including the control of invasive species and eradication of insect-borne diseases such as malaria and dengue.

The idea is not new, but a team of researchers has now outlined a technically feasible way to build gene drives that might spread almost any genomic change through populations of sexually reproducing species.

“We all rely on healthy ecosystems and share a responsibility to keep them intact for future generations,” said Kevin Esvelt, PhD, of the Wyss Institute at Harvard University in Boston.

“Given the broad potential of gene drives to address ecological problems, we hope to initiate a transparent, inclusive, and informed public discussion—well in advance of any testing—to collectively decide how we might use this technology for the betterment of humanity and the environment.”

Dr Esvelt and his colleagues have initiated this discussion by publishing papers on gene drives in Science and eLife.

The eLife paper describes the proposed technical methods of building gene drives in different species, defines their theoretical capabilities and limitations, and outlines possible applications.

The Science paper provides an initial assessment of potential environmental and security effects, an analysis of regulatory coverage, and recommendations to ensure responsible development and testing prior to use.

The new technical work in eLife builds upon research by Austin Burt, PhD, of Imperial College London in the UK, who, more than a decade ago, first proposed using a type of gene drive based on cutting DNA to alter populations.

The authors noted that the gene editing tool CRISPR—which is used to precisely insert, replace, and regulate genes—now makes it feasible to create gene drives that work in many different species.

“Our proposal represents a potentially powerful ecosystem management tool for global sustainability, but one that carries with it new concerns, as with any emerging technology,” said George Church, PhD, also of the Wyss Institute.

Dr Esvelt noted that the genomic changes made by gene drives should be reversible. The team has outlined in the eLife publication numerous precautionary measures intended to guide the safe and responsible development of gene drives, many of which were not possible with earlier technologies.

“If the public ever considers making use of a gene drive, we will need to develop appropriate safeguards,” he said. “Ensuring that we have a working reversal drive on hand to quickly undo the proposed genomic change would be one such precaution.”

Because the drives can spread traits only over generations, they will be most effective in species that reproduce quickly or can be released in large numbers, the researchers noted.

For insects, it could take only a couple of years to see a desired change in the population at large, while slower-reproducing organisms would require much longer. Altering human populations would require many centuries.

Gene drives could strike a powerful blow against malaria by altering mosquito populations so they can no longer spread the disease, according to the researchers.

Gene drives might also be used to rid local environments of invasive species or to pave the way toward more sustainable agriculture by reversing mutations that allow particular weed species, such as horseweed, to resist herbicides that are important for no-till farming.

However, the innovative nature of gene drives poses regulatory challenges.

“Simply put, gene drives do not fit comfortably within existing US regulations and international conventions,” said Kenneth Oye, PhD, of the Massachusetts Institute of Technology in Cambridge.

“For example, animal applications of gene drives would be regulated by the FDA as veterinary medicines. Potential implications of gene drives fall beyond the purview of the lists of bacteriological and viral agents that now define security regimes. We’ll need both regulatory reform and public engagement before we can consider beneficial uses. That is why we are excited about getting the conversation on gene drives going early.”

Malaria-carrying mosquito

Credit: James Gathany

Scientists have proposed that gene drives might be used to combat malaria and other insect-borne diseases, control invasive species, and promote sustainable agriculture.

Engineered gene drives are genetic systems that circumvent traditional rules of sexual reproduction and greatly increase the odds that the drive will be passed on to offspring.

This enables the spread of specified genetic alterations through targeted wild populations over many generations.

Gene drives represent a potentially powerful tool to confront regional or global challenges, including the control of invasive species and eradication of insect-borne diseases such as malaria and dengue.

The idea is not new, but a team of researchers has now outlined a technically feasible way to build gene drives that might spread almost any genomic change through populations of sexually reproducing species.

“We all rely on healthy ecosystems and share a responsibility to keep them intact for future generations,” said Kevin Esvelt, PhD, of the Wyss Institute at Harvard University in Boston.

“Given the broad potential of gene drives to address ecological problems, we hope to initiate a transparent, inclusive, and informed public discussion—well in advance of any testing—to collectively decide how we might use this technology for the betterment of humanity and the environment.”

Dr Esvelt and his colleagues have initiated this discussion by publishing papers on gene drives in Science and eLife.

