Doctor and patient

Photo courtesy of NIH

 

A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.

The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.

Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.

“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.

“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”

Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.

This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).

The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.

There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.

Results

The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.

In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.

In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.

The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.

The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.

CLL patients

Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).

Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).

Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.

The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.

MCL patients

Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).

Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.

Three patients progressed after an initial response. Four patients were not evaluable because they progressed.

The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.

DLBCL patients

All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3

(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.

Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.

The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.

The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.

Toxicity

AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.

Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).

There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.

“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.

“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”

 

 

Doctor and patient

Photo courtesy of NIH

 

A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.

The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.

Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.

“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.

“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”

Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.

This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).

The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.

There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.

Results

The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.

In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.

In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.

The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.

The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.

CLL patients

Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).

Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).

Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.

The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.

MCL patients

Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).

Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.

Three patients progressed after an initial response. Four patients were not evaluable because they progressed.

The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.

DLBCL patients

All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3

(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.

Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.

The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.

The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.

Toxicity

AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.

Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).

There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.

“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.

“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”

 

 

Doctor and patient

Photo courtesy of NIH

 

A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.

The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.

Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.

“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.

“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”

Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.

This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).

The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.

There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.

Results

The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.

In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.

In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.

The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.

The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.

CLL patients

Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).

Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).

Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.

The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.

MCL patients

Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).

Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.

Three patients progressed after an initial response. Four patients were not evaluable because they progressed.

The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.

DLBCL patients

All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3

(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.

Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.

The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.

The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.

Toxicity

AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.

Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).

There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.

“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.

“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”

Rivaroxaban tablets

An investigational antidote to factor Xa inhibitors has proven succesful in reversing the effects of apixaban and rivaroxaban in a pair of phase 3 studies of healthy

volunteers.

In the ANNEXA-R and ANNEXA-A studies, researchers evaluated the safety and efficacy of the antidote, andexanet alfa, in volunteers receiving rivaroxaban and apixaban, respectively.

In both studies, andexanet alfa met all efficacy endpoints.

There were no serious or severe adverse events and no thrombotic events in either study.

“The findings of [these studies] are an advance towards resolving major bleeding complications effectively within minutes,” said Deborah Siegal, MD, of McMaster University in Hamilton, Ontario, Canada.

Dr Siegal and her colleagues reported the findings in NEJM. The studies were funded by Portola Pharmaceuticals, the company developing andexanet alfa.

The randomized, double-blind, placebo-controlled ANNEXA-R and ANNEXA-A studies were conducted to evaluate the safety and efficacy of andexanet alfa in reversing the anticoagulant effect of rivaroxaban and apixaban, respectively, in healthy volunteers ages 50 to 68.

The primary endpoint was reduction in anti-factor Xa levels. Secondary endpoints included reduction in plasma levels of unbound rivaroxaban or apixaban and restoration of the endogenous thrombin potential, a measure of thrombin generation.

ANNEXA-R efficacy

In part 1 of this study, 41 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg intravenous (IV) bolus (n=27) or placebo (n=14).

Within 2 to 5 minutes of bolus completion, andexanet alfa significantly reduced the anti-factor Xa activity of rivaroxaban compared with placebo—92% and 18%, respectively (P<0.001).

And andexanet alfa significantly reduced the level of unbound rivaroxaban in the plasma compared with placebo—23.4 ng/mL and 4.2 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 96% of subjects who received andexanet alfa and 7% of placebo-treated subjects (P<0.001).

In part 2 of the study, 39 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes (n=26) or placebo (n=13).

Andexanet alfa significantly reduced anti-factor Xa activity compared with placebo—97% and 45%, respectively (P<0.001). And reversal persisted in andexanet alfa-treated subjects for 1 to 2 hours after the infusion was complete.

The reduction in unbound rivaroxaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of unbound rivaroxaban compared with placebo—30.3 ng/mL and 12.1 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 0% of placebo-treated subjects (P<0.001).

ANNEXA-A efficacy

In part 1 of this study, 33 subjects received apixaban at 5 mg twice daily for 3.5 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus (n=24) or placebo (n=9).

Within 2 to 5 minutes of bolus completion, andexanet alfa reduced the anti-factor Xa activity of apixaban compared with placebo—94% and 21%, respectively (P<0.001).

Andexanet alfa significantly reduced the level of unbound apixaban in the plasma compared with placebo—9.3 ng/mL and 1.9 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 11% of placebo-treated subjects (P<0.001).

In part 2, 31 healthy volunteers received apixaban at 5 mg twice daily for 4 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=24) or placebo (n=8).

Andexanet alfa significantly reduced anti-factor Xa activity compared with placebo—92% and 33%, respectively (P<0.001). And reversal persisted in andexanet alfa-treated subjects for 1 to 2 hours after the infusion was complete.

The reduction in unbound apixaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of unbound apixaban compared with placebo—6.5 ng/mL and 3.0 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 25% of placebo-treated subjects (P<0.001).

ANNEXA safety results

There were no serious or severe adverse events and no thrombotic events in either study. All adverse events related to andexanet alfa were considered mild.

Among subjects who received andexanet alfa in the ANNEXA-A study, there were 4 cases of gastrointestinal disorders—2 cases of constipation and 2 cases of dysgeusia. There were 3 cases in which subjects felt hot after administration of the drug, 4 cases of flushing, and 1 case of urticaria.

Among subjects who received andexanet alfa in the ANNEXA-R study, there were 2 cases of flushing and 1 case of urticaria.

Among subjects who received placebo in either study, there was 1 case of flushing.

One subject with a history of hives developed erythematous hives after receiving andexanet alfa. The infusion was stopped after 35 minutes, the subject received a single dose of diphenhydramine, and the hives resolved.

None of the subjects developed antibodies to factor X or factor Xa, and there were no neutralizing antibodies against andexanet alfa.

However, 1 subject who received placebo (2%) and 17 subjects who received andexanet alfa (17%) had non-neutralizing antibodies against andexanet alfa. Two of the subjects had non-neutralizing antibodies before andexanet alfa administration.

The antibodies tended to appear within 15 to 30 days of andexanet administration, and the titers were generally low (at or below 1:640). The exception was 1 subject who had a titer of 1:2560.

About andexanet alfa

Andexanet alfa is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

Portola Pharmaceuticals is currently evaluating andexanet alfa in ANNEXA-4, a phase 4, single-arm, confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.

Data from a small number of patients from ANNEXA-4, as well as data from ANNEXA-A and ANNEXA-R, will serve as the clinical basis for the biologics license application to the US Food and Drug Administration.

A rolling submission of the application has been initiated under accelerated approval, and the submission package is expected to be complete by the end of this year. The Food and Drug Administration has already granted andexanet alfa orphan drug designation and breakthrough therapy designation.

Rivaroxaban tablets

An investigational antidote to factor Xa inhibitors has proven succesful in reversing the effects of apixaban and rivaroxaban in a pair of phase 3 studies of healthy

volunteers.

In the ANNEXA-R and ANNEXA-A studies, researchers evaluated the safety and efficacy of the antidote, andexanet alfa, in volunteers receiving rivaroxaban and apixaban, respectively.

In both studies, andexanet alfa met all efficacy endpoints.

There were no serious or severe adverse events and no thrombotic events in either study.

“The findings of [these studies] are an advance towards resolving major bleeding complications effectively within minutes,” said Deborah Siegal, MD, of McMaster University in Hamilton, Ontario, Canada.

Dr Siegal and her colleagues reported the findings in NEJM. The studies were funded by Portola Pharmaceuticals, the company developing andexanet alfa.

The randomized, double-blind, placebo-controlled ANNEXA-R and ANNEXA-A studies were conducted to evaluate the safety and efficacy of andexanet alfa in reversing the anticoagulant effect of rivaroxaban and apixaban, respectively, in healthy volunteers ages 50 to 68.

The primary endpoint was reduction in anti-factor Xa levels. Secondary endpoints included reduction in plasma levels of unbound rivaroxaban or apixaban and restoration of the endogenous thrombin potential, a measure of thrombin generation.

ANNEXA-R efficacy

In part 1 of this study, 41 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg intravenous (IV) bolus (n=27) or placebo (n=14).

Within 2 to 5 minutes of bolus completion, andexanet alfa significantly reduced the anti-factor Xa activity of rivaroxaban compared with placebo—92% and 18%, respectively (P<0.001).

And andexanet alfa significantly reduced the level of unbound rivaroxaban in the plasma compared with placebo—23.4 ng/mL and 4.2 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 96% of subjects who received andexanet alfa and 7% of placebo-treated subjects (P<0.001).

In part 2 of the study, 39 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes (n=26) or placebo (n=13).

Andexanet alfa significantly reduced anti-factor Xa activity compared with placebo—97% and 45%, respectively (P<0.001). And reversal persisted in andexanet alfa-treated subjects for 1 to 2 hours after the infusion was complete.

The reduction in unbound rivaroxaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of unbound rivaroxaban compared with placebo—30.3 ng/mL and 12.1 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 0% of placebo-treated subjects (P<0.001).

