Hematology Times

Micrograph showing

multiple myeloma

ROME—Combination therapy incorporating a novel monoclonal antibody (mAb) can provide “encouraging, long-lasting tumor control” in heavily pretreated patients with relapsed/refractory multiple myeloma (MM), according to investigators.

The mAb, MOR202, was also considered to be well-tolerated in this ongoing phase 1/2a study.

Early results from this study were presented at the 15th International Myeloma Workshop (poster #156). The study was sponsored by MorphoSys AG, makers of MOR202. The poster is available on the company’s website.

MOR202 is a HuCAL-derived mAb directed against CD38. In the phase 1/2a study, 50 MM patients have received the drug thus far.

At baseline, the patients’ median age was 67. They had received a median of 4 prior therapies, including bortezomib (98%), lenalidomide (92%), melphalan (92%), cyclophosphamide (76%), doxorubicin (60%), thalidomide (32%), pomalidomide (14%), carfilzomib (6%), elotuzumab (4%), and panobinostat (4%). Seventy-six percent had received a stem cell transplant.

Study design

The study consists of several parts and dosing cohorts in which the investigators are assessing MOR202 alone or in combination with other agents.

Treatment in Part A consists of a 2-hour intravenous infusion of MOR202 once every 2 weeks at several different doses: 0.01 mg/kg , 0.04 mg/kg, 0.15 mg/kg,  0.5 mg/kg, 1.5 mg/kg, 4.0 mg/kg, 8.0 mg/kg, or 16.0 mg/kg.

Part B is a 2-hour intravenous infusion of MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.

Part C is dexamethasone plus MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.

Part D is pomalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.

Part E is lenalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.

In the confirmatory cohorts, patients receive MOR202 with or without dexamethasone once a week or once every 2 weeks, MOR202 with pomalidomide and dexamethasone once a week, or MOR202 with lenalidomide and dexamethasone once a week.

Efficacy

Of the 50 patients treated thus far, 27 were evaluable for efficacy. One patient achieved a very good partial response, 2 had a partial response, and 2 had a minor response. Eleven patients had stable disease, and 11 progressed.

The very good partial response occurred in a patient receiving weekly MOR202 at 4 mg/kg plus dexamethasone.

One partial response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone. The other occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and pomalidomide.

One minor response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and lenalidomide. The other occurred in a patient receiving weekly MOR202 at 16 mg/kg plus dexamethasone.

“[T]he preliminary efficacy seen so far with MOR202 as single agent and in combinations is promising,” said investigator Marc-Steffen Raab, MD, of Heidelberg University Hospital and the German Cancer Research Center DKFZ in Heidelberg, Germany.

Safety

All 50 patients were evaluable for safety. Ninety-eight percent experienced an adverse event (AE), 66% of which were grade 3 or higher.

The most frequent AEs (overall and grade 3 or higher) were anemia (34%, 6%), leukopenia (30%, 10%), neutropenia (20%, 10%), thrombocytopenia (18%, 8%), fatigue (30%, 0%), nausea (22%, 0%), diarrhea (20%, 0%), and headache (16%, 0%).

Thirty-six percent of patients discontinued MOR202 due to treatment-emergent AEs. However, only 6% (n=3) of these AEs were considered possibly related to MOR202.

Infusion-related reactions occurred in 15 patients (30%). One of these patients received dexamethasone as well and experienced an infusion-related reaction (grade 1).

In the absence of dexamethasone, nearly all infusion reactions were grade 1-2. The exception was 1 patient with a grade 3 reaction that was mainly limited to the first infusion.

The maximum tolerated dose of MOR202 has not been reached.

“Considering the low rate of infusion reactions, even in cohorts without dexamethasone, the short infusion time, and other aspects, MOR202 may turn out to be an excellent choice in terms of safety and tolerability,” Dr Raab concluded.

Micrograph showing

multiple myeloma

ROME—Combination therapy incorporating a novel monoclonal antibody (mAb) can provide “encouraging, long-lasting tumor control” in heavily pretreated patients with relapsed/refractory multiple myeloma (MM), according to investigators.

The mAb, MOR202, was also considered to be well-tolerated in this ongoing phase 1/2a study.

Early results from this study were presented at the 15th International Myeloma Workshop (poster #156). The study was sponsored by MorphoSys AG, makers of MOR202. The poster is available on the company’s website.

MOR202 is a HuCAL-derived mAb directed against CD38. In the phase 1/2a study, 50 MM patients have received the drug thus far.

At baseline, the patients’ median age was 67. They had received a median of 4 prior therapies, including bortezomib (98%), lenalidomide (92%), melphalan (92%), cyclophosphamide (76%), doxorubicin (60%), thalidomide (32%), pomalidomide (14%), carfilzomib (6%), elotuzumab (4%), and panobinostat (4%). Seventy-six percent had received a stem cell transplant.

Study design

The study consists of several parts and dosing cohorts in which the investigators are assessing MOR202 alone or in combination with other agents.

Treatment in Part A consists of a 2-hour intravenous infusion of MOR202 once every 2 weeks at several different doses: 0.01 mg/kg , 0.04 mg/kg, 0.15 mg/kg,  0.5 mg/kg, 1.5 mg/kg, 4.0 mg/kg, 8.0 mg/kg, or 16.0 mg/kg.

Part B is a 2-hour intravenous infusion of MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.

Part C is dexamethasone plus MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.

Part D is pomalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.

Part E is lenalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.

In the confirmatory cohorts, patients receive MOR202 with or without dexamethasone once a week or once every 2 weeks, MOR202 with pomalidomide and dexamethasone once a week, or MOR202 with lenalidomide and dexamethasone once a week.

Efficacy

Of the 50 patients treated thus far, 27 were evaluable for efficacy. One patient achieved a very good partial response, 2 had a partial response, and 2 had a minor response. Eleven patients had stable disease, and 11 progressed.

The very good partial response occurred in a patient receiving weekly MOR202 at 4 mg/kg plus dexamethasone.

One partial response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone. The other occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and pomalidomide.

One minor response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and lenalidomide. The other occurred in a patient receiving weekly MOR202 at 16 mg/kg plus dexamethasone.

“[T]he preliminary efficacy seen so far with MOR202 as single agent and in combinations is promising,” said investigator Marc-Steffen Raab, MD, of Heidelberg University Hospital and the German Cancer Research Center DKFZ in Heidelberg, Germany.

Safety

All 50 patients were evaluable for safety. Ninety-eight percent experienced an adverse event (AE), 66% of which were grade 3 or higher.

The most frequent AEs (overall and grade 3 or higher) were anemia (34%, 6%), leukopenia (30%, 10%), neutropenia (20%, 10%), thrombocytopenia (18%, 8%), fatigue (30%, 0%), nausea (22%, 0%), diarrhea (20%, 0%), and headache (16%, 0%).

Thirty-six percent of patients discontinued MOR202 due to treatment-emergent AEs. However, only 6% (n=3) of these AEs were considered possibly related to MOR202.

Infusion-related reactions occurred in 15 patients (30%). One of these patients received dexamethasone as well and experienced an infusion-related reaction (grade 1).

In the absence of dexamethasone, nearly all infusion reactions were grade 1-2. The exception was 1 patient with a grade 3 reaction that was mainly limited to the first infusion.

The maximum tolerated dose of MOR202 has not been reached.

“Considering the low rate of infusion reactions, even in cohorts without dexamethasone, the short infusion time, and other aspects, MOR202 may turn out to be an excellent choice in terms of safety and tolerability,” Dr Raab concluded.