The eLife paper describes the proposed technical methods of building gene drives in different species, defines their theoretical capabilities and limitations, and outlines possible applications.

The Science paper provides an initial assessment of potential environmental and security effects, an analysis of regulatory coverage, and recommendations to ensure responsible development and testing prior to use.

The new technical work in eLife builds upon research by Austin Burt, PhD, of Imperial College London in the UK, who, more than a decade ago, first proposed using a type of gene drive based on cutting DNA to alter populations.

The authors noted that the gene editing tool CRISPR—which is used to precisely insert, replace, and regulate genes—now makes it feasible to create gene drives that work in many different species.

“Our proposal represents a potentially powerful ecosystem management tool for global sustainability, but one that carries with it new concerns, as with any emerging technology,” said George Church, PhD, also of the Wyss Institute.

Dr Esvelt noted that the genomic changes made by gene drives should be reversible. The team has outlined in the eLife publication numerous precautionary measures intended to guide the safe and responsible development of gene drives, many of which were not possible with earlier technologies.

“If the public ever considers making use of a gene drive, we will need to develop appropriate safeguards,” he said. “Ensuring that we have a working reversal drive on hand to quickly undo the proposed genomic change would be one such precaution.”

Because the drives can spread traits only over generations, they will be most effective in species that reproduce quickly or can be released in large numbers, the researchers noted.

For insects, it could take only a couple of years to see a desired change in the population at large, while slower-reproducing organisms would require much longer. Altering human populations would require many centuries.

Gene drives could strike a powerful blow against malaria by altering mosquito populations so they can no longer spread the disease, according to the researchers.

Gene drives might also be used to rid local environments of invasive species or to pave the way toward more sustainable agriculture by reversing mutations that allow particular weed species, such as horseweed, to resist herbicides that are important for no-till farming.

However, the innovative nature of gene drives poses regulatory challenges.

“Simply put, gene drives do not fit comfortably within existing US regulations and international conventions,” said Kenneth Oye, PhD, of the Massachusetts Institute of Technology in Cambridge.

“For example, animal applications of gene drives would be regulated by the FDA as veterinary medicines. Potential implications of gene drives fall beyond the purview of the lists of bacteriological and viral agents that now define security regimes. We’ll need both regulatory reform and public engagement before we can consider beneficial uses. That is why we are excited about getting the conversation on gene drives going early.”

Malaria-carrying mosquito

Credit: James Gathany

Scientists have proposed that gene drives might be used to combat malaria and other insect-borne diseases, control invasive species, and promote sustainable agriculture.

Engineered gene drives are genetic systems that circumvent traditional rules of sexual reproduction and greatly increase the odds that the drive will be passed on to offspring.

This enables the spread of specified genetic alterations through targeted wild populations over many generations.

Gene drives represent a potentially powerful tool to confront regional or global challenges, including the control of invasive species and eradication of insect-borne diseases such as malaria and dengue.

The idea is not new, but a team of researchers has now outlined a technically feasible way to build gene drives that might spread almost any genomic change through populations of sexually reproducing species.

“We all rely on healthy ecosystems and share a responsibility to keep them intact for future generations,” said Kevin Esvelt, PhD, of the Wyss Institute at Harvard University in Boston.

“Given the broad potential of gene drives to address ecological problems, we hope to initiate a transparent, inclusive, and informed public discussion—well in advance of any testing—to collectively decide how we might use this technology for the betterment of humanity and the environment.”

Dr Esvelt and his colleagues have initiated this discussion by publishing papers on gene drives in Science and eLife.

The eLife paper describes the proposed technical methods of building gene drives in different species, defines their theoretical capabilities and limitations, and outlines possible applications.

The Science paper provides an initial assessment of potential environmental and security effects, an analysis of regulatory coverage, and recommendations to ensure responsible development and testing prior to use.

The new technical work in eLife builds upon research by Austin Burt, PhD, of Imperial College London in the UK, who, more than a decade ago, first proposed using a type of gene drive based on cutting DNA to alter populations.

The authors noted that the gene editing tool CRISPR—which is used to precisely insert, replace, and regulate genes—now makes it feasible to create gene drives that work in many different species.