ANNEXA-A efficacy

In part 1 of this study, 33 subjects received apixaban at 5 mg twice daily for 3.5 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus (n=24) or placebo (n=9).

Within 2 to 5 minutes of bolus completion, andexanet alfa reduced the anti-factor Xa activity of apixaban compared with placebo—94% and 21%, respectively (P<0.001).

Andexanet alfa significantly reduced the level of unbound apixaban in the plasma compared with placebo—9.3 ng/mL and 1.9 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 11% of placebo-treated subjects (P<0.001).

In part 2, 31 healthy volunteers received apixaban at 5 mg twice daily for 4 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=24) or placebo (n=8).

Andexanet alfa significantly reduced anti-factor Xa activity compared with placebo—92% and 33%, respectively (P<0.001). And reversal persisted in andexanet alfa-treated subjects for 1 to 2 hours after the infusion was complete.

The reduction in unbound apixaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of unbound apixaban compared with placebo—6.5 ng/mL and 3.0 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 25% of placebo-treated subjects (P<0.001).

ANNEXA safety results

There were no serious or severe adverse events and no thrombotic events in either study. All adverse events related to andexanet alfa were considered mild.

Among subjects who received andexanet alfa in the ANNEXA-A study, there were 4 cases of gastrointestinal disorders—2 cases of constipation and 2 cases of dysgeusia. There were 3 cases in which subjects felt hot after administration of the drug, 4 cases of flushing, and 1 case of urticaria.

Among subjects who received andexanet alfa in the ANNEXA-R study, there were 2 cases of flushing and 1 case of urticaria.

Among subjects who received placebo in either study, there was 1 case of flushing.

One subject with a history of hives developed erythematous hives after receiving andexanet alfa. The infusion was stopped after 35 minutes, the subject received a single dose of diphenhydramine, and the hives resolved.

None of the subjects developed antibodies to factor X or factor Xa, and there were no neutralizing antibodies against andexanet alfa.

However, 1 subject who received placebo (2%) and 17 subjects who received andexanet alfa (17%) had non-neutralizing antibodies against andexanet alfa. Two of the subjects had non-neutralizing antibodies before andexanet alfa administration.

The antibodies tended to appear within 15 to 30 days of andexanet administration, and the titers were generally low (at or below 1:640). The exception was 1 subject who had a titer of 1:2560.

About andexanet alfa

Andexanet alfa is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

Portola Pharmaceuticals is currently evaluating andexanet alfa in ANNEXA-4, a phase 4, single-arm, confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.

Data from a small number of patients from ANNEXA-4, as well as data from ANNEXA-A and ANNEXA-R, will serve as the clinical basis for the biologics license application to the US Food and Drug Administration.

A rolling submission of the application has been initiated under accelerated approval, and the submission package is expected to be complete by the end of this year. The Food and Drug Administration has already granted andexanet alfa orphan drug designation and breakthrough therapy designation.

Rivaroxaban tablets

An investigational antidote to factor Xa inhibitors has proven succesful in reversing the effects of apixaban and rivaroxaban in a pair of phase 3 studies of healthy

volunteers.

In the ANNEXA-R and ANNEXA-A studies, researchers evaluated the safety and efficacy of the antidote, andexanet alfa, in volunteers receiving rivaroxaban and apixaban, respectively.

In both studies, andexanet alfa met all efficacy endpoints.

There were no serious or severe adverse events and no thrombotic events in either study.

“The findings of [these studies] are an advance towards resolving major bleeding complications effectively within minutes,” said Deborah Siegal, MD, of McMaster University in Hamilton, Ontario, Canada.

Dr Siegal and her colleagues reported the findings in NEJM. The studies were funded by Portola Pharmaceuticals, the company developing andexanet alfa.

The randomized, double-blind, placebo-controlled ANNEXA-R and ANNEXA-A studies were conducted to evaluate the safety and efficacy of andexanet alfa in reversing the anticoagulant effect of rivaroxaban and apixaban, respectively, in healthy volunteers ages 50 to 68.

The primary endpoint was reduction in anti-factor Xa levels. Secondary endpoints included reduction in plasma levels of unbound rivaroxaban or apixaban and restoration of the endogenous thrombin potential, a measure of thrombin generation.

ANNEXA-R efficacy

In part 1 of this study, 41 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg intravenous (IV) bolus (n=27) or placebo (n=14).

Within 2 to 5 minutes of bolus completion, andexanet alfa significantly reduced the anti-factor Xa activity of rivaroxaban compared with placebo—92% and 18%, respectively (P<0.001).

And andexanet alfa significantly reduced the level of unbound rivaroxaban in the plasma compared with placebo—23.4 ng/mL and 4.2 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 96% of subjects who received andexanet alfa and 7% of placebo-treated subjects (P<0.001).

In part 2 of the study, 39 healthy volunteers received rivaroxaban at 20 mg once daily for 4 days. They were then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes (n=26) or placebo (n=13).

Andexanet alfa significantly reduced anti-factor Xa activity compared with placebo—97% and 45%, respectively (P<0.001). And reversal persisted in andexanet alfa-treated subjects for 1 to 2 hours after the infusion was complete.

The reduction in unbound rivaroxaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of unbound rivaroxaban compared with placebo—30.3 ng/mL and 12.1 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 0% of placebo-treated subjects (P<0.001).

ANNEXA-A efficacy

In part 1 of this study, 33 subjects received apixaban at 5 mg twice daily for 3.5 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus (n=24) or placebo (n=9).

Within 2 to 5 minutes of bolus completion, andexanet alfa reduced the anti-factor Xa activity of apixaban compared with placebo—94% and 21%, respectively (P<0.001).

Andexanet alfa significantly reduced the level of unbound apixaban in the plasma compared with placebo—9.3 ng/mL and 1.9 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 11% of placebo-treated subjects (P<0.001).

In part 2, 31 healthy volunteers received apixaban at 5 mg twice daily for 4 days. They were then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=24) or placebo (n=8).

Andexanet alfa significantly reduced anti-factor Xa activity compared with placebo—92% and 33%, respectively (P<0.001). And reversal persisted in andexanet alfa-treated subjects for 1 to 2 hours after the infusion was complete.

The reduction in unbound apixaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of unbound apixaban compared with placebo—6.5 ng/mL and 3.0 ng/mL, respectively (P<0.001).

Thrombin generation was fully restored in 100% of subjects who received andexanet alfa and 25% of placebo-treated subjects (P<0.001).

ANNEXA safety results

There were no serious or severe adverse events and no thrombotic events in either study. All adverse events related to andexanet alfa were considered mild.

Among subjects who received andexanet alfa in the ANNEXA-A study, there were 4 cases of gastrointestinal disorders—2 cases of constipation and 2 cases of dysgeusia. There were 3 cases in which subjects felt hot after administration of the drug, 4 cases of flushing, and 1 case of urticaria.

Among subjects who received andexanet alfa in the ANNEXA-R study, there were 2 cases of flushing and 1 case of urticaria.

Among subjects who received placebo in either study, there was 1 case of flushing.

One subject with a history of hives developed erythematous hives after receiving andexanet alfa. The infusion was stopped after 35 minutes, the subject received a single dose of diphenhydramine, and the hives resolved.

None of the subjects developed antibodies to factor X or factor Xa, and there were no neutralizing antibodies against andexanet alfa.

However, 1 subject who received placebo (2%) and 17 subjects who received andexanet alfa (17%) had non-neutralizing antibodies against andexanet alfa. Two of the subjects had non-neutralizing antibodies before andexanet alfa administration.

The antibodies tended to appear within 15 to 30 days of andexanet administration, and the titers were generally low (at or below 1:640). The exception was 1 subject who had a titer of 1:2560.

About andexanet alfa

Andexanet alfa is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

Portola Pharmaceuticals is currently evaluating andexanet alfa in ANNEXA-4, a phase 4, single-arm, confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.

Data from a small number of patients from ANNEXA-4, as well as data from ANNEXA-A and ANNEXA-R, will serve as the clinical basis for the biologics license application to the US Food and Drug Administration.

A rolling submission of the application has been initiated under accelerated approval, and the submission package is expected to be complete by the end of this year. The Food and Drug Administration has already granted andexanet alfa orphan drug designation and breakthrough therapy designation.

Warfarin tablets

ORLANDO, FL—Interim results from a long-term, “real world” study suggest dabigatran etexilate mesylate (Pradaxa) may be safer than warfarin in routine

clinical practice.

The data, which come from a pooled analysis of 2 large US commercial health insurance databases, showed that patients with non-valvular atrial fibrillation (NVAF) who received dabigatran had fewer strokes and major bleeding events than NVAF patients who received warfarin.

The results were presented at the American Heart Association (AHA) Scientific Sessions 2015 (abstract M 2129*).

The research was supported by Boehringer Ingelheim, the company developing dabigatran, and employees from the company were involved in the study.

“Beyond clinical trials, there is a wealth of available health insurance data that provides an excellent opportunity to grow our knowledge of oral anticoagulant use and outcomes for patients,” said study investigator John Seeger, PharmD, DrPH, of Brigham and Women’s Hospital in Boston, Massachusetts.