Micrograph showing

multiple myeloma

ROME—Combination therapy incorporating a novel monoclonal antibody (mAb) can provide “encouraging, long-lasting tumor control” in heavily pretreated patients with relapsed/refractory multiple myeloma (MM), according to investigators.

The mAb, MOR202, was also considered to be well-tolerated in this ongoing phase 1/2a study.

Early results from this study were presented at the 15th International Myeloma Workshop (poster #156). The study was sponsored by MorphoSys AG, makers of MOR202. The poster is available on the company’s website.

MOR202 is a HuCAL-derived mAb directed against CD38. In the phase 1/2a study, 50 MM patients have received the drug thus far.

At baseline, the patients’ median age was 67. They had received a median of 4 prior therapies, including bortezomib (98%), lenalidomide (92%), melphalan (92%), cyclophosphamide (76%), doxorubicin (60%), thalidomide (32%), pomalidomide (14%), carfilzomib (6%), elotuzumab (4%), and panobinostat (4%). Seventy-six percent had received a stem cell transplant.

Study design

The study consists of several parts and dosing cohorts in which the investigators are assessing MOR202 alone or in combination with other agents.

Treatment in Part A consists of a 2-hour intravenous infusion of MOR202 once every 2 weeks at several different doses: 0.01 mg/kg , 0.04 mg/kg, 0.15 mg/kg,  0.5 mg/kg, 1.5 mg/kg, 4.0 mg/kg, 8.0 mg/kg, or 16.0 mg/kg.

Part B is a 2-hour intravenous infusion of MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.

Part C is dexamethasone plus MOR202 once a week at 4 mg/kg, 8 mg/kg, or 16 mg/kg.

Part D is pomalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.

Part E is lenalidomide, dexamethasone, and MOR202 once a week at 8 mg/kg or 16 mg/kg.

In the confirmatory cohorts, patients receive MOR202 with or without dexamethasone once a week or once every 2 weeks, MOR202 with pomalidomide and dexamethasone once a week, or MOR202 with lenalidomide and dexamethasone once a week.

Efficacy

Of the 50 patients treated thus far, 27 were evaluable for efficacy. One patient achieved a very good partial response, 2 had a partial response, and 2 had a minor response. Eleven patients had stable disease, and 11 progressed.

The very good partial response occurred in a patient receiving weekly MOR202 at 4 mg/kg plus dexamethasone.

One partial response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone. The other occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and pomalidomide.

One minor response occurred in a patient receiving weekly MOR202 at 8 mg/kg plus dexamethasone and lenalidomide. The other occurred in a patient receiving weekly MOR202 at 16 mg/kg plus dexamethasone.

“[T]he preliminary efficacy seen so far with MOR202 as single agent and in combinations is promising,” said investigator Marc-Steffen Raab, MD, of Heidelberg University Hospital and the German Cancer Research Center DKFZ in Heidelberg, Germany.

Safety

All 50 patients were evaluable for safety. Ninety-eight percent experienced an adverse event (AE), 66% of which were grade 3 or higher.

The most frequent AEs (overall and grade 3 or higher) were anemia (34%, 6%), leukopenia (30%, 10%), neutropenia (20%, 10%), thrombocytopenia (18%, 8%), fatigue (30%, 0%), nausea (22%, 0%), diarrhea (20%, 0%), and headache (16%, 0%).

Thirty-six percent of patients discontinued MOR202 due to treatment-emergent AEs. However, only 6% (n=3) of these AEs were considered possibly related to MOR202.

Infusion-related reactions occurred in 15 patients (30%). One of these patients received dexamethasone as well and experienced an infusion-related reaction (grade 1).

In the absence of dexamethasone, nearly all infusion reactions were grade 1-2. The exception was 1 patient with a grade 3 reaction that was mainly limited to the first infusion.

The maximum tolerated dose of MOR202 has not been reached.

“Considering the low rate of infusion reactions, even in cohorts without dexamethasone, the short infusion time, and other aspects, MOR202 may turn out to be an excellent choice in terms of safety and tolerability,” Dr Raab concluded.

Micrograph showing CLL

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending that the PI3Kδ inhibitor idelalisib (Zydelig) be made available on the National Health Service (NHS) for some adults with chronic lymphocytic leukemia (CLL).

NICE is recommending idelalisib in combination with rituximab for adults with previously untreated CLL who have a 17p deletion or TP53 mutation and for adults with CLL who have relapsed within 24 months of their previous treatment.

This decision follows a preliminary decision earlier this year, when NICE asked Gilead Sciences, the company developing idelalisib, to provide further information on the cost-effectiveness of the drug.

Gilead responded by submitting new economic analyses and a simple discount agreement to the list price of idelalisib.

NICE’s recommendation for idelalisib is contingent upon the company providing the agreed upon discount.

NICE’s draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues a final guidance, NHS bodies should make decisions locally on the funding of specific treatments.

Patients whose treatment with idelalisib is not recommended in this NICE guidance but was started within the NHS before this guidance was published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.

Clinical effectiveness

The committee advising NICE concluded that idelalisib could not be recommended for patients whose disease had relapsed more than 24 months after previous treatment, as no evidence was submitted for this patient group.

For the other populations, the clinical effectiveness data from Study 116 showed that idelalisib plus rituximab produced a significant improvement in progression-free survival and overall survival, compared with rituximab alone, for patients with high-risk, relapsed or refractory CLL.

Cost-effectiveness

Idelalisib is priced at £3114.75 for sixty 150-mg tablets (British national formulary 2015). The mean cost of a 1-year treatment course is £37,922.

Gilead’s agreement provides a discount to the list price of idelalisib, but the level of the discount is currently confidential.

Analyses suggested that, at the discount agreement price, idelalisib plus rituximab was associated with higher costs and greater quality-adjusted life-year (QALY) gains when compared with rituximab alone.

The deterministic incremental cost-effectiveness ratio (ICER) for idelalisib plus rituximab compared with rituximab alone was £13,634 per QALY gained (incremental costs £26,128; incremental QALYs 1.92).

Compared with best supportive care, the ICER for idelalisib plus rituximab was £20,461 per QALY gained (incremental costs £39,211; incremental QALYs 1.92). And compared with ofatumumab, the ICER was £1527 per QALY gained (incremental costs £2926; incremental QALYs 1.92).

Micrograph showing CLL

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending that the PI3Kδ inhibitor idelalisib (Zydelig) be made available on the National Health Service (NHS) for some adults with chronic lymphocytic leukemia (CLL).

NICE is recommending idelalisib in combination with rituximab for adults with previously untreated CLL who have a 17p deletion or TP53 mutation and for adults with CLL who have relapsed within 24 months of their previous treatment.

This decision follows a preliminary decision earlier this year, when NICE asked Gilead Sciences, the company developing idelalisib, to provide further information on the cost-effectiveness of the drug.

Gilead responded by submitting new economic analyses and a simple discount agreement to the list price of idelalisib.

NICE’s recommendation for idelalisib is contingent upon the company providing the agreed upon discount.

NICE’s draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues a final guidance, NHS bodies should make decisions locally on the funding of specific treatments.

Patients whose treatment with idelalisib is not recommended in this NICE guidance but was started within the NHS before this guidance was published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.

Clinical effectiveness

The committee advising NICE concluded that idelalisib could not be recommended for patients whose disease had relapsed more than 24 months after previous treatment, as no evidence was submitted for this patient group.