“Our proposal represents a potentially powerful ecosystem management tool for global sustainability, but one that carries with it new concerns, as with any emerging technology,” said George Church, PhD, also of the Wyss Institute.

Dr Esvelt noted that the genomic changes made by gene drives should be reversible. The team has outlined in the eLife publication numerous precautionary measures intended to guide the safe and responsible development of gene drives, many of which were not possible with earlier technologies.

“If the public ever considers making use of a gene drive, we will need to develop appropriate safeguards,” he said. “Ensuring that we have a working reversal drive on hand to quickly undo the proposed genomic change would be one such precaution.”

Because the drives can spread traits only over generations, they will be most effective in species that reproduce quickly or can be released in large numbers, the researchers noted.

For insects, it could take only a couple of years to see a desired change in the population at large, while slower-reproducing organisms would require much longer. Altering human populations would require many centuries.

Gene drives could strike a powerful blow against malaria by altering mosquito populations so they can no longer spread the disease, according to the researchers.

Gene drives might also be used to rid local environments of invasive species or to pave the way toward more sustainable agriculture by reversing mutations that allow particular weed species, such as horseweed, to resist herbicides that are important for no-till farming.

However, the innovative nature of gene drives poses regulatory challenges.

“Simply put, gene drives do not fit comfortably within existing US regulations and international conventions,” said Kenneth Oye, PhD, of the Massachusetts Institute of Technology in Cambridge.

“For example, animal applications of gene drives would be regulated by the FDA as veterinary medicines. Potential implications of gene drives fall beyond the purview of the lists of bacteriological and viral agents that now define security regimes. We’ll need both regulatory reform and public engagement before we can consider beneficial uses. That is why we are excited about getting the conversation on gene drives going early.”

Malaria parasite infecting a

red blood cell; Credit: St Jude

Children’s Research Hospital

Two groups of researchers have found they can kill the malaria parasite by targeting a protein complex.

The research showed that a protein complex known as the Plasmodium translocon of exported proteins (PTEX) is needed for the export of malaria-parasite proteins into the cytoplasm of infected red blood cells, and such export is essential for parasite survival.

When the researchers disrupted passage of the proteins in cell cultures, malaria parasites stopped growing and died.

“The malaria parasite secretes hundreds of diverse proteins to seize control of red blood cells,” said Josh R. Beck, PhD, of the Washington University School of Medicine in St Louis.

“We’ve been searching for a single step that all those various proteins have to take to be secreted, and this looks like just such a bottleneck.”

He and his colleagues detailed their findings in a letter to Nature.

The researchers focused on heat shock protein 101 (HSP101), a component of PTEX. Previous studies had suggested that HSP101 might be involved in protein secretion.

So Dr Beck and his colleagues disabled HSP101 in cell cultures, expecting to block the discharge of some malarial proteins. To their surprise, they stopped all of them.

“We think this is a very promising target for drug development,” said study author Daniel Goldberg, MD, PhD, also of Washington University.

“We’re a long way from getting a new drug, but, in the short term, we may look at screening a variety of compounds to see if they have the potential to block HSP101.”

The researchers think HSP101 may ready malarial proteins for secretion through a pore that opens into the red blood cell. Part of this preparation may involve unfolding the proteins into a linear form that allows them to more easily pass through the pore. HSP101 may also give the proteins a biochemical kick that pushes them through the pore.

A separate study published in the same issue of Nature also highlights the importance of PTEX to the malaria parasite’s survival.

Brendan Elsworth, of the Macfarlane Burnet Institute for Medical Research and Public Health in Melbourne, Australia, and his colleagues neutralized the malaria parasite by disabling either HSP101 or PTEX150, another component of PTEX.

“That suggests there are multiple components of the process that we may be able to target with drugs,” Dr Beck said. “In addition, many of the proteins involved in secretion are unlike any human proteins, which means we may be able to disable them without adversely affecting important human proteins.”

Malaria parasite infecting a

red blood cell; Credit: St Jude

Children’s Research Hospital

Two groups of researchers have found they can kill the malaria parasite by targeting a protein complex.

The research showed that a protein complex known as the Plasmodium translocon of exported proteins (PTEX) is needed for the export of malaria-parasite proteins into the cytoplasm of infected red blood cells, and such export is essential for parasite survival.