“These real-world data further define the safety and effectiveness of dabigatran for patients and its use in routine care, and are consistent with the results of the pivotal RE-LY clinical trial.”

Dr Seeger and his colleagues analyzed data collected over 32 months and encompassing 44,672 NVAF patients—22,336 propensity-score-matched patients receiving dabigatran or warfarin for the first time.

The data were collected from 2 insurance databases—Truven MarketScan (18,276 patients per group) and Optum Clinformatics (4060 patients per group).

Patients were followed until they switched or discontinued anticoagulant treatment, experienced an outcome event, or discontinued enrollment. The average follow-up period was 5 months for dabigatran-treated patients and 4 months for warfarin-treated patients.

The primary outcomes of the study were stroke and major bleeding rates.

There were 65 strokes among dabigatran-treated patients (0.73 incidence rate per 100 patient-years) and 78 strokes among warfarin-treated patients (1.08 incidence rate per 100 patient-years).

The investigators said this represents a 28% reduction in stroke risk for dabigatran compared to warfarin. (The hazard ratio was 0.72.)

There were 395 major bleeding events among dabigatran-treated patients (4.47 incidence rate per 100 patient-years) and 459 events for warfarin-treated patients (6.42 incidence rate per 100 patient-years).

This represents a 26% reduction in the risk of major bleeding events with dabigatran compared to warfarin. (The hazard ratio was 0.74.)

The investigators said effectiveness assessments beyond the first 6 months of therapy were limited by the short average follow-up time. But future analyses from this long-term study program will yield more stable estimates.

This study is part of an ongoing research program to evaluate prescribing patterns and real-world safety and effectiveness of novel oral anticoagulants, including dabigatran, for reducing stroke risk.

*Data in the abstract differ from data presented at the meeting.

Warfarin tablets

ORLANDO, FL—Interim results from a long-term, “real world” study suggest dabigatran etexilate mesylate (Pradaxa) may be safer than warfarin in routine

clinical practice.

The data, which come from a pooled analysis of 2 large US commercial health insurance databases, showed that patients with non-valvular atrial fibrillation (NVAF) who received dabigatran had fewer strokes and major bleeding events than NVAF patients who received warfarin.

The results were presented at the American Heart Association (AHA) Scientific Sessions 2015 (abstract M 2129*).

The research was supported by Boehringer Ingelheim, the company developing dabigatran, and employees from the company were involved in the study.

“Beyond clinical trials, there is a wealth of available health insurance data that provides an excellent opportunity to grow our knowledge of oral anticoagulant use and outcomes for patients,” said study investigator John Seeger, PharmD, DrPH, of Brigham and Women’s Hospital in Boston, Massachusetts.

“These real-world data further define the safety and effectiveness of dabigatran for patients and its use in routine care, and are consistent with the results of the pivotal RE-LY clinical trial.”

Dr Seeger and his colleagues analyzed data collected over 32 months and encompassing 44,672 NVAF patients—22,336 propensity-score-matched patients receiving dabigatran or warfarin for the first time.

The data were collected from 2 insurance databases—Truven MarketScan (18,276 patients per group) and Optum Clinformatics (4060 patients per group).

Patients were followed until they switched or discontinued anticoagulant treatment, experienced an outcome event, or discontinued enrollment. The average follow-up period was 5 months for dabigatran-treated patients and 4 months for warfarin-treated patients.

The primary outcomes of the study were stroke and major bleeding rates.

There were 65 strokes among dabigatran-treated patients (0.73 incidence rate per 100 patient-years) and 78 strokes among warfarin-treated patients (1.08 incidence rate per 100 patient-years).

The investigators said this represents a 28% reduction in stroke risk for dabigatran compared to warfarin. (The hazard ratio was 0.72.)

There were 395 major bleeding events among dabigatran-treated patients (4.47 incidence rate per 100 patient-years) and 459 events for warfarin-treated patients (6.42 incidence rate per 100 patient-years).

This represents a 26% reduction in the risk of major bleeding events with dabigatran compared to warfarin. (The hazard ratio was 0.74.)

The investigators said effectiveness assessments beyond the first 6 months of therapy were limited by the short average follow-up time. But future analyses from this long-term study program will yield more stable estimates.

This study is part of an ongoing research program to evaluate prescribing patterns and real-world safety and effectiveness of novel oral anticoagulants, including dabigatran, for reducing stroke risk.

*Data in the abstract differ from data presented at the meeting.

Warfarin tablets

ORLANDO, FL—Interim results from a long-term, “real world” study suggest dabigatran etexilate mesylate (Pradaxa) may be safer than warfarin in routine

clinical practice.

The data, which come from a pooled analysis of 2 large US commercial health insurance databases, showed that patients with non-valvular atrial fibrillation (NVAF) who received dabigatran had fewer strokes and major bleeding events than NVAF patients who received warfarin.

The results were presented at the American Heart Association (AHA) Scientific Sessions 2015 (abstract M 2129*).

The research was supported by Boehringer Ingelheim, the company developing dabigatran, and employees from the company were involved in the study.

“Beyond clinical trials, there is a wealth of available health insurance data that provides an excellent opportunity to grow our knowledge of oral anticoagulant use and outcomes for patients,” said study investigator John Seeger, PharmD, DrPH, of Brigham and Women’s Hospital in Boston, Massachusetts.

“These real-world data further define the safety and effectiveness of dabigatran for patients and its use in routine care, and are consistent with the results of the pivotal RE-LY clinical trial.”

Dr Seeger and his colleagues analyzed data collected over 32 months and encompassing 44,672 NVAF patients—22,336 propensity-score-matched patients receiving dabigatran or warfarin for the first time.

The data were collected from 2 insurance databases—Truven MarketScan (18,276 patients per group) and Optum Clinformatics (4060 patients per group).

Patients were followed until they switched or discontinued anticoagulant treatment, experienced an outcome event, or discontinued enrollment. The average follow-up period was 5 months for dabigatran-treated patients and 4 months for warfarin-treated patients.

The primary outcomes of the study were stroke and major bleeding rates.

There were 65 strokes among dabigatran-treated patients (0.73 incidence rate per 100 patient-years) and 78 strokes among warfarin-treated patients (1.08 incidence rate per 100 patient-years).

The investigators said this represents a 28% reduction in stroke risk for dabigatran compared to warfarin. (The hazard ratio was 0.72.)

There were 395 major bleeding events among dabigatran-treated patients (4.47 incidence rate per 100 patient-years) and 459 events for warfarin-treated patients (6.42 incidence rate per 100 patient-years).

This represents a 26% reduction in the risk of major bleeding events with dabigatran compared to warfarin. (The hazard ratio was 0.74.)

The investigators said effectiveness assessments beyond the first 6 months of therapy were limited by the short average follow-up time. But future analyses from this long-term study program will yield more stable estimates.

This study is part of an ongoing research program to evaluate prescribing patterns and real-world safety and effectiveness of novel oral anticoagulants, including dabigatran, for reducing stroke risk.

*Data in the abstract differ from data presented at the meeting.

The Diagnosis: Agminated Blue Nevus

Agminated blue nevus is a rare melanocytic nevus that characteristically presents as a group of multiple small, bluish papules occurring in a well-circumscribed area.¹ It also has been referred to as a plaque-type nevus^2,3 and an eruptive blue nevus.⁴ Originally described by Upshaw et al² in 1947, agminated blue nevi may be congenital or arise in early childhood and almost always occur on the trunk. The skin between the papules often is unaffected or sometimes may show bluish or brown pigmentation.⁴ Agminated blue nevi usually are smaller than 10 cm in diameter; however, rare cases have measured up to 24 cm.^1,4-6 The incidence of agminated blue nevi is 2 times higher in males than in females.¹

A biopsy of the lesion revealed pigmented dendritic melanocytes admixed with melanophages, forming fascicles and bundles (A)(H&E, original magnification ×10). In some areas the dermis was uninvolved. Higher magnification showed dendritic and epithelioid melanocytes extending down along the adnexal structures (B)(H&E, original magnification ×40).

Histopathologically, agminated blue nevi typically demonstrate the features of common and/or cellular blue nevi. Cytologic atypia and mitoses are rare.¹ The degree of cellularity and pigmentation of the lesions is variable, and the presence of subcutaneous cellular nodules also has been described.⁵

In our patient, histologic evaluation revealed foci of diffuse dermal spindle cell proliferation composed of heavily pigmented dendritic melanocytes admixed with melanophages in a fibrotic stroma (Figure, A). The dermis was uninvolved in some areas and the melanocytes were epithelioid and formed fascicles and bundles that extended down adnexal structures in other areas (Figure, B). Junctional involvement of melanocytes, cellular atypia, and mitoses were not identified. Our case demonstrated a combination of histologic findings of a cellular blue nevus as well as features reminiscent of a deep penetrating nevus. The differential diagnosis of agminated blue nevus includes agminated Spitz nevus arising in a speckled lentiginous nevus,⁷ dermal melanocytosis, melanoma, and pilar neurocristic hamartoma. Pilar neurocristic hamartomas may resemble plaque-type blue nevi; however, the former show a predilection for the scalp, histologically demonstrate features that overlap with blue nevi and congenital nevi, and are associated with neural structures that show Schwannian differentiation.⁸ Agminated blue nevi usually are characterized by a benign clinical course, but few cases describing malignant changes with development of malignant melanoma have been reported.^9,10 Therefore, recognition of the clinical and histopathologic spectrum of agminated blue nevus is critical in order to avoid diagnostic pitfalls and confusion with melanoma.