For the other populations, the clinical effectiveness data from Study 116 showed that idelalisib plus rituximab produced a significant improvement in progression-free survival and overall survival, compared with rituximab alone, for patients with high-risk, relapsed or refractory CLL.

Cost-effectiveness

Idelalisib is priced at £3114.75 for sixty 150-mg tablets (British national formulary 2015). The mean cost of a 1-year treatment course is £37,922.

Gilead’s agreement provides a discount to the list price of idelalisib, but the level of the discount is currently confidential.

Analyses suggested that, at the discount agreement price, idelalisib plus rituximab was associated with higher costs and greater quality-adjusted life-year (QALY) gains when compared with rituximab alone.

The deterministic incremental cost-effectiveness ratio (ICER) for idelalisib plus rituximab compared with rituximab alone was £13,634 per QALY gained (incremental costs £26,128; incremental QALYs 1.92).

Compared with best supportive care, the ICER for idelalisib plus rituximab was £20,461 per QALY gained (incremental costs £39,211; incremental QALYs 1.92). And compared with ofatumumab, the ICER was £1527 per QALY gained (incremental costs £2926; incremental QALYs 1.92).

Micrograph showing CLL

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending that the PI3Kδ inhibitor idelalisib (Zydelig) be made available on the National Health Service (NHS) for some adults with chronic lymphocytic leukemia (CLL).

NICE is recommending idelalisib in combination with rituximab for adults with previously untreated CLL who have a 17p deletion or TP53 mutation and for adults with CLL who have relapsed within 24 months of their previous treatment.

This decision follows a preliminary decision earlier this year, when NICE asked Gilead Sciences, the company developing idelalisib, to provide further information on the cost-effectiveness of the drug.

Gilead responded by submitting new economic analyses and a simple discount agreement to the list price of idelalisib.

NICE’s recommendation for idelalisib is contingent upon the company providing the agreed upon discount.

NICE’s draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues a final guidance, NHS bodies should make decisions locally on the funding of specific treatments.

Patients whose treatment with idelalisib is not recommended in this NICE guidance but was started within the NHS before this guidance was published should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.

Clinical effectiveness

The committee advising NICE concluded that idelalisib could not be recommended for patients whose disease had relapsed more than 24 months after previous treatment, as no evidence was submitted for this patient group.

For the other populations, the clinical effectiveness data from Study 116 showed that idelalisib plus rituximab produced a significant improvement in progression-free survival and overall survival, compared with rituximab alone, for patients with high-risk, relapsed or refractory CLL.

Cost-effectiveness

Idelalisib is priced at £3114.75 for sixty 150-mg tablets (British national formulary 2015). The mean cost of a 1-year treatment course is £37,922.

Gilead’s agreement provides a discount to the list price of idelalisib, but the level of the discount is currently confidential.

Analyses suggested that, at the discount agreement price, idelalisib plus rituximab was associated with higher costs and greater quality-adjusted life-year (QALY) gains when compared with rituximab alone.

The deterministic incremental cost-effectiveness ratio (ICER) for idelalisib plus rituximab compared with rituximab alone was £13,634 per QALY gained (incremental costs £26,128; incremental QALYs 1.92).

Compared with best supportive care, the ICER for idelalisib plus rituximab was £20,461 per QALY gained (incremental costs £39,211; incremental QALYs 1.92). And compared with ofatumumab, the ICER was £1527 per QALY gained (incremental costs £2926; incremental QALYs 1.92).

Carfilzomib

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion of the proteasome inhibitor carfilzomib (Kyprolis).

The CHMP is recommending the drug be approved for use in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.

The CHMP’s positive opinion will be reviewed by the European Commission (EC).

The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union (EU), as well as Iceland, Lichtenstein, and Norway.

ASPIRE trial

The CHMP’s positive opinion of carfilzomib was based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.

The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.

Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.

The study’s primary endpoint was progression-free survival. And the median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).

At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.

The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.

The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.

The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).

Serious AEs were reported in 60% of the patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).

Carfilzomib development

Carfilzomib was granted orphan drug designation in the EU in 2008. Last February, the drug’s application for EU approval was granted accelerated assessment.

Carfilzomib was approved as monotherapy in the US in July 2012 and in combination with lenalidomide and dexamethasone in July 2015. Carfilzomib is also approved for use in Argentina, Israel, Kuwait, Mexico, and Thailand.

Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan. For more information on the drug, visit www.kyprolis.com.

Carfilzomib

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion of the proteasome inhibitor carfilzomib (Kyprolis).

The CHMP is recommending the drug be approved for use in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.

The CHMP’s positive opinion will be reviewed by the European Commission (EC).

The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union (EU), as well as Iceland, Lichtenstein, and Norway.

ASPIRE trial

The CHMP’s positive opinion of carfilzomib was based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.

The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.

Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.

The study’s primary endpoint was progression-free survival. And the median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).

At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.

The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.

The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.

The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).

Serious AEs were reported in 60% of the patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).

Carfilzomib development

Carfilzomib was granted orphan drug designation in the EU in 2008. Last February, the drug’s application for EU approval was granted accelerated assessment.

Carfilzomib was approved as monotherapy in the US in July 2012 and in combination with lenalidomide and dexamethasone in July 2015. Carfilzomib is also approved for use in Argentina, Israel, Kuwait, Mexico, and Thailand.

Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan. For more information on the drug, visit www.kyprolis.com.

Carfilzomib

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion of the proteasome inhibitor carfilzomib (Kyprolis).

The CHMP is recommending the drug be approved for use in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.

The CHMP’s positive opinion will be reviewed by the European Commission (EC).

The EC usually follows the CHMP’s recommendations and is expected to deliver its final decision within 3 months. The EC’s decision will apply to the 28 member countries of the European Union (EU), as well as Iceland, Lichtenstein, and Norway.

ASPIRE trial

The CHMP’s positive opinion of carfilzomib was based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.

The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.

Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.

The study’s primary endpoint was progression-free survival. And the median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).

At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.

The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.

The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.

The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).

Serious AEs were reported in 60% of the patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).

Carfilzomib development

Carfilzomib was granted orphan drug designation in the EU in 2008. Last February, the drug’s application for EU approval was granted accelerated assessment.

Carfilzomib was approved as monotherapy in the US in July 2012 and in combination with lenalidomide and dexamethasone in July 2015. Carfilzomib is also approved for use in Argentina, Israel, Kuwait, Mexico, and Thailand.

Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan. For more information on the drug, visit www.kyprolis.com.

Wendell Lim, PhD

Photo courtesy of UCSF

Researchers have reported progress in developing an “on/off switch” to temper the over-active immune response and severe toxicities that can result from chimeric antigen receptor (CAR) T-cell therapy.

The team created CAR T cells that are “off” by default, homing to CD19-expressing cancer cells but remaining inactive until a small molecule is administered.

This system effectively targeted leukemia and lymphoma cells in preclinical experiments.

But the researchers said it’s not ready for clinical testing, as the small-molecule “trigger” is expensive and lasts only 4 hours.

Still, the team believes this type of CAR T-cell therapy could eventually help doctors gradually increase the immune response to treatment and therefore avoid toxicities such as cytokine release syndrome and tumor lysis syndrome.

Wendell Lim, PhD, of University of California, San Francisco, and his colleagues described this work in Science.

“T cells are really powerful beasts, and they can be lethal when they’re activated,” Dr Lim said. “We’ve needed a remote control system that retains the power of these engineered T cells but allows us to communicate specifically with them and manage them while they’re in the body.”