When the researchers disrupted passage of the proteins in cell cultures, malaria parasites stopped growing and died.

“The malaria parasite secretes hundreds of diverse proteins to seize control of red blood cells,” said Josh R. Beck, PhD, of the Washington University School of Medicine in St Louis.

“We’ve been searching for a single step that all those various proteins have to take to be secreted, and this looks like just such a bottleneck.”

He and his colleagues detailed their findings in a letter to Nature.

The researchers focused on heat shock protein 101 (HSP101), a component of PTEX. Previous studies had suggested that HSP101 might be involved in protein secretion.

So Dr Beck and his colleagues disabled HSP101 in cell cultures, expecting to block the discharge of some malarial proteins. To their surprise, they stopped all of them.

“We think this is a very promising target for drug development,” said study author Daniel Goldberg, MD, PhD, also of Washington University.

“We’re a long way from getting a new drug, but, in the short term, we may look at screening a variety of compounds to see if they have the potential to block HSP101.”

The researchers think HSP101 may ready malarial proteins for secretion through a pore that opens into the red blood cell. Part of this preparation may involve unfolding the proteins into a linear form that allows them to more easily pass through the pore. HSP101 may also give the proteins a biochemical kick that pushes them through the pore.

A separate study published in the same issue of Nature also highlights the importance of PTEX to the malaria parasite’s survival.

Brendan Elsworth, of the Macfarlane Burnet Institute for Medical Research and Public Health in Melbourne, Australia, and his colleagues neutralized the malaria parasite by disabling either HSP101 or PTEX150, another component of PTEX.

“That suggests there are multiple components of the process that we may be able to target with drugs,” Dr Beck said. “In addition, many of the proteins involved in secretion are unlike any human proteins, which means we may be able to disable them without adversely affecting important human proteins.”

Malaria parasite infecting a

red blood cell; Credit: St Jude

Children’s Research Hospital

Two groups of researchers have found they can kill the malaria parasite by targeting a protein complex.

The research showed that a protein complex known as the Plasmodium translocon of exported proteins (PTEX) is needed for the export of malaria-parasite proteins into the cytoplasm of infected red blood cells, and such export is essential for parasite survival.

When the researchers disrupted passage of the proteins in cell cultures, malaria parasites stopped growing and died.

“The malaria parasite secretes hundreds of diverse proteins to seize control of red blood cells,” said Josh R. Beck, PhD, of the Washington University School of Medicine in St Louis.

“We’ve been searching for a single step that all those various proteins have to take to be secreted, and this looks like just such a bottleneck.”

He and his colleagues detailed their findings in a letter to Nature.

The researchers focused on heat shock protein 101 (HSP101), a component of PTEX. Previous studies had suggested that HSP101 might be involved in protein secretion.

So Dr Beck and his colleagues disabled HSP101 in cell cultures, expecting to block the discharge of some malarial proteins. To their surprise, they stopped all of them.

“We think this is a very promising target for drug development,” said study author Daniel Goldberg, MD, PhD, also of Washington University.

“We’re a long way from getting a new drug, but, in the short term, we may look at screening a variety of compounds to see if they have the potential to block HSP101.”

The researchers think HSP101 may ready malarial proteins for secretion through a pore that opens into the red blood cell. Part of this preparation may involve unfolding the proteins into a linear form that allows them to more easily pass through the pore. HSP101 may also give the proteins a biochemical kick that pushes them through the pore.

A separate study published in the same issue of Nature also highlights the importance of PTEX to the malaria parasite’s survival.

Brendan Elsworth, of the Macfarlane Burnet Institute for Medical Research and Public Health in Melbourne, Australia, and his colleagues neutralized the malaria parasite by disabling either HSP101 or PTEX150, another component of PTEX.

“That suggests there are multiple components of the process that we may be able to target with drugs,” Dr Beck said. “In addition, many of the proteins involved in secretion are unlike any human proteins, which means we may be able to disable them without adversely affecting important human proteins.”

Over the last few years, I have spoken with hundreds of physicians who tell me that they want to be engaged on social media, but they just don’t have the time or resources. I understand. If this sounds like you, then it’s time to consider hiring a social media consultant.