The Diagnosis: Agminated Blue Nevus

Agminated blue nevus is a rare melanocytic nevus that characteristically presents as a group of multiple small, bluish papules occurring in a well-circumscribed area.¹ It also has been referred to as a plaque-type nevus^2,3 and an eruptive blue nevus.⁴ Originally described by Upshaw et al² in 1947, agminated blue nevi may be congenital or arise in early childhood and almost always occur on the trunk. The skin between the papules often is unaffected or sometimes may show bluish or brown pigmentation.⁴ Agminated blue nevi usually are smaller than 10 cm in diameter; however, rare cases have measured up to 24 cm.^1,4-6 The incidence of agminated blue nevi is 2 times higher in males than in females.¹

A biopsy of the lesion revealed pigmented dendritic melanocytes admixed with melanophages, forming fascicles and bundles (A)(H&E, original magnification ×10). In some areas the dermis was uninvolved. Higher magnification showed dendritic and epithelioid melanocytes extending down along the adnexal structures (B)(H&E, original magnification ×40).

Histopathologically, agminated blue nevi typically demonstrate the features of common and/or cellular blue nevi. Cytologic atypia and mitoses are rare.¹ The degree of cellularity and pigmentation of the lesions is variable, and the presence of subcutaneous cellular nodules also has been described.⁵

In our patient, histologic evaluation revealed foci of diffuse dermal spindle cell proliferation composed of heavily pigmented dendritic melanocytes admixed with melanophages in a fibrotic stroma (Figure, A). The dermis was uninvolved in some areas and the melanocytes were epithelioid and formed fascicles and bundles that extended down adnexal structures in other areas (Figure, B). Junctional involvement of melanocytes, cellular atypia, and mitoses were not identified. Our case demonstrated a combination of histologic findings of a cellular blue nevus as well as features reminiscent of a deep penetrating nevus. The differential diagnosis of agminated blue nevus includes agminated Spitz nevus arising in a speckled lentiginous nevus,⁷ dermal melanocytosis, melanoma, and pilar neurocristic hamartoma. Pilar neurocristic hamartomas may resemble plaque-type blue nevi; however, the former show a predilection for the scalp, histologically demonstrate features that overlap with blue nevi and congenital nevi, and are associated with neural structures that show Schwannian differentiation.⁸ Agminated blue nevi usually are characterized by a benign clinical course, but few cases describing malignant changes with development of malignant melanoma have been reported.^9,10 Therefore, recognition of the clinical and histopathologic spectrum of agminated blue nevus is critical in order to avoid diagnostic pitfalls and confusion with melanoma.

The Diagnosis: Agminated Blue Nevus

Agminated blue nevus is a rare melanocytic nevus that characteristically presents as a group of multiple small, bluish papules occurring in a well-circumscribed area.¹ It also has been referred to as a plaque-type nevus^2,3 and an eruptive blue nevus.⁴ Originally described by Upshaw et al² in 1947, agminated blue nevi may be congenital or arise in early childhood and almost always occur on the trunk. The skin between the papules often is unaffected or sometimes may show bluish or brown pigmentation.⁴ Agminated blue nevi usually are smaller than 10 cm in diameter; however, rare cases have measured up to 24 cm.^1,4-6 The incidence of agminated blue nevi is 2 times higher in males than in females.¹

A biopsy of the lesion revealed pigmented dendritic melanocytes admixed with melanophages, forming fascicles and bundles (A)(H&E, original magnification ×10). In some areas the dermis was uninvolved. Higher magnification showed dendritic and epithelioid melanocytes extending down along the adnexal structures (B)(H&E, original magnification ×40).

Histopathologically, agminated blue nevi typically demonstrate the features of common and/or cellular blue nevi. Cytologic atypia and mitoses are rare.¹ The degree of cellularity and pigmentation of the lesions is variable, and the presence of subcutaneous cellular nodules also has been described.⁵

In our patient, histologic evaluation revealed foci of diffuse dermal spindle cell proliferation composed of heavily pigmented dendritic melanocytes admixed with melanophages in a fibrotic stroma (Figure, A). The dermis was uninvolved in some areas and the melanocytes were epithelioid and formed fascicles and bundles that extended down adnexal structures in other areas (Figure, B). Junctional involvement of melanocytes, cellular atypia, and mitoses were not identified. Our case demonstrated a combination of histologic findings of a cellular blue nevus as well as features reminiscent of a deep penetrating nevus. The differential diagnosis of agminated blue nevus includes agminated Spitz nevus arising in a speckled lentiginous nevus,⁷ dermal melanocytosis, melanoma, and pilar neurocristic hamartoma. Pilar neurocristic hamartomas may resemble plaque-type blue nevi; however, the former show a predilection for the scalp, histologically demonstrate features that overlap with blue nevi and congenital nevi, and are associated with neural structures that show Schwannian differentiation.⁸ Agminated blue nevi usually are characterized by a benign clinical course, but few cases describing malignant changes with development of malignant melanoma have been reported.^9,10 Therefore, recognition of the clinical and histopathologic spectrum of agminated blue nevus is critical in order to avoid diagnostic pitfalls and confusion with melanoma.

These days you can do anything from a phone application; buy theater tickets, order groceries, and watch television. So why not do something better for your health? Here is a list of apps to assist veterans and active-duty service men and women in improving their overall wellness via smart phones.

1. CBT-i Coach

Created through a collaboration of the VA National Center for PTSD, the DoD National Center for Telehealth and Technology, and Stanford School of Medicine, the cognitive behavioral therapy for insomnia (CBT-i) application assists users with symptoms of insomnia by improving their sleep habits for a better daytime experience.

2. ACT Coach

The Acceptance and Commitment Therapy (ACT) Coach app is a tool for use while receiving face-to-face ACT treatment. It assists the user in coping with emotions and symptoms related to mental health conditions by providing mindfulness and acceptance strategies. 

3. Breathe2Relax

Breathe2Relax is a stress management tool designed by the National Center for Telehealth and Technology (T2) to help the user focus on “diaphragmatic breathing.” Through exercises in the app, the user learns to concentrate on breathing to provide deep relaxation and a stable mood that could be strained from PTSD or traumatic brain injury.

4. T2 MoodTracker

T2 MoodTracker allows the user to record their daily mood and psychological health. Within the app users can rate their mood, set daily reminders to keep track of their daily health, record new events such as starting therapy, and share information with health care providers.

5. Parenting2Go

As part of the DoD/VA Integrated Mental Health Strategy the Parenting2Go app was designed to assist service members and veterans build closer and healthier relationships with their families after a deployment. The app provides tips and tools on how to be more “present,” how to deal with being overwhelmed by the demands of parenting, and how to get support for their parenting efforts.  

6. Mindfulness Coach

Developed by psychologists the Mindfulness Coach app aids the user in learning mindfulness to help focus their attention on the present experience to reduce worrying and stress. The app provides walkthroughs of various forms of mindfulness activities, a log for tracking practice, and educational materials.

7. CEMM Virtual Medical Center 

The Center of Excellence for Medical Multimedia (CEMM) app provides TRICARE customer service to service members and their families. By providing an educational resource tool, information on the nearest medical treatment facility, news, and information on various TRICARE plans users can access TRICARE services anywhere.

8. MOVE! Coach App

The MOVE! Coach App helps veterans, service members, and their families in their weight loss journeys. The app provides self-management guides on a 19-week program, weight and diet diaries, a progress tracker, and other resources on how to breakthrough personal barriers to a healthier lifestyle.

9.  ASCVD Risk Estimator

In collaboration between the American Heart Association and the American College of Cardiology this app calculates the patient risk for developing atherosclerotic cardiovascular disease (ASCVD). Although primarily for health care providers veterans can assess their cardiovascular risk by indicating lifestyle choices, cholesterol levels, and body weight to determine the 10-year and lifetime risk for developing ASCVD.

10. 311VET

311VET is a tool designed for veterans who have questions and need answers about VA Benefits anytime and anywhere. The app allows veterans to receive information on survivors benefits, pensions, life insurance and more from the convenience of their smart phone or through text messaging if the user doesn’t have a smart phone.

Visit your Android or Apple iOS app store to download these apps.

These days you can do anything from a phone application; buy theater tickets, order groceries, and watch television. So why not do something better for your health? Here is a list of apps to assist veterans and active-duty service men and women in improving their overall wellness via smart phones.