To that end, he and his colleagues created a CAR that requires both an antigen and a small molecule for activation. They dubbed it the “ON-switch CAR.”

ON-switch CAR

The researchers explained that the ON-switch CAR consists of 2 parts that assemble in a small molecule-dependent manner.

Part 1 consists of a CD8α signal sequence, Myc epitope, anti-CD19 single-chain variable fragment, CD8α hinge and transmembrane domain, 4-1BB costimulatory motif, and FK506 Binding Protein (FKBP) domain for heterodimerization.

Part 2 consists of the ectodomain of DNAX-activating protein 10 (DAP10) for homodimerization, CD8α transmembrane domain for membrane anchoring, 4-1BB costimulatory motif, T2089L mutant of FKBP-rapamycin binding (FRB*) domain, T-cell receptor CD3ζ signaling chain, and mCherry tag.

The FKBP and FRB* domains heterodimerize in the presence of the rapamycin analog AP21967, referred to as the “rapalog.”

The researchers conducted in vitro experiments with this ON-switch CAR in cells expressing CD19 (K562, Raji, and Daudi).

The ON-switch CAR T cells homed to CD19-expressing cells but did nothing else until the rapalog was added. Once the rapalog was added, CD19-expressing cells were killed off in a dose-dependent manner.

The team observed similar results in mice with leukemia. Leukemia cells (K562) were selectively eliminated by the ON-switch CARs only after the rapalog had been administered.

Dr Lim stressed that this work should be considered a proof of principle, as the rapalog has too short a half-life to be clinically useful. Nevertheless, he believes the research provides the foundation for practical remote control of CAR T cells.

Members of his lab are exploring other techniques to accomplish this goal, such as controlling CAR T-cell activation with light.

The team is also working to reduce side effects of CAR T-cell therapy by introducing multiple CARs into T cells so the cells will respond to multiple characteristics that are distinctive to an individual patient’s tumor, rather than to a single protein that may also be found on normal cells.

“That we can engineer CAR T cells to have slightly different, quite powerful effects—even if for a subset of patients or for certain types of cancer—is really remarkable,” Dr Lim said. “And this is just the tip of the iceberg.”

Wendell Lim, PhD

Photo courtesy of UCSF

Researchers have reported progress in developing an “on/off switch” to temper the over-active immune response and severe toxicities that can result from chimeric antigen receptor (CAR) T-cell therapy.

The team created CAR T cells that are “off” by default, homing to CD19-expressing cancer cells but remaining inactive until a small molecule is administered.

This system effectively targeted leukemia and lymphoma cells in preclinical experiments.

But the researchers said it’s not ready for clinical testing, as the small-molecule “trigger” is expensive and lasts only 4 hours.

Still, the team believes this type of CAR T-cell therapy could eventually help doctors gradually increase the immune response to treatment and therefore avoid toxicities such as cytokine release syndrome and tumor lysis syndrome.

Wendell Lim, PhD, of University of California, San Francisco, and his colleagues described this work in Science.

“T cells are really powerful beasts, and they can be lethal when they’re activated,” Dr Lim said. “We’ve needed a remote control system that retains the power of these engineered T cells but allows us to communicate specifically with them and manage them while they’re in the body.”

To that end, he and his colleagues created a CAR that requires both an antigen and a small molecule for activation. They dubbed it the “ON-switch CAR.”

ON-switch CAR

The researchers explained that the ON-switch CAR consists of 2 parts that assemble in a small molecule-dependent manner.

Part 1 consists of a CD8α signal sequence, Myc epitope, anti-CD19 single-chain variable fragment, CD8α hinge and transmembrane domain, 4-1BB costimulatory motif, and FK506 Binding Protein (FKBP) domain for heterodimerization.

Part 2 consists of the ectodomain of DNAX-activating protein 10 (DAP10) for homodimerization, CD8α transmembrane domain for membrane anchoring, 4-1BB costimulatory motif, T2089L mutant of FKBP-rapamycin binding (FRB*) domain, T-cell receptor CD3ζ signaling chain, and mCherry tag.

The FKBP and FRB* domains heterodimerize in the presence of the rapamycin analog AP21967, referred to as the “rapalog.”

The researchers conducted in vitro experiments with this ON-switch CAR in cells expressing CD19 (K562, Raji, and Daudi).

The ON-switch CAR T cells homed to CD19-expressing cells but did nothing else until the rapalog was added. Once the rapalog was added, CD19-expressing cells were killed off in a dose-dependent manner.

The team observed similar results in mice with leukemia. Leukemia cells (K562) were selectively eliminated by the ON-switch CARs only after the rapalog had been administered.

Dr Lim stressed that this work should be considered a proof of principle, as the rapalog has too short a half-life to be clinically useful. Nevertheless, he believes the research provides the foundation for practical remote control of CAR T cells.

Members of his lab are exploring other techniques to accomplish this goal, such as controlling CAR T-cell activation with light.

The team is also working to reduce side effects of CAR T-cell therapy by introducing multiple CARs into T cells so the cells will respond to multiple characteristics that are distinctive to an individual patient’s tumor, rather than to a single protein that may also be found on normal cells.

“That we can engineer CAR T cells to have slightly different, quite powerful effects—even if for a subset of patients or for certain types of cancer—is really remarkable,” Dr Lim said. “And this is just the tip of the iceberg.”

Wendell Lim, PhD

Photo courtesy of UCSF

Researchers have reported progress in developing an “on/off switch” to temper the over-active immune response and severe toxicities that can result from chimeric antigen receptor (CAR) T-cell therapy.

The team created CAR T cells that are “off” by default, homing to CD19-expressing cancer cells but remaining inactive until a small molecule is administered.

This system effectively targeted leukemia and lymphoma cells in preclinical experiments.

But the researchers said it’s not ready for clinical testing, as the small-molecule “trigger” is expensive and lasts only 4 hours.

Still, the team believes this type of CAR T-cell therapy could eventually help doctors gradually increase the immune response to treatment and therefore avoid toxicities such as cytokine release syndrome and tumor lysis syndrome.

Wendell Lim, PhD, of University of California, San Francisco, and his colleagues described this work in Science.

“T cells are really powerful beasts, and they can be lethal when they’re activated,” Dr Lim said. “We’ve needed a remote control system that retains the power of these engineered T cells but allows us to communicate specifically with them and manage them while they’re in the body.”

To that end, he and his colleagues created a CAR that requires both an antigen and a small molecule for activation. They dubbed it the “ON-switch CAR.”

ON-switch CAR

The researchers explained that the ON-switch CAR consists of 2 parts that assemble in a small molecule-dependent manner.

Part 1 consists of a CD8α signal sequence, Myc epitope, anti-CD19 single-chain variable fragment, CD8α hinge and transmembrane domain, 4-1BB costimulatory motif, and FK506 Binding Protein (FKBP) domain for heterodimerization.

Part 2 consists of the ectodomain of DNAX-activating protein 10 (DAP10) for homodimerization, CD8α transmembrane domain for membrane anchoring, 4-1BB costimulatory motif, T2089L mutant of FKBP-rapamycin binding (FRB*) domain, T-cell receptor CD3ζ signaling chain, and mCherry tag.

The FKBP and FRB* domains heterodimerize in the presence of the rapamycin analog AP21967, referred to as the “rapalog.”

The researchers conducted in vitro experiments with this ON-switch CAR in cells expressing CD19 (K562, Raji, and Daudi).

The ON-switch CAR T cells homed to CD19-expressing cells but did nothing else until the rapalog was added. Once the rapalog was added, CD19-expressing cells were killed off in a dose-dependent manner.