Hiring the right social media consultant or agency for your medical practice can provide many benefits, including:

• Shaping and marketing your brand.

• Handling daily social media updates and tasks.

• Devising a strategic plan to engage with social media influencers in your specialty.

• Developing a strategic plan to engage with your desired audience. Do you want new patients? More traffic to your practice website?

• Directing you to the best social media platforms for your specific goals, such as Facebook, YouTube, or Pinterest.

• If applicable, developing a plan to promote and market your products and unique services.

• Coaching you and your staff to become better and more efficient at social media.

• Helping you navigate social media analytics.

• Taking the stress off doing it all yourself.

There is no foolproof formula for choosing the best social media consultant for your practice, but here are some key points to keep in mind when considering candidates:

• Do they have experience? How long have they been consulting? How many clients have they had? How many do they currently have? Have they been published online or in print magazines? Do they teach any courses, either online or in person? Do they have success stories they can share?

• Check out their website. It is modern? User friendly? Does it include bios of the employees and client testimonials?

• Check out their social media involvement. Are they actively engaged on social media sites that they suggest you use? Look at their Facebook, Twitter, LinkedIn, and Pinterest accounts, as well as any other sites they may use.

• Are they willing to create unique content for your practice? Some agencies create boilerplate content that they use on multiple client sites. You want to be certain that the content they create for your practice aligns with your marketing and branding goals.

• Do you like them? This is a critical question because social media is, by nature, social. Do the staff members of your potential agency have likable personalities? Are they good listeners? Do they respond promptly to e-mails and phone calls? Do they seem confident or perpetually stressed?

• Do they understand your business? If the firm you hire has only restaurants as clients, then you might be at a disadvantage. Make certain that whomever you hire understands your area of medicine and has a track record of success with medical practices.

• Do they have clearly defined costs? Many firms will offer pricing based on 1- to 3-month intervals. Will they be creating and posting new content daily, weekly, biweekly? Will they work weekends and off-hours? How frequently will they meet with you in person? All of these factors will affect price. Of course, the more hands-on your social media consultants are, the higher the price is likely to be.

Outsourcing your social media is a decision that you and staff must consider carefully. As with most important decisions, it’s advisable to interview several different firms before choosing one. As for price, it ranges dramatically. Some agencies might charge $300 a month, while others might charge $3,000. It’s up to you and your office staff to determine which agency is best suited for your practice’s budget, needs, and goals.

In my next column, I’ll address pitfalls to avoid when choosing a social media consultant or agency.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is on Twitter @Dermdoc.

Over the last few years, I have spoken with hundreds of physicians who tell me that they want to be engaged on social media, but they just don’t have the time or resources. I understand. If this sounds like you, then it’s time to consider hiring a social media consultant.

Hiring the right social media consultant or agency for your medical practice can provide many benefits, including:

• Shaping and marketing your brand.

• Handling daily social media updates and tasks.

• Devising a strategic plan to engage with social media influencers in your specialty.

• Developing a strategic plan to engage with your desired audience. Do you want new patients? More traffic to your practice website?

• Directing you to the best social media platforms for your specific goals, such as Facebook, YouTube, or Pinterest.

• If applicable, developing a plan to promote and market your products and unique services.

• Coaching you and your staff to become better and more efficient at social media.

• Helping you navigate social media analytics.

• Taking the stress off doing it all yourself.

There is no foolproof formula for choosing the best social media consultant for your practice, but here are some key points to keep in mind when considering candidates:

• Do they have experience? How long have they been consulting? How many clients have they had? How many do they currently have? Have they been published online or in print magazines? Do they teach any courses, either online or in person? Do they have success stories they can share?

• Check out their website. It is modern? User friendly? Does it include bios of the employees and client testimonials?

• Check out their social media involvement. Are they actively engaged on social media sites that they suggest you use? Look at their Facebook, Twitter, LinkedIn, and Pinterest accounts, as well as any other sites they may use.

• Are they willing to create unique content for your practice? Some agencies create boilerplate content that they use on multiple client sites. You want to be certain that the content they create for your practice aligns with your marketing and branding goals.