1. CBT-i Coach

Created through a collaboration of the VA National Center for PTSD, the DoD National Center for Telehealth and Technology, and Stanford School of Medicine, the cognitive behavioral therapy for insomnia (CBT-i) application assists users with symptoms of insomnia by improving their sleep habits for a better daytime experience.

2. ACT Coach

The Acceptance and Commitment Therapy (ACT) Coach app is a tool for use while receiving face-to-face ACT treatment. It assists the user in coping with emotions and symptoms related to mental health conditions by providing mindfulness and acceptance strategies. 

3. Breathe2Relax

Breathe2Relax is a stress management tool designed by the National Center for Telehealth and Technology (T2) to help the user focus on “diaphragmatic breathing.” Through exercises in the app, the user learns to concentrate on breathing to provide deep relaxation and a stable mood that could be strained from PTSD or traumatic brain injury.

4. T2 MoodTracker

T2 MoodTracker allows the user to record their daily mood and psychological health. Within the app users can rate their mood, set daily reminders to keep track of their daily health, record new events such as starting therapy, and share information with health care providers.

5. Parenting2Go

As part of the DoD/VA Integrated Mental Health Strategy the Parenting2Go app was designed to assist service members and veterans build closer and healthier relationships with their families after a deployment. The app provides tips and tools on how to be more “present,” how to deal with being overwhelmed by the demands of parenting, and how to get support for their parenting efforts.  

6. Mindfulness Coach

Developed by psychologists the Mindfulness Coach app aids the user in learning mindfulness to help focus their attention on the present experience to reduce worrying and stress. The app provides walkthroughs of various forms of mindfulness activities, a log for tracking practice, and educational materials.

7. CEMM Virtual Medical Center 

The Center of Excellence for Medical Multimedia (CEMM) app provides TRICARE customer service to service members and their families. By providing an educational resource tool, information on the nearest medical treatment facility, news, and information on various TRICARE plans users can access TRICARE services anywhere.

8. MOVE! Coach App

The MOVE! Coach App helps veterans, service members, and their families in their weight loss journeys. The app provides self-management guides on a 19-week program, weight and diet diaries, a progress tracker, and other resources on how to breakthrough personal barriers to a healthier lifestyle.

9.  ASCVD Risk Estimator

In collaboration between the American Heart Association and the American College of Cardiology this app calculates the patient risk for developing atherosclerotic cardiovascular disease (ASCVD). Although primarily for health care providers veterans can assess their cardiovascular risk by indicating lifestyle choices, cholesterol levels, and body weight to determine the 10-year and lifetime risk for developing ASCVD.

10. 311VET

311VET is a tool designed for veterans who have questions and need answers about VA Benefits anytime and anywhere. The app allows veterans to receive information on survivors benefits, pensions, life insurance and more from the convenience of their smart phone or through text messaging if the user doesn’t have a smart phone.

Visit your Android or Apple iOS app store to download these apps.

These days you can do anything from a phone application; buy theater tickets, order groceries, and watch television. So why not do something better for your health? Here is a list of apps to assist veterans and active-duty service men and women in improving their overall wellness via smart phones.

1. CBT-i Coach

Created through a collaboration of the VA National Center for PTSD, the DoD National Center for Telehealth and Technology, and Stanford School of Medicine, the cognitive behavioral therapy for insomnia (CBT-i) application assists users with symptoms of insomnia by improving their sleep habits for a better daytime experience.

2. ACT Coach

The Acceptance and Commitment Therapy (ACT) Coach app is a tool for use while receiving face-to-face ACT treatment. It assists the user in coping with emotions and symptoms related to mental health conditions by providing mindfulness and acceptance strategies. 

3. Breathe2Relax

Breathe2Relax is a stress management tool designed by the National Center for Telehealth and Technology (T2) to help the user focus on “diaphragmatic breathing.” Through exercises in the app, the user learns to concentrate on breathing to provide deep relaxation and a stable mood that could be strained from PTSD or traumatic brain injury.

4. T2 MoodTracker

T2 MoodTracker allows the user to record their daily mood and psychological health. Within the app users can rate their mood, set daily reminders to keep track of their daily health, record new events such as starting therapy, and share information with health care providers.

5. Parenting2Go

As part of the DoD/VA Integrated Mental Health Strategy the Parenting2Go app was designed to assist service members and veterans build closer and healthier relationships with their families after a deployment. The app provides tips and tools on how to be more “present,” how to deal with being overwhelmed by the demands of parenting, and how to get support for their parenting efforts.  

6. Mindfulness Coach

Developed by psychologists the Mindfulness Coach app aids the user in learning mindfulness to help focus their attention on the present experience to reduce worrying and stress. The app provides walkthroughs of various forms of mindfulness activities, a log for tracking practice, and educational materials.

7. CEMM Virtual Medical Center 

The Center of Excellence for Medical Multimedia (CEMM) app provides TRICARE customer service to service members and their families. By providing an educational resource tool, information on the nearest medical treatment facility, news, and information on various TRICARE plans users can access TRICARE services anywhere.

8. MOVE! Coach App

The MOVE! Coach App helps veterans, service members, and their families in their weight loss journeys. The app provides self-management guides on a 19-week program, weight and diet diaries, a progress tracker, and other resources on how to breakthrough personal barriers to a healthier lifestyle.

9.  ASCVD Risk Estimator

In collaboration between the American Heart Association and the American College of Cardiology this app calculates the patient risk for developing atherosclerotic cardiovascular disease (ASCVD). Although primarily for health care providers veterans can assess their cardiovascular risk by indicating lifestyle choices, cholesterol levels, and body weight to determine the 10-year and lifetime risk for developing ASCVD.

10. 311VET

311VET is a tool designed for veterans who have questions and need answers about VA Benefits anytime and anywhere. The app allows veterans to receive information on survivors benefits, pensions, life insurance and more from the convenience of their smart phone or through text messaging if the user doesn’t have a smart phone.

Visit your Android or Apple iOS app store to download these apps.

FROM A TELECONFERENCE – The American Society of Hematology’s (ASH) 57th annual meeting in Orlando is chock-full of much-anticipated results in cancer immunotherapies such as CAR T cell therapies and checkpoint inhibitors, advances in sickle cell disease, and practical advice on managing the latest drugs in the clinic, ASH officials said in a teleconference. Here are some of the day-by-day picks selected by ASH president Dr. David Williams and ASH secretary Dr. Stephanie J. Lee, who gave their recommendations during a conference call for the press. Meeting abstracts are now available online.

Saturday, Dec. 5

Clinical applications of newly approved drugs

The popular special education session on clinical applications of newly approved drugs returns on Saturday, Dec. 5 at 9:30 a.m., with didactic presentations that address issues clinicians may face such as drug-drug interactions, side effects, and adverse events. The three drugs to be discussed this year are: idarucizumab (Praxbind), the first specific reversal agent approved for dabigatran reversal; blinatumomab (Blincyto), approved for second-line treatment of Philadelphia chromosomenegative acute lymphoblastic leukemia; and the histone deacetylase (HDAC) inhibitor panobinostat (Farydak), approved for the treatment of multiple myeloma.

Adoptive immunotherapy

One presentation to look out for next month is abstract 99at 12:30 p.m. on Saturday, Dec. 5 in the adoptive immunotherapy session, Dr. Williams told reporters. The chimeric antigen receptor (CAR)-T-cell approach has relied on genetically engineering the patient’s own T cells to rev up the immune system. This group’s approach is to treat B-cell malignancies after allogeneic hematopoietic stem cell transplantation using a single infusion of anti-CD19 CAR-T cells from the patient’s transplant donor.

Eight of 20 patients treated with this strategy achieved remission, including six complete remissions and two partial remissions. Importantly, none of these patients developed acute graft-versus-host disease, a potential consequence of using allogeneic rather than autologous T cells, he said. The authors also noted that patients who responded and went into remission were marked by higher numbers of these infused CAR-T cells in their circulation, suggesting a biomarker of response.

Checkpoint, please?

Immunotherapy is a “very hot area,” so ASH has put together a special session at 4 p.m. Saturday called “Checkpoint, Please?” Dr. Williams said. Topics include the role of programmed death (PD)-1 and PD-ligand 1 in acute and chronic graft-versus-host disease, checkpoint blockade with neoantigen cancer vaccines, and insights into the mechanisms of action of anti-CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) antibody therapy.

Sunday, Dec. 6

Precision medicine

Sunday’s plenary scientific session will include several noteworthy personalized medicine abstracts featuring emerging therapies targeted to specific genetic subtypes, Dr. Lee, from the University of Washington, Seattle, said.

Plenary abstract 6 is a large, multinational study looking at whether adding the multikinase inhibitor midostaurin to standard induction therapy and carried through 1 year of maintenance would improve outcomes in newly diagnosed acute myeloid leukemia with FLT3 mutations. Patients with these deleterious mutations do enter remission with chemotherapy, but often relapse.