The team observed similar results in mice with leukemia. Leukemia cells (K562) were selectively eliminated by the ON-switch CARs only after the rapalog had been administered.

Dr Lim stressed that this work should be considered a proof of principle, as the rapalog has too short a half-life to be clinically useful. Nevertheless, he believes the research provides the foundation for practical remote control of CAR T cells.

Members of his lab are exploring other techniques to accomplish this goal, such as controlling CAR T-cell activation with light.

The team is also working to reduce side effects of CAR T-cell therapy by introducing multiple CARs into T cells so the cells will respond to multiple characteristics that are distinctive to an individual patient’s tumor, rather than to a single protein that may also be found on normal cells.

“That we can engineer CAR T cells to have slightly different, quite powerful effects—even if for a subset of patients or for certain types of cancer—is really remarkable,” Dr Lim said. “And this is just the tip of the iceberg.”

Drug production

Photo courtesy of the FDA

Two newly published studies have raised concerns about the drug approval process in the US.

One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.

Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.

The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.

Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”

Expedited approval

For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.

The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).

The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).

The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”

They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.

Supplemental approval

For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.

The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.

Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).

Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).

The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”

Drug production

Photo courtesy of the FDA

Two newly published studies have raised concerns about the drug approval process in the US.

One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.

Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.

The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.

Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”

Expedited approval

For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.

The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).

The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).

The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”

They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.

Supplemental approval

For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.

The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.

Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).

Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).

The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”

Drug production

Photo courtesy of the FDA

Two newly published studies have raised concerns about the drug approval process in the US.

One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.

Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.

The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.

Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”

Expedited approval

For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.

The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).

The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).

The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”

They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.

Supplemental approval

For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.

The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.

Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).

Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).

The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”

Prescription medications

Photo courtesy of the CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).

The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.

In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.

NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.

Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.

NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.

For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.

Clinical effectiveness

NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.

A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.

The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.

The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.

However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.

The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.

Cost-effectiveness

Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.

The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.

Prescription medications

Photo courtesy of the CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).

The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.

In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.

NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.

Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.

NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.

For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.

Clinical effectiveness

NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.

A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.

The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.

The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.

However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.

The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.

Cost-effectiveness

Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.

The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.

Prescription medications

Photo courtesy of the CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).

The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.

In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.

NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.

Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.

NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.

For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.

Clinical effectiveness

NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.

A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.

The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.

The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.

However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.

The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.

Cost-effectiveness

Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.

The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.

Young cancer patient

Photo by Bill Branson

Results of a small study reveal the material hardships families experience when a child is undergoing cancer treatment.

Researchers surveyed 99 families of children with cancer.

Six months after the child’s diagnosis, 29% of the families reported having at least one household material hardship, such as food, housing, or energy insecurity.

Twenty percent of the families had reported having such hardships at the time of the child’s diagnosis.

Kira Bona, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and her colleagues reported results from this survey in Pediatric Blood & Cancer.

The researchers surveyed 99 families of pediatric cancer patients treated at Dana-Farber/Boston Children’s, first within a month of diagnosis and then 6 months later.

At diagnosis, 20% of the families were low-income, which was defined as 200% of the federal poverty level. Six months later, an additional 12% suffered income losses that pushed them into the low-income group.

At 6 months, 25% of the families said they had lost more than 40% of their household income due to treatment-related work disruptions. A total of 56% of adults who supported their families experienced a disruption of their work.

This included 15% of parents who either quit their jobs or were laid off as a result of their child’s illness, as well as 37% of respondents who cut their hours or took a leave of absence. Thirty-four percent of these individuals were paid during their leave.

At 6 months, 29% of families said they had at least one material hardship. Twenty percent reported food insecurity, 17% reported energy insecurity, and 8% reported housing insecurity.*

These findings surprised researchers, who said they expected lower levels of need at their center because it provides psychosocial support for patients and has resource specialists to help families facing financial difficulties.

“What it says is that even at a well-resourced, large referral center, about a third of families are reporting food, housing, or energy insecurity 6 months into treatment,” Dr Bona said. “If anything, the numbers in our study are an underestimate of what might be seen at less well-resourced institutions, which was somewhat surprising to us.”

By focusing on specific material hardships, which can be addressed through governmental or philanthropic support, the researchers hope they have identified variables that are easier for clinicians to ameliorate than overall income.

Dr Bona said subsequent research will examine whether material hardship has the same effect on patient outcomes as low-income status.

“If household material hardship is linked to poorer outcomes in pediatric oncology, just like income is, then we can design interventions to fix food, housing, and energy insecurity,” she said. “It’s not clear what you do about income in a clinical setting.”

*Definitions for household material hardships were as follows.

Food insecurity was measured via the US Household Food Security Survey Module: Six-Item Short Form, which includes questions to asses if respondents:

• sometimes/often do not have enough food to eat
• sometimes/often cannot afford to eat balanced meals
• sometimes/often worry about having enough money to buy food, etc.

Families met the definition for housing insecurity if they reported any of the following:

• crowding (defined as >2 people per bedroom in the home)
• multiple moves (>1 move in the prior year)
• doubling up (having to live with other people, even temporarily, because of financial difficulties in the past 6 months).

Families met the definition for energy insecurity if, in the prior 6 months, they had experienced any of the following:

• received a letter threatening to shut off the gas/electricity/oil to their house because they had not paid the bills
• had the gas/electric/oil company shut off electricity or refused to deliver oil/gas because they had not paid the bills
• had any days that their home was not heated/cooled because they couldn’t pay the bills
• had ever used a cooking stove to heat their home because they couldn’t pay the bills.

Young cancer patient

Photo by Bill Branson

Results of a small study reveal the material hardships families experience when a child is undergoing cancer treatment.

Researchers surveyed 99 families of children with cancer.

Six months after the child’s diagnosis, 29% of the families reported having at least one household material hardship, such as food, housing, or energy insecurity.

Twenty percent of the families had reported having such hardships at the time of the child’s diagnosis.

Kira Bona, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and her colleagues reported results from this survey in Pediatric Blood & Cancer.

The researchers surveyed 99 families of pediatric cancer patients treated at Dana-Farber/Boston Children’s, first within a month of diagnosis and then 6 months later.

At diagnosis, 20% of the families were low-income, which was defined as 200% of the federal poverty level. Six months later, an additional 12% suffered income losses that pushed them into the low-income group.

At 6 months, 25% of the families said they had lost more than 40% of their household income due to treatment-related work disruptions. A total of 56% of adults who supported their families experienced a disruption of their work.

This included 15% of parents who either quit their jobs or were laid off as a result of their child’s illness, as well as 37% of respondents who cut their hours or took a leave of absence. Thirty-four percent of these individuals were paid during their leave.

At 6 months, 29% of families said they had at least one material hardship. Twenty percent reported food insecurity, 17% reported energy insecurity, and 8% reported housing insecurity.*

These findings surprised researchers, who said they expected lower levels of need at their center because it provides psychosocial support for patients and has resource specialists to help families facing financial difficulties.

“What it says is that even at a well-resourced, large referral center, about a third of families are reporting food, housing, or energy insecurity 6 months into treatment,” Dr Bona said. “If anything, the numbers in our study are an underestimate of what might be seen at less well-resourced institutions, which was somewhat surprising to us.”

By focusing on specific material hardships, which can be addressed through governmental or philanthropic support, the researchers hope they have identified variables that are easier for clinicians to ameliorate than overall income.

Dr Bona said subsequent research will examine whether material hardship has the same effect on patient outcomes as low-income status.