• Do you like them? This is a critical question because social media is, by nature, social. Do the staff members of your potential agency have likable personalities? Are they good listeners? Do they respond promptly to e-mails and phone calls? Do they seem confident or perpetually stressed?

• Do they understand your business? If the firm you hire has only restaurants as clients, then you might be at a disadvantage. Make certain that whomever you hire understands your area of medicine and has a track record of success with medical practices.

• Do they have clearly defined costs? Many firms will offer pricing based on 1- to 3-month intervals. Will they be creating and posting new content daily, weekly, biweekly? Will they work weekends and off-hours? How frequently will they meet with you in person? All of these factors will affect price. Of course, the more hands-on your social media consultants are, the higher the price is likely to be.

Outsourcing your social media is a decision that you and staff must consider carefully. As with most important decisions, it’s advisable to interview several different firms before choosing one. As for price, it ranges dramatically. Some agencies might charge $300 a month, while others might charge $3,000. It’s up to you and your office staff to determine which agency is best suited for your practice’s budget, needs, and goals.

In my next column, I’ll address pitfalls to avoid when choosing a social media consultant or agency.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is on Twitter @Dermdoc.

Over the last few years, I have spoken with hundreds of physicians who tell me that they want to be engaged on social media, but they just don’t have the time or resources. I understand. If this sounds like you, then it’s time to consider hiring a social media consultant.

Hiring the right social media consultant or agency for your medical practice can provide many benefits, including:

• Shaping and marketing your brand.

• Handling daily social media updates and tasks.

• Devising a strategic plan to engage with social media influencers in your specialty.

• Developing a strategic plan to engage with your desired audience. Do you want new patients? More traffic to your practice website?

• Directing you to the best social media platforms for your specific goals, such as Facebook, YouTube, or Pinterest.

• If applicable, developing a plan to promote and market your products and unique services.

• Coaching you and your staff to become better and more efficient at social media.

• Helping you navigate social media analytics.

• Taking the stress off doing it all yourself.

There is no foolproof formula for choosing the best social media consultant for your practice, but here are some key points to keep in mind when considering candidates:

• Do they have experience? How long have they been consulting? How many clients have they had? How many do they currently have? Have they been published online or in print magazines? Do they teach any courses, either online or in person? Do they have success stories they can share?

• Check out their website. It is modern? User friendly? Does it include bios of the employees and client testimonials?

• Check out their social media involvement. Are they actively engaged on social media sites that they suggest you use? Look at their Facebook, Twitter, LinkedIn, and Pinterest accounts, as well as any other sites they may use.

• Are they willing to create unique content for your practice? Some agencies create boilerplate content that they use on multiple client sites. You want to be certain that the content they create for your practice aligns with your marketing and branding goals.

• Do you like them? This is a critical question because social media is, by nature, social. Do the staff members of your potential agency have likable personalities? Are they good listeners? Do they respond promptly to e-mails and phone calls? Do they seem confident or perpetually stressed?

• Do they understand your business? If the firm you hire has only restaurants as clients, then you might be at a disadvantage. Make certain that whomever you hire understands your area of medicine and has a track record of success with medical practices.

• Do they have clearly defined costs? Many firms will offer pricing based on 1- to 3-month intervals. Will they be creating and posting new content daily, weekly, biweekly? Will they work weekends and off-hours? How frequently will they meet with you in person? All of these factors will affect price. Of course, the more hands-on your social media consultants are, the higher the price is likely to be.

Outsourcing your social media is a decision that you and staff must consider carefully. As with most important decisions, it’s advisable to interview several different firms before choosing one. As for price, it ranges dramatically. Some agencies might charge $300 a month, while others might charge $3,000. It’s up to you and your office staff to determine which agency is best suited for your practice’s budget, needs, and goals.

In my next column, I’ll address pitfalls to avoid when choosing a social media consultant or agency.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is on Twitter @Dermdoc.

Smiling infant

Credit: Petr Kratochvil

Investigators say they’ve discovered the genetic defect that underlies STING-associated vasculopathy with onset in infancy (SAVI), which has led to a potential treatment for this rare condition.

The team found that SAVI patients have a mutation in a gene that encodes the protein STING, a signaling molecule whose activation leads to interferon production.

So it followed that JAK inhibitors, which block the interferon pathway, showed activity in samples from SAVI patients.