Overall and event-free survival were better at 5 years by about 7% to 8% in the experimental arm using midostaurin, she said. Caveats are that complete response rates were similar in both arms and lower than reported in other trials.

“Because we know that patients with this FLT3 mutation have a very poor prognosis with standard chemotherapy, more than half of the patients in this trial received an allogeneic transplant,” Dr. Lee noted. “But the abstract does say that the results are similar if you censor at the time of the transplant.”

In this same vein of precision medicine is plenary abstract 1, testing whether adding rituximab to standard chemotherapy improves outcomes in adults with CD-20–positive, Philadelphia chromosome–negative, B-cell precursor acute lymphoblastic leukemia (ALL). Rituximab (Rituxan) binds to CD-20, which is found in about 30% to 50% of adult B-cell ALL, she said.

At 2 years, patients treated with rituximab had longer event-free survival than controls (65% vs. 52%; P = .038), but similar overall survival (71% vs. 64%; P = .09), according to the abstract. The rituximab arm also received more allogeneic transplants, but again, after censoring the data, the abstract states that both event-free and overall survival were longer with rituximab, Dr. Lee said.

Sickle cell anemia

Sunday’s plenary session will also feature the very important TWiTCH (TCD with Transfusions Changing to Hydroxyurea) study evaluating hydroxyurea therapy as an alternative to chronic blood transfusions to prevent stroke. Stroke is one of the most dreaded complications of sickle cell disease, occurring in up to 10% of children, Dr. Williams said. Though transfusions are effective, they have to be continued indefinitely and lead to iron overload. Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and has become a standard therapy to attenuate the complications of sickle cell.

The phase III noninferiority study, which used Transcranial Doppler (TCD) screening to identify children at elevated risk for stroke, showed that hydroxyurea “was as good as current therapy with red cell transfusions and there was some indication, although not significant, that it might even be superior in lowering the TCD levels,” Dr. Williams said. An added benefit of the hydroxyurea was that it improved the patients’ iron overload status. There were no strokes in either group.

Sunday’s abstract 202 is another presentation “that I’m sure will get a lot of attention,” Dr. Williams said. It offers updated details on outcomes from patients with sickle cell disease (SCD) treated with a novel gene therapy transduced with the LentiGlobin BB305 (Bluebird Bio) lentiviral vector. Patients with beta thalassemia major have remained transfusion-independent for more than a year after this treatment, with results now available from four patients with SCD. One patient with a severe phenotype has had no sickle cell complications and has been able to stop his transfusion therapy, while two of the other four patients are also transfusion-independent.

“This is an early study showing what appears to be efficacy of the gene therapy approach not in thalassemia, but in sickle cell disease,” Dr. Williams said, noting that abstract 3233 will also feature results using LentiGlobin gene therapy in severe SCD.

ASH/EHA joint symposium

Also noteworthy is a special joint ASH/European Hematology Association symposium looking at how well genomic data are being incorporated into practice in the U.S. and Europe.

Monday, Dec. 7

ASH/FDA joint symposium

A joint ASH/FDA symposium on late-breaking drug approvals is new this year and features drugs that gained approval in November 2015. FDA product-reviewers will discuss safety and efficacy issues in the clinical approval trials and toxicity studies, while clinicians will share their experiences in the real-world use of these drugs.

“This is information that is really going to be very hot off the press and presented in conjunction with the FDA,” Dr. Lee said.

Dr. Williams reported research funding from Bluebird Bio. Dr. Lee reported having no conflicts of interest.

[email protected]

FROM A TELECONFERENCE – The American Society of Hematology’s (ASH) 57th annual meeting in Orlando is chock-full of much-anticipated results in cancer immunotherapies such as CAR T cell therapies and checkpoint inhibitors, advances in sickle cell disease, and practical advice on managing the latest drugs in the clinic, ASH officials said in a teleconference. Here are some of the day-by-day picks selected by ASH president Dr. David Williams and ASH secretary Dr. Stephanie J. Lee, who gave their recommendations during a conference call for the press. Meeting abstracts are now available online.

Saturday, Dec. 5

Clinical applications of newly approved drugs

The popular special education session on clinical applications of newly approved drugs returns on Saturday, Dec. 5 at 9:30 a.m., with didactic presentations that address issues clinicians may face such as drug-drug interactions, side effects, and adverse events. The three drugs to be discussed this year are: idarucizumab (Praxbind), the first specific reversal agent approved for dabigatran reversal; blinatumomab (Blincyto), approved for second-line treatment of Philadelphia chromosomenegative acute lymphoblastic leukemia; and the histone deacetylase (HDAC) inhibitor panobinostat (Farydak), approved for the treatment of multiple myeloma.

Adoptive immunotherapy

One presentation to look out for next month is abstract 99at 12:30 p.m. on Saturday, Dec. 5 in the adoptive immunotherapy session, Dr. Williams told reporters. The chimeric antigen receptor (CAR)-T-cell approach has relied on genetically engineering the patient’s own T cells to rev up the immune system. This group’s approach is to treat B-cell malignancies after allogeneic hematopoietic stem cell transplantation using a single infusion of anti-CD19 CAR-T cells from the patient’s transplant donor.

Eight of 20 patients treated with this strategy achieved remission, including six complete remissions and two partial remissions. Importantly, none of these patients developed acute graft-versus-host disease, a potential consequence of using allogeneic rather than autologous T cells, he said. The authors also noted that patients who responded and went into remission were marked by higher numbers of these infused CAR-T cells in their circulation, suggesting a biomarker of response.

Checkpoint, please?

Immunotherapy is a “very hot area,” so ASH has put together a special session at 4 p.m. Saturday called “Checkpoint, Please?” Dr. Williams said. Topics include the role of programmed death (PD)-1 and PD-ligand 1 in acute and chronic graft-versus-host disease, checkpoint blockade with neoantigen cancer vaccines, and insights into the mechanisms of action of anti-CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) antibody therapy.

Sunday, Dec. 6

Precision medicine

Sunday’s plenary scientific session will include several noteworthy personalized medicine abstracts featuring emerging therapies targeted to specific genetic subtypes, Dr. Lee, from the University of Washington, Seattle, said.

Plenary abstract 6 is a large, multinational study looking at whether adding the multikinase inhibitor midostaurin to standard induction therapy and carried through 1 year of maintenance would improve outcomes in newly diagnosed acute myeloid leukemia with FLT3 mutations. Patients with these deleterious mutations do enter remission with chemotherapy, but often relapse.

Overall and event-free survival were better at 5 years by about 7% to 8% in the experimental arm using midostaurin, she said. Caveats are that complete response rates were similar in both arms and lower than reported in other trials.

“Because we know that patients with this FLT3 mutation have a very poor prognosis with standard chemotherapy, more than half of the patients in this trial received an allogeneic transplant,” Dr. Lee noted. “But the abstract does say that the results are similar if you censor at the time of the transplant.”

In this same vein of precision medicine is plenary abstract 1, testing whether adding rituximab to standard chemotherapy improves outcomes in adults with CD-20–positive, Philadelphia chromosome–negative, B-cell precursor acute lymphoblastic leukemia (ALL). Rituximab (Rituxan) binds to CD-20, which is found in about 30% to 50% of adult B-cell ALL, she said.

At 2 years, patients treated with rituximab had longer event-free survival than controls (65% vs. 52%; P = .038), but similar overall survival (71% vs. 64%; P = .09), according to the abstract. The rituximab arm also received more allogeneic transplants, but again, after censoring the data, the abstract states that both event-free and overall survival were longer with rituximab, Dr. Lee said.

Sickle cell anemia

Sunday’s plenary session will also feature the very important TWiTCH (TCD with Transfusions Changing to Hydroxyurea) study evaluating hydroxyurea therapy as an alternative to chronic blood transfusions to prevent stroke. Stroke is one of the most dreaded complications of sickle cell disease, occurring in up to 10% of children, Dr. Williams said. Though transfusions are effective, they have to be continued indefinitely and lead to iron overload. Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and has become a standard therapy to attenuate the complications of sickle cell.

The phase III noninferiority study, which used Transcranial Doppler (TCD) screening to identify children at elevated risk for stroke, showed that hydroxyurea “was as good as current therapy with red cell transfusions and there was some indication, although not significant, that it might even be superior in lowering the TCD levels,” Dr. Williams said. An added benefit of the hydroxyurea was that it improved the patients’ iron overload status. There were no strokes in either group.

Sunday’s abstract 202 is another presentation “that I’m sure will get a lot of attention,” Dr. Williams said. It offers updated details on outcomes from patients with sickle cell disease (SCD) treated with a novel gene therapy transduced with the LentiGlobin BB305 (Bluebird Bio) lentiviral vector. Patients with beta thalassemia major have remained transfusion-independent for more than a year after this treatment, with results now available from four patients with SCD. One patient with a severe phenotype has had no sickle cell complications and has been able to stop his transfusion therapy, while two of the other four patients are also transfusion-independent.

“This is an early study showing what appears to be efficacy of the gene therapy approach not in thalassemia, but in sickle cell disease,” Dr. Williams said, noting that abstract 3233 will also feature results using LentiGlobin gene therapy in severe SCD.