“If household material hardship is linked to poorer outcomes in pediatric oncology, just like income is, then we can design interventions to fix food, housing, and energy insecurity,” she said. “It’s not clear what you do about income in a clinical setting.”

*Definitions for household material hardships were as follows.

Food insecurity was measured via the US Household Food Security Survey Module: Six-Item Short Form, which includes questions to asses if respondents:

• sometimes/often do not have enough food to eat
• sometimes/often cannot afford to eat balanced meals
• sometimes/often worry about having enough money to buy food, etc.

Families met the definition for housing insecurity if they reported any of the following:

• crowding (defined as >2 people per bedroom in the home)
• multiple moves (>1 move in the prior year)
• doubling up (having to live with other people, even temporarily, because of financial difficulties in the past 6 months).

Families met the definition for energy insecurity if, in the prior 6 months, they had experienced any of the following:

• received a letter threatening to shut off the gas/electricity/oil to their house because they had not paid the bills
• had the gas/electric/oil company shut off electricity or refused to deliver oil/gas because they had not paid the bills
• had any days that their home was not heated/cooled because they couldn’t pay the bills
• had ever used a cooking stove to heat their home because they couldn’t pay the bills.

Young cancer patient

Photo by Bill Branson

Results of a small study reveal the material hardships families experience when a child is undergoing cancer treatment.

Researchers surveyed 99 families of children with cancer.

Six months after the child’s diagnosis, 29% of the families reported having at least one household material hardship, such as food, housing, or energy insecurity.

Twenty percent of the families had reported having such hardships at the time of the child’s diagnosis.

Kira Bona, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and her colleagues reported results from this survey in Pediatric Blood & Cancer.

The researchers surveyed 99 families of pediatric cancer patients treated at Dana-Farber/Boston Children’s, first within a month of diagnosis and then 6 months later.

At diagnosis, 20% of the families were low-income, which was defined as 200% of the federal poverty level. Six months later, an additional 12% suffered income losses that pushed them into the low-income group.

At 6 months, 25% of the families said they had lost more than 40% of their household income due to treatment-related work disruptions. A total of 56% of adults who supported their families experienced a disruption of their work.

This included 15% of parents who either quit their jobs or were laid off as a result of their child’s illness, as well as 37% of respondents who cut their hours or took a leave of absence. Thirty-four percent of these individuals were paid during their leave.

At 6 months, 29% of families said they had at least one material hardship. Twenty percent reported food insecurity, 17% reported energy insecurity, and 8% reported housing insecurity.*

These findings surprised researchers, who said they expected lower levels of need at their center because it provides psychosocial support for patients and has resource specialists to help families facing financial difficulties.

“What it says is that even at a well-resourced, large referral center, about a third of families are reporting food, housing, or energy insecurity 6 months into treatment,” Dr Bona said. “If anything, the numbers in our study are an underestimate of what might be seen at less well-resourced institutions, which was somewhat surprising to us.”

By focusing on specific material hardships, which can be addressed through governmental or philanthropic support, the researchers hope they have identified variables that are easier for clinicians to ameliorate than overall income.

Dr Bona said subsequent research will examine whether material hardship has the same effect on patient outcomes as low-income status.

“If household material hardship is linked to poorer outcomes in pediatric oncology, just like income is, then we can design interventions to fix food, housing, and energy insecurity,” she said. “It’s not clear what you do about income in a clinical setting.”

*Definitions for household material hardships were as follows.

Food insecurity was measured via the US Household Food Security Survey Module: Six-Item Short Form, which includes questions to asses if respondents:

• sometimes/often do not have enough food to eat
• sometimes/often cannot afford to eat balanced meals
• sometimes/often worry about having enough money to buy food, etc.

Families met the definition for housing insecurity if they reported any of the following:

• crowding (defined as >2 people per bedroom in the home)
• multiple moves (>1 move in the prior year)
• doubling up (having to live with other people, even temporarily, because of financial difficulties in the past 6 months).

Families met the definition for energy insecurity if, in the prior 6 months, they had experienced any of the following:

• received a letter threatening to shut off the gas/electricity/oil to their house because they had not paid the bills
• had the gas/electric/oil company shut off electricity or refused to deliver oil/gas because they had not paid the bills
• had any days that their home was not heated/cooled because they couldn’t pay the bills
• had ever used a cooking stove to heat their home because they couldn’t pay the bills.

Mette Hazenberg, MD, PhD

NEW YORK—Investigators have found that B cells may play a role in stimulating graft-versus-leukemia (GvL) responses in patients with acute myeloid leukemia (AML) who have undergone allogeneic hematopoietic stem cell transplant (HSCT).

The team created B cell lines from these patients, isolated AML-specific antibodies, and found that these antibodies can induce the death of AML cells through oncosis.

Oncosis is a non-apoptotic type of cell death that involves swelling and coagulation of the cytoplasm.

Mette Hazenberg, MD, PhD, from the Academic Medical Center in Amsterdam, The Netherlands, reported these findings at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference as poster B052.

The investigators cloned B cells from 3 high-risk AML patients who had a strong GvL response after HSCT.

The team transduced memory B cells from the patients’ peripheral blood using BCL-6 and BCL-xL. They then screened the B cells for those that produced antibodies that bound specifically to surface antigens on AML cell lines and blasts.

Six of the 15 AML antibodies retrieved from the patients bound specifically to snRNp200. In normal cells, snRNp200 is in the nucleus, but, in AML, it is exposed on the cell membrane.

The investigators then confirmed this by ELISA.

They found 7 of the 15 AML antibodies directly lysed AML blasts without the addition of effector cells or complement. Time-lapse images showed that cell death by the AML antibodies occurred rapidly, within minutes after incubation.

“The leukemia blasts popped like balloons,” Dr Hazenberg said.

The investigators confirmed that the antibodies induced cell death by oncosis and that oncosis occurred independently of temperature. The antibodies were cytotoxic at 4°C and 37°C.

Cytotoxicity of the antibodies could be blocked by the membrane stabilizer cytochalasin D but not by apoptosis inhibitors.

The team concluded that a potent GvL response could be mediated by these antibodies against tumor-associated antigens on AML cells.

Dr Hazenberg’s hope is that, at some point, these antibodies can be combined with chemotherapy—as is rituximab—so patients won’t need to undergo transplant.

Mette Hazenberg, MD, PhD

NEW YORK—Investigators have found that B cells may play a role in stimulating graft-versus-leukemia (GvL) responses in patients with acute myeloid leukemia (AML) who have undergone allogeneic hematopoietic stem cell transplant (HSCT).

The team created B cell lines from these patients, isolated AML-specific antibodies, and found that these antibodies can induce the death of AML cells through oncosis.

Oncosis is a non-apoptotic type of cell death that involves swelling and coagulation of the cytoplasm.

Mette Hazenberg, MD, PhD, from the Academic Medical Center in Amsterdam, The Netherlands, reported these findings at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference as poster B052.

The investigators cloned B cells from 3 high-risk AML patients who had a strong GvL response after HSCT.

The team transduced memory B cells from the patients’ peripheral blood using BCL-6 and BCL-xL. They then screened the B cells for those that produced antibodies that bound specifically to surface antigens on AML cell lines and blasts.

Six of the 15 AML antibodies retrieved from the patients bound specifically to snRNp200. In normal cells, snRNp200 is in the nucleus, but, in AML, it is exposed on the cell membrane.

The investigators then confirmed this by ELISA.