And based on these results, the investigators are enrolling SAVI patients on a compassionate use protocol for the JAK1/2 inhibitor baricitinib.

Raphaela Goldbach-Mansky, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, and her colleagues described the results in NEJM.

The research began in 2004, when Dr Goldbach-Mansky was called upon to advise on a patient with a baffling problem. The 10-year-old girl had signs of systemic inflammation, especially in the blood vessels, and she had not responded to any treatments.

She had blistering rashes on her fingers, toes, ears, nose, and cheeks, and she had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. She died a few years later.

By 2010, Dr Goldbach-Mansky had seen 2 other patients with the same symptoms. She suspected that all 3 had the same disease, and it was caused by a genetic defect that arose in the children, as their parents were not affected.

Her hunch suggested a strategy for identifying the genetic defect. By comparing the DNA of an affected child with the DNA of the child’s parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.

The DNA comparison revealed a novel mutation in TMEM173, the gene encoding STING, a protein whose activation leads to the production of interferon. When overproduced, interferon can trigger inflammation.

“Blood tests on the affected children had shown high levels of interferon-induced proteins, so we were not surprised when the mutated gene turned out to be related to interferon signaling,” Dr Goldbach-Mansky said.

When they tested the DNA of 5 other patients with similar symptoms, the investigators found mutations in the same gene, confirming STING’s role in the disease. The excessive inflammation observed in the patients, along with other evidence of interferon pathway activation, indicated that mutations in STING boosted the protein’s activity.

The investigators found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by SAVI.

Dr Goldbach-Mansky’s team next looked for ways to dampen the inflammatory response in patients with SAVI.

“When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal,” Dr Goldbach-Mansky said. “But because SAVI is caused by a single gene defect and interferon has such a strong role, I’m optimistic that we’ll be able to target the pathway and potentially make a huge difference in the lives of these children.”

The JAK inhibitors tofacitinib, ruxolitinib, and baricitinib are known to work by blocking the interferon pathway, so the investigators reasoned the drugs might be effective in patients with SAVI as well.

When they tested the effect of the drugs on SAVI patients’ blood cells in the lab, the team saw a marked reduction in interferon-pathway activation.

The investigators are now enrolling SAVI patients in a compassionate use protocol for baricitinib.

Dr Goldbach-Mansky’s team is also planning to investigate STING’s exact role in the interferon pathway and examine how the mutations that cause SAVI lead to interferon overproduction.

Smiling infant

Credit: Petr Kratochvil

Investigators say they’ve discovered the genetic defect that underlies STING-associated vasculopathy with onset in infancy (SAVI), which has led to a potential treatment for this rare condition.

The team found that SAVI patients have a mutation in a gene that encodes the protein STING, a signaling molecule whose activation leads to interferon production.

So it followed that JAK inhibitors, which block the interferon pathway, showed activity in samples from SAVI patients.

And based on these results, the investigators are enrolling SAVI patients on a compassionate use protocol for the JAK1/2 inhibitor baricitinib.

Raphaela Goldbach-Mansky, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, and her colleagues described the results in NEJM.

The research began in 2004, when Dr Goldbach-Mansky was called upon to advise on a patient with a baffling problem. The 10-year-old girl had signs of systemic inflammation, especially in the blood vessels, and she had not responded to any treatments.

She had blistering rashes on her fingers, toes, ears, nose, and cheeks, and she had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. She died a few years later.

By 2010, Dr Goldbach-Mansky had seen 2 other patients with the same symptoms. She suspected that all 3 had the same disease, and it was caused by a genetic defect that arose in the children, as their parents were not affected.

Her hunch suggested a strategy for identifying the genetic defect. By comparing the DNA of an affected child with the DNA of the child’s parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.

The DNA comparison revealed a novel mutation in TMEM173, the gene encoding STING, a protein whose activation leads to the production of interferon. When overproduced, interferon can trigger inflammation.

“Blood tests on the affected children had shown high levels of interferon-induced proteins, so we were not surprised when the mutated gene turned out to be related to interferon signaling,” Dr Goldbach-Mansky said.