ASH/EHA joint symposium

Also noteworthy is a special joint ASH/European Hematology Association symposium looking at how well genomic data are being incorporated into practice in the U.S. and Europe.

Monday, Dec. 7

ASH/FDA joint symposium

A joint ASH/FDA symposium on late-breaking drug approvals is new this year and features drugs that gained approval in November 2015. FDA product-reviewers will discuss safety and efficacy issues in the clinical approval trials and toxicity studies, while clinicians will share their experiences in the real-world use of these drugs.

“This is information that is really going to be very hot off the press and presented in conjunction with the FDA,” Dr. Lee said.

Dr. Williams reported research funding from Bluebird Bio. Dr. Lee reported having no conflicts of interest.

[email protected]

FROM A TELECONFERENCE – The American Society of Hematology’s (ASH) 57th annual meeting in Orlando is chock-full of much-anticipated results in cancer immunotherapies such as CAR T cell therapies and checkpoint inhibitors, advances in sickle cell disease, and practical advice on managing the latest drugs in the clinic, ASH officials said in a teleconference. Here are some of the day-by-day picks selected by ASH president Dr. David Williams and ASH secretary Dr. Stephanie J. Lee, who gave their recommendations during a conference call for the press. Meeting abstracts are now available online.

Saturday, Dec. 5

Clinical applications of newly approved drugs

The popular special education session on clinical applications of newly approved drugs returns on Saturday, Dec. 5 at 9:30 a.m., with didactic presentations that address issues clinicians may face such as drug-drug interactions, side effects, and adverse events. The three drugs to be discussed this year are: idarucizumab (Praxbind), the first specific reversal agent approved for dabigatran reversal; blinatumomab (Blincyto), approved for second-line treatment of Philadelphia chromosomenegative acute lymphoblastic leukemia; and the histone deacetylase (HDAC) inhibitor panobinostat (Farydak), approved for the treatment of multiple myeloma.

Adoptive immunotherapy

One presentation to look out for next month is abstract 99at 12:30 p.m. on Saturday, Dec. 5 in the adoptive immunotherapy session, Dr. Williams told reporters. The chimeric antigen receptor (CAR)-T-cell approach has relied on genetically engineering the patient’s own T cells to rev up the immune system. This group’s approach is to treat B-cell malignancies after allogeneic hematopoietic stem cell transplantation using a single infusion of anti-CD19 CAR-T cells from the patient’s transplant donor.

Eight of 20 patients treated with this strategy achieved remission, including six complete remissions and two partial remissions. Importantly, none of these patients developed acute graft-versus-host disease, a potential consequence of using allogeneic rather than autologous T cells, he said. The authors also noted that patients who responded and went into remission were marked by higher numbers of these infused CAR-T cells in their circulation, suggesting a biomarker of response.

Checkpoint, please?

Immunotherapy is a “very hot area,” so ASH has put together a special session at 4 p.m. Saturday called “Checkpoint, Please?” Dr. Williams said. Topics include the role of programmed death (PD)-1 and PD-ligand 1 in acute and chronic graft-versus-host disease, checkpoint blockade with neoantigen cancer vaccines, and insights into the mechanisms of action of anti-CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) antibody therapy.

Sunday, Dec. 6

Precision medicine

Sunday’s plenary scientific session will include several noteworthy personalized medicine abstracts featuring emerging therapies targeted to specific genetic subtypes, Dr. Lee, from the University of Washington, Seattle, said.

Plenary abstract 6 is a large, multinational study looking at whether adding the multikinase inhibitor midostaurin to standard induction therapy and carried through 1 year of maintenance would improve outcomes in newly diagnosed acute myeloid leukemia with FLT3 mutations. Patients with these deleterious mutations do enter remission with chemotherapy, but often relapse.

Overall and event-free survival were better at 5 years by about 7% to 8% in the experimental arm using midostaurin, she said. Caveats are that complete response rates were similar in both arms and lower than reported in other trials.

“Because we know that patients with this FLT3 mutation have a very poor prognosis with standard chemotherapy, more than half of the patients in this trial received an allogeneic transplant,” Dr. Lee noted. “But the abstract does say that the results are similar if you censor at the time of the transplant.”

In this same vein of precision medicine is plenary abstract 1, testing whether adding rituximab to standard chemotherapy improves outcomes in adults with CD-20–positive, Philadelphia chromosome–negative, B-cell precursor acute lymphoblastic leukemia (ALL). Rituximab (Rituxan) binds to CD-20, which is found in about 30% to 50% of adult B-cell ALL, she said.

At 2 years, patients treated with rituximab had longer event-free survival than controls (65% vs. 52%; P = .038), but similar overall survival (71% vs. 64%; P = .09), according to the abstract. The rituximab arm also received more allogeneic transplants, but again, after censoring the data, the abstract states that both event-free and overall survival were longer with rituximab, Dr. Lee said.

Sickle cell anemia

Sunday’s plenary session will also feature the very important TWiTCH (TCD with Transfusions Changing to Hydroxyurea) study evaluating hydroxyurea therapy as an alternative to chronic blood transfusions to prevent stroke. Stroke is one of the most dreaded complications of sickle cell disease, occurring in up to 10% of children, Dr. Williams said. Though transfusions are effective, they have to be continued indefinitely and lead to iron overload. Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and has become a standard therapy to attenuate the complications of sickle cell.

The phase III noninferiority study, which used Transcranial Doppler (TCD) screening to identify children at elevated risk for stroke, showed that hydroxyurea “was as good as current therapy with red cell transfusions and there was some indication, although not significant, that it might even be superior in lowering the TCD levels,” Dr. Williams said. An added benefit of the hydroxyurea was that it improved the patients’ iron overload status. There were no strokes in either group.

Sunday’s abstract 202 is another presentation “that I’m sure will get a lot of attention,” Dr. Williams said. It offers updated details on outcomes from patients with sickle cell disease (SCD) treated with a novel gene therapy transduced with the LentiGlobin BB305 (Bluebird Bio) lentiviral vector. Patients with beta thalassemia major have remained transfusion-independent for more than a year after this treatment, with results now available from four patients with SCD. One patient with a severe phenotype has had no sickle cell complications and has been able to stop his transfusion therapy, while two of the other four patients are also transfusion-independent.

“This is an early study showing what appears to be efficacy of the gene therapy approach not in thalassemia, but in sickle cell disease,” Dr. Williams said, noting that abstract 3233 will also feature results using LentiGlobin gene therapy in severe SCD.

ASH/EHA joint symposium

Also noteworthy is a special joint ASH/European Hematology Association symposium looking at how well genomic data are being incorporated into practice in the U.S. and Europe.

Monday, Dec. 7

ASH/FDA joint symposium

A joint ASH/FDA symposium on late-breaking drug approvals is new this year and features drugs that gained approval in November 2015. FDA product-reviewers will discuss safety and efficacy issues in the clinical approval trials and toxicity studies, while clinicians will share their experiences in the real-world use of these drugs.

“This is information that is really going to be very hot off the press and presented in conjunction with the FDA,” Dr. Lee said.

Dr. Williams reported research funding from Bluebird Bio. Dr. Lee reported having no conflicts of interest.

[email protected]

ORLANDO – Starting varenicline in smokers while hospitalized for an acute coronary syndrome resulted in substantially higher smoking abstinence rates than with placebo at all time points through 6 months of follow-up in the double-blind, randomized EVITA trial.

“The ACS population is typically older, they’re long-term smokers, and they come into the hospital with a life-threatening condition. Their family is all around them. They’ve had angioplasty or CABG [coronary artery bypass graft] surgery. So they have pressure on them to stop smoking. This is a teachable moment, a window of opportunity. The public health benefit for smoking cessation in this population is huge. You can cut their risk of death and significant morbidity in half if you can get them to stop,” Dr. Mark J. Eisenberg said in presenting the EVITA results at the American Heart Association scientific sessions.

“To our knowledge, this is the highest-risk population that’s been exposed to varenicline,” said Dr. Eisenberg, professor of medicine at McGill University and director of the cardiovascular health services research program at Jewish General Hospital in Montreal.

The primary study endpoint was continuous self-reported abstinence since baseline backed by biochemical confirmation in the form of an exhaled carbon monoxide level of 10 ppm or less at week 24 as well as at all the earlier follow-up visits. The rate was 47.3% in the varenicline group, compared with 32.5% in placebo-treated controls. That placebo response rate is in line with numerous prior studies that have shown that less than one-third of smokers with ACS remain abstinent after leaving the hospital.

“Most cardiologists would say, ‘All my patients stop smoking.’ But in the clinic if you look in the patients’ pockets, you find a pack of cigarettes. They stop smoking while in hospital, but as soon as they’re discharged, the relapse rate is almost immediate. Most patients are smoking the day they get out of hospital,” according to Dr. Eisenberg.

In EVITA, the number-needed-to-treat with varenicline for 12 weeks in order to produce 1 extra nonsmoker at 6 months was 6.8 patients.