They found 7 of the 15 AML antibodies directly lysed AML blasts without the addition of effector cells or complement. Time-lapse images showed that cell death by the AML antibodies occurred rapidly, within minutes after incubation.

“The leukemia blasts popped like balloons,” Dr Hazenberg said.

The investigators confirmed that the antibodies induced cell death by oncosis and that oncosis occurred independently of temperature. The antibodies were cytotoxic at 4°C and 37°C.

Cytotoxicity of the antibodies could be blocked by the membrane stabilizer cytochalasin D but not by apoptosis inhibitors.

The team concluded that a potent GvL response could be mediated by these antibodies against tumor-associated antigens on AML cells.

Dr Hazenberg’s hope is that, at some point, these antibodies can be combined with chemotherapy—as is rituximab—so patients won’t need to undergo transplant.

Mette Hazenberg, MD, PhD

NEW YORK—Investigators have found that B cells may play a role in stimulating graft-versus-leukemia (GvL) responses in patients with acute myeloid leukemia (AML) who have undergone allogeneic hematopoietic stem cell transplant (HSCT).

The team created B cell lines from these patients, isolated AML-specific antibodies, and found that these antibodies can induce the death of AML cells through oncosis.

Oncosis is a non-apoptotic type of cell death that involves swelling and coagulation of the cytoplasm.

Mette Hazenberg, MD, PhD, from the Academic Medical Center in Amsterdam, The Netherlands, reported these findings at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference as poster B052.

The investigators cloned B cells from 3 high-risk AML patients who had a strong GvL response after HSCT.

The team transduced memory B cells from the patients’ peripheral blood using BCL-6 and BCL-xL. They then screened the B cells for those that produced antibodies that bound specifically to surface antigens on AML cell lines and blasts.

Six of the 15 AML antibodies retrieved from the patients bound specifically to snRNp200. In normal cells, snRNp200 is in the nucleus, but, in AML, it is exposed on the cell membrane.

The investigators then confirmed this by ELISA.

They found 7 of the 15 AML antibodies directly lysed AML blasts without the addition of effector cells or complement. Time-lapse images showed that cell death by the AML antibodies occurred rapidly, within minutes after incubation.

“The leukemia blasts popped like balloons,” Dr Hazenberg said.

The investigators confirmed that the antibodies induced cell death by oncosis and that oncosis occurred independently of temperature. The antibodies were cytotoxic at 4°C and 37°C.

Cytotoxicity of the antibodies could be blocked by the membrane stabilizer cytochalasin D but not by apoptosis inhibitors.

The team concluded that a potent GvL response could be mediated by these antibodies against tumor-associated antigens on AML cells.

Dr Hazenberg’s hope is that, at some point, these antibodies can be combined with chemotherapy—as is rituximab—so patients won’t need to undergo transplant.

Blood for transfusion

Photo courtesy of UAB Hospital

Scientists say they have discovered a new virus that can be transmitted through the blood supply.

It is currently unclear whether the virus is harmful or not, but researchers found that it shares genetic features with hepatitis C virus (HCV) and human

pegivirus (HPgV), which was formerly known as hepatitis G virus.

The new virus, which the researchers have named human hepegivirus-1 (HHpgV-1), is described in the journal mBio.

“HHpgV-1 is unique because it shares genetic similarity with both highly pathogenic HCV and the apparently non-pathogenic HPgV,” said study author Amit Kapoor, PhD, of Columbia University in New York, New York. “People need to be aware of this new infection in humans.”

To identify HHpgV-1, Dr Kapoor and his colleagues performed high-throughput sequencing on blood samples from 46 individuals in the Transfusion-Transmitted Viruses Study. The samples were collected between July 1974 and June 1980.

The researchers analyzed samples both pre- and post-transfusion and, along with a variety of known viruses, they identified HHpgV-1 in 2 individuals.

The virus was only present in post-transfusion samples, and additional tests showed that both patients were able to clear HHpgV-1.

Genetic analysis revealed that the virus was related to HCV and HPgV. Genomic testing of 70 additional individuals in the Transfusion-Transmitted Viruses Study did not detect further cases of HHpgV-1.

The researchers also performed high-throughput sequencing on samples from 106 individuals in the Multicenter Hemophilia Cohort Study who received plasma-derived clotting factor concentrates.

The team identified HHpgV-1 in 2 individuals, one of whom had persistent long-term infection (5.4 years).

“We just don’t know how many viruses are transmitted through the blood supply,” Dr Kapoor said. “There are so many viruses out there, and they need to be characterized in order to ensure that transfusions are safe.”

He said the next steps are to determine the prevalence of HHpgV-1 and whether it causes disease. If it causes disease, screening the blood supply for the virus will be appropriate.

“Ultimately, once we know more about this, we will look for the presence of this virus in people with certain diseases,” Dr Kapoor said.

“The unusually high infection prevalence of HCV, HBV, and HIV in hemophilia patients and other transfusion recipients could have been prevented by earlier identification of these viruses and development of accurate diagnostic assays.”

Blood for transfusion

Photo courtesy of UAB Hospital

Scientists say they have discovered a new virus that can be transmitted through the blood supply.

It is currently unclear whether the virus is harmful or not, but researchers found that it shares genetic features with hepatitis C virus (HCV) and human

pegivirus (HPgV), which was formerly known as hepatitis G virus.

The new virus, which the researchers have named human hepegivirus-1 (HHpgV-1), is described in the journal mBio.

“HHpgV-1 is unique because it shares genetic similarity with both highly pathogenic HCV and the apparently non-pathogenic HPgV,” said study author Amit Kapoor, PhD, of Columbia University in New York, New York. “People need to be aware of this new infection in humans.”

To identify HHpgV-1, Dr Kapoor and his colleagues performed high-throughput sequencing on blood samples from 46 individuals in the Transfusion-Transmitted Viruses Study. The samples were collected between July 1974 and June 1980.

The researchers analyzed samples both pre- and post-transfusion and, along with a variety of known viruses, they identified HHpgV-1 in 2 individuals.

The virus was only present in post-transfusion samples, and additional tests showed that both patients were able to clear HHpgV-1.

Genetic analysis revealed that the virus was related to HCV and HPgV. Genomic testing of 70 additional individuals in the Transfusion-Transmitted Viruses Study did not detect further cases of HHpgV-1.

The researchers also performed high-throughput sequencing on samples from 106 individuals in the Multicenter Hemophilia Cohort Study who received plasma-derived clotting factor concentrates.

The team identified HHpgV-1 in 2 individuals, one of whom had persistent long-term infection (5.4 years).

“We just don’t know how many viruses are transmitted through the blood supply,” Dr Kapoor said. “There are so many viruses out there, and they need to be characterized in order to ensure that transfusions are safe.”

He said the next steps are to determine the prevalence of HHpgV-1 and whether it causes disease. If it causes disease, screening the blood supply for the virus will be appropriate.

“Ultimately, once we know more about this, we will look for the presence of this virus in people with certain diseases,” Dr Kapoor said.

“The unusually high infection prevalence of HCV, HBV, and HIV in hemophilia patients and other transfusion recipients could have been prevented by earlier identification of these viruses and development of accurate diagnostic assays.”

Blood for transfusion

Photo courtesy of UAB Hospital

Scientists say they have discovered a new virus that can be transmitted through the blood supply.

It is currently unclear whether the virus is harmful or not, but researchers found that it shares genetic features with hepatitis C virus (HCV) and human

pegivirus (HPgV), which was formerly known as hepatitis G virus.