When they tested the DNA of 5 other patients with similar symptoms, the investigators found mutations in the same gene, confirming STING’s role in the disease. The excessive inflammation observed in the patients, along with other evidence of interferon pathway activation, indicated that mutations in STING boosted the protein’s activity.

The investigators found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by SAVI.

Dr Goldbach-Mansky’s team next looked for ways to dampen the inflammatory response in patients with SAVI.

“When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal,” Dr Goldbach-Mansky said. “But because SAVI is caused by a single gene defect and interferon has such a strong role, I’m optimistic that we’ll be able to target the pathway and potentially make a huge difference in the lives of these children.”

The JAK inhibitors tofacitinib, ruxolitinib, and baricitinib are known to work by blocking the interferon pathway, so the investigators reasoned the drugs might be effective in patients with SAVI as well.

When they tested the effect of the drugs on SAVI patients’ blood cells in the lab, the team saw a marked reduction in interferon-pathway activation.

The investigators are now enrolling SAVI patients in a compassionate use protocol for baricitinib.

Dr Goldbach-Mansky’s team is also planning to investigate STING’s exact role in the interferon pathway and examine how the mutations that cause SAVI lead to interferon overproduction.

Smiling infant

Credit: Petr Kratochvil

Investigators say they’ve discovered the genetic defect that underlies STING-associated vasculopathy with onset in infancy (SAVI), which has led to a potential treatment for this rare condition.

The team found that SAVI patients have a mutation in a gene that encodes the protein STING, a signaling molecule whose activation leads to interferon production.

So it followed that JAK inhibitors, which block the interferon pathway, showed activity in samples from SAVI patients.

And based on these results, the investigators are enrolling SAVI patients on a compassionate use protocol for the JAK1/2 inhibitor baricitinib.

Raphaela Goldbach-Mansky, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, and her colleagues described the results in NEJM.

The research began in 2004, when Dr Goldbach-Mansky was called upon to advise on a patient with a baffling problem. The 10-year-old girl had signs of systemic inflammation, especially in the blood vessels, and she had not responded to any treatments.

She had blistering rashes on her fingers, toes, ears, nose, and cheeks, and she had lost parts of her fingers to the disease. The child also had severe scarring in her lungs and was having trouble breathing. She had shown signs of the disease as an infant and had progressively worsened. She died a few years later.

By 2010, Dr Goldbach-Mansky had seen 2 other patients with the same symptoms. She suspected that all 3 had the same disease, and it was caused by a genetic defect that arose in the children, as their parents were not affected.

Her hunch suggested a strategy for identifying the genetic defect. By comparing the DNA of an affected child with the DNA of the child’s parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.

The DNA comparison revealed a novel mutation in TMEM173, the gene encoding STING, a protein whose activation leads to the production of interferon. When overproduced, interferon can trigger inflammation.

“Blood tests on the affected children had shown high levels of interferon-induced proteins, so we were not surprised when the mutated gene turned out to be related to interferon signaling,” Dr Goldbach-Mansky said.

When they tested the DNA of 5 other patients with similar symptoms, the investigators found mutations in the same gene, confirming STING’s role in the disease. The excessive inflammation observed in the patients, along with other evidence of interferon pathway activation, indicated that mutations in STING boosted the protein’s activity.

The investigators found that STING was present in high levels in the cells lining the blood vessels and the lungs, which would likely explain why these tissues are predominantly affected by SAVI.

Dr Goldbach-Mansky’s team next looked for ways to dampen the inflammatory response in patients with SAVI.

“When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal,” Dr Goldbach-Mansky said. “But because SAVI is caused by a single gene defect and interferon has such a strong role, I’m optimistic that we’ll be able to target the pathway and potentially make a huge difference in the lives of these children.”

The JAK inhibitors tofacitinib, ruxolitinib, and baricitinib are known to work by blocking the interferon pathway, so the investigators reasoned the drugs might be effective in patients with SAVI as well.

When they tested the effect of the drugs on SAVI patients’ blood cells in the lab, the team saw a marked reduction in interferon-pathway activation.

The investigators are now enrolling SAVI patients in a compassionate use protocol for baricitinib.

Dr Goldbach-Mansky’s team is also planning to investigate STING’s exact role in the interferon pathway and examine how the mutations that cause SAVI lead to interferon overproduction.