The secondary endpoint of at least a 50% reduction in the number of cigarettes per day from baseline to 6 months was met by 67.4% of the varenicline group and 55.6% of controls, with a number-needed-to-treat of 8.5, he continued.

No safety issues emerged in the study, although as Dr. Eisenberg noted, EVITA wasn’t sufficiently powered to look at safety. The only side effect more common in varenicline-treated patients was abnormal dreams, with a 12-week incidence of 15%, threefold higher than in controls, a phenomenon seen in other, larger varenicline studies as well.

The EVITA investigators plan to follow participants out to 12 months. “If we see someone who at 1 year post MI is still smoking, maybe it’s time to go after them again, perhaps with another medication or behavioral therapy,” he said.

There are no randomized clinical trials demonstrating that starting nicotine patches or bupropion in the hospital is effective for smoking cessation in the ACS population, according to the cardiologist.

Dr. Eisenberg predicted this study will change clinical practice. In much the same way physicians now routinely start ACS patients on a statin, beta-blocker, and aspirin before they leave the hospital, physicians will capitalize on this opportunity to help ACS patients quit smoking as well, he said.

“The use of varenicline in ACS patients before they leave the hospital is a very important step forward. Cardiologists are increasingly comfortable with the idea of starting secondary prevention medications in the hospital, and there’s very little more important for a person with heart disease who smokes cigarettes than to help them quit smoking. It’s probably the No. 1 priority. So evidence that we can start a medication in the hospital and get more people who smoke cigarettes to quit smoking is definitely game changing, I think,” said Dr. Goff, professor of epidemiology and dean of the Colorado School of Public Health in Aurora.

Dr. Eisenberg reported receiving funding from Pfizer to perform the EVITA trial. He has also gotten honoraria from the company for providing continuing medical education talks on smoking cessation.

[email protected]

ORLANDO – Starting varenicline in smokers while hospitalized for an acute coronary syndrome resulted in substantially higher smoking abstinence rates than with placebo at all time points through 6 months of follow-up in the double-blind, randomized EVITA trial.

“The ACS population is typically older, they’re long-term smokers, and they come into the hospital with a life-threatening condition. Their family is all around them. They’ve had angioplasty or CABG [coronary artery bypass graft] surgery. So they have pressure on them to stop smoking. This is a teachable moment, a window of opportunity. The public health benefit for smoking cessation in this population is huge. You can cut their risk of death and significant morbidity in half if you can get them to stop,” Dr. Mark J. Eisenberg said in presenting the EVITA results at the American Heart Association scientific sessions.

“To our knowledge, this is the highest-risk population that’s been exposed to varenicline,” said Dr. Eisenberg, professor of medicine at McGill University and director of the cardiovascular health services research program at Jewish General Hospital in Montreal.

The primary study endpoint was continuous self-reported abstinence since baseline backed by biochemical confirmation in the form of an exhaled carbon monoxide level of 10 ppm or less at week 24 as well as at all the earlier follow-up visits. The rate was 47.3% in the varenicline group, compared with 32.5% in placebo-treated controls. That placebo response rate is in line with numerous prior studies that have shown that less than one-third of smokers with ACS remain abstinent after leaving the hospital.

“Most cardiologists would say, ‘All my patients stop smoking.’ But in the clinic if you look in the patients’ pockets, you find a pack of cigarettes. They stop smoking while in hospital, but as soon as they’re discharged, the relapse rate is almost immediate. Most patients are smoking the day they get out of hospital,” according to Dr. Eisenberg.

In EVITA, the number-needed-to-treat with varenicline for 12 weeks in order to produce 1 extra nonsmoker at 6 months was 6.8 patients.

The secondary endpoint of at least a 50% reduction in the number of cigarettes per day from baseline to 6 months was met by 67.4% of the varenicline group and 55.6% of controls, with a number-needed-to-treat of 8.5, he continued.

No safety issues emerged in the study, although as Dr. Eisenberg noted, EVITA wasn’t sufficiently powered to look at safety. The only side effect more common in varenicline-treated patients was abnormal dreams, with a 12-week incidence of 15%, threefold higher than in controls, a phenomenon seen in other, larger varenicline studies as well.

The EVITA investigators plan to follow participants out to 12 months. “If we see someone who at 1 year post MI is still smoking, maybe it’s time to go after them again, perhaps with another medication or behavioral therapy,” he said.

There are no randomized clinical trials demonstrating that starting nicotine patches or bupropion in the hospital is effective for smoking cessation in the ACS population, according to the cardiologist.

Dr. Eisenberg predicted this study will change clinical practice. In much the same way physicians now routinely start ACS patients on a statin, beta-blocker, and aspirin before they leave the hospital, physicians will capitalize on this opportunity to help ACS patients quit smoking as well, he said.

“The use of varenicline in ACS patients before they leave the hospital is a very important step forward. Cardiologists are increasingly comfortable with the idea of starting secondary prevention medications in the hospital, and there’s very little more important for a person with heart disease who smokes cigarettes than to help them quit smoking. It’s probably the No. 1 priority. So evidence that we can start a medication in the hospital and get more people who smoke cigarettes to quit smoking is definitely game changing, I think,” said Dr. Goff, professor of epidemiology and dean of the Colorado School of Public Health in Aurora.

Dr. Eisenberg reported receiving funding from Pfizer to perform the EVITA trial. He has also gotten honoraria from the company for providing continuing medical education talks on smoking cessation.

[email protected]

ORLANDO – Starting varenicline in smokers while hospitalized for an acute coronary syndrome resulted in substantially higher smoking abstinence rates than with placebo at all time points through 6 months of follow-up in the double-blind, randomized EVITA trial.

“The ACS population is typically older, they’re long-term smokers, and they come into the hospital with a life-threatening condition. Their family is all around them. They’ve had angioplasty or CABG [coronary artery bypass graft] surgery. So they have pressure on them to stop smoking. This is a teachable moment, a window of opportunity. The public health benefit for smoking cessation in this population is huge. You can cut their risk of death and significant morbidity in half if you can get them to stop,” Dr. Mark J. Eisenberg said in presenting the EVITA results at the American Heart Association scientific sessions.

“To our knowledge, this is the highest-risk population that’s been exposed to varenicline,” said Dr. Eisenberg, professor of medicine at McGill University and director of the cardiovascular health services research program at Jewish General Hospital in Montreal.

The primary study endpoint was continuous self-reported abstinence since baseline backed by biochemical confirmation in the form of an exhaled carbon monoxide level of 10 ppm or less at week 24 as well as at all the earlier follow-up visits. The rate was 47.3% in the varenicline group, compared with 32.5% in placebo-treated controls. That placebo response rate is in line with numerous prior studies that have shown that less than one-third of smokers with ACS remain abstinent after leaving the hospital.

“Most cardiologists would say, ‘All my patients stop smoking.’ But in the clinic if you look in the patients’ pockets, you find a pack of cigarettes. They stop smoking while in hospital, but as soon as they’re discharged, the relapse rate is almost immediate. Most patients are smoking the day they get out of hospital,” according to Dr. Eisenberg.

In EVITA, the number-needed-to-treat with varenicline for 12 weeks in order to produce 1 extra nonsmoker at 6 months was 6.8 patients.

The secondary endpoint of at least a 50% reduction in the number of cigarettes per day from baseline to 6 months was met by 67.4% of the varenicline group and 55.6% of controls, with a number-needed-to-treat of 8.5, he continued.

No safety issues emerged in the study, although as Dr. Eisenberg noted, EVITA wasn’t sufficiently powered to look at safety. The only side effect more common in varenicline-treated patients was abnormal dreams, with a 12-week incidence of 15%, threefold higher than in controls, a phenomenon seen in other, larger varenicline studies as well.

The EVITA investigators plan to follow participants out to 12 months. “If we see someone who at 1 year post MI is still smoking, maybe it’s time to go after them again, perhaps with another medication or behavioral therapy,” he said.

There are no randomized clinical trials demonstrating that starting nicotine patches or bupropion in the hospital is effective for smoking cessation in the ACS population, according to the cardiologist.

Dr. Eisenberg predicted this study will change clinical practice. In much the same way physicians now routinely start ACS patients on a statin, beta-blocker, and aspirin before they leave the hospital, physicians will capitalize on this opportunity to help ACS patients quit smoking as well, he said.

“The use of varenicline in ACS patients before they leave the hospital is a very important step forward. Cardiologists are increasingly comfortable with the idea of starting secondary prevention medications in the hospital, and there’s very little more important for a person with heart disease who smokes cigarettes than to help them quit smoking. It’s probably the No. 1 priority. So evidence that we can start a medication in the hospital and get more people who smoke cigarettes to quit smoking is definitely game changing, I think,” said Dr. Goff, professor of epidemiology and dean of the Colorado School of Public Health in Aurora.

Dr. Eisenberg reported receiving funding from Pfizer to perform the EVITA trial. He has also gotten honoraria from the company for providing continuing medical education talks on smoking cessation.

[email protected]