The new virus, which the researchers have named human hepegivirus-1 (HHpgV-1), is described in the journal mBio.

“HHpgV-1 is unique because it shares genetic similarity with both highly pathogenic HCV and the apparently non-pathogenic HPgV,” said study author Amit Kapoor, PhD, of Columbia University in New York, New York. “People need to be aware of this new infection in humans.”

To identify HHpgV-1, Dr Kapoor and his colleagues performed high-throughput sequencing on blood samples from 46 individuals in the Transfusion-Transmitted Viruses Study. The samples were collected between July 1974 and June 1980.

The researchers analyzed samples both pre- and post-transfusion and, along with a variety of known viruses, they identified HHpgV-1 in 2 individuals.

The virus was only present in post-transfusion samples, and additional tests showed that both patients were able to clear HHpgV-1.

Genetic analysis revealed that the virus was related to HCV and HPgV. Genomic testing of 70 additional individuals in the Transfusion-Transmitted Viruses Study did not detect further cases of HHpgV-1.

The researchers also performed high-throughput sequencing on samples from 106 individuals in the Multicenter Hemophilia Cohort Study who received plasma-derived clotting factor concentrates.

The team identified HHpgV-1 in 2 individuals, one of whom had persistent long-term infection (5.4 years).

“We just don’t know how many viruses are transmitted through the blood supply,” Dr Kapoor said. “There are so many viruses out there, and they need to be characterized in order to ensure that transfusions are safe.”

He said the next steps are to determine the prevalence of HHpgV-1 and whether it causes disease. If it causes disease, screening the blood supply for the virus will be appropriate.

“Ultimately, once we know more about this, we will look for the presence of this virus in people with certain diseases,” Dr Kapoor said.

“The unusually high infection prevalence of HCV, HBV, and HIV in hemophilia patients and other transfusion recipients could have been prevented by earlier identification of these viruses and development of accurate diagnostic assays.”

Hematopoietic stem cells

in the bone marrow

By imaging the bone marrow of mice, researchers have uncovered new details about hematopoietic stem cells (HSCs).

The team’s deep imaging technique confirmed some previous findings and unearthed new information about where HSCs are located and how they are maintained.

The researchers said these findings, published in Nature, provide a significant advance toward understanding the microenvironment in which HSCs reside.

“The bone marrow and [HSCs] are like a haystack with needles inside,” said study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas.

“Researchers in the past have been able to find a few stem cells, but they’ve only seen a small percentage of the stem cells that are there, so there has been some controversy about where exactly they’re located.”

“We developed a technique that allows us to digitally reconstruct the entire haystack and see all the needles—all the [HSCs] that are present in the bone marrow—and to know exactly where they are and how far they are from every other cell type.”

The team began by identifying a genetic marker that is almost exclusively expressed in HSCs. They then took green fluorescent protein from jellyfish and inserted it into the genetic marker, Ctnnal1, so they could identify the HSCs.

“Using a tissue-clearing technique that makes the bone and bone marrow see-through, and employing a high-resolution, confocal microscope to scan the entire bone marrow compartment, we were able to image large segments of bone marrow to locate every [HSC] and its relation to other cells,” said Melih Acar, PhD, also of the University of Texas Southwestern Medical Center.

The team’s work yielded new findings and confirmed others. They found that HSCs tend to be clustered in the center of the bone marrow, not closer to bone surfaces as some researchers previously thought.

They also found that HSCs are indeed associated with sinusoidal blood vessels, and there are no spatially distinct niches for dividing and non-dividing HSCs.

“With this improved understanding of the microenvironment and mechanisms that maintain [HSCs], we are closer to being able to replicate the environment for [HSCs] in culture,” Dr Morrison said.

“That achievement would significantly improve the safety and effectiveness of bone marrow transplants and potentially save thousands of additional lives each year.”

Hematopoietic stem cells

in the bone marrow

By imaging the bone marrow of mice, researchers have uncovered new details about hematopoietic stem cells (HSCs).

The team’s deep imaging technique confirmed some previous findings and unearthed new information about where HSCs are located and how they are maintained.

The researchers said these findings, published in Nature, provide a significant advance toward understanding the microenvironment in which HSCs reside.

“The bone marrow and [HSCs] are like a haystack with needles inside,” said study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas.

“Researchers in the past have been able to find a few stem cells, but they’ve only seen a small percentage of the stem cells that are there, so there has been some controversy about where exactly they’re located.”

“We developed a technique that allows us to digitally reconstruct the entire haystack and see all the needles—all the [HSCs] that are present in the bone marrow—and to know exactly where they are and how far they are from every other cell type.”

The team began by identifying a genetic marker that is almost exclusively expressed in HSCs. They then took green fluorescent protein from jellyfish and inserted it into the genetic marker, Ctnnal1, so they could identify the HSCs.

“Using a tissue-clearing technique that makes the bone and bone marrow see-through, and employing a high-resolution, confocal microscope to scan the entire bone marrow compartment, we were able to image large segments of bone marrow to locate every [HSC] and its relation to other cells,” said Melih Acar, PhD, also of the University of Texas Southwestern Medical Center.

The team’s work yielded new findings and confirmed others. They found that HSCs tend to be clustered in the center of the bone marrow, not closer to bone surfaces as some researchers previously thought.

They also found that HSCs are indeed associated with sinusoidal blood vessels, and there are no spatially distinct niches for dividing and non-dividing HSCs.

“With this improved understanding of the microenvironment and mechanisms that maintain [HSCs], we are closer to being able to replicate the environment for [HSCs] in culture,” Dr Morrison said.

“That achievement would significantly improve the safety and effectiveness of bone marrow transplants and potentially save thousands of additional lives each year.”

Hematopoietic stem cells

in the bone marrow

By imaging the bone marrow of mice, researchers have uncovered new details about hematopoietic stem cells (HSCs).

The team’s deep imaging technique confirmed some previous findings and unearthed new information about where HSCs are located and how they are maintained.

The researchers said these findings, published in Nature, provide a significant advance toward understanding the microenvironment in which HSCs reside.

“The bone marrow and [HSCs] are like a haystack with needles inside,” said study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas.

“Researchers in the past have been able to find a few stem cells, but they’ve only seen a small percentage of the stem cells that are there, so there has been some controversy about where exactly they’re located.”

“We developed a technique that allows us to digitally reconstruct the entire haystack and see all the needles—all the [HSCs] that are present in the bone marrow—and to know exactly where they are and how far they are from every other cell type.”

The team began by identifying a genetic marker that is almost exclusively expressed in HSCs. They then took green fluorescent protein from jellyfish and inserted it into the genetic marker, Ctnnal1, so they could identify the HSCs.

“Using a tissue-clearing technique that makes the bone and bone marrow see-through, and employing a high-resolution, confocal microscope to scan the entire bone marrow compartment, we were able to image large segments of bone marrow to locate every [HSC] and its relation to other cells,” said Melih Acar, PhD, also of the University of Texas Southwestern Medical Center.

The team’s work yielded new findings and confirmed others. They found that HSCs tend to be clustered in the center of the bone marrow, not closer to bone surfaces as some researchers previously thought.

They also found that HSCs are indeed associated with sinusoidal blood vessels, and there are no spatially distinct niches for dividing and non-dividing HSCs.

“With this improved understanding of the microenvironment and mechanisms that maintain [HSCs], we are closer to being able to replicate the environment for [HSCs] in culture,” Dr Morrison said.

“That achievement would significantly improve the safety and effectiveness of bone marrow transplants and potentially save thousands of additional lives each year